JAMA Network Open

Sexual Orientation and Cervical Cancer Screening Among Cisgender Women

ImportanceLesbian, gay, and bisexual populations face barriers accessing health care in Chicago, Illinois.ObjectiveTo describe the prevalence of up-to-date cervical cancer screening among lesbian, gay, and bisexual vs heterosexual cisgender women in Chicago.Design, Setting, and ParticipantsThis retrospective, cross-sectional, population-based study of cisgender women residing in Chicago was completed from 2020 to 2022 using data from the Healthy Chicago Survey, which is conducted annually by the Chicago Department of Public Health. Participants included cisgender women aged 25 to 64 years with no history of hysterectomy. Respondents who self-identified as lesbian, gay, or bisexual or other than straight, lesbian, or bisexual were coded as lesbian, gay, or bisexual (LGB). Respondents who self-identified as straight were coded as heterosexual. Those who reported having a Papanicolaou test within the past 3 years were considered up-to-date with cervical cancer screening. Data analysis was performed from June to October 2023.ExposuresThe primary exposure was sexual orientation. Covariates included age, income level, race, ethnicity, having a primary care practitioner (PCP), and insurance coverage.Main Outcomes and MeasuresPrevalence ratios (PRs), log-based regression models, and interaction analysis were used to describe the association of sexual orientation with up-to-date screening.ResultsThe sample included 5167 cisgender women (447 LGB and 4720 heterosexual), aged 25 to 64 years, with no history of hysterectomy. Among LGB cisgender women, 318 (71.14%) reported previous cervical cancer screening compared with 3632 (76.95%) heterosexual cisgender women. The prevalence of up-to-date screening was 10% lower in the LGB group compared with the heterosexual group (PR, 0.90; 95% CI, 0.82-1.00). In regression analysis, having a PCP (PR, 1.43; 95% CI, 1.29-1.59) was associated with up-to-date screening. In interaction analysis, LGB cisgender women with a PCP were 93% more likely to be up-to-date compared with those without a PCP (PR, 1.93; 95% CI, 1.37-2.72).Conclusions and RelevanceIn this cross-sectional study of cervical cancer screening rates between the heterosexual and LGB populations in Chicago, up-to-date cervical cancer screening was associated with having a PCP, regardless of sexual orientation, but this association was greater for LGB individuals. Although LGB populations were less likely to be screened, this disparity may be reduced with more consistent health care access and established care with PCPs.

Self-Acupressure for Fatigue in Patients Surviving Ovarian Cancer

Importance Fatigue is a burdensome effect of ovarian cancer that is associated with poor sleep and quality of life. Self-acupressure is recommended in clinical guidelines but has substantial barriers to implementation. Use of a mobile app may address these barriers. Objective To investigate whether 6 weeks of true self-acupressure (TSA), learned via a mobile app, improves cancer fatigue, sleep, and quality of life in women with ovarian cancer compared with sham self-acupressure (SSA) and usual care (UC) and whether changes are sustained during an 18-week washout period. Design, Setting, and Participants This phase 3 single-blind randomized clinical trial was conducted from October 2019 to December 2023. Data collection ended in November 2024. Participants included ovarian cancer survivors who were fatigued (based on a Brief Fatigue Inventory [BFI] score ≥4) and who were recruited from tumor registries and social media. Intervention Randomization (1:1:1) to 6 weeks of TSA or SSA, taught via mobile app, or UC. Main Outcomes and Measures The primary outcome was the change in the BFI from baseline to week 6. Secondary analyses were the BFI score at week 24 and sleep disturbance (based on the Pittsburgh Sleep Quality Index) and quality of life (based on the Functional Assessment of Cancer Therapy-Ovarian) administered at baseline and at weeks 6, 12, and 24. Results Among the 360 participants who were screened, 171 women were randomized (mean [SD] age, 56 [12] years). Of the 160 participants who were allocated to the arms, 53 (33.1%) received TSA, 56 (35.0%) received SSA, and 51 (31.9%) received UC. Of these, the proportion achieving a clinically normal fatigue level at the end of treatment was 58.5% for the TSA arm, 51.1% for the SSA arm, and 17.6% for the UC arm. At 6 weeks, the BFI change scores were significantly better in the TSA arm but not in the SSA arm when they were compared with the UC-only arm (TSA vs UC: adjusted mean difference, −1.23 [95% CI, −2.17 to −0.29] and SSA vs UC: adjusted mean difference, −0.91 [95% CI, −1.83 to 0.02]). TSA and SSA change scores did not differ significantly from one another. The relative benefit of self-acupressure compared with UC on fatigue persisted at 24 weeks (TSA vs UC: mean difference, −1.38 [95% CI, −2.36 to −0.41] and SSA vs UC: mean difference, −0.97 [95% CI, −1.93 to −0.02]). Neither TSA nor SSA was significantly different than UC or each other for sleep quality. Only TSA significantly improved quality of life vs UC (odds ratio, 2.85 [95% CI, 1.20 to 6.80]). Neither true nor sham self-acupressure led to any adverse events. Conclusions and Relevance In this randomized clinical trial, TSA and SSA significantly reduced fatigue compared with UC, and these changes were both clinically meaningful and sustained. No impact was observed on sleep quality. Self-acupressure, taught via a mobile app, offered a safe and low-cost option for managing cancer fatigue. Trial registration ClinicalTrials.gov Identifier: NCT03763838

Women’s Preferences for Home-Based Self-Sampling or Clinic-Based Testing for Cervical Cancer Screening

Importance While home-based self-sampling for cervical cancer screening is an evidence-based strategy proven to increase screening access and uptake, it is not currently recommended in the US despite recent Food and Drug Administration approval of the first at-home self-sampling device. Little nationally representative research has examined preference for and drivers of home-based self-sampling over clinic-based testing (the standard of care). Objective To assess women’s perspectives about, reasons for considering, and factors associated with preferring at-home self-sampling for cervical cancer screening. Design, Setting, and Participants This population-based cross-sectional study used data from the 2024 Health Interview National Trends Survey (HINTS 7), a nationally representative survey of the civilian, noninstitutionalized US adult population offered between March and September 2024. Respondents included in this study were individuals aged between 21 and 65 years who were eligible for cervical cancer screening per the US Preventive Services Task Force guidelines and who self-reported their gender identity. Respondents who indicated not needing cervical cancer screening or who did not report their preference for any screening modality (home-based self-sampling or clinician-collected sampling) were excluded. Data were analyzed from May 12 to 25, 2025. Exposures Age, race and ethnicity, income, educational level, sexual orientation, marital status, health insurance, urbanicity of residence, trust in the health care system, past-year number of visits to a health care practitioner, and prior experience of discrimination or prejudice when getting medical care. Main Outcomes and Measures The main outcome was preference for at-home vaginal self-sampling over clinic-based testing, measured using the HINTS 7 question, “If you had choice, how would you prefer to do the cervical cancer screening test?” Responses were: preference to have a health care practitioner do the test in his or her office, preference to self-collect specimen for the test at home, not knowing which option to choose, and not applicable. Weights were assigned to improve representativeness of the general US adult population. The proportion of individuals who reported preferring either screening modality was estimated using weighted percentages. Survey-weighted odds ratios (ORs), adjusted for covariates, were calculated to identify factors associated with preference for at-home self-sampling. Results Among the 2300 women included (mean [SD] age, 45.5 [29.2] years), most were married or living as married (weighted percentage, 58.2% [95% CI, 56.5%-60.0%]), health insured (91.9%; 95% CI, 90.7%-93.1%), and educated up to some college (61.6%; 95% CI, 60.1%-63.0%). Overall, 462 (20.4%; 95% CI, 17.4%-23.4%) preferred at-home self-sampling, 1402 (60.8%; 95% CI, 57.2%-64.4%) preferred clinic-based testing, and 436 (18.8%; 95% CI, 15.5%-22.1%) were uncertain about their choice. Non-Hispanic Black respondents (adjusted OR [AOR], 0.45; 95% CI, 0.21-0.96) had lower odds of preferring at-home self-sampling compared with non-Hispanic White individuals. Women who had experienced prejudice or discrimination when getting medical care had higher odds (AOR, 1.94; 95% CI, 1.16-3.22) of preferring at-home self-sampling. The most commonly self-reported reasons for preferring at-home self-sampling were privacy (54.9%; 95% CI, 49.8%-60.0%), time constraints (35.1%; 95% CI, 29.0%-41.2%), and fear of embarrassment (33.4%; 95% CI, 28.0%-38.8%). Conclusions and Relevance In this cross-sectional study, marginalized populations, individuals with low income, and individuals who do not trust the health care system were more likely to prefer at-home self-sampling for cervical cancer screening or not know which option to choose. To address cervical cancer inequities and increase screening uptake, the findings suggest US guidelines should incorporate home-based self-sampling as an alternative to clinic-based testing, women’s education and empowerment should be enhanced, and tailored interventions focusing on high-risk groups are needed to increase awareness and self-confidence in performing home-based self-sampling.

PARP Inhibitor Maintenance After First-Line Chemotherapy in Advanced-Stage Epithelial Ovarian Cancer

Importance First-line maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARP inhibitors) after platinum-based chemotherapy improves progression-free survival (PFS) in advanced epithelial ovarian cancer (EOC), particularly in patients with BRCA -variant or homologous recombination-deficient tumors. However, overall survival (OS) benefits remain uncertain, and toxic effect profiles emphasize the need for optimized patient and agent selection. Objective To evaluate the efficacy and safety of first-line PARP inhibitor maintenance therapy compared with chemotherapy alone in advanced-stage EOC, with subgroup analyses by BRCA and HRD status, up-front or interval surgery, chemotherapy response, and residual disease. Data sources Medline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from database inception to August 19, 2024. Study Selection Randomized clinical trials and prospective 2-arm studies evaluating PARP inhibitor maintenance therapy in patients with advanced-stage EOC responding to first-line platinum-based chemotherapy were included. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed in reporting this study. Data were independently extracted by 2 reviewers. Random-effects models were used for meta-analysis. Risk of bias was assessed with Cochrane risk of bias and certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Main Outcomes and Measures Primary outcomes were PFS and OS; secondary outcomes included high-grade adverse events. Results A total of 7 randomized clinical trials with 4013 patients with advanced-stage epithelial ovarian cancer responding to first-line platinum-based chemotherapy were included. PARP inhibitor maintenance was associated with improved PFS in the overall population (hazard ratio [HR], 0.57; 95% CI, 0.46-0.70; high certainty) and in all molecular subgroups except the homologous recombination proficient group ( BRCA variant: HR, 0.40; 95% CI, 0.35-0.45; BRCA wild type: HR, 0.62; 95% CI, 0.44-0.86; homologous recombination deficient: HR, 0.44; 95% CI, 0.39-0.50; all high certainty). PFS benefits were consistent across surgical timing, chemotherapy responses, and residual disease; for example, surgical timing had HRs of 0.51 (95% CI, 0.31-0.84) for neoadjuvant chemotherapy and 0.54 (95% CI, 0.36-0.81) for primary cytoreductive surgery (all high certainty). No molecular subgroup showed a statistically significant OS improvement (high to low certainty). High-grade adverse events were more common in the PARP inhibitor group (HR, 2.40; 95% CI, 1.16-4.93; high certainty). Observed treatment efficacy and toxic effects varied across PARP inhibitor regimens; for example, the risk ratio for any recurrence or death in the overall study group ranged from 0.53 (95% CI, 0.40-0.70) for senaparib to 0.83 (95% CI, 0.68-1.00) for olaparib, while the risk ratio for high-grade adverse events ranged from 1.15 (95% CI, 0.64-2.06) for veliparib to 4.73 (95% CI, 2.77-8.07) for niraparib. Conclusions and Relevance In this study, no subgroup showed an association between first-line PARP inhibitor maintenance therapy in advanced-stage EOC and improved OS, and findings suggest that the consistency of associated PFS benefits may vary, particularly in homologous recombination proficient and BRCA wild type tumors. Variability in efficacy and toxic effects across subgroups and PARP inhibitor regimens underscores the importance of individualized treatment decisions.

Association of Neoadjuvant Chemotherapy With Overall Survival in Women With Metastatic Endometrial Cancer

Although primary debulking surgery (PDS) is often considered the criterion standard for treatment of stage IV endometrial cancer, PDS is associated with significant morbidity and poor survival. Neoadjuvant chemotherapy (NACT) has been proposed as an alternative treatment strategy. To determine the use of and outcomes associated with NACT for women with stage IV endometrial cancer. This cohort study used the National Cancer Database to identify women with stage IV endometrial cancer treated from January 1, 2010, to December 31, 2015. The cohort was limited to women aged 70 years or younger with minimal comorbidity (comorbidity score = 0). Women were stratified based on receipt of NACT or PDS. A propensity score analysis with inverse probability weighting was performed to balance the clinical characteristics of the groups. Survival was examined using flexible parametric Royston-Parmer models to account for time-varying hazards associated with use of NACT. An intention-to-treat (ITT) analysis was performed, as was a per-protocol (PP) analysis that included only women who received treatment with both chemotherapy and surgery (in either sequence). Data were analyzed from March 15, 2018, to July 20, 2018. Use of NACT and overall survival. Of a total of 4890 women (median age, 60 years [interquartile range, 54-65 years]) with stage IV endometrial cancer, NACT was used in 952 women (19.5%). Use of NACT increased from 106 of 661 women (16.0%; 95% CI, 13.2%-18.8%) in 2010 to 224 of 938 women (23.9%; 95% CI, 21.2%-26.6%) in 2015 (P < .001). In a multivariate model, more recent year of diagnosis (risk ratio [RR], 1.42; 95% CI, 1.21-1.79 for 2015 vs 2010), stage IVB disease (RR, 1.31; 95% CI, 1.03-1.67 for stage IVB vs IVA), and serous histology (RR, 1.38; 95% CI, 1.13-1.69 for serous vs endometrioid histology) were associated with use of NACT. In a propensity score-balanced cohort, use of NACT displayed a time-varying association with survival. In the ITT analysis, use of NACT was associated with decreased mortality for the first 3 months after diagnosis (hazard ratio [HR] at 2 months, 0.81; 95% CI, 0.66-0.99). After 4 months, the survival curves crossed, and receipt of NACT was associated with increased mortality (HR at 6 months, 1.23; 95% CI, 1.09-1.39). In the PP analysis, use of NACT was associated with decreased mortality for the first 8 months after diagnosis (HR at 6 months, 0.79; 95% CI, 0.63-0.98). After 9 months, the survival curves crossed, and receipt of NACT was associated with increased mortality (HR at 12 months, 1.22; 95% CI, 1.04-1.43). The results of this cohort study suggest that women treated with PDS are at increased risk of early death but have a more favorable long-term prognosis. In contrast, results suggest that women treated with NACT, particularly if they ultimately undergo surgery, may have superior survival in the short term. Based on these findings, NACT may be appropriate for select patients with advanced uterine serous carcinoma.

Development and Validation of a Serum Metabolomic Signature for Endometrial Cancer Screening in Postmenopausal Women

Endometrial carcinoma (EC) is the most commonly diagnosed gynecologic cancer. Its early detection is advisable because 20% of women have advanced disease at the time of diagnosis. To clinically validate a metabolomics-based classification algorithm as a screening test for EC. This diagnostic study enrolled 2 cohorts. A multicenter prospective cohort, with 50 cases (postmenopausal women with EC; International Federation of Gynecology and Obstetrics stage I-III and grade G1-G3) and 70 controls (no EC but matched on age, years from menopause, tobacco use, and comorbidities), was used to train multiple classification models. The accuracy of each trained model was then used as a statistical weight to produce an ensemble machine learning algorithm for testing, which was validated with a subsequent prospective cohort of 1430 postmenopausal women. The study was conducted at the San Giovanni di Dio e Ruggi d'Aragona University Hospital of Salerno (Italy) and Lega Italiana per la Lotta contro i Tumori clinic in Avellino (Italy). Data collection was conducted from January 2018 to February 2019, and analysis was conducted from January to March 2019. The presence or absence of EC based on evaluation of the blood metabolome. Metabolites were extracted from dried blood samples from all participants and analyzed by gas chromatography-mass spectrometry. A confusion matrix was used to summarize test results. Performance indices included sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and accuracy. Confirmation or exclusion of EC in women with a positive test result was by means of hysteroscopy. Participants with negative results were followed up 1 year after enrollment to investigate the appearance of EC signs. The study population consisted of 1550 postmenopausal women. The mean (SD) age was 68.2 (11.7) years for participants with no EC in the training cohort, 69.4 (13.8) years for women with EC in the training cohort, and 59.7 (7.7) years for women in the validation cohort. Application of the ensemble machine learning to the validation cohort resulted in 16 true-positives, 2 false-positives, and 0 false-negatives, and it correctly classified more than 99% of samples. Disease prevalence was 1.12% (16 of 1430). In this study, dried blood metabolomic profile was used to assess the presence or absence of EC in postmenopausal women not receiving hormonal therapy with greater than 99% accuracy.

Primary Cytoreduction and Survival for Patients With Less-Common Epithelial Ovarian Cancer

This cohort study examines the association between primary cytoreduction status and survival for patients with less-common, advanced-stage epithelial ovarian carcinoma.

Economic Evaluation of Population-Based BRCA1 and BRCA2 Testing in Canada

ImportancePopulation-based BRCA testing can identify many more BRCA carriers who will be missed by the current practice of BRCA testing based on family history (FH) and clinical criteria. These carriers can benefit from screening and prevention, potentially preventing many more breast and ovarian cancers and deaths than the current practice.ObjectiveTo estimate the incremental lifetime health outcomes, costs, and cost-effectiveness associated with population-based BRCA testing compared with FH-based testing in Canada.Design, Setting, and ParticipantsFor this economic evaluation, a Markov model was developed to compare the lifetime costs and outcomes of BRCA1/BRCA2 testing for all general population women aged 30 years compared with FH-based testing. BRCA carriers are offered risk-reducing salpingo-oophorectomy to reduce their ovarian cancer risk and magnetic resonance imaging (MRI) and mammography screening, medical prevention, and risk-reducing mastectomy to reduce their breast cancer risk. The analyses were conducted from both payer and societal perspectives. This study was conducted from October 1, 2022, to February 20, 2024.Main Outcomes and MeasuresOutcomes of interest were ovarian cancer, breast cancer, additional heart disease deaths, and incremental cost-effectiveness ratio ICER per quality-adjusted life-year (QALY). One-way and probabilistic-sensitivity-analyses (PSA) were undertaken to explore the uncertainty.ResultsIn the simulated cohort of 1 000 000 women aged 30 years in Canada, the base case ICERs of population-based BRCA testing were CAD $32 276 (US $23 402.84) per QALY from the payer perspective or CAD $16 416 (US $11 903.00) per QALY from the societal perspective compared with FH-based testing, well below the established Canadian cost-effectiveness thresholds. Population testing remained cost-effective for ages 40 to 60 years but not at age 70 years. The results were robust for multiple scenarios, 1-way sensitivity, and PSA. More than 99% of simulations from payer and societal perspectives were cost-effective on PSA (5000 simulations) at the CAD $50 000 (US $36 254.25) per QALY willingness-to-pay threshold. Population-based BRCA testing could potentially prevent an additional 2555 breast cancers and 485 ovarian cancers in the Canadian population, corresponding to averting 196 breast cancer deaths and 163 ovarian cancer deaths per 1 000 000 population.Conclusions and RelevanceIn this economic evaluation, population-based BRCA testing was cost-effective compared with FH-based testing in Canada from payer and societal perspectives. These findings suggest that changing the genetic testing paradigm to population-based testing could prevent thousands of breast and ovarian cancers.

Geographic Variation of Racial and Ethnic Differences in Uterine Cancer Survival

ImportanceRacial and ethnic disparities in uterine cancer survival are well-documented; however, limited data exist regarding the interplay of geography, diversity, and race and ethnicity in survival disparities.ObjectiveTo examine associations of race and ethnicity with uterine cancer–specific survival according to geographic region and regional diversity.Design, Setting, and ParticipantsThis retrospective cohort study included patients with uterine cancer diagnosed from 2000 to 2019, from 17 Surveillance, Epidemiology, End Results registries, grouped by US location and ranked according to the US Census Bureau’s Diversity Index (DI; range, 0%-100%; higher values indicate greater diversity), a metric of racial and ethnic composition. Analyses were conducted from June 8, 2024 to October 30, 2024.ExposuresRace and ethnicity of patients with uterine cancer, categorized as Asian, Black, Hispanic, and White.Main Outcomes and MeasuresCox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for multivariable-adjusted associations of race and ethnicity with uterine cancer–specific survival (primary outcome) in the overall sample and stratified by location. Location-stratified models were used to examine whether associations of race and ethnicity with survival varied by tumor characteristics.ResultsAmong 162 500 patients with uterine cancer (median [IQR] age at diagnosis, 61 [54-69] years), there were 12 226 Asian patients (7.5%), 14 007 Black patients (8.6%), 20 799 Hispanic patients (12.8%), and 115 468 White patients (71.1%). Cancer-specific survival was better among Asian patients (HR, 0.91; 95% CI, 0.86-0.97), worse among Black patients (HR, 1.34; 95% CI, 1.28-1.40), and not different among Hispanic patients (HR, 1.01; 95% CI, 0.97-1.06) compared with White patients. Location-stratified analyses found worse uterine cancer–specific survival among Black patients compared with White patients in both higher DI locations (California: HR, 1.34; 95% CI, 1.25-1.44; DI, 69.7%; New Jersey: HR, 1.34; 95% CI, 1.21-1.50; DI, 65.8%; Georgia: HR, 1.39; 95% CI, 1.26-1.53; DI = 64.1%) and lower DI locations (Louisiana: HR, 1.34; 95% CI, 1.16-1.54; DI = 58.6%; Connecticut: HR, 1.42; 95% CI, 1.17-1.72; DI, 55.7%; Iowa: HR, 1.71; 95% CI, 1.01-2.89; DI, 30.8%). Hispanic patients, compared with White patients, had worse survival in Hawaii (HR, 2.09; 95% CI, 1.28-3.42) and Georgia (HR, 1.44; 95% CI, 1.13-1.82), whereas Asian patients had better survival than White patients in California (HR, 0.91; 95% CI, 0.84-0.97). In locations demonstrating survival disparities between Black and White patients, these patterns were evident in most tumor characteristic–defined strata.Conclusions and RelevanceIn this cohort study of patients with uterine cancer, racial and ethnic disparities in survival within specific geographic areas were identified. Targeted research may reduce national disparities.

Delivering Guideline-Concordant Care for Patients With High-Risk HPV and Normal Cytologic Findings

ImportanceAs US health care systems shift to human papillomavirus (HPV)–based cervical cancer screening, more patients are receiving positive high-risk non–16/18 genotype HPV results and negative for intraepithelial lesion or malignancy (NILM) cytological findings. Risk-based management guidelines recommend 2 consecutive negative annual results to return to routine screening.ObjectiveTo quantify patterns of surveillance testing and associated outcomes for patients after an HPV-positive results and NILM cytologic findings.Design, Setting, and ParticipantsThis cohort study analyzed patients in the METRICS (Multi-level Optimization of the Cervical Cancer Screening Process in Diverse Settings and Populations) cohort of the PROSPR II (Population-Based Research to Optimize the Screening Process) Cervical Consortium. Population-based data were obtained from 3 diverse health care systems (Mass General Brigham [MGB] in Massachusetts, Kaiser Permanente Washington [KPWA] in Washington, and Parkland Health [PH] in Texas) in the METRICS cohort. Participants were patients aged 21 to 65 years who received an HPV-positive (non-16/18 or pooled genotypes) result and NILM cytologic finding from January 2010 to August 2018 and were followed up through December 2019. Data analyses were performed between April 2021 and November 2024.Main Outcomes and MeasuresTest receipt and outcomes delivered within 16 months after the index result (round 1 surveillance).ResultsThe final sample across the 3 health care systems comprised 13 158 female patients (3228 Hispanic or Latine [24.5%], 1990 non-Hispanic African American or Black [15.1%], 749 non-Hispanic Asian [5.7%], and 6559 non-Hispanic White [49.8%] individuals). Sociodemographic characteristics varied by site, with more non-Hispanic White (2277 [63.7%] and 4061 [61.2%]) and commercially insured patients (3137 [87.8%] and 4365 [65.7%]) at KPWA and MGB, and more Hispanic or Latine (1664 [56.5%]) and uninsured patients (2352 [79.9%]) at PH. During round 1 surveillance, 43.7% of patients were tested, of whom 18.2% (2394) had HPV-negative results and NILM cytologic findings and 25.5% (3351) had abnormal results. Many patients remained in the cohort and were untested through round 1 surveillance (overall: 49.4% [6505]; across sites: 39.0% [1395] to 69.4% [2043]), while fewer exited the cohort (overall: 6.9% [908]; across sites: 0.2% [12] to 24.6% [879]). Groups with lower odds of timely testing were younger adults (aged 25-29 vs 30-39 years: adjusted odds ratio [AOR], 0.65; 95% CL, 0.53-0.81), non-Hispanic African American or Black compared with non-Hispanic White patients (AOR, 0.78; 95% CL, 0.68-0.89), and those with Medicaid compared with commercial insurance (AOR, 0.81; 95% CL, 0.72-0.91), while those with a primary care clinician were more likely to have timely testing (AOR, 1.44; 95% CL, 1.21-1.70). Cancer was diagnosed in 10 patients (0.2%) untested in round 1 surveillance compared with 0 cancers in those with an HPV-negative results and NILM cytologic findings.Conclusions and RelevanceThis cohort study found that among patients with HPV-positive results and NILM cytologic findings, less than half received a surveillance cotest during the guideline-recommended time frame. Health care systems should monitor annual surveillance and gather evidence on interventions to optimize the delivery of surveillance testing.

Cost-effectiveness of Population-Wide Genomic Screening for Hereditary Breast and Ovarian Cancer in the United States

Genomic screening for hereditary breast and ovarian cancer (HBOC) in unselected women offers an opportunity to prevent cancer morbidity and mortality, but the potential clinical impact and cost-effectiveness of such screening have not been well studied. To estimate the lifetime incremental incidence of HBOC and the quality-adjusted life-years (QALYs), costs, and cost-effectiveness of HBOC genomic screening in an unselected population vs family history-based testing. In this study conducted from October 27, 2017, to May 3, 2020, a decision analytic Markov model was developed that included health states for precancer, for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO), for earlier- and later-stage HBOC, after cancer, and for death. A complimentary cascade testing module was also developed to estimate outcomes in first-degree relatives. Age-specific RRM and RRSO uptake probabilities were estimated from the Geisinger MyCode Community Health Initiative and published sources. Parameters including RRM and RRSO effectiveness, variant-specific cancer risk, costs, and utilities were derived from published sources. Sensitivity and scenario analyses were conducted to evaluate model assumptions and uncertainty. Lifetime cancer incidence, QALYs, life-years, and direct medical costs for genomic screening in an unselected population vs family history-based testing only were calculated. The incremental cost-effectiveness ratio (ICER) was calculated as the difference in cost between strategies divided by the difference in QALYs between strategies. Earlier-stage and later-stage cancer cases prevented and total cancer cases prevented were also calculated. The model found that population screening of 30-year-old women was associated with 75 (95% credible range [CR], 60-90) fewer overall cancer cases and 288 QALYs (95% CR, 212-373 QALYs) gained per 100 000 women screened, at an incremental cost of $25 million (95% CR, $21 millon to $30 million) vs family history-based testing; the ICER was $87 700 (78% probability of being cost-effective at a threshold of $100 000 per QALY). In contrast, population screening of 45-year-old women was associated with 24 (95% CR, 18-29) fewer cancer cases and 97 QALYs (95% CR, 66-130 QALYs) gained per 100 000 women screened, at an incremental cost of $26 million (95% CR, $22 million to $30 million); the ICER was $268 200 (0% probability of being cost-effective at a threshold of $100 000 per QALY). A scenario analysis without cascade testing increased the ICER to $92 600 for 30-year-old women and $354 500 for 45-year-old women. A scenario analysis assuming a 5% absolute decrease in mammography screening in women without a variant was associated with the potential for net harm (-90 QALYs per 100 000 women screened; 95% CR, -180 to 10 QALYs). The results of this study suggest that population HBOC screening may be cost-effective among younger women but not among older women. Cascade testing of first-degree relatives added a modest improvement in clinical and economic value. The potential for harm conferred by inappropriate reduction in mammography among noncarriers should be quantified.

Diet and Survival in Black Women With Epithelial Ovarian Cancer

ImportanceOvarian cancer survival among Black women is the lowest across all racial and ethnic groups. Poor dietary quality also disproportionately affects Black populations, but its association with ovarian cancer survival in this population remains largely unknown.ObjectiveTo examine associations between dietary patterns and survival among Black women diagnosed with epithelial ovarian cancer (EOC).Design, Setting, and ParticipantsThis prospective cohort study was conducted among self-identified Black women aged 20 to 79 years newly diagnosed with histologically confirmed EOC in the African American Cancer Epidemiology Study (AACES) between December 2010 and December 2015, with follow-up until October 2022. AACES is a population-based study of ovarian cancer risk and survival among Black women in 11 US regions. Data were analyzed from March 2023 to June 2024.ExposuresDietary patterns were assessed by the Healthy Eating Index-2020 (HEI-2020) and Alternative Healthy Eating Index-2010 (AHEI-2010), with scores calculated based on dietary intake in the year prior to diagnosis and collected via the validated Block 2005 Food Frequency Questionnaire. Higher scores indicate better dietary quality.Main outcomes and measuresHazard ratios (HRs) and 95% CIs were estimated from multivariable Cox models for the association between adherence to dietary recommendations and overall mortality among all participants and those with high-grade serous ovarian cancer (HGSOC).ResultsAmong 483 Black women with EOC (mean [SD] age, 58.1 [10.5] years), 310 deaths were recorded during a median (IQR) follow-up of 4.3 (2.0-8.2) years. No association of dietary patterns with mortality was found among women with EOC overall. However, among 325 women with HGSOC, better adherence to HEI-2020 was associated with decreased mortality in later quartiles compared with the first quartile (HR, 0.63; 95% CI, 0.44-0.92 for quartile 2; HR, 0.67; 95% CI, 0.46-0.97 for quartile 3; HR, 0.63; 95% CI, 0.44-0.91 for quartile 4 ). Similar results were observed with AHEI-2010 among women with HGSOC for the second (HR, 0.62; 95% CI, 0.43-0.89) and fourth (HR, 0.67; 95% CI, 0.45-0.98) quartiles compared with quartile 1.Conclusions and relevanceIn this study, women with moderate and high prediagnosis dietary quality had significantly lower mortality rates from HGSOC compared with women with the lowest prediagnosis dietary quality. These findings suggest that even moderate adherence to dietary guidelines prior to diagnosis may be associated with improved survival among Black women with HGSOC, the most lethal form of ovarian cancer.

Prevalence and Landscape of Pathogenic or Likely Pathogenic Germline Variants and Their Association With Somatic Phenotype in Unselected Chinese Patients With Gynecologic Cancers

ImportanceUnderstanding germline and somatic status in patients with gynecologic cancers could improve risk assessment and guide therapeutic decision-making.ObjectiveTo evaluate the prevalence and landscape of germline pathogenic or likely pathogenic (P/LP) variants and explore whether these variants are associated with somatic phenotypes and cancer risk in unselected patients with gynecologic cancers.Design, Setting, and ParticipantsThis cross-sectional study retrospectively enrolled unselected patients in China with a gynecologic cancer, including ovarian, cervical, and endometrial, who underwent tumor-normal sequencing using a 520-gene panel from October 1, 2017, through May 31, 2021.ExposureGermline variants in gynecologic cancers.Main Outcomes and MeasuresThe P/LP germline variant rates in 62 cancer predisposition genes were assessed using descriptive statistics. The associations of P/LP variant status with age, somatic profiles, and cancer risk were also investigated using the Fisher exact test or Student t test.ResultsA total of 1610 women (median [IQR] age, 54 [47-62] years; 1201 [74.6%] with stage III-IV disease) were included (945 with ovarian cancer, 307 with endometrial cancer, and 358 with cervical cancer). The prevalence of patients with P/LP variants was 20.5% (194 of 945) for ovarian cancer, 13.4% (41 of 307) for endometrial cancer, and 6.4% (23 of 358) for cervical cancer; 95.1% of the germline findings (n = 252) were potentially actionable, mainly in homologous recombination repair (HRR) and mismatch repair genes. Chinese patients with endometrial cancer had a higher rate of P/LP variants than a White population from The Cancer Genome Atlas (42 of 307 [13.7%] vs 24 of 367 [6.5%]; P = .003). In endometrial and cervical cancers, the prevalence of P/LP variants was 12.7% (30 of 237) and 4.8% (13 of 270), respectively, in patients diagnosed at age 45 years or older and increased to 25.0% (9 of 36; P = .09) and 12.0% (10 of 83; P = .04), respectively, for those with an onset age of less than 45 years. Mismatch repair P/LP variants were associated with a younger age at onset for ovarian cancer (46 vs 54 years; P = .02) and endometrial cancer (48 vs 57 years; P &amp;amp;lt; .001), while HRR P/LP variants were associated with a younger age at onset for cervical cancer (46 vs 52 years; P = .04). Carriers of HRR P/LP variants had more prevalent somatic TP53 variants and less common somatic variants in oncogenic driver genes vs noncarriers. BRCA1/2 P/LP variants were also associated with moderate risks for endometrial and cervical cancer.Conclusions and RelevanceThis study delineates the landscape of germline P/LP variants in Chinese women with gynecologic cancers. The findings highlight the hereditary factor in cervical cancer that has long been neglected and suggest the importance of next-generation sequencing–based genetic testing with a large gene panel for gynecologic cancers.

GLP-1 Receptor Agonists Plus Progestins and Endometrial Cancer Risk in Nonmalignant Uterine Diseases

Importance As endometrial cancer (EC) incidence rises, particularly among individuals with obesity and metabolic disorders, effective strategies targeting hormonal and metabolic risks are needed. Objective To evaluate EC risk in patients with endometrial hyperplasia (EH) or benign uterine pathology treated with progestins vs combined progestins and glucagon-like peptide-1 receptor agonists (GLP-1RAs). Design, Setting, and Participants This cohort study used TriNetX to analyze EC and hysterectomy among adult women with EH or benign uterine pathology who received progestins between May 1, 2005 (GLP-1RA approval date), and December 31, 2022. Analyses were based on deidentified electronic health records identified via International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes, and data were obtained on February 23, 2025. Four treatment comparisons were analyzed: GLP-1RA plus progestins vs progestins only; GLP-1RA plus progestins vs metformin progestins; triple therapy (GLP-1RA, metformin, and progestins) vs metformin plus progestins; triple therapy vs progestins only. Subgroup analyses GLP-1RA plus progestins vs progestins only stratified patients by progestin route, risk level, body mass index (BMI), and age. Exposures GLP-1RAs, progestins, and/or metformin. Main outcomes and measures The primary outcome was the incidence of EC. The secondary outcome was the incidence of subsequent hysterectomy. Results A total of 18 414 and 426 406 adult female patients received GLP-1RA combined with progestin and progestin alone, respectively (mean [SD] age, 43.1 [10.2] years vs 35.2 [10.9] years). GLP-1RA with progestins was associated with a significantly lower risk of EC compared with progestins only (HR, 0.34 [95% CI, 0.27-0.44]). This protective association remained consistent across subgroups, stratified by progestin route, baseline risk, BMI, and age. GLP-1RA plus progestins also showed a lower EC risk than metformin plus progestins (HR, 0.30 [95% CI, 0.15-0.59]). Triple therapy was more effective in reducing EC risk than dual (metformin plus progestins) (HR, 0.37 [95% CI, 0.25-0.53]) or progestin monotherapy (HR, 0.44 [95% CI, 0.29-0.66]). Hysterectomy rates were lower in the GLP-1RA plus progestins group at 2-year (HR, 0.47 [95% CI, 0.42-0.53]) and 5-year (HR, 0.59 [95% CI, 0.54-0.64]) follow-up. Conclusions and Relevance In this cohort study of women with benign uterine pathology or endometrial hyperplasia, combined GLP-1RA and progestin was associated with reduced EC risk. Further investigation is warranted to assess its applicability and underlying mechanisms.

Surgical Deescalation Within Gynecologic Oncology

ImportanceThe goal of surgical deescalation is to minimize tissue damage, enhance patient outcomes, and reduce the adverse effects often associated with extensive or traditional surgical procedures. This shift toward less invasive techniques has the potential to revolutionize surgical practices, profoundly impacting the methods and training of future surgeons.ObjectiveTo evaluate adoption of surgical deescalation within the field of gynecologic oncology using The National Cancer Database.Design, Setting, and ParticipantsThis cohort study used prospectively collected data from the National Cancer Database from January 2004 to December 2020. Eligible participants included women in the US who received a diagnosis of clinical stage I to IV endometrial, ovarian, cervical, or vulvar cancer within this time frame. Data were analyzed between January and June 2024.ExposureDiagnosis of stage I to IV endometrial, ovarian, cervical, or vulvar cancer.Main Outcomes and MeasuresThe primary outcome was surgical deescalation, which included evaluation of receipt of surgical intervention, the surgical approach, the type of lymph node assessment, and salvage interventions for disease-affected organs. A Poisson model was applied to estimate the average annual percentage change (AAPC) in the receipt of surgical treatment.ResultsA total of 1 218 490 patients (mean [SD] age at diagnosis, 61.2 [13.7] years) were included. Over the study period, the percentage of patients undergoing surgery decreased from 47.4% to 39.9% for those with cervical cancer (AAPC, −1.3%; 95% CI, −1.6% to −1.1%), from 72.0% to 67.9% for those with ovarian cancer (AAPC, −0.5%; 95% CI, −0.6% to −0.4%), from 83.7% to 79.1% for those with endometrial cancer (AAPC, −0.5%; 95% CI, −0.7% to 11 −0.4%), and from 81.1% to 72.6% for those with vulvar cancer (AAPC, −1.3%; 95% CI, −1.6% to −0.9%). The use of minimally invasive surgery increased from 45.8% to 82.2% for those with endometrial cancer (AAPC, 4.6%; 95% CI, 4.5% to 4.8%) and from 13.3% to 37.0% for those with ovarian cancer (AAPC, 9.4%; 95% CI, 9.0% to 9.7%). Sentinel lymph node dissection increased from 0.7% to 39.6% for patients with endometrial cancer (AAPC, 51.8%; 95% CI, 50.5% to 53.2%), from 0.2% to 10.6% for patients with cervical cancer (AAPC, 44.0%; 95% CI, 39.3% to 48.9%), and from 12.3% to 36.9% for patients with vulvar cancer (AAPC, 10.7%; 95% CI, 8.0% to 13.5%) cancers, whereas the rate of complete lymphadenectomies decreased in all 3 groups. The rate of fertility-sparing surgery for patients with cervical cancer younger than 40 years rose from 17.8% to 28.1% (AAPC, 3.1%; 95% CI, 2.3%-3.9%).Conclusions and RelevanceThese findings suggest that over the past 15 years, the field of gynecologic oncology has moved toward surgical deescalation through an overall reduction in the number of patients who undergo surgery, increased use of minimally invasive surgical techniques, and increased use of sentinel lymph node techniques. Future research should focus not only on understanding the impact of surgical escalation on patients (including disease outcomes, quality of life, and equitable access to these services), but also on surgical training.

Trial Enrollment and Survival Disparities Among Patients With Advanced Epithelial Ovarian Carcinoma

Importance Racial differences in epithelial ovarian cancer (EOC) might result in survival inequities. Objective To evaluate enrollment and outcomes by race in Gynecologic Oncology Group (GOG) randomized clinical trials (RCTs) among patients with EOC. Design, Setting, and Participants This cohort study used ancillary data from completed RCTs using protocols GOG-111, GOG-114, GOG-158, and GOG-172 under a data sharing agreement with National Research Group Oncology. Patients with stage III or IV EOC in first-line RCT protocol GOG-111 had suboptimally resected disease, whereas those in GOG-114, GOG-158, or GOG-172 had optimally resected disease. RCTs were conducted and published between 1996 and 2006, and data for this study were analyzed in August 2024. Exposure Race was categorized as Asian, Black or African American (Black), or White or Caucasian (White). Patients of other races were excluded. Spanish ethnicity and additional details regarding residual disease status were not available for analysis. Main Outcomes and Measures Overall survival (OS) was the primary end point and progression-free survival (PFS) was the secondary end point, evaluated using multivariable Cox proportional-hazards modeling and log-rank testing. Statistical significance was set at P  &amp;amp;lt; .05. Results This study included 1903 evaluable participants, of whom 35 (1.84%) self-identified as Asian, 121 (6.36%) as Black, and 1747 (91.80%) as White. Black patients had lower OS (median [IQR], 36.8 [19.2-73.4] months) than Asian (50.9 [23.9-109.2] months) or White (48.4 [24.5-93.4] months) patients ( P  = .03), with a higher risk of death than White patients (adjusted hazard ratio, 1.30; 95% CI, 1.06-1.59; P  = .01). PFS and adjusted risk of disease progression were statistically similar across racial groups. Median (IQR) PFS was 18.9 (9.7-84.6), 18.0 (9.1-34.0), and 19.7 (11.5-43.3) months among Asian, Black, and White patients, respectively ( P  = .08). Adjusted risk of disease progression was similar for Black patients compared with White patients (adjusted hazard ratio, 1.21; 95% CI, 1.00-1.47; P  = .06). Conclusions and Relevance In this cohort study, Black and Asian patients were underrepresented in RCT trial populations. Black patients had lower OS than White and Asian patients but similar PFS. Equitable enrollment in clinical trials ensures access to cutting-edge treatments and can lead to outcomes comparable to those of White counterparts. Sustained efforts to improve RCT diversity remain essential to long-term equity in cancer care and survival.

Geographic Disparities in Gynecologic Oncology Clinical Trial Availability in the US

ImportanceDisparities in minoritized racial and ethnic populations’ participation in gynecologic cancer clinical trials are well documented despite the high rates of endometrial cancer in these populations. Geographic proximity to trials is a critical component to ensure equitable trial access.ObjectiveTo characterize the geographic distribution of gynecological cancer trials across the US and identify disparities.Design, Setting, and ParticipantsThis study is a cross-sectional analysis of trials first posted on ClinicalTrials.gov from January 1, 2013, through January 10, 2024. This study involved a state-level analysis of clinical trials located in the US. Enrollment criteria of clinical trials for ovarian, uterine, cervical, endometrial, vaginal and/or vulvar, and other gynecological cancers were reviewed to exclude nongynecological cancers (1643 trials) or noninvasive gynecological conditions (224 trials).ExposureThe number of gynecological trials per 100 000 persons in each state.Main Outcomes and MeasuresA state-level analysis was performed to determine whether gynecologic cancer clinical trial availability in the US is associated with other state-level characteristics to identify areas of increased need. Census data, state-level total population size, percentage of non-Hispanic White persons, and the Federal Emergency Management Agency expected annual loss per state as a measure of social vulnerability were aggregated. The association between these variables and the number of gynecological trials per 100 000 persons was measured using Spearman rank correlation.ResultsOf the 1561 invasive gynecological cancer trials that met the inclusion criteria, most cancer trials were ovarian (911 trials [58.4%]), followed by cervical (438 trials [28.1%]), and endometrial (385 trials [24.7%]). Predominantly minoritized population–serving states (ie, those with &amp;amp;lt;50% non-Hispanic White persons) had fewer than 4 trials per 100 000 persons, but this was not significant nationally (ρ = 0.20; 95% CI, −0.08 to 0.45; P = .16). States with higher Federal Emergency Management Agency expected annual loss had lower numbers of gynecological trials per 100 000 persons, which was significant nationally (ρ = −0.53; 95% CI, −0.70 to −0.29; P &amp;amp;lt; .001).Conclusions and RelevanceIn this cross-sectional study of female gynecological cancer trials by state, states with particularly high economic vulnerability and minoritized populations had low clinical trial availability. Further efforts are needed to address disparities identified in this study to ensure equitable trial access.

Chemoradiotherapy With or Without Simultaneous Integrated Boost for Cervical Cancer With Full-Thickness Stromal Invasion

ImportancePatients with cervical cancer exhibiting full-thickness (FT) and outer full-thickness (OFT) stromal invasion after radical hysterectomy face high risks of recurrence, yet optimal adjuvant radiotherapy strategies remain debated.ObjectiveTo determine if simultaneous integrated boost (SIB) radiotherapy increases 3-year progression-free survival (PFS) by 13% vs conventional chemoradiotherapy (CRT) among patients with cervical cancer exhibiting FT or OFT stromal invasion after surgery.Design, Setting, and ParticipantsThis phase 3, single-center, randomized clinical superiority trial enrolled 466 patients in Shanghai Cancer Center with FIGO (International Federation of Gynecology and Obstetrics) 2018 stage IB to IIA and IIIC cervical cancer and pathologically confirmed FT or OFT stromal invasion from October 15, 2019, to September 20, 2024. Data were analyzed in October 2024.InterventionsPatients were randomized to receive conventional CRT (50.4 Gy in 28 fractions plus cisplatin, 40 mg/m2/wk) or CRT plus SIB radiotherapy (58.8 Gy in 28 fractions).Main Outcomes and MeasuresThe primary end point was 3-year PFS. Secondary end points included overall survival (OS), acute and late toxic effects, and progression patterns. All outcomes were analyzed under the intention-to-treat principle.ResultsA total of 466 patients with cervical cancer presenting with FT or OFT stromal invasion after radical hysterectomy were randomized (233 in non-SIB radiotherapy group: median age, 53 years [IQR, 46-59 years]; 233 in SIB radiotherapy group: median age, 55 years [IQR, 48-60 years]). At a median follow-up of 33 months (range, 8-54 months), SIB radiotherapy significantly improved 3-year PFS compared with conventional CRT (84.6% vs 76.8%; P = .04), corresponding to a 35.7% reduction in progression risk (hazard ratio [HR], 0.64; 95% CI, 0.42-0.99; P = .04). Multivariable analysis identified adenocarcinoma (HR, 2.68; 95% CI, 1.62-4.44; P &amp;amp;lt; .001), adenosquamous carcinoma (HR, 2.66; 95% CI, 1.06-6.66; P = .04), tumor size of 4 cm or more (HR, 1.81; 95% CI, 1.17-2.81; P = .01), lymphovascular space invasion (HR, 2.88; 95% CI, 1.45-5.72; P = .003), and positive vaginal margins (HR, 4.60; 95% CI, 1.97-10.73; P &amp;amp;lt; .001) as independent risk factors of poorer PFS, while SIB radiotherapy remained protective (HR, 0.59; 95% CI, 0.38-0.91; P = .02). Profiles of toxic effects were comparable between groups.Conclusions and RelevanceIn this randomized clinical trial of postoperative patients with cervical cancer presenting with FT or OFT stromal invasion, SIB radiotherapy significantly enhanced PFS without increased toxic effects. The clinical benefits and comparable profiles of toxic effects support its integration into adjuvant care.Trial RegistrationChinese Clinical Trial Registry Identifier: ChiCTR1900027272

Geographic Variation in Late-Stage Cervical Cancer Diagnosis

ImportanceThere are stark disparities in cervical cancer burden in the United States, notably by race and ethnicity and geography. Late-stage diagnosis is an indicator of inadequate access to and utilization of screening.ObjectiveTo identify geospatial clusters of late-stage cervical cancer at time of diagnosis in Texas.Design, Setting, and ParticipantsThis population-based cross-sectional study used incident cervical cancer data from the Texas Cancer Registry from 2014 to 2018 of female patients aged 18 years or older. Late-stage cervical cancer cases were geocoded at the census tract level (n = 5265) using their residential coordinates (latitude and longitude) at the time of diagnosis. Statistical analysis was performed from April to September 2023.ExposuresCensus tract of residence at diagnosis.Main Outcome and MeasuresLate-stage cervical cancer diagnosis (ie, cases classified by the National Cancer Institute Surveillance, Epidemiology and End Results summary stages 2 to 4 [regional spread] or 7 [distant metastasis]). A Poisson probability-based model of the SaTScan purely spatial scan statistics was applied at the census tract–level to identify geographic clusters of higher (hot spots) or lower (cold spots) proportions than expected of late-stage cervical cancer diagnosis and adjusted for age.ResultsAmong a total of 6484 female patients with incident cervical cancer cases (mean [SD] age, 48.7 [14.7] years), 2300 (35.5%) were Hispanic, 798 (12.3%) were non-Hispanic Black, 3090 (47.6%) were non-Hispanic White, and 296 (4.6%) were other race or ethnicity. Of the 6484 patients, 2892 with late-stage diagnosis (mean [SD] age, 51.8 [14.4] years were analyzed. Among patients with late-stage diagnosis, 1069 (37.0%) were Hispanic, 417 (14.4%) were non-Hispanic Black, 1307 (45.2%) were non-Hispanic White, and 99 (3.4%) were other race or ethnicity. SaTScan spatial analysis identified 7 statistically significant clusters of late-stage cervical cancer diagnosis in Texas, of which 4 were hot spots and 3 were cold spots. Hot spots included 1128 census tracts, predominantly in the South Texas Plains, Gulf Coast, and Prairies and Lakes (North Texas) regions. Of the 2892 patients with late-stage cervical cancer, 880 (30.4%) were observed within hot spots. Census tract–level comparison of characteristics of clusters suggested that hot spots differed significantly from cold spots and the rest of Texas by proportions of racial and ethnic groups, non–US born persons, and socioeconomic status.Conclusions and RelevanceIn this cross-sectional study examining geospatial clusters of late-stage cervical cancer diagnosis, place-based disparities were found in late-stage cervical cancer diagnosis in Texas. These findings suggest that these communities may benefit from aggressive cervical cancer interventions.

Screening Familial Risk for Hereditary Breast and Ovarian Cancer

ImportanceMost patients with pathogenic or likely pathogenic (P/LP) variants for breast cancer have not undergone genetic testing.ObjectiveTo identify patients meeting family history criteria for genetic testing in the electronic health record (EHR).Design, Setting, and ParticipantsThis study included both cross-sectional (observation date, February 1, 2024) and retrospective cohort (observation period, January 1, 2018, to February 1, 2024) analyses. Participants included patients aged 18 to 79 years enrolled in Renown Health, a large health system in Northern Nevada. Genotype was known for 38 003 patients enrolled in Healthy Nevada Project (HNP), a population genomics study.ExposureAn EHR indicating that a patient is positive for criteria according to the Seven-Question Family History Questionnaire (hereafter, FHS7 positive) assessing familial risk for hereditary breast and ovarian cancer (HBOC).Main Outcomes and MeasuresThe primary outcomes were the presence of P/LP variants in the ATM, BRCA1, BRCA2, CHEK2, or PALB2 genes (cross-sectional analysis) or a diagnosis of cancer (cohort analysis). Age-adjusted cancer incidence rates per 100 000 patients per year were calculated using the 2020 US population as the standard. Hazard ratios (HRs) for cancer attributable to FHS7-positive status were estimated using cause-specific hazard models.ResultsAmong 835 727 patients, 423 393 (50.7%) were female and 29 913 (3.6%) were FHS7 positive. Among those who were FHS7 positive, 24 535 (82.0%) had no evidence of prior genetic testing for HBOC in their EHR. Being FHS7 positive was associated with increased prevalence of P/LP variants in BRCA1/BRCA2 (odds ratio [OR], 3.34; 95% CI, 2.48-4.47), CHEK2 (OR, 1.62; 95% CI, 1.05-2.43), and PALB2 (OR, 2.84; 95% CI, 1.23-6.16) among HNP female individuals, and in BRCA1/BRCA2 (OR, 3.35; 95% CI, 1.93-5.56) among HNP male individuals. Being FHS7 positive was also associated with significantly increased risk of cancer among 131 622 non-HNP female individuals (HR, 1.44; 95% CI, 1.22-1.70) but not among 114 982 non-HNP male individuals (HR, 1.11; 95% CI, 0.87-1.42). Among 1527 HNP survey respondents, 352 of 383 EHR-FHS7 positive patients (91.9%) were survey-FHS7 positive, but only 352 of 883 survey-FHS7 positive patients (39.9%) were EHR-FHS7 positive. Of the 29 913 FHS7-positive patients, 19 764 (66.1%) were identified only after parsing free-text family history comments. Socioeconomic differences were also observed between EHR-FHS7-negative and EHR-FHS7-positive patients, suggesting disparities in recording family history.Conclusions and RelevanceIn this cross-sectional study, EHR-derived FHS7 identified thousands of patients with familial risk for breast cancer, indicating a substantial gap in genetic testing. However, limitations in EHR family history data suggested that other identification methods, such as direct-to-patient questionnaires, are required to fully address this gap.

Characteristics of Patients With Cancer and COVID-19 Who Discontinued Cancer Treatment

This cross-sectional study evaluates the prevalence of and characteristics associated with discontinuation of cancer treatment among patients who received a diagnosis of COVID-19 during their treatment planning.

Assessment of Adjuvant Endocrine Therapy With Ovarian Function Suppression by Breast Cancer Index

Importance The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]–low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)–containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor–positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure 5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)–low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)–low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)–high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)–low tumors, and more variable relative treatment effects among BCI (H/I)–high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P  &amp;amp;lt; .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P  &amp;amp;lt; .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance In this study of premenopausal women with hormone receptor–positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)–low tumors than for those with BCI (H/I)–high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)–low tumors may benefit from more intensive endocrine therapy.

Cost-Effectiveness of Population-Based Multigene Testing for Breast and Ovarian Cancer Prevention

ImportanceThe current method of BRCA testing for breast and ovarian cancer prevention, which is based on family history, often fails to identify many carriers of pathogenic variants. Population-based genetic testing offers a transformative approach in cancer prevention by allowing for proactive identification of any high-risk individuals and enabling early interventions.ObjectiveTo assess the lifetime incremental effectiveness, costs, and cost-effectiveness of population-based multigene testing vs family history–based testing.Design, Setting, and ParticipantsThis economic evaluation used a microsimulation model to assess the cost-effectiveness of multigene testing (BRCA1, BRCA2, and PALB2) for all women aged 30 to 35 years compared with the current standard of care that is family history based. Carriers of pathogenic variants were offered interventions, such as magnetic resonance imaging with or without mammography, chemoprevention, or risk-reducing mastectomy and salpingo-oophorectomy, to reduce cancer risk. A total of 2000 simulations were run on 1 000 000 women, using a lifetime time horizon and payer perspective, and costs were adjusted to 2022 US dollars. This study was conducted from September 1, 2020, to December 15, 2023.Main Outcomes and MeasuresThe main outcome measure was the incremental cost-effectiveness ratio (ICER), quantified as cost per quality-adjusted life-year (QALY) gained. Secondary outcomes included incremental cost, additional breast and ovarian cancer cases prevented, and excess deaths due to coronary heart disease (CHD).ResultsThe study assessed 1 000 000 simulated women aged 30 to 35 years in the US. In the base case, population-based multigene testing was more cost-effective compared with family history–based testing, with an ICER of $55 548 per QALY (95% CI, $47 288-$65 850 per QALY). Population-based multigene testing would be able to prevent an additional 1338 cases of breast cancer and 663 cases of ovarian cancer, but it would also result in 69 cases of excess CHD and 10 excess CHD deaths per million women. The probabilistic sensitivity analyses show that the probability that population-based multigene testing is cost-effective was 100%. When the cost of the multigene test exceeded $825, population-based testing was no longer cost-effective (ICER, $100 005 per QALY; 95% CI, $87 601-$11 6323).Conclusions and RelevanceIn this economic analysis of population-based multigene testing, population-based testing was a more cost-effective strategy for the prevention of breast cancer and ovarian cancer when compared with the current family history–based testing strategy at the $100 000 per QALY willingness-to-pay threshold. These findings support the need for more comprehensive genetic testing strategies to identify pathogenic variant carriers and enable informed decision-making for personalized risk management.

Assessment of a Peer Physician Coaching Partnership Between a Designated Cancer Center Genetics Service and a Community Cancer Network Hospital

BackgroundPatients with cancer seen in rural and underserved areas disproportionately face barriers to access genetic services. Genetic testing is critical to inform treatment decisions, for early detection of another cancer, and to identify at-risk family members who may benefit from screening and prevention.ObjectiveTo examine medical oncologists’ genetic testing ordering trends for patients with cancer.Design, Setting, and ParticipantsThis prospective quality improvement study was performed in 2 phases over 6 months between August 1, 2020, and January 31, 2021, at a community network hospital. Phase 1 focused on observation of clinic processes. Phase 2 incorporated peer coaching from cancer genetics experts for medical oncologists at the community network hospital. The follow-up period lasted 9 months.Main Outcomes and MeasuresThe number of genetic tests ordered was compared between phases.ResultsThe study included 634 patients (mean [SD] age, 71.0 [10.8] years [range, 39-90 years]; 409 women [64.5%]; 585 White [92.3%]); 353 (55.7%) had breast cancer, 184 (29.0%) had prostate cancer, and 218 (34.4%) had a family history of cancer. Of the 634 patients with cancer, 29 of 415 (7.0%) received genetic testing in phase 1, and 25 of 219 (11.4%) received genetic testing in phase 2. Of the 29 patients who received testing in phase 1, 20 (69.0%) had germline genetic testing; 23 of 25 patients (92.0%) had germline genetic testing in phase 2. Uptake of germline genetic testing increased by 23.0% between phases, but the difference was not statistically significant (P = .06). Uptake of germline genetic testing was highest among patients with pancreatic cancer (4 of 19 [21.1%]) and ovarian cancer (6 of 35 [17.1%]); the National Comprehensive Cancer Network (NCCN) recommends offering genetic testing to all patients with pancreatic cancer and ovarian cancer.Conclusions and RelevanceThis study suggests that peer coaching from cancer genetics experts was associated with an increase in ordering of genetic testing by medical oncologists. Efforts made to (1) standardize gathering of personal and family history of cancer, (2) review biomarker data suggestive of a hereditary cancer syndrome, (3) facilitate ordering tumor and/or germline genetic testing every time NCCN criteria are met, (4) encourage data sharing between institutions, and (5) advocate for universal coverage for genetic testing may help realize the benefits associated with precision oncology for patients and their families seeking care at community cancer centers.

Patient Preferences for Ovarian Cancer Risk–Reducing Treatments Revealed Through Choice Experiments

Trends in Positive BRCA Test Results Among Older Women in the United States, 2008-2018

Genetic testing for BRCA1/2 pathogenic variants has been used for targeted, individualized cancer prevention and treatment. A positive BRCA test result indicates a higher risk for developing BRCA-related cancers. During the past decade, testing criteria have loosened. The impact of these loosened criteria on BRCA testing in older women has not previously been studied. To assess whether the rate of positive BRCA test results changed between 2008 and 2018 among older women in the United States. This cross-sectional study used a 10% random sample of women 65 years of age or older from Optum's deidentified Integrated Claims-Clinical data set (2008-2018), a large national electronic health record data set. A total of 5533 women with BRCA test results from January 1, 2008, to March 31, 2018, were evaluated. Annual percentage change in positive BRCA test results was evaluated. Multivariable logistic regression models were used to assess the association between positive test results and race/ethnicity, region of residence, income, educational level, and personal history of breast or ovarian cancer. Of 5533 women 65 years of age or older (mean age, 68.1 years [95% CI, 67.9-68.4 years]) who underwent BRCA testing from 2008 to 2018, most (4679 [84.6%]) were non-Hispanic White women, and 1915 (34.6%) resided in the Midwest. Positive BRCA test results decreased from 85.7% (36 of 42) in 2008 to 55.6% (140 of 252) in 2018 (annual percentage change, -2.55; 95% CI, -3.45 to -1.64). Among patients with breast or ovarian cancer, positive test results decreased from 83.3% (20 of 24) in 2008 to 61.6% (61 of 99) in 2018, while among women without breast or ovarian cancer, positive test results decreased from 87.5% (21 of 24) in 2008 to 48.4% (74 of 153) in 2018 (annual percentage change, -3.17 vs -2.49; P = .29). Women with positive test results were more likely to be non-Hispanic Black women, to live in the West or South, to live in areas with a low percentage of college graduates, or to not have a personal history of breast or ovarian cancer. This study suggests that there was a significantly decreasing rate of positive BRCA test results among women 65 years of age or older. Socioeconomic and regional disparities in testing use remain an issue.

Modeling Cervical Cancer Screening Strategies With Varying Levels of Human Papillomavirus Vaccination

Cervical cancer screening is a lifesaving intervention, with an array of approaches, including liquid-based cytology (LBC), molecular testing for human papillomavirus (HPV) infection, and combinations via parallel cotesting or sequential triage. Maximizing screening efficacy while minimizing overtreatment is vital, especially when considering how the HPV vaccine will affect the interpretation of results. To estimate the likely outcomes of different screening modalities and to model how the increasing uptake of the HPV vaccine could affect the interpretation of screening results. This decision analytic model established a simple Markov model to compare the outcomes of different cervical cancer screening modalities on a simulated population of women (aged ≥25 years), considering different levels of HPV vaccination. The number of cases of cervical intraepithelial neoplasia (CIN) grade 2 and 3 detected and missed, the number of false positives, and the number of tests required to achieve a given level of accuracy. Positive and negative predictive values of different modalities were simulated under varying levels of HPV vaccination and therefore HPV prevalence. In a simulated population of 1000 women aged 25 years and older with an HPV prevalence of 2%, HPV-based modalities outperformed LBC-based approaches, detecting 19% more true positives (HPV test sensitivity, 89.9% [95% CI, 88.6%-91.1%]; LBC test sensitivity, 75.5% [95% CI, 66.6%-82.7%]). While cotesting markedly reduced missed cases, detecting 29% more true positives than LBC alone (19.5 [95% CI, 19.3-19.7] per 1000 women screened vs 15.1 [95% CI, 13.3-16.5] per 1000 women screened), it unacceptably increased excess colposcopy referral by 94% (184.4 [95% CI, 181.8-188.0] false positives per 1000 women screened vs 95.1 [95% CI, 93.1-97.0] false positives per 1000 women screened). By contrast, triage testing with reflex screening substantially reduced false positives by a factor of approximately 10 (eg, HPV with LBC triage, 9.6 [95% CI, 9.3-10.0] per 1000 women screened). Over a lifetime of screening, reflex approaches with appropriate test intervals maximized therapeutic efficacy; as HPV vaccination rates increased, HPV-based screening approaches resulted in fewer unnecessary colposcopies than LBC approaches (HPV testing, 80% vaccine coverage: 44.1 [95% CI, 40-45.9] excess colposcopies; LBC testing, 80% vaccine coverage: 96.9 [95% CI, 96.8-97.0] excess colposcopies). In this decision analytic model, the effectiveness of cervical cancer screening was dependent on the prevalence of cervical dysplasia and/or HPV infection or vaccination in a population as well as the sensitivity and specificity of various modalities. Although screening is lifesaving, overtesting or modalities inappropriate to the target population may cause significant harm, including overtreatment.

Point-of-Care Digital Cytology With Artificial Intelligence for Cervical Cancer Screening in a Resource-Limited Setting

Cervical cancer is highly preventable but remains a common and deadly cancer in areas without screening programs. The creation of a diagnostic system to digitize Papanicolaou test samples and analyze them using a cloud-based deep learning system (DLS) may provide needed cervical cancer screening to resource-limited areas. To determine whether artificial intelligence-supported digital microscopy diagnostics can be implemented in a resource-limited setting and used for analysis of Papanicolaou tests. In this diagnostic study, cervical smears from 740 HIV-positive women aged between 18 and 64 years were collected between September 1, 2018, and September 30, 2019. The smears were digitized with a portable slide scanner, uploaded to a cloud server using mobile networks, and used to train and validate a DLS for the detection of atypical cervical cells. This single-center study was conducted at a local health care center in rural Kenya. Detection of squamous cell atypia in the digital samples by analysis with the DLS. The accuracy of the DLS in the detection of low- and high-grade squamous intraepithelial lesions in Papanicolaou test whole-slide images. Papanicolaou test results from 740 HIV-positive women (mean [SD] age, 41.8 [10.3] years) were collected. The DLS was trained using 350 whole-slide images and validated on 361 whole-slide images (average size, 100 387 × 47 560 pixels). For detection of cervical cellular atypia, sensitivities were 95.7% (95% CI, 85.5%-99.5%) and 100% (95% CI, 82.4%-100%), and specificities were 84.7% (95% CI, 80.2%-88.5%) and 78.4% (95% CI, 73.6%-82.4%), compared with the pathologist assessment of digital and physical slides, respectively. Areas under the receiver operating characteristic curve were 0.94 and 0.96, respectively. Negative predictive values were high (99%-100%), and accuracy was high, particularly for the detection of high-grade lesions. Interrater agreement was substantial compared with the pathologist assessment of digital slides (κ = 0.72) and fair compared with the assessment of glass slides (κ = 0.36). No samples that were classified as high grade by manual sample analysis had false-negative assessments by the DLS. In this study, digital microscopy with artificial intelligence was implemented at a rural clinic and used to detect atypical cervical smears with a high sensitivity compared with visual sample analysis.

Interval Cytoreductive Surgery and Cisplatin- or Paclitaxel-Based HIPEC for Advanced Ovarian Cancer

ImportanceOvarian cancer, often diagnosed at advanced stages, presents significant challenges in treatment and survival. Evaluation of different hyperthermic intraperitoneal chemotherapy (HIPEC) regimens could provide crucial insights to improve patient outcomes.ObjectiveTo evaluate whether HIPEC with paclitaxel (HIPEC-paclitaxel) is associated with similar oncological outcomes as HIPEC with cisplatin (HIPEC-cisplatin) in patients with advanced ovarian cancer undergoing interval cytoreductive surgery (iCRS).Design, Setting, and ParticipantsThis multicenter retrospective cohort study included patients with advanced ovarian cancer who received iCRS and HIPEC. Patients with primary or secondary surgical procedures or nonovarian cancers were excluded. Data came from the National Registry of Peritoneal Carcinomatosis, which includes 27 Spanish specialized peritoneal oncology centers. Cases were included from January 2012 to December 2022. The study used propensity score matching to balance the groups and ensure comparability.ExposureHIPEC-cisplatin and HIPEC-paclitaxel, administered during iCRS. The HIPEC regimen was selected based on the standard clinical protocol for advanced ovarian cancer.Main Outcomes and MeasuresThe primary end points were overall survival (OS) and disease-free survival (DFS). The secondary end point was the rate of complications in each group. These outcomes were predefined prior to data collection.ResultsA total of 846 patients (mean [SD] age, 59.04 [11.01] years) were included (325 [38.4%] in HIPEC-cisplatin group; 521 [61.6%] in HIPEC-paclitaxel group), and 199 patients in each group were propensity score matched. Among these 398 matched patients, the HIPEC-paclitaxel group had similar DFS and OS compared with the HIPEC-cisplatin group. Additionally, similar morbidity was observed. Equivalence in OS and DFS was observed during the initial 20 and 15 months of follow-up, respectively, with an equivalence margin of 0.1 respectively.Conclusions and RelevanceIn this cohort study of patients with advanced ovarian cancer, HIPEC-paclitaxel was associated with comparable oncologic outcomes as HIPEC-cisplatin, suggesting that it could be a viable alternative. These findings support its use, especially in patients in whom cisplatin could be contraindicated. Further studies may help refine treatment protocols and improve patient-specific outcomes.

Comparison of Quality Performance Measures for Patients Receiving In-Person vs Telemedicine Primary Care in a Large Integrated Health System

ImportanceDespite its rapid adoption during the COVID-19 pandemic, it is unknown how telemedicine augmentation of in-person office visits has affected quality of patient care.ObjectiveTo examine whether quality of care among patients exposed to telemedicine differs from patients with only in-person office-based care.Design, Setting, and ParticipantsIn this retrospective cohort study, standardized quality measures were compared between patients with office-only (in-person) visits vs telemedicine visits from March 1, 2020, to November 30, 2021, across more than 200 outpatient care sites in Pennsylvania and Maryland.ExposuresPatients completing telemedicine (video) visits.Main Outcomes and Measuresχ2 tests determined statistically significant differences in Health Care Effectiveness Data and Information Set (HEDIS) quality performance measures between office-only and telemedicine-exposed groups. Multivariable logistic regression controlled for sociodemographic factors and comorbidities.ResultsThe study included 526 874 patients (409 732 office-only; 117 142 telemedicine exposed) with a comparable distribution of sex (196 285 [49.7%] and 74 878 [63.9%] women), predominance of non-Hispanic (348 127 [85.0%] and 105 408 [90.0%]) and White individuals (334 215 [81.6%] and 100 586 [85.9%]), aged 18 to 65 years (239 938 [58.6%] and 91 100 [77.8%]), with low overall health risk scores (373 176 [91.1%] and 100 076 [85.4%]) and commercial (227 259 [55.5%] and 81 552 [69.6%]) or Medicare or Medicaid (176 671 [43.1%] and 52 513 [44.8%]) insurance. For medication-based measures, patients with office-only visits had better performance, but only 3 of 5 measures had significant differences: patients with cardiovascular disease (CVD) receiving antiplatelets (absolute percentage difference [APD], 6.71%; 95% CI, 5.45%-7.98%; P &amp;amp;lt; .001), patients with CVD receiving statins (APD, 1.79%; 95% CI, 0.88%-2.71%; P = .001), and avoiding antibiotics for patients with upper respiratory infections (APD, 2.05%; 95% CI, 1.17%-2.96%; P &amp;amp;lt; .001); there were insignificant differences for patients with heart failure receiving β-blockers and those with diabetes receiving statins. For all 4 testing-based measures, patients with telemedicine exposure had significantly better performance differences: patients with CVD with lipid panels (APD, 7.04%; 95% CI, 5.95%-8.10%; P &amp;amp;lt; .001), patients with diabetes with hemoglobin A1c testing (APD, 5.14%; 95% CI, 4.25%-6.01%; P &amp;amp;lt; .001), patients with diabetes with nephropathy testing (APD, 9.28%; 95% CI, 8.22%-10.32%; P &amp;amp;lt; .001), and blood pressure control (APD, 3.55%; 95% CI, 3.25%-3.85%; P &amp;amp;lt; .001); this was also true for all 7 counseling-based measures: cervical cancer screening (APD, 12.33%; 95% CI, 11.80%-12.85%; P &amp;amp;lt; .001), breast cancer screening (APD, 16.90%; 95% CI, 16.07%-17.71%; P &amp;amp;lt; .001), colon cancer screening (APD, 8.20%; 95% CI, 7.65%-8.75%; P &amp;amp;lt; .001), tobacco counseling and intervention (APD, 12.67%; 95% CI, 11.84%-13.50%; P &amp;amp;lt; .001), influenza vaccination (APD, 9.76%; 95% CI, 9.47%-10.05%; P &amp;amp;lt; .001), pneumococcal vaccination (APD, 5.41%; 95% CI, 4.85%-6.00%; P &amp;amp;lt; .001), and depression screening (APD, 4.85%; 95% CI, 4.66%-5.04%; P &amp;amp;lt; .001).Conclusions and RelevanceIn this cohort study of patients with telemedicine exposure, there was a largely favorable association with quality of primary care. This supports telemedicine’s value potential for augmenting care capacity, especially in chronic disease management and preventive care. This study also identifies a need for understanding relationships between the optimal blend of telemedicine and in-office care.

Cost-Effectiveness of HPV Self-Testing Options for Cervical Cancer Screening

ImportanceMailing human papillomavirus (HPV) self-sampling kits to underscreened individuals increases cervical cancer screening and can be cost-effective. However, cost-effectiveness has not been evaluated across other screening histories.ObjectiveTo conduct an economic evaluation of mailed HPV self-sampling among members of a US health care system with adherent, overdue, or unknown screening histories.Design, Setting, and ParticipantsThis economic evaluation was a cost-effectiveness analysis (CEA) and budget impact analysis (BIA) based on results of a randomized clinical trial (RCT) conducted between November 20, 2020, to July 29, 2022, in an integrated health care system in Washington State. Intervention delivery costs were calculated from Kaiser Permanente Washington and Medicare perspectives and used wellness-based or screening-only visit costs. Participants included female members aged 30 to 64 years identified through electronic medical records. Data were analyzed from August 1, 2022, to July 29, 2025.InterventionMembers were randomized by screening history. Adherent participants were assigned to 4 groups: usual care (UC), patient reminders, clinician electronic health record [HER] alerts), education (UC and mailed educational materials), direct mail (UC, education, and mailed self-sampling kit), or opt-in (UC, education, and mailed invitation to request kit). Overdue participants were assigned to 3 groups: UC, education, or direct mail. Participants with unknown adherence were assigned to UC, education, or opt-in.Main Outcome and MeasuresPrimary RCT outcome was screening completion 6 months postrandomization. CEA outcome was incremental cost-effectiveness ratio for screening completion. BIA outcome was annual program implementation cost over 4 years.ResultsAnalyses included 31 355 individuals (mean [SD] age, 45.9 [10.4] years). Among screening adherent members, direct mail dominated all other strategies (more effective and cost-saving). Among overdue members, direct mail was also more effective than UC and generated an additional completed screen at a cost ranging from −$19 (95% CI, −$21 to −$16) (cost saving) to $63 (95% CI, $39 to $87) depending on cost basis and visit type. Among unknown members, opt-in generally dominated UC (more effective and cost-saving). The BIA indicated that although the screening adherent subgroup had the largest year 1 program budget, its budget declined fastest and, by year 4, was lowest among the 3 subgroups. Conversely, the smallest annual budget decreases were among eligible individuals with unknown history.Conclusions and RelevanceIn this economic analysis of a randomized clinical trial, directly mailing HPV kits to individuals who were screening adherent and overdue for screening was economically dominant over other strategies. Program costs declined rapidly over 4 years. Results support directly mailing HPV kits to eligible individuals as an effective, efficient, and affordable outreach strategy.

Survival by Treatment Recommendation and Receipt Among Older Patients With Early-Stage Cervical Cancer

ImportanceCervical cancer remains a substantial public health concern among older women, particularly those who are beyond the age of routine screening. Understanding the survival benefits of treating early-stage cervical cancer in this population is essential for optimizing care and improving outcomes.ObjectiveTo analyze the survival outcomes based on the receipt of treatment and treatment recommendations among patients with early-stage cervical cancer aged 65 years and older.Design, Setting, and ParticipantsThis retrospective cohort study of patients aged 65 years and older with a first diagnosis of localized, microscopically confirmed invasive cervical cancer used data from 17 Surveillance, Epidemiology, and End Results (SEER) cancer registries in the US from 2000 to 2020. Data were analyzed from May 2023 to January 2024.ExposureReceipt of recommended treatment, specifically surgery and/or radiotherapy, as recorded in the SEER database. Treatment modalities were categorized based on recommendation status and actual receipt.Main Outcomes and MeasuresSurvival outcomes based on treatment recommendation and receipt status by treatment type expressed as (1) 5-year relative survival rates, (2) cervical cancer-specific mortality, estimated using competing risks models, and (3) adjusted hazard ratios (AHRs) calculated using Fine-Gray competing risk regression.ResultsAmong 2236 females included in the study, 66.3% (1482) were aged 65 to 74 years, 25.3% (565) were 75 to 84 years, and 8.4% (189) were aged 85 years or older. In the group aged 65 to 74 years, those who received surgery had significantly higher 5-year survival rates (91.2%, 95% CI, 88.4%-93.4%) compared with those not recommended for surgery (69.6%, 95% CI, 62.8%-75.4%) or those who were recommended but did not receive surgery (52.3%, 95% CI, 24.2%-74.3%). Similar patterns were observed in the group aged 75 to 84 years, in which receiving surgery was associated with higher survival rates (88.6%, 95% CI, 79.8%-93.7%). In multivariable analyses, receiving surgery (AHR, 0.28; 95% CI, 0.16-0.50) and radiotherapy (AHR, 0.48; 95% CI, 0.26-0.87) were significantly associated with lower cervical cancer–specific mortality compared with not receiving the recommended treatment.Conclusions and RelevanceIn this cohort study, receipt of recommended treatment was associated with higher survival rates among older patients with early-stage cervical cancer. Addressing barriers to treatment adherence and improving early detection and preventive measures in this older population may enhance population health and reduce cervical cancer mortality in the aging population.

Clinical Validation of a Vaginal Cervical Cancer Screening Self-Collection Method for At-Home Use

ImportanceOne-quarter of US women who are at risk for cervical cancer delay screening. Self-collected (SC) cervical screening was recently US Food and Drug Administration (FDA)–approved in the US for use in a health care setting only; an at-home SC option is crucial to address clinic-related barriers to screening.ObjectiveTo clinically validate the use of an SC device that was designed for optimal at-home performance, safety, ease-of-use, and dry storage and transport.Design, Setting, and ParticipantsThis nonrandomized clinical trial used a prospective method comparison study design. Participants aged 25 to 65 years were recruited from 16 clinical sites in the US including community and academic practices from November 20, 2023, to April 5, 2024. Data analysis was conducted from April to August 2024.InterventionEligible participants collected a sample with the SC method, followed by a clinician-collected (CC) sample. The SC sample was eluted into PreservCyt at the laboratory and both samples were tested on an FDA-approved high risk human papillomavirus (hrHPV) test approved for primary screening. Participants were followed up for safety and completed usability and screening preference surveys.Main Outcome and MeasuresThe primary outcome measures were positive percentage agreement (PPA) and negative percentage agreement for detection of hrHPV between the SC and CC samples. Other study measures included clinical sensitivity for high grade cervical dysplasia and usability.ResultsOf 609 screening-eligible participants, 599 (262 aged 30-39 years [43.7%]; 583 identified as female [97.3%]) had paired SC-CC samples, of which 582 had valid paired samples included in the end point analysis. Among the 582 evaluable paired samples, the PPA between SC compared with paired CC samples for detection of hrHPV was 95.2% (95% CI, 92.1%-97.1%; 278 of 292 participants). The absolute clinical sensitivity for detection of high-grade cervical dysplasia was 95.8% (95% CI, 86.0%-98.8%; 46 of 48 participants), equivalent to the CC (relative sensitivity, 1.00). Nearly all participants (555 of 601 participants [92.3%]) reported that the device instructions were easy or very easy to understand and also that they would choose SC if they knew the results were comparable to CC results (560 of 602 participants [93.0%]).Conclusions and RelevanceIn this nonrandomized clinical trial, SC samples collected with the device showed equivalent clinical sensitivity and exceeded the PPA end point for cervical screening. This SC method was found to be easy to use and to be a preferred option with high clinical performance intended for use in an at-home setting.Trial RegistrationClinicalTrials.gov Identifier: NCT06120205

Cancer Incidence in Women After Medically Assisted Reproduction

Importance High-quality evidence on cancer occurrence for women who have used medically assisted reproduction (MAR) is required to guide care. Objective To compare cancer incidence in MAR-exposed women with the general population of women. Design, Setting, and Participants This is a population-based cohort study of Australian women. MAR treatments, pregnancies, incident cancers, and deaths were ascertained using linkage between population-based administrative health datasets and statutory registries. Women aged 18 to 55 years who used MAR from 1991 to 2018 were identified and analyzed from April to November 2024. Exposures Three MAR cohorts were created: assisted reproductive therapy (ART), intrauterine insemination with ovarian stimulation (IUI/OS), and ovulation induction using clomiphene citrate (clomiphene citrate). Main Outcomes and Measures Cancer incidence among MAR-exposed women was compared with the age-, jurisdiction-, and calendar year–matched general population. The main outcomes were cancer standardized incidence ratios (SIRs) and rate differences. Results A total of 417 984 MAR-exposed women were included, with 274 676 (65.7%) having ever used ART (median [IQR] age, 34 [31-38] years; median [IQR] follow-up time, 9.42 [5.08-15.42] years), 120 739 (28.9%) having ever used IUI/OS (median [IQR] age, 34 [30-38] years; median [IQR] follow-up time, 11.67 [6.25-18.42] years), and 175 510 (42.0%) having ever used clomiphene citrate (median [IQR] age, 32 [28-36] years; median [IQR] follow-up time, 9.42 [5.42-13.58] years). The overall incidence of invasive cancer was comparable with the general population for the ART (SIR, 1.00; 95% CI, 0.98-1.02) and IUI/OS (SIR, 0.99; 95% CI, 0.97-1.02) cohorts and slightly elevated for the clomiphene citrate cohort (SIR, 1.04; 95% CI, 1.00-1.07). For all cohorts, incidence of uterine cancer (SIRs, 1.23-1.83) and in situ and invasive melanoma (SIRs, 1.07-1.15) were elevated, and incidence of cervical cancer (SIRs, 0.52-0.61) and cancer of the trachea, bronchus, and lung (SIRs, 0.62-0.70) were lower. Ovarian cancer incidence was elevated for the ART (SIR, 1.23; 95% CI, 1.10-1.37) and IUI/OS (SIR, 1.18; 95% CI, 1.01-1.37) cohorts. In situ breast cancer incidence was elevated for the ART cohort only (SIR, 1.24; 95% CI, 1.12-1.38). Incidence of invasive breast cancer was not elevated. Rate differences for invasive cancers with elevated incidence were all small (&amp;amp;lt;1 to 6.51 cases per 100 000 person-years). Conclusions and Relevance In this cohort study of cancer incidence in women who received MAR, the overall incidence of cancer was comparable with that of the general population. The incidence of certain cancers appeared elevated; however, the excess numbers of these cancers were small, and there was reduced incidence of other cancers. Causation cannot be inferred from this descriptive evidence, but findings may guide women and their health care practitioners.

Uterine Fibroid Diagnosis by Race and Ethnicity in an Integrated Health Care System

ImportanceUterine fibroids are benign tumors that can cause severe symptoms. Fibroid burden among Asian or Pacific Islander individuals, particularly in specific subgroups, remains largely unexamined.ObjectiveTo describe fibroid diagnosis rates by race and ethnicity.Design, Setting, and ParticipantsThis retrospective cohort study (January 2009 to December 2022) used data from electronic health records of the Kaiser Permanente Northern California (KPNC) integrated health care system. Eligible participants included female (sex assigned at birth) KPNC members aged 18 to 54 years with at least 12 months of continuous membership, no prior fibroid diagnosis, and no history of hysterectomy. Data were analyzed January to September 2024.ExposureRace and ethnicity was categorized into 9 groups: Black (African American, other Black [ie, any Black race or ethnicity not otherwise specified], and unknown Black race or ethnicity), East Asian (Chinese, Japanese, and Korean), Hispanic (Hispanic or Latino), South Asian (Asian Indian, Bangladeshi, East Indian, Nepali, Sri Lankan, and any South Asian ethnicity not otherwise specified), Southeast Asian (Filipino, Vietnamese, and other Southeast Asian [ie, any Southeast Asian ethnicity not otherwise specified]), White (White or White Middle Eastern), other Asian or Pacific Islander (Native Hawaiian or Pacific Islander, multiethnic Asian, and other or unspecified Asian ethnicity [ie, any Asian ethnicity not otherwise specified]), other races and ethnicities (American Indian or Alaska Native and multiracial), and unknown race or ethnicity.Main Outcomes and MeasuresIncident fibroid diagnosis was identified using diagnostic codes. Poisson regression models were used to calculate incidence rates of fibroid diagnosis by racial and ethnic group, standardized to the 2022 US female population. Incidence rate ratios (IRRs) and 95% CIs compared incidence within each racial and ethnic group with White participants.ResultsA total of 1 917 794 patients were included (median [IQR] percentage, 7% [6%-7%] Black; 5% [5%-6%] East Asian; 22% [21%-23%] Hispanic; 3% [2%-3%] South Asian; 7% [7%-8%] Southeast Asian; 42% [39%-45%] White; 8% [6%-10%] other Asian or Pacific Islander; 2% [2%-2%] of other races and ethnicities; 4% [4%-5%] unknown or missing race and ethnicity), and 84 206 patients (4.4%) received a first fibroid diagnosis during the study period. Compared with White patients, there was a higher rate of fibroid diagnosis among Southeast Asian (IRR, 1.29; 95% CI, 1.26-1.33), East Asian (IRR, 1.47; 95% CI, 1.43-1.51), and South Asian patients (IRR, 1.71; 95% CI, 1.65-1.78). Black (IRR, 3.11; 95% CI, 3.05-3.17) and Hispanic patients (IRR, 1.37; 95% CI, 1.34-1.39) also had elevated rates of fibroid diagnosis. All Asian patients were less likely than other groups to have ICD-9 or ICD-10 coded symptoms before diagnosis.Conclusions and RelevanceIn this cohort study of nearly 2 million KPNC patients, South Asian, East Asian, Southeast Asian, Hispanic, and Black patients had higher fibroid diagnosis rates than White patients. If diagnosis rates reflect true variation in disease prevalence, future research should identify sources of these disparities and strategies to reduce them.

Cancer Incidence and Mortality Across 43 Cancer Registries in India

ImportanceCancer is a significant global health concern, with India ranking second in Asia and third in the world in terms of cancer incidence. Regular monitoring and updates on cancer statistics are vital for assessing the impact and burden of the disease and the effectiveness of cancer control measures.ObjectiveTo measure the recent patterns and trends in cancer incidence and mortality across 43 geographic regions in India from 2015 to 2019 and to provide estimates for 2024.Design, Setting, and ParticipantsThis cross-sectional study used data from 43 population-based cancer registries across India, covering varying periods between January 1, 2015, and December 31, 2019. Population at-risk data were obtained from the Census of India, and findings were assessed by registry area. Data were analyzed from May 1 to December 20, 2024.Main Outcomes and MeasuresNumber of cases, crude rates, and age-adjusted rates (per 100 000 population) for cancer incidence and mortality, estimated average annual percent change (AAPC) from time trends, and estimated cancer cases in India for 2024.ResultsIncidence of 708 223 cases with 206 457 deaths from 43 population-based cancer registries were included. The lifetime risk of developing cancer in India was 11.0%, while Mizoram in the Northeastern region reported lifetime risks of 21.1% in males and 18.9% in females. The district of Aizawl reported the highest age-adjusted incidence rate (AAIR) in both males (256.1; 95% CI, 245.2-267.0) and females (217.2; 95% CI, 207.6-226.7). The most common cancers were oral, lung, and prostate in males and breast, cervical, and ovarian in females. Among metropolitan cities (defined as an urban agglomeration with a population of over 1 million), Delhi had the highest overall cancer AAIR for males (146.7; 95% CI, 145.1-148.3), while Srinagar recorded the highest AAIR for lung cancer (39.5; 95% CI, 35.8-43.2). Oral cancer showed significant increases in 14 population-based cancer registries (PBCRs) among males and 4 PBCRs among females; Ahmedabad Urban had an increase of 4.7% (95% CI, 2.9% to 6.6%) in males and 6.9% (95% CI, 4.1% to 9.7%) in females. The estimated AAPC in AAIR (all sites) showed a significant increase over time in Kamrup Urban in males (3.3%; 95% CI, 2.3%-4.3%) and Thiruvananthapuram Taluk in females (3.4%; 95% CI, 3.1%-3.8%). The estimated cancer incidence for 2024 was 1 562 099 cases; estimated cancer mortality, 874 404 cases.Conclusions and RelevanceThis cross-sectional study highlighted significant regional disparities in cancer incidence across India and the increasing cancer burden. The findings provide key insights for policymakers to enhance resource allocation and strengthen cancer control strategies nationwide.

Neoadjuvant Chemotherapy, Case Volume, and Mortality in Advanced Ovarian Cancer

ImportanceDeath after cytoreductive surgery for advanced-stage ovarian cancer is more frequent in low-volume hospitals. Neoadjuvant chemotherapy (NACT) has been shown to reduce surgical complexity, complications, and surgical mortality without compromising oncologic outcomes.ObjectiveTo measure whether more frequent NACT utilization is associated with postoperative mortality and overall survival after cytoreductive surgery, especially in low-volume hospitals.Design, Setting, and ParticipantsThis cross-sectional study included patients treated for newly diagnosed stage III or IV epithelial ovarian cancer at Commission on Cancer–accredited cancer programs in the United States between January 2010 and December 2019. Data were analyzed from August 2023 to April 2025.ExposuresThe main exposures of interest were cancer program–level rates of NACT and tertile of program mean annual volume of cytoreductive surgery (&amp;amp;lt;12.0, 12.0-23.9, or ≥24.0 cases/y).Main Outcomes and MeasuresStandardized rates and odds ratios (ORs) for 90-day perioperative morality and differences in 60-month life expectancy (restricted mean survival time).ResultsA total of 70 707 patients (mean [SD] age, 63.1 [12.1] years; 5807 [8.2%] Black, 4745 [6.7%] Hispanic, and 56 336 [79.7%] White) treated in 1333 programs were identified. After adjusting for observed demographic and clinical covariates, 90-day surgical mortality was lower in centers with higher NACT rates, and the magnitude of this association differed by hospital volume (P for interaction &amp;amp;lt; .001). High utilization of NACT (59%) compared with low utilization (22%) was associated with a larger decrease in 90-day mortality in high-volume centers (OR, 0.26; 95% CI, 0.17-0.41; rates, 10.0% vs 2.9%) compared with average-volume centers (OR, 0.49; 95% CI, 0.33-0.72; rates, 7.3% vs 3.7%) or low-volume centers (OR, 0.48; 95% CI, 0.39-0.60; rates, 9.5% vs 4.8%). Among high-volume centers, high utilization was associated with a 4.0 month (95% CI, 1.6-6.5 month)–improvement in 60-month life expectancy compared with low NACT utilization (42.2 vs 38.1 months).Conclusions and RelevanceIn this cross-sectional study, treatment in high-volume centers with high NACT utilization was associated with the lowest 90-day surgical mortality and longest 60-month survival for patients with advanced stage ovarian cancer.

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype

Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.

Olaparib Addition to Maintenance Bevacizumab Therapy in Ovarian Carcinoma With BRCA-Like Genomic Aberrations

ImportanceTesting for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing.ObjectiveTo investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile.Design, Setting, and ParticipantsThis cohort study was a secondary analysis of the PAOLA-1 randomized clinical trial that compared olaparib plus bevacizumab with placebo plus bevacizumab as maintenance treatment in patients with advanced high-grade ovarian cancer after a good response to first-line platinum with taxane chemotherapy plus bevacizumab, irrespective of germline or tumor BRCA1/2 mutation status. All patients with available tumor DNA were included in the analysis. The current analysis tested for an interaction between BRCA-like status and olaparib treatment on survival outcomes. The original trial was conducted between July 2015 and September 2017; at the time of data extraction for analysis in March 2022, a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up time of 21 711 months was available, with 336 PFS and 245 OS events.ExposuresTumor homologous recombination deficiency was assessed using the BRCA-like copy number aberration profile classifier. Myriad MyChoice CDx was previously measured. The trial was randomized between the olaparib and bevacizumab and placebo plus bevacizumab groups.Main Outcomes and MeasuresThis secondary analysis assessed hazard ratios (HRs) of olaparib vs placebo among biomarker strata and tested for interaction between BRCA-like status and olaparib treatment on PFS and OS, using Cox proportional hazards regression.ResultsA total of 469 patients (median age, 60 [range 26-80] years) were included in this study. The patient cohort consisted of women with International Federation of Gynaecology and Obstetrics stage III (76%) high-grade serous (95%) ovarian cancer who had no evaluable disease or complete remission at initial or interval debulking surgery (76%). Thirty-one percent of the tumor samples (n = 138) harbored a pathogenic BRCA mutation, and BRCA-like classification was performed for 442 patients. Patients with a BRCA-like tumor had a longer PFS after olaparib treatment than after placebo (36.4 vs 18.6 months; HR, 0.49; 95% CI, 0.37-0.65; P &amp;amp;lt; .001). No association of olaparib with PFS was found in patients with a non–BRCA-like tumor (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93). The interaction was significant (P = .004), and HRs and P values (for interaction) were similar in the relevant subgroups, OS, and multivariable analyses.Conclusions and RelevanceIn this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non–BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

Universal Genetic Testing for Newly Diagnosed Invasive Breast Cancer

ImportanceBetween 5% and 10% of breast cancer cases are associated with an inherited germline pathogenic or likely pathogenic variant (GPV) in a breast cancer susceptibility gene (BCSG), which could alter local and systemic therapy recommendations. Traditional genetic testing criteria misses a proportion of these cases.ObjectiveTo evaluate the prevalence and clinicopathological associations of GPVs in 2 groups of BCSGs among an ethnically diverse cohort of women with newly diagnosed breast cancer.Design, Setting, and ParticipantsThis cross-sectional study, conducted at 3 Montreal hospitals between September 2019 and April 2022, offered universal genetic counseling and testing to all women with a first diagnosis of invasive breast cancer. Women were offered an obligatory primary panel of BRCA1, BRCA2, and PALB2 (B1B2P2) and an optional secondary panel of 14 additional BCSGs. Eligible participants were women 18 years of age or older who received a diagnosis of a first primary invasive breast cancer not more than 6 months before the time of referral to the study. Data were analyzed from November 2023 to June 2024.ResultsOf 1017 referred patients, 805 were eligible and offered genetic counseling and testing, and 729 of those 805 (90.6%) consented to be tested. The median age at breast cancer diagnosis was 53 years (range, 23-91 years), and 65.4% were White and of European ancestry. Fifty-four GPVs were identified in 53 patients (7.3%), including 39 patients (5.3%) with B1B2P2 and 15 patients (2.1%) with 6 of the 14 secondary panel BCSGs (ATM, BARD1, BRIP1, CHEK2, RAD51D, and STK11). On multivariable analysis, clinical factors independently associated with B1B2P2-positive status included being younger than 40 years of age at diagnosis (odds ratio [OR], 6.83; 95% CI, 2.22-20.90), triple-negative breast cancer (OR, 3.19; 95% CI, 1.20-8.43), high grade disease (OR, 1.68; 95% CI, 1.05-2.70), and family history of ovarian cancer (OR, 9.75; 95% CI, 2.65-35.85). Of 39 B1B2P2-positive patients, 13 (33.3%) were eligible for poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.Conclusions and RelevanceIn this cross-sectional universal genetic testing study of women with newly diagnosed invasive breast cancer, the prevalence of GPVs was 7.3%, with 5.3% of patients testing positive for B1B2P2. Among B1B2P2-women women, one-third were eligible for PARP inhibitors.

Chemotherapy-Related Amenorrhea and Quality of Life Among Premenopausal Women With Breast Cancer

ImportanceYounger survivors of breast cancer frequently report more treatment-related symptoms, mostly related to the menopausal transition.ObjectiveTo assess factors associated with chemotherapy-related amenorrhea (CRA) and to evaluate its association with long-term quality of life (QOL).Design, Setting, and ParticipantsThe prospective, longitudinal Cancer Toxicities Study, a multicenter French cohort study, includes women with a diagnosis of stage I to III breast cancer and collects data approximately yearly after diagnosis. The current study reports outcomes up to 4 years after diagnosis for participants enrolled from 2012 to 2017. Participants included premenopausal women younger than 50 years treated with chemotherapy and not receiving adjuvant ovarian function suppression. Data analysis was performed from September 2021 to June 2023.ExposuresClinical, socioeconomic, tumor, and treatment characteristics assessed at diagnosis (for the analysis of factors associated with CRA) and persistent CRA (for the QOL analysis).Main Outcomes and MeasuresThe main outcome of interest was CRA at year 1 (Y1), year 2 (Y2), and year 4 (Y4) after diagnosis. Generalized estimating equations assessed associations of exposure variables with CRA. In the QOL analysis, QOL at Y4 (assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BR23) was the outcome of interest. Multivariable random-effect mixed models assessed the association of persistent CRA (ie, never recovering menses after treatment) with QOL.ResultsAmong 1636 women, the mean (SD) age at diagnosis was 42.2 (5.6) years. Overall, 1242 of 1497 women (83.0%) reported CRA at Y1, 959 of 1323 women (72.5%) reported it at Y2, and 599 of 906 women (66.1%) reported it at Y4. Older age vs 18 to 34 years (adjusted odds ratio [OR] for 35 to 39 years, 1.84 [95% CI, 1.32 to 2.56]; adjusted OR for 40 to 44 years, 5.90 [95% CI, 4.23 to 8.24]; and adjusted OR for ≥45 years, 21.29 [95% CI, 14.34 to 31.61]) and receipt of adjuvant tamoxifen (adjusted OR, 1.97 [95% CI, 1.53 to 2.53]) were associated with higher likelihood of CRA. In the QOL analysis, 416 of 729 women (57.1%) had persistent CRA. However, late menses recovery among women aged 18 to 34 years with no menses at Y2 were reported by 11 of 21 women (52.4%) between Y2 and Y4. Persistent CRA was associated with worse insomnia (mean difference vs recovery at any time, 9.9 points [95% CI, 3.2 to 16.5 points]; P = .004), systemic therapy–related adverse effects (mean difference, 3.0 points [95% CI, 0.2 to 5.8 points]; P = .04), and sexual functioning (mean difference, −9.2 points [95% CI, −14.3 to −4.1 points]; P &amp;amp;lt; .001) at Y4.Conclusions and RelevanceIn this cohort study of premenopausal women with breast cancer, persistent CRA was common, although some women recovered menses late, and was associated with worse long-term QOL. This study can help inform risk communication, personalized counseling, and early supportive care referrals for such patients.

Residential Radon Levels and Ovarian Cancer Among Postmenopausal Women

Importance Few environmental risk factors for ovarian cancer have been discovered. Women exposed to ionizing radiation from the atomic bomb during World War II experienced an increased risk of ovarian cancer. Today, the largest source of ionizing radiation is radon gas in the home, but whether ionizing radiation is associated with increased risk of ovarian cancer more broadly is unknown. Objective To evaluate whether higher home radon levels are associated with increased risk of ovarian cancer. Design, Setting, and Participants This prospective cohort study included 127 547 women from the Women’s Health Initiative, including 40 clinical centers across the US, with outcomes followed up for 31 years (1993-2024). Postmenopausal women aged 50 to 79 years were enrolled in an observational study or 1 or more randomized clinical trials. All cases of ovarian cancer were physician adjudicated. Exposure Radon measurements from the 1993 US Geological Survey, classified into low (&amp;amp;lt;2 pCi/L), medium (2-4 pCi/L), and high zones (&amp;amp;gt;4 pCi/L), were linked with the geocoded home addresses of participants at baseline (1993-1998). Main Outcomes and Measures Hazard ratios (HRs) for ovarian cancer, adjusted for covariates with 95% CIs. Results Among the 127 547 women (mean [SD] age, 63.1 [7.2] years) with available radon zone values, 1645 incident ovarian cancers and 1048 ovarian cancer deaths were observed over a mean (SD) follow-up of 17.7 (8.4) years. After adjustment for covariates, the HR for all ovarian cancers for women living in the medium radon zone compared with women living in the low radon zone was not significantly higher (HR, 1.13 [95% CI, 1.00-1.29]). However, the HR was significantly higher for women living in the high radon zone compared with those living in the low radon zone (HR, 1.31 [95% CI, 1.11-1.54]). Similar findings were observed for the most common histologic type, serous ovarian cancer, for which the HR in the medium zone was 1.06 (95% CI, 0.88-1.27) and the HR in the high zone was 1.38 (95% CI, 1.09-1.74). Ovarian cancer mortality also was significantly higher in the high radon zone compared with the low radon zone (HR, 1.31 [95% CI, 1.07-1.60]). Sensitivity analyses using 3 alternate radon measures produced similar results. Conclusions and Relevance In this large, prospective cohort of postmenopausal women, the risks of ovarian cancer incidence and mortality were significantly higher for women living in homes in the high radon zone. Residential radon is a ubiquitous and modifiable risk factor. This is the first epidemiologic study of radon and ovarian cancer among postmenopausal women to date, and its findings suggest a potential target for mitigating cancer risk.

Hormone Therapy After Oophorectomy and Breast Cancer Risk in Women With BRCA Pathogenic Variant

Importance Risk-reducing bilateral salpingo-oophorectomy is recommended to substantially lower ovarian cancer risk in women carrying BRCA1 or BRCA2 pathogenic variant (PV). The use of hormone replacement therapy (HRT) after risk-reducing bilateral oophorectomy (RRBO), although generally recommended, remains debated due to concerns about its possible role in breast cancer (BC) risk. Objective To assess the possible association between HRT use and BC incidence after RRBO in women harboring a limited range of germline BRCA PVs. Design, Setting, and Participants This retrospective multicenter cohort study was conducted at 3 medical centers, including both referral and primary care facilities, in Israel. Cancer-free women (aged ≥18 years) with BRCA1 PV or BRCA2 PV, with no prior mastectomy, who underwent RRBO between January 1, 2000, and December 31, 2024, and who had at least 1 year of follow-up after RRBO were included. Exposures HRT use after RRBO. Main Outcomes and Measures First diagnosis or incidence of invasive BC. BC diagnoses were ascertained through pathology reports and diagnostic codes used in the electronic health records; some were confirmed via participant interviews. HRT use was assessed through medical records, pharmacy dispensing data, clinic visits, and telephone interviews. Cox proportional hazards regression models, with HRT modeled as a time-varying covariate, evaluated the associations with BC risk while adjusting for potential confounders. Results A total of 919 women (mean [SD] age at RRBO, 47.6 [8.9] years) were included, of whom 496 had BRCA1 PV and 423 had BRCA2 PV. During a mean (SD) follow-up of 8.8 (6.2) years, 144 women (16%) were diagnosed with invasive BC. Overall, 381 participants (42%) had ever used and 538 (58%) had never used HRT following RRBO. Ever use of HRT was not associated with increased BC risk (combined estrogen-progestin: hazard ratio [HR], 1.06 [95% CI, 0.67-1.68]; estrogen only: HR, 0.89 [95% CI, 0.48-1.63]). In duration of use analyses, each year of estrogen-only HRT was associated with a reduction in BC risk overall (HR, 0.90; 95% CI, 0.81-0.99) and a reduction among participants with BRCA1 PV (HR, 0.87; 95% CI, 0.77-0.98). Conclusions and Relevance In this cohort study of women with BRCA PV who received HRT after RRBO, estrogen-only HRT was not associated with an increased risk of BC and was associated with a lower risk of BC among women with BRCA1 PV. Combined estrogen-progestin HRT was not associated with BC risk modification.

Longitudinal Patterns of Symptoms in Patients Undergoing Chemotherapy

Importance The longitudinal patterns of patient-reported outcomes and their association with mortality in routine oncology care are largely unexplored. Objectives To characterize the longitudinal patient-reported outcomes among patients undergoing chemotherapy and evaluate their association with mortality. Design, Setting, and Participants This secondary analysis assessed patients in the intervention arm of a cluster randomized clinical trial conducted by the Symptom Management Implementation of Patient Reported Outcomes in Oncology (SIMPRO) consortium. Patients with gastrointestinal, gynecologic, or thoracic cancer who started a new chemotherapy regimen and completed at least 1 symptom questionnaire within 180 days at medical oncology clinics at 6 hospitals (Northeast and Southern US) were assessed from September 1, 2019, to August 31, 2023. Data analysis was performed from March to September 2025. Exposure Electronic health record–integrated symptom questionnaires along with patient education, decision support alerts, and clinical reports to facilitate symptom management. Main Outcomes and Measures Outcomes were patient-reported symptoms, physical function, overall well-being, and mortality. Multivariable regression identified factors associated with mortality during the 180-day follow-up period with symptoms included as time-varying covariates. Results Overall, 3735 patients (median [IQR] age, 67 [59-74] years; 2196 [59%] female) submitted 35 059 symptom questionnaires; 1710 (46%) were diagnosed with gastrointestinal, 1163 (31%) with thoracic, and 852 (23%) with gynecologic cancer. On multivariable analysis, moderate (hazard ratio [HR], 2.07; 95% CI, 1.34-3.20; P  &amp;amp;lt; .001) and severe (HR, 3.39; 95% CI, 2.20-5.22; P  &amp;amp;lt; .001) physical function deficits were associated with a higher hazard of death. Fatigue was the most common symptom reported (29 138 [83%]) followed by pain (19 959 [57%]). The prevalence of severe symptom reports decreased from 1440 of 30 660 reported symptoms (5%) in week 1 to 40 of 3528 reported symptoms (1%) in week 26, whereas moderate symptom reports decreased from 3522 of 30 660 symptoms (11%) to 265 of 3528 (8%). Other time-varying factors associated with higher hazard of death were moderate pain (HR, 1.43; 95%, CI 1.08-1.90; P  = .01), severe pain (HR, 1.66; 94% CI, 1.21-2.26; P  = .001), moderate dyspnea (HR, 1.31; 95% CI, 1.02-1.69; P  = .04), severe dyspnea (HR, 1.62; 95% CI, 1.17-2.24; P  = .004), moderate loss in appetite (HR, 1.40; 95% CI, 1.02-1.92; P  = .04), and severe loss in appetite (HR, 2.27; 95% CI, 1.55-3.33; P  &amp;amp;lt; .001). Conclusions and Relevance This secondary analysis of a cluster randomized clinical trial of patients with cancer characterized the burden of cancer-related symptoms and described normative experiences for patients receiving chemotherapy for 3 common types of cancer and found that mortality was associated with patients’ evolving health status. These findings may help inform programs to monitor and manage symptoms and to deliver targeted interventions that enhance outcomes. Trial Registration ClinicalTrials.gov Identifier: NCT03850912

Streamlined Self-Collection Screening for Sexually Transmitted Infections and Human Papillomavirus

Importance Human papillomavirus (HPV) self-collection increases cervical cancer screening uptake among women underscreened for cervical cancer, particularly those from marginalized low-income and racial and ethnic backgrounds. Underscreened women are also at high risk for other sexually transmitted infections (STIs) that can be similarly screened via self-collection. Objective To evaluate an intervention streamlining testing for other STIs alongside HPV self-collected samples among low-income women. Design, Setting, and Participants This is a secondary analysis of the My Body, My Test–3 study, a randomized clinical trial testing a mailed self-collection intervention to improve cervical cancer screening. The My Body, My Test–3 study was conducted from April 2016 to December 2019 in 22 counties in North Carolina among low-income women overdue for cervical cancer screening. This analysis included participants randomized to the trial intervention group with valid STI and HPV results. Data analysis occurred from October 2024 to February 2025. Intervention The intervention included a mailed self-collection kit and instructions to self-collect a cervicovaginal sample. Samples were tested for other STIs and HPV using the Aptima assay. Main Outcomes and Measures The primary outcome was a positive test result for other STIs (including chlamydia, gonorrhea, and trichomoniasis). A risk factor analysis was conducted to identify factors associated with testing positive for other STIs. Secondary outcomes included rate of follow-up care and perceptions of self-collection among participants with positive STI results. Results Among 327 participants (median [IQR] age, 42 [25-63] years; 38 [8.6%] Hispanic, 146 [44.7%] non-Hispanic Black, and 133 [40.7%] non-Hispanic White), 51 (15.6%) tested positive for other STIs and 51 (15.6%) tested positive for HPV; 7 (2.1%) tested positive for both. Risk factors for other STIs included non-Hispanic Black race and ethnicity compared with non-Hispanic White race and ethnicity (adjusted odds ratio [aOR], 4.1; 95% CI, 1.5-11.6), having 2 or more sexual partners in the last year compared with having none (aOR, 5.7; 95% CI, 1.0-31.4), single marital status compared with married or partnered status (aOR, 5.6; 95% CI, 1.1-27.9), and current smoking compared with none (aOR, 4.1; 95% CI, 1.7-10.4). Among participants who tested positive for other STIs, 34 (66.7%) received follow-up care. Most participants (130 [84.4%]) preferred testing for both HPV and other STIs in the future. Conclusions and Relevance In this secondary analysis of a randomized clinical trial of 327 participants, nearly 1 in 6 tested positive for other STIs via streamlined testing in a mailed HPV self-collection intervention. Self-collection may improve both cervical cancer and STI screening for women from marginalized backgrounds. Trial Registration ClinicalTrials.gov Identifier: NCT02651883

Estimated Cancer Risk in Females Who Meet the Criteria to Exit Cervical Cancer Screening

ImportanceCervical screening guidelines in the US recommend that most females can exit routine screening at age 65 years following 2 recent consecutive negative cotest results (concurrent human papillomavirus and cytology tests). However, empirical data on the subsequent risks of cancer and cancer death in this subgroup of females are limited.ObjectiveTo estimate the risks of cervical cancer and cervical cancer death among females who meet the cotesting criteria to exit screening.Design, Setting, and ParticipantsIn this decision analytical comparative modeling study, 4 decision analytical models from the Cancer Intervention and Surveillance Modeling Network–Cervical modeling consortium that fit common US epidemiological data targets were validated against published estimates of 3- and 5-year risks of cervical intraepithelial neoplasia grade 3 (CIN3) among females meeting exit criteria at Kaiser Permanente Northern California (KPNC).Main Outcomes and MeasuresAge-conditional and cumulative risks of cervical cancer and cervical cancer death at ages 65, 70, 75, 80, and 85 years were estimated by performing a comparative modeling analysis of the 4 models to estimate the risks of cervical cancer and cervical cancer death after exiting screening.ResultsAll models estimated a 5-year risk of CIN3 that was within the range of empirical data from KPNC. Projections of the cumulative and age-conditional risks of cervical cancer and cervical cancer death increased with time since exiting screening. The cumulative risks of cervical cancer and cervical cancer death by age 70 years were estimated to range from 0.001% to 0.003% and from 0% to 0.001%, respectively. The cumulative risks of cervical cancer and cervical cancer death by age 85 years ranged from 0.026% to 0.081% and from 0.005% to 0.038%, respectively, across models. Results were sensitive to assumptions about screening test sensitivity and incidence of high-risk human papillomavirus.Conclusions and RelevanceIn this decision analytical comparative modeling study, a low risk of cervical cancer and cervical cancer death was estimated among females who fulfilled the US criteria to exit screening with cotesting; however, the risks increased with age and/or time since screening exit. The findings suggest that future guidelines should consider acceptable risk levels when defining screening modality and exit age requirements.

Association of Frequent Aspirin Use With Ovarian Cancer Risk According to Genetic Susceptibility

ImportanceFrequent aspirin use is associated with reduced ovarian cancer risk, but it is unknown whether genetic factors modify this association. Understanding effect modifiers is important given that any use of aspirin for ovarian cancer chemoprevention will likely need to focus on specific higher-risk subgroups.ObjectiveTo evaluate whether the association between frequent aspirin use and ovarian cancer is modified by a polygenic score (PGS) for nonmucinous ovarian cancer.Design, Setting, and ParticipantsWe pooled individual-level data from 8 population-based case-control studies from the Ovarian Cancer Association Consortium conducted in the US, UK, and Australia between 1995 and 2009. We included case patients and control participants with both genetic data and data on frequent aspirin use. Case patients with mucinous ovarian cancer were excluded. Data were analyzed between November 1, 2021, and July 31, 2022.ExposuresFrequent aspirin use, defined as daily or almost daily use for 6 months or longer.Main Outcomes and MeasuresThe main outcome was nonmucinous epithelial ovarian cancer. We used logistic regression to estimate odds ratios (ORs) and 95% CIs and likelihood ratio tests to investigate effect modification by the PGS.ResultsThere were 4476 case patients with nonmucinous ovarian cancer and 6659 control participants included in this analysis. At study enrollment, the median (IQR) age was 58 (50-66) years for case patients and 57 (49-65) years for control participants. Case patients and control participants self-reported that they were Black (122 [3%] vs 218 [3%]), White (3995 [89%] vs 5851 [88%]), or of other race and ethnicity (348 [8%] vs 580 [9%]; race and ethnicity were unknown for 11 [0%] vs 10 [0%]). There were 575 case patients (13%) and 1030 control participants (15%) who reported frequent aspirin use. The 13% reduction in ovarian cancer risk associated with frequent aspirin use (OR, 0.87 [95% CI, 0.76-0.99]) was not modified by the PGS. Consistent ORs were observed among individuals with a PGS less than (0.85 [0.70-1.02]) and greater than (0.86 [0.74-1.01]) the median. Results were similar by histotype.Conclusions and RelevanceThe findings of this study suggest that genetic susceptibility to ovarian cancer based on currently identified common genetic variants does not appear to modify the protective association between frequent aspirin use and ovarian cancer risk. Future work should continue to explore the role of aspirin use for ovarian cancer prevention among individuals who are at higher risk for ovarian cancer.

Estimated US Cancer Deaths Prevented With Increased Use of Lung, Colorectal, Breast, and Cervical Cancer Screening

ImportanceIncreased use of recommended screening could help achieve the Cancer Moonshot goal of reducing US cancer deaths.ObjectiveTo estimate the number of cancer deaths that could be prevented with a 10–percentage point increase in the use of US Preventive Services Task Force (USPSTF)-recommended screening.Design, Setting, and ParticipantsThis decision analytical model study is an extension of previous studies conducted for the USPSTF from 2018 to 2023. This study simulated contemporary cohorts of US adults eligible for lung, colorectal, breast, and cervical cancer screening.ExposuresAnnual low-dose computed lung tomography among eligible adults aged 50 to 80 years; colonoscopy every 10 years among adults aged 45 to 75 years; biennial mammography among female adults aged 40 to 74 years; and triennial cervical cytology screening among female adults aged 21 to 29 years, followed by human papillomavirus testing every 5 years from ages 30 to 65 years.Main Outcomes and MeasuresEstimated number of cancer deaths prevented with a 10–percentage point increase in screening use, assuming screening commences at the USPSTF-recommended starting age and continues throughout the lifetime. Outcomes were presented 2 ways: (1) per 100 000 and (2) among US adults in 2021; and they were expressed among the target population at the age of screening initiation. For lung cancer, estimates were among those who will also meet the smoking eligibility criteria during their lifetime. Harms from increased uptake were also reported.ResultsA 10–percentage point increase in screening use at the age that USPSTF recommended screening commences was estimated to prevent 226 lung cancer deaths (range across models within the cancer site, 133-332 deaths), 283 (range, 263-313) colorectal cancer deaths, 82 (range, 61-106) breast cancer deaths, and 81 (1 model; no range available) cervical cancer deaths over the lifetimes of 100 000 persons eligible for screening. These rates corresponded with an estimated 1010 (range, 590-1480) lung cancer deaths prevented, 11 070 (range, 10 280-12 250) colorectal cancer deaths prevented, 1790 (range, 1330-2310) breast cancer deaths prevented, and 1710 (no range available) cervical cancer deaths prevented over the lifetimes of eligible US residents at the recommended age to initiate screening in 2021. Increased uptake was also estimated to generate harms, including 100 000 (range, 45 000-159 000) false-positive lung scans, 6000 (range, 6000-7000) colonoscopy complications, 300 000 (range, 295 000-302 000) false-positive mammograms, and 348 000 (no range available) colposcopies over the lifetime.Conclusions and RelevanceIn this decision analytical model study, a 10–percentage point increase in uptake of USPSTF-recommended lung, colorectal, breast, and cervical cancer screening at the recommended starting age was estimated to yield important reductions in cancer deaths. Achieving these reductions is predicated on ensuring equitable access to screening.

Relevance of Molecular Profiling in Patients With Low-Grade Endometrial Cancer

ImportancePatients with low-grade (ie, grade 1-2) endometrial cancer (EC) are characterized by their favorable prognosis compared with patients with high-grade (ie, grade 3) EC. With the implementation of molecular profiling, the prognostic relevance of tumor grading might lose attention. As most patients present with low-grade EC and have an excellent outcome, the value of molecular profiling for these patients is unclear.ObjectiveTo determine the association of molecular profiling with outcomes among patients with low-grade EC.Design, Setting, and ParticipantsThis retrospective cohort study included a multicenter international European cohort of patients diagnosed with EC between 1994 and 2018, with a median follow-up of 5.9 years. Molecular subgroups were determined by next-generation sequencing using single-molecule molecular inversion probes and by immunohistochemistry. Subsequently, tumors were classified as polymerase epsilon (POLE)-altered, microsatellite instable (MSI), tumor protein p53 (TP53)-altered, or no specific molecular profile (NSMP). Patients diagnosed with any histological subtypes and FIGO (International Federation of Gynecology and Obstetrics) stages of EC were included, but patients with early-stage EC (FIGO I-II) were only included if they had known lymph node status. Data were analyzed February 20 to June 16, 2022.ExposuresMolecular testing of the 4 molecular subgroups.Main Outcomes and MeasuresThe main outcome was disease-specific survival (DSS) within the molecular subgroups.ResultsA total of 393 patients with EC were included, with a median (range) age of 64.0 (31.0-86.0) years and median (range) body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 29.1 (18.0-58.3). Most patients presented with early-stage (290 patients [73.8%]) and low-grade (209 patients [53.2%]) disease. Of all patients, 33 (8.4%) had POLE-altered EC, 78 (19.8%) had MSI EC, 72 (18.3%) had TP53-altered EC, and 210 (53.4%) had NSMP EC. Across all molecular subgroups, patients with low-grade EC had superior 5-year DSS compared with those with high-grade EC, varying between 90% to 100% vs 41% to 90% (P &amp;amp;lt; .001). Multivariable analysis in the entire cohort including age, tumor grade, FIGO stage, lymphovascular space invasion, and the molecular subgroups as covariates found that only high-grade (hazard ratio [HR], 4.29; 95% CI, 2.15-8.53; P &amp;amp;lt; .001), TP53-altered (HR, 1.76; 95% CI, 1.04-2.95; P = .03), and FIGO stage III or IV (HR, 4.26; 95% CI, 2.50-7.26; P &amp;amp;lt; .001) disease were independently associated with reduced DSS.Conclusions and RelevanceThis cohort study found that patients with low-grade EC had an excellent prognosis independent of molecular subgroup. These findings do not support routine molecular profiling in patients with low-grade EC, and they demonstrate the importance of primary diagnostic tumor grading and selective profiling in low-grade EC to increase cost-effectiveness.

Overall and Cervical Cancer Survival in Patients With and Without Mental Disorders

ImportanceIndividuals with a mental disorder experience substantial health disparity and are less likely to participate in cervical screening and human papillomavirus vaccination. Additionally, this population may benefit less from tertiary cancer prevention.ObjectiveTo compare clinical characteristics and survival patterns between patients with cervical cancer with and without a preexisting diagnosis of a mental disorder at the time of cervical cancer diagnosis.Design, Setting, and ParticipantsThis cohort study obtained data from Swedish population-based (Swedish Cancer Register, Swedish Cause of Death Register, Swedish Total Population Register, Swedish Patient Register, and Swedish Longitudinal Integration Database for Health Insurance and Labor Market Studies) and quality registries (Swedish Quality Register of Gynecologic Cancer and Swedish National Cervical Screening Register) on patients with cervical cancer. Patients who were included in the analysis were identified using the Swedish Cancer Register and were diagnosed with cervical cancer between 1978 and 2018. The Swedish Patient Register was used to identify patients with mental disorders using codes from the International Classification of Diseases, Eighth Revision and Ninth Revision and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Because data on clinical characteristics at the time of cancer diagnosis were available for only for part of the study population, 2 patient groups were created: those with cervical cancer diagnosed from 2002 to 2016 and all patients diagnosed with cervical cancer (1978-2018). Data analyses were carried out between March and September 2022.ExposureClinical diagnoses of a mental disorder, including substance abuse, psychotic disorders, depression, anxiety, stress-related disorders, attention-deficit/hyperactivity disorder, autism, and intellectual disability, prior to cervical cancer.Main Outcomes and MeasuresDeath due to any cause or due to cervical cancer as ascertained from the Swedish Cause of Death Register.ResultsThe sample included 20 177 females (mean [SD] age, 53.4 [17.7] years) diagnosed with cervical cancer from 1978 to 2018. In a subgroup of 6725 females (mean [SD] age, 52.2 [18.0] years) with cervical cancer diagnosed from 2002 to 2016, 893 (13.3%) had a preexisting diagnosis of a mental disorder. Compared with patients with no preexisting mental disorder diagnosis, those with a preexisting mental disorder had a higher risk of death due to any cause (hazard ratio [HR], 1.32; 95% CI, 1.17-1.48) and due to cervical cancer (HR, 1.23; 95% CI, 1.07-1.42). These risks were lower after adjustment for cancer characteristics at the time of cancer diagnosis (death due to any cause: HR, 1.19 [95% CI, 1.06-1.34] and death due to cervical cancer: HR, 1.12 [95% CI, 0.97-1.30]). Risk of death was higher for patients with substance abuse, psychotic disorders, or mental disorders requiring inpatient care. Among patients with cervical cancer diagnosed from 1978 to 2018, the estimated 5-year survival improved continuously during the study period regardless of preexisting diagnosis of a mental disorder status. For example, in 2018, the estimated 5-year overall survival proportion was 0.66 (95% CI, 0.60-0.71) and 0.74 (95% CI, 0.72-0.76) for patients with and without a preexisting diagnosis of a mental disorder, respectively.Conclusions and RelevanceFindings of this cohort study suggest that patients with cervical cancer and a preexisting diagnosis of a mental disorder have worse overall and cervical cancer–specific survival than patients without a preexisting mental disorder diagnosis, which may be partly attributable to cancer and sociodemographic characteristics at diagnosis. Hence, individuals with mental disorders deserve special attention in the tertiary prevention of cervical cancer.

Diagnostic Performance of the Ovarian-Adnexal Reporting and Data System (O-RADS) Ultrasound Risk Score in Women in the United States

The American College of Radiology (ACR) Ovarian-Adnexal Reporting and Data System (O-RADS) ultrasound (US) risk scoring system has been studied in a selected population of women referred for suspected or known adnexal lesions. This population has a higher frequency of malignant neoplasms than women presenting to radiology departments for pelvic ultrasonography for a variety of indications, potentially impacting the diagnostic performance of the risk scoring system. To evaluate the risk of malignant neoplasm and diagnostic performance of O-RADS US risk scoring system in a multi-institutional, nonselected cohort. This multi-institutional cohort study included a population of nonselected women in the United States who presented to radiology departments for routine pelvic ultrasonography between 2011 and 2014, with pathology confirmation imaging follow up or 2 years of clinical follow up. Analysis of 1014 adnexal lesions using the O-RADS US risk stratification system. Frequency of ovarian cancer and diagnostic performance of the O-RADS US risk stratification system. This study included 913 women with 1014 adnexal lesions. The mean (SD) age of the patients was 42.4 (13.9 years), and 674 of 913 (73.8%) were premenopausal. The overall frequency of malignant neoplasm was 8.4% (85 of 1014 adnexal lesions). The frequency of malignant neoplasm for O-RADS US 2 was 0.5% (3 of 657 lesions; 50% expected). O-RADS US 4 was the optimum cutoff for diagnosing cancer with sensitivity of 90.6% (95% CI, 82.3%-95.9%), specificity of 81.9% (95% CI, 79.3%-84.3%), positive predictive value of 31.4% (95% CI, 25.7%-37.7%) and negative predictive value of 99.0% (95% CI, 98.0%-99.6%). In this cohort study of a nonselected patient population, the O-RADS US risk stratification system performed within the expected range as published by the ACR O-RADS US committee. The frequency of malignant neoplasm was at the lower end of the published range, partially because of the lower prevalence of cancer in a nonselected population. However, a high negative predictive value was maintained, and when a lesion can be classified as an O-RADS US 2, the risk of cancer is low, which is reassuring for both clinician and patient.

Outcomes From Opportunistic Salpingectomy for Ovarian Cancer Prevention

Opportunistic salpingectomy (OS), which is the removal of fallopian tubes during hysterectomy or instead of tubal ligation without removal of ovaries, is recommended to prevent ovarian cancer, particularly serous ovarian cancer. However, the effectiveness of OS is still undetermined. To examine observed vs expected rates of ovarian cancer among individuals who have undergone OS. This is a population-based, retrospective cohort study of all individuals in British Columbia, Canada, who underwent OS or a control surgery (hysterectomy alone or tubal ligation) between 2008 and 2017, with follow-up until December 31, 2017. Those with any gynecological cancer diagnosed before or within 6 months of their procedure were excluded. Data analysis was performed from April to August 2021. Removal of both fallopian tubes at the time of hysterectomy or instead of tubal ligation while leaving ovaries intact. An ovarian cancer diagnosis listed in the British Columbia Cancer Registry. Age-specific rates of epithelial and serous ovarian cancer in the control group were combined with the specific follow-up time in the OS group to calculate expected numbers (and 95% CIs) of ovarian cancers in the OS group. These were compared with observed numbers. Age-adjusted expected and observed numbers of breast and colorectal cancers were also examined in the OS group. There were 25 889 individuals who underwent OS (mean [SD] age, 40.2 [7.1] years; median [IQR] follow-up, 3.2 [1.6-5.1] years) and 32 080 who underwent hysterectomy alone or tubal ligation (mean [SD] age, 38.2 [7.9] years; median [IQR] follow-up, 7.3 [4.6-8.7] years). There were no serous ovarian cancers in the OS group and 5 or fewer epithelial ovarian cancers. The age-adjusted expected number was 5.27 (95% CI, 1.78-19.29) serous cancers and 8.68 (95% CI, 3.36-26.58) epithelial ovarian cancers. Age-adjusted expected vs observed numbers of breast cancers (22.1 expected vs 23 observed) and colorectal cancers (9.35 expected vs 8 observed) were not significantly different. In this cohort study, the OS group had significantly fewer serous and epithelial ovarian cancers than were expected according to the rate at which they arose in the control group. These findings suggest that OS is associated with reduced ovarian cancer risk.

Fine Mapping of the Major Histocompatibility Complex Region and Association of the HLA-B*52:01 Allele With Cervical Cancer in Japanese Women

Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC. To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. This was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020. Loci within the MHC region associated with CC risk, and the direction and size of association. A total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10-10). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population-specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue-based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10-9). The results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.

Computed Tomographic Radiomics in Differentiating Histologic Subtypes of Epithelial Ovarian Carcinoma

ImportanceEpithelial ovarian carcinoma is heterogeneous and classified according to the World Health Organization Tumour Classification, which is based on histologic features and molecular alterations. Preoperative prediction of the histologic subtypes could aid in clinical management and disease prognostication.ObjectiveTo assess the value of radiomics based on contrast-enhanced computed tomography (CT) in differentiating histologic subtypes of epithelial ovarian carcinoma in multicenter data sets.Design, Setting, and ParticipantsIn this diagnostic study, 665 patients with histologically confirmed epithelial ovarian carcinoma were retrospectively recruited from 4 centers (Hong Kong, Guangdong Province of China, and Seoul, South Korea) between January 1, 2012, and February 28, 2022. The patients were randomly divided into a training cohort (n = 532) and a testing cohort (n = 133) with a ratio of 8:2. This process was repeated 100 times. Tumor segmentation was manually delineated on each section of contrast-enhanced CT images to encompass the entire tumor. The Mann-Whitney U test and voted least absolute shrinkage and selection operator were performed for feature reduction and selection. Selected features were used to build the logistic regression model for differentiating high-grade serous carcinoma and non–high-grade serous carcinoma.ExposuresContrast-enhanced CT-based radiomics.Main Outcomes and MeasuresIntraobserver and interobserver reproducibility of tumor segmentation were measured by Dice similarity coefficients. The diagnostic efficiency of the model was assessed by receiver operating characteristic curve and area under the curve.ResultsIn this study, 665 female patients (mean [SD] age, 53.6 [10.9] years) with epithelial ovarian carcinoma were enrolled and analyzed. The Dice similarity coefficients of intraobserver and interobserver were all greater than 0.80. Twenty radiomic features were selected for modeling. The areas under the curve of the logistic regression model in differentiating high-grade serous carcinoma and non–high-grade serous carcinoma were 0.837 (95% CI, 0.835-0.838) for the training cohort and 0.836 (95% CI, 0.833-0.840) for the testing cohort.Conclusions and RelevanceIn this diagnostic study, radiomic features extracted from contrast-enhanced CT were useful in the classification of histologic subtypes in epithelial ovarian carcinoma. Intraobserver and interobserver reproducibility of tumor segmentation was excellent. The proposed logistic regression model offered excellent discriminative ability among histologic subtypes.

Geographic Variation in Overscreening for Colorectal, Cervical, and Breast Cancer Among Older Adults

National guidelines balance risks and benefits of population-level cancer screening among adults with average risk. Older adults are not recommended to receive routine screening, but many continue to be screened (ie, are overscreened). To assess the prevalence of overscreening for colorectal, cervical, and breast cancers among older adults as well as differences in overscreening by metropolitan status. The cross-sectional study examined responses to a telephone survey of 176 348 community-dwelling adults. Participants were included if they met age and sex criteria, and they were excluded from each cancer-specific subsample if they had a history of that cancer. Data came from the 2018 Behavioral Risk Factor Surveillance System, administered by the US Centers for Disease Control and Prevention. Metropolitan status, according to whether participants lived in a metropolitan statistical area. Overscreening was assessed using US Preventive Services Task Force definitions, ie, whether participants self-reported having a screening after the recommended upper age limit for colorectal (75 years), cervical (65 years), or breast (74 years) cancer. Of 176 348 participants (155 411 [88.1%] women; mean [SE] age, 75.0 [0.04] years; 150 871 [85.6%] non-Hispanic white; 60 456 [34.3%] with nonmetropolitan residence) the cancer-specific subsamples contained 20 937 [11.9%] men and 34 244 [19.4%] women for colorectal cancer, 82 811 [47.0%] women for cervical cancer, and 38 356 [21.8%] women for breast cancer. Overall, 9461 men (59.3%; 95% CI, 57.6%-61.1%) were overscreened for colorectal cancer; 14 463 women (56.2%; 95% CI, 54.7%-57.6%), for colorectal cancer; 31 988 women (45.8%; 95% CI, 44.9%-46.7%), for cervical cancer; and 26 198 women (74.1%; 95% CI, 73.0%-75.3%), for breast cancer. Overscreening was more common in metropolitan than nonmetropolitan areas for colorectal cancer among women (adjusted odds ratio [aOR], 1.23; 95% CI, 1.08-1.39), cervical cancer (aOR, 1.20; 95% CI, 1.11-1.29), and breast cancer (aOR, 1.36; 95% CI, 1.17-1.57). Overscreening for cervical and breast cancers was also associated with having a usual source of care compared with not (eg, cervical cancer: aOR, 1.87; 95% CI, 1.56-2.25; breast cancer: aOR, 2.08; 95% CI, 1.58-2.76), good, very good, or excellent self-reported health compared with fair or poor self-reported health (eg, cervical cancer: aOR, 1.21; 95% CI, 1.11-1.32; breast cancer: aOR, 1.47; 95% CI, 1.28-1.69), an educational attainment greater than a high school diploma compared with a high school diploma or less (eg, cervical cancer: aOR, 1.14; 95% CI, 1.06-1.23; breast cancer: aOR, 1.30; 95% CI, 1.16-1.46), and being married or living as married compared with other marital status (eg, cervical cancer: OR, 1.36; 95% CI, 1.26-1.46; breast cancer: OR, 1.54; 95% CI, 1.34-1.77). In this study, overscreening for cancer among older adults was high, particularly for women living in metropolitan areas. Overscreening could be associated with health care access and patient-clinician relationships. Additional research on why overscreening persists and how to reduce overscreening is needed to minimize risks associated with cancer screening among older adults.

Development of a Deep Learning Model to Identify Lymph Node Metastasis on Magnetic Resonance Imaging in Patients With Cervical Cancer

Accurate identification of lymph node metastasis preoperatively and noninvasively in patients with cervical cancer can avoid unnecessary surgical intervention and benefit treatment planning. To develop a deep learning model using preoperative magnetic resonance imaging for prediction of lymph node metastasis in cervical cancer. This diagnostic study developed an end-to-end deep learning model to identify lymph node metastasis in cervical cancer using magnetic resonance imaging (MRI). A total of 894 patients with stage IB to IIB cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy were reviewed. All patients underwent radical hysterectomy and pelvic lymphadenectomy, received pelvic MRI within 2 weeks before the operations, had no concurrent cancers, and received no preoperative treatment. To achieve the optimal model, the diagnostic value of 3 MRI sequences was compared, and the outcomes in the intratumoral and peritumoral regions were explored. To mine tumor information from both image and clinicopathologic levels, a hybrid model was built and its prognostic value was assessed by Kaplan-Meier analysis. The deep learning model and hybrid model were developed on a primary cohort consisting of 338 patients (218 patients from Sun Yat-sen University Cancer Center, Guangzhou, China, between January 2011 and December 2017 and 120 patients from Henan Provincial People's Hospital, Zhengzhou, China, between December 2016 and June 2018). The models then were evaluated on an independent validation cohort consisting of 141 patients from Yunnan Cancer Hospital, Kunming, China, between January 2011 and December 2017. The primary diagnostic outcome was lymph node metastasis status, with the pathologic characteristics diagnosed by lymphadenectomy. The secondary primary clinical outcome was survival. The primary diagnostic outcome was assessed by receiver operating characteristic (area under the curve [AUC]) analysis; the primary clinical outcome was assessed by Kaplan-Meier survival analysis. A total of 479 patients (mean [SD] age, 49.1 [9.7] years) fulfilled the eligibility criteria and were enrolled in the primary (n = 338) and validation (n = 141) cohorts. A total of 71 patients (21.0%) in the primary cohort and 32 patients (22.7%) in the validation cohort had lymph node metastais confirmed by lymphadenectomy. Among the 3 image sequences, the deep learning model that used both intratumoral and peritumoral regions on contrast-enhanced T1-weighted imaging showed the best performance (AUC, 0.844; 95% CI, 0.780-0.907). These results were further improved in a hybrid model that combined tumor image information mined by deep learning model and MRI-reported lymph node status (AUC, 0.933; 95% CI, 0.887-0.979). Moreover, the hybrid model was significantly associated with disease-free survival from cervical cancer (hazard ratio, 4.59; 95% CI, 2.04-10.31; P < .001). The findings of this study suggest that deep learning can be used as a preoperative noninvasive tool to diagnose lymph node metastasis in cervical cancer.

Association of Neighborhood Measures of Social Determinants of Health With Breast, Cervical, and Colorectal Cancer Screening Rates in the US Midwest

Despite advances in cancer treatment and cancer-related outcomes, disparities in cancer mortality remain. Lower rates of cancer prevention screening and consequent delays in diagnosis may exacerbate these disparities. Better understanding of the association between area-level social determinants of health and cancer screening may be helpful to increase screening rates. To examine the association between area deprivation, rurality, and screening for breast, cervical, and colorectal cancer in patients from an integrated health care delivery system in 3 US Midwest states (Minnesota, Iowa, and Wisconsin). In this cross-sectional study of adults receiving primary care at 75 primary care practices in Minnesota, Iowa, and Wisconsin, rates of recommended breast, cervical, and colorectal cancer screening completion were ascertained using electronic health records between July 1, 2016, and June 30, 2017. The area deprivation index (ADI) is a composite measure of social determinants of health composed of 17 US Census indicators and was calculated for all census block groups in Minnesota, Iowa, and Wisconsin (11 230 census block groups). Rurality was defined at the zip code level. Using multivariable logistic regression, this study examined the association between the ADI, rurality, and completion of cancer screening after adjusting for age, Charlson Comorbidity Index, race, and sex (for colorectal cancer only). Completion of recommended breast, cervical, and colorectal cancer screening. The study cohorts were composed of 78 302 patients eligible for breast cancer screening (mean [SD] age, 61.8 [7.1] years), 126 731 patients eligible for cervical cancer screening (mean [SD] age, 42.6 [13.2] years), and 145 550 patients eligible for colorectal cancer screening (mean [SD] age, 62.4 [7.0] years; 52.9% [77 048 of 145 550] female). The odds of completing recommended screening were decreased for individuals living in the most deprived (highest ADI) census block group quintile compared with the least deprived (lowest ADI) quintile: the odds ratios were 0.51 (95% CI, 0.46-0.57) for breast cancer, 0.58 (95% CI, 0.54-0.62) for cervical cancer, and 0.57 (95% CI, 0.53-0.61) for colorectal cancer. Individuals living in rural areas compared with urban areas also had lower rates of cancer screening: the odds ratios were 0.76 (95% CI, 0.72-0.79) for breast cancer, 0.81 (95% CI, 0.79-0.83) for cervical cancer, and 0.93 (95% CI, 0.91-0.96) for colorectal cancer. Individuals living in areas of greater deprivation and rurality had lower rates of recommended cancer screening, signaling the need for effective intervention strategies that may include improved community partnerships and patient engagement to enhance access to screening in highest-risk populations.

Association of Maternal Cervical Disease With Human Papillomavirus Vaccination Among Offspring

Barriers to childhood vaccination against vaccine-preventable diseases, such as those due to human papillomavirus (HPV), are well known. However, the role of salience bias-the change in perception of risk due to increased familiarity with the outcome-in decisions to vaccinate children has not been explicitly studied. To assess for salience bias in parental decisions to vaccinate children. This retrospective cohort study used a time-to-event (survival) analysis to compare vaccination rates of children whose mothers had a history of cervical cancer or a cervical biopsy, who have experienced adverse vaccine-preventable outcomes, and for whom vaccination may be more salient, with a control group of children whose mothers had no such history. Participants were accrued from the MarketScan Commercial Database, including US children who turned 11 years old, when HPV vaccination is recommended, from January 1, 2014, to December 31, 2018. Data were analyzed from December 29, 2020, to September 17, 2021. Maternal history of cervical cancer or cervical biopsy. Vaccination against HPV. A total of 757 428 children (370 878 girls [49.0%] and 386 550 boys [51.0%]) were identified, of whom 38 366 had mothers with a history of cervical biopsy alone and 1084 had mothers with a history of cervical cancer. Overall, 54.2% of children (55.7% of girls and 52.7% of boys) received at least 1 vaccination by 16 years of age. In a time-to-event analysis, HPV vaccination did not differ between children whose mothers had cervical cancer vs those whose mothers did not (hazard ratio [HR] for girls, 0.99 [95% CI, 0.86-1.13]; HR for boys, 1.08 [95% CI, 0.94-1.24]). Maternal history of cervical biopsy was associated with a minimally increased hazard of vaccination (HR for girls, 1.06 [95% CI, 1.04-1.09]; HR for boys, 1.04 [95% CI, 1.01-1.06]). There were no clinically meaningful differences between groups for the tetanus/diphtheria/acellular pertussis and meningococcal vaccinations, which are also recommended at 11 years of age. In this analysis of salience bias in childhood vaccination decisions, mothers' personal history of cervical cancer or cervical biopsy was not associated with greater vaccination rates among children against HPV. These findings suggest that salience of vaccine-preventable outcomes may not have a major impact on childhood vaccine hesitancy in HPV; the role of salience should be investigated for other vaccines.

Outcomes Among Racial and Ethnic Minority Patients With Advanced Cancers in Phase 1 Trials

ImportancePatients from racial and ethnic minority groups (eg, Asian, Hispanic, and non-Hispanic Black patients) have low representation in clinical trials, especially in phase 1 trials in cancer. These trials represent valuable options for patients with advanced cancer who experience disease progression with standard therapy.ObjectiveTo determine whether the benefit of enrollment to phase 1 cancer trials extends to Asian, Hispanic, and non-Hispanic Black patients as much as it does for non-Hispanic White patients.Data SourcesPatient records at a single institution from January 1999 to December 2016 were reviewed. Treatment-related responses, toxic effects, and deaths were recorded.Study SelectionAll phase 1 studies were included.Data Extraction and SynthesisData underwent independent extraction by multiple observers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.Main Outcomes and MeasuresThe primary outcome was overall survival (OS), assessed using univariate and multivariable time-to-event analyses.ResultsA total of 738 patients (median [range], 60 [22-93] years; 467 [63.3] female) including 197 Hispanic patients (26.7%), 238 non-Hispanic Black patients (32.2%), and 282 non-Hispanic White patients (38.2%), were enrolled in 64 phase 1 trials, including 33 cytotoxic trials (51.5%), 21 biologic trials (32.8%), and 10 combined therapy trials (15.6%). The primary cancer diagnoses were colorectal (187 patients [25.3%]), ovarian (141 patients [19.1%]), lung (58 patients [7.9%]), uterine (49 patients [6.6%]), and breast (41 patients [5.6%]). Patients underwent a median (range) of 3 (0-13) therapies prior to trial enrollment. Among 558 patients evaluated for response, the clinical benefit rate (ie, stable disease plus response rates) was 49.1%, and the overall response rate was 6.5%. Grade 3 or 4 nonhematological toxic effects were observed in 27.8% (95% CI, 24.6%-31.3%) of patients and grade 3 or 4 hematological toxic effects were observed in 19.7% (95% CI, 17.0%-22.8%) of patients. The treatment-related mortality rate was 0.9% (95% CI, 0.4%-1.9%). Median OS was 9.6 (95% CI, 8.2-11.0) months among Hispanic patients, 8.3 (95% CI, 6.7-10.4) months among non-Hispanic Black patients, and 9.8 (95% CI, 8.5-11.4) months among non-Hispanic White patients (P = .13). In a multivariable analysis, age older than 60 years, Eastern Cooperative Oncology Group performance status score of 2 or greater, more than 2 metastatic sites, lactate dehydrogenase grade 1 or 2, grade 2 or greater low albumin, grade 1 or greater total bilirubin, and grade 2 or greater anemia were associated with worse prognosis, whereas leukocytosis greater than grade 1 was associated with better OS.Conclusions and RelevanceIn this meta-analysis assessing outcomes in phase 1 cancer trials among patients from racial and ethnic minority groups, Hispanic and non-Hispanic Black patients had benefits similar to those of non-Hispanic White patients.

Racial and Ethnic Inequities in Cancer Care Continuity During the COVID-19 Pandemic Among Those With SARS-CoV-2

ImportanceRacially and ethnically minoritized US adults were disproportionately impacted by the COVID-19 pandemic and experience poorer cancer outcomes, including inequities in cancer treatment delivery.ObjectiveTo evaluate racial and ethnic disparities in cancer treatment delays and discontinuations (TDDs) among patients with cancer and SARS-CoV-2 during different waves of the COVID-19 pandemic in the United States.Design, Setting, and ParticipantsThis cross-sectional study used data from the American Society of Clinical Oncology Survey on COVID-19 in Oncology Registry (data collected from April 2020 to September 2022), including patients with cancer also diagnosed with SARS-CoV-2 during their care at 69 US practices. Racial and ethnic differences were examined during 5 different waves of the COVID-19 pandemic in the United States based on case surge (before July 2020, July to November 2020, December 2020 to March 2021, April 2021 to February 2022, and March to September 2022).ExposuresRace and ethnicity.Main Outcomes and MeasuresTDD was defined as any cancer treatment postponed more than 2 weeks or cancelled with no plans to reschedule. To evaluate TDD associations with race and ethnicity, adjusted prevalence ratios (aPRs) were estimated using multivariable Poisson regression, accounting for nonindependence of patients within clinics, adjusting for age, sex, body mass index, comorbidities, cancer type, cancer extent, and SARS-CoV-2 severity (severe defined as death, hospitalization, intensive care unit admission, or mechanical ventilation).ResultsA total of 4054 patients with cancer and SARS-CoV-2 were included (143 [3.5%] American Indian or Alaska Native, 176 [4.3%] Asian, 517 [12.8%] Black or African American, 469 [11.6%] Hispanic or Latinx, and 2747 [67.8%] White; 2403 [59.3%] female; 1419 [35.1%] aged 50-64 years; 1928 [47.7%] aged ≥65 years). The analysis focused on patients scheduled (at SARS-CoV-2 diagnosis) to receive drug-based therapy (3682 [90.8%]), radiation therapy (382 [9.4%]), surgery (218 [5.4%]), or transplant (30 [0.7%]), of whom 1853 (45.7%) experienced TDD. Throughout the pandemic, differences in racial and ethnic inequities based on case surge with overall TDD decreased over time. In multivariable analyses, non-Hispanic Black (third wave: aPR, 1.56; 95% CI, 1.31-1.85) and Hispanic or Latinx (third wave: aPR, 1.35; 95% CI, 1.13-1.62) patients with cancer were more likely to experience TDD compared with non-Hispanic White patients during the first year of the pandemic. By 2022, non-Hispanic Asian patients (aPR, 1.51; 95% CI, 1.08-2.12) were more likely to experience TDD compared with non-Hispanic White patients, and non-Hispanic American Indian or Alaska Native patients were less likely (aPR, 0.37; 95% CI, 0.16-0.89).Conclusions and RelevanceIn this cross-sectional study of patients with cancer and SARS-CoV-2, racial and ethnic inequities existed in TDD throughout the pandemic; however, the disproportionate burden among racially and ethnically minoritized patients with cancer varied across SARS-CoV-2 waves. These inequities may lead to downstream adverse impacts on cancer mortality among minoritized adults in the United States.

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer

ImportanceRAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival.ObjectiveTo characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status.Design, Setting, and ParticipantsThis retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023.Main Outcomes and MeasuresClinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test.ResultsA total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C&amp;amp;gt;T (9 of 56 [16.1%]) in RAD51C and c.694C&amp;amp;gt;T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD.Conclusions and RelevanceIn this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor–positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate–ribose] polymerase) inhibitors.

Adjuvant Ovarian Function Suppression in Premenopausal Hormone Receptor–Positive Breast Cancer

ImportanceFew oncology studies have assessed the effectiveness of adjuvant ovarian function suppression (OFS) in observational settings for premenopausal hormone receptor–positive breast cancer. Target trial emulation is increasingly used for estimating treatment outcomes in observational cohorts.ObjectivesTo describe hormone therapy and OFS treatment patterns (aim 1), examine the association between adding OFS to tamoxifen (TAM) or aromatase inhibitor (AI) and survival (aim 2), and examine the association between duration of hormone treatment (TAM or AI) plus OFS (H-OFS) and survival (aim 3).Design, Setting, and ParticipantsThis population-based cohort study included all premenopausal, early-stage breast cancer diagnoses between 2010 and 2020 in Alberta, Canada. Target trial emulation was conducted. Eligibility criteria were directly modeled after the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Participants were followed up for a maximum of 5 years. Data were analyzed from July 2022 through March 2023.ExposuresFor aim 2, exposures were receiving the following baseline treatments for 2 years: AI + OFS (AI-OFS), TAM + OFS (T-OFS), and TAM alone. For aim 3, exposures were a 2-year or greater and a less than 2-year duration of H-OFS.Main Outcomes and MeasuresRecurrence-free survival was the primary outcome of interest. Marginal structural Cox models with inverse probability treatment and censoring weights were used to estimate hazard ratios (HRs), adjusted for baseline and time-varying confounding variables.ResultsAmong 3434 female patients with premenopausal, early-stage breast cancer diagnoses (median [IQR] age, 45 [40-48] years), 2647 individuals satisfied SOFT and TEXT eligibility criteria. There were 2260 patients who initiated TAM, 232 patients who initiated T-OFS, and 155 patients who initiated AI-OFS; 192 patients received H-OFS for 2 or more years, and 195 patients received H-OFS for less than 2 years. The 5-year recurrence risks were not significantly lower in AI-OFS vs TAM (HR, 0.76; 95% CI, 0.38-1.33) or T-OFS vs TAM (HR, 0.87; 95% CI, 0.50-1.45) groups. Patients receiving H-OFS for 2 or more years had significantly better 5-year recurrence-free survival compared with those receiving H-OFS for less than 2 years (HR, 0.69; 95% CI, 0.54-0.90).Conclusions and RelevanceThis study found no significant reductions in recurrence risk for AI-OFS and T-OFS compared with TAM alone. H-OFS duration for at least 2 years was associated with significantly improved recurrence-free survival.

Tumor-Stroma Proportion to Predict Chemoresistance in Patients With Ovarian Cancer

IMPORTANCEPlatinum-based chemotherapy is the backbone of standard-of-care treatment for patients with advanced-stage, high-grade serous carcinoma (HGSC), the most common form of ovarian cancer; however, one-third of patients have or acquire chemoresistance toward platinum-based therapies.OBJECTIVETo demonstrate the utility of tumor-stroma proportion (TSP) as a predictive biomarker of chemoresistance of HGSC, progression-free survival (PFS), and overall survival (OS).DESIGN, SETTING, AND PARTICIPANTSThis prognostic study leveraged tumors from patients with HGSC in The Cancer Genome Atlas (TCGA) cohort (1993-2013) and an independent cohort of resected clinical specimens from patients with HGSC (2004-2014) available in diagnostic and tissue microarray formats from the University of Tübingen in Germany. Data analysis was conducted from January 2021 to January 2024.EXPOSUREDiagnosis of HGSC.MAIN OUTCOMES AND MEASURESPrincipal outcome measures were the ability of TSP to predict platinum chemoresistance, PFS, and OS. Using hematoxylin and eosin–stained slides from the Tübingen cohort (used for routine diagnostic assessment from surgical specimens) as well as tissue microarrays, representative sections of tumors for scoring of TSP were identified using previously evaluated cutoffs of 50% stroma or greater (high TSP) and less than 50% stroma (low TSP). Digitized slides from the TCGA Cohort were analyzed and scored in a similar fashion. Kaplan-Meier time-to-event functions were fit to estimate PFS and OS.RESULTSThe study included 103 patients (mean [SD] age, 61.6 [11.1] years) from the TCGA cohort and 192 patients (mean [SD] age at diagnosis, 63.7 [11.1] years) from the Tübingen cohort. In the TCGA cohort, there was no significant association of TSP levels with chemoresistance, PFS, or OS. However, in the Tübingen cohort, high TSP was associated with significantly shorter PFS (HR, 1.586; 95% CI, 1.093-2.302; P = .02) and OS (hazard ratio [HR], 1.867; 1.249-2.789; P = .002). Patients with chemoresistant tumors were twice as likely to have high TSP as compared to patients with chemosensitive tumors (HR, 2.861; 95% CI, 1.256-6.515; P = .01). In tissue microarrays from 185 patients from the Tübingen cohort, high TSP was again associated with significantly shorter PFS (HR, 1.675; 95% CI, 1.012-2.772 P = .04) and OS (HR, 2.491; 95% CI, 1.585-3.912; P &amp;amp;lt; .001).CONCLUSIONS AND RELEVANCEIn this prognostic study, TSP was a consistent and reproducible marker of clinical outcome measures of HGSC, including PFS, OS, and platinum chemoresistance. Accurate and cost-effective predictive biomarkers of platinum chemotherapy resistance are needed to identify patients most likely to benefit from standard treatments, and TSP can easily be implemented and integrated into prospective clinical trial design and adapted to identify patients who are least likely to benefit long-term from conventional platinum-based cytotoxic chemotherapy treatment at the time of initial diagnosis.

Lymph Node Isolated Tumor Cells in Patients With Endometrial Cancer

ImportanceIsolated tumor cells (ITCs) are the histopathological finding of small clusters of cancer cells no greater than 0.2 mm in diameter in the regional lymph nodes. For endometrial cancer, the prognostic significance of ITCs is uncertain.ObjectiveTo assess clinico-pathological characteristics and oncologic outcomes associated with ITCs in endometrial cancer.Design, Setting, and ParticipantsThis retrospective cohort study using the National Cancer Database included patients with endometrial cancer who had primary hysterectomy and nodal evaluation from 2018 to 2020. Patients with microscopic and macroscopic nodal metastases and distant metastases were excluded. Data were analyzed from June to September 2023.ExposureRegional nodal status with ITCs (N0[i+] classification) or no nodal metastasis (N0 classification).Main Outcomes and Measures(1) Clinical and tumor characteristics associated with ITCs, assessed with multivariable binary logistic regression model, and (2) overall survival (OS) associated with ITCs, evaluated by nonproportional hazard analysis with restricted mean survival time at 36 months.ResultsA total of 56 527 patients were included, with a median (IQR) age of 64 (57-70) years. The majority had T1a lesion (37 836 [66.9%]) and grade 1 or 2 endometrioid tumors (40 589 [71.8%]). ITCs were seen in 1462 cases (2.6%). In a multivariable analysis, ITCs were associated with higher T classification, larger tumor size, lymphovascular space invasion (LVSI), and malignant peritoneal cytology. Of those tumor factors, LVSI had the largest association with ITCs (7.9% vs 1.4%; adjusted odds ratio [aOR], 4.37; 95% CI, 3.87-4.93), followed by T1b classification (5.3% vs 1.3%; aOR, 2.62; 95% CI, 2.30-2.99). At the cohort level, 24-month OS rates were 94.3% (95% CI, 92.4%-95.7%) for the ITC group and 96.1% (95% CI, 95.9%-96.3%) for the node-negative group, and the between-group difference in expected mean OS time at 36 months was 0.35 (SE, 0.19) months, but it was not statistically significant (P = .06). There was a statistically significant difference in OS when the low-risk group (stage IA, grade 1-2 endometrioid tumors with no LVSI) was assessed per nodal status and adjuvant therapy use (P &amp;amp;lt; .001): (1) among the cases treated with surgical therapy alone, 24-month OS rates were 95.9% (95% CI, 89.5%-98.5%) for the ITC group and 98.8% (95% CI, 98.6%-99.0%) for the node-negative group, and the between-group mean OS time difference at 36 months was 0.61 (SE, 0.43) months (P = .16); and (2) among the cases with ITCs, adjuvant therapy (radiotherapy alone, systemic chemotherapy alone, or both) was associated with improved survival compared with no adjuvant therapy (24-month OS rates, 100% vs 95.9%; between-group mean OS time difference at 36 months, 0.95 [SE, 0.43] months; P = .03).Conclusions and RelevanceIn this cohort study of patients with surgically staged endometrial cancer, the results of exploratory analysis suggested that presence of ITCs in the regional lymph node may be associated with OS in the low-risk group. While adjuvant therapy was associated with improved OS in the low-risk group with ITCs, careful interpretation is necessary given the favorable outcomes regardless of adjuvant therapy use. This hypothesis-generating observation in patients with low-risk endometrial cancer warrants further investigation, especially with prospective setting.

Laparoscopic Cytoreduction After Neoadjuvant Chemotherapy in High-Grade Epithelial Ovarian Cancer

ImportanceDespite the absence of high-quality evidence of its safety and effectiveness, minimally invasive surgery (MIS) is increasingly used to treat advanced epithelial ovarian cancer (EOC).ObjectiveTo assess the feasibility of conducting a full-scale randomized clinical trial (RCT) designed to compare the efficacy of MIS vs laparotomy in patients with advanced-stage EOC and a complete or partial response to neoadjuvant chemotherapy (NACT).Design, Setting, and ParticipantsThis lead-in pilot phase of LANCE (Laparoscopic Cytoreduction After Neoadjuvant Chemotherapy), an international, open-label, noninferiority RCT, opened to enrollment in September 2020 and enrolled the 100th eligible patient in February 2023. It was conducted at 11 academic cancer centers in North America and Europe. Participants were adults with stage IIIC or IV epithelial ovarian, fallopian, or primary peritoneal carcinoma who had normal cancer antigen 125 levels and at least a partial radiologic response after 3 to 4 cycles of NACT. Patients were randomly assigned to receive either interval cytoreductive surgery performed using MIS or laparotomy. Data analysis was based on the evaluable population.InterventionsThe MIS arm underwent laparoscopic or robotic surgery, vs laparotomy for the control arm. Resection of all visible tumor was attempted, and conversion from MIS to laparotomy was performed when necessary to attain complete resection.Main Outcomes and MeasuresTrial feasibility was defined by 3 primary end points: patient accrual rate of at least 5.6 patients per month by the last month of the lead-in pilot phase, conversion from MIS to laparotomy in less than 25% of patients, and a difference in complete gross resection rates of fewer than 20 percentage points between study arms.ResultsOne hundred women (median [IQR] age, 63 [39-82] years) were included, of whom 49 were randomly assigned to MIS and 51 to laparotomy; 95 were evaluable for surgical outcomes. Most patients (34 [67%] in the laparotomy arm, and 33 [67%] in the MIS arm) had stage IIIC cancer. The monthly accrual rate reached 5.9 patients per month in the final month of the study. Six of 48 evaluable patients (12.5%; 95% CI, 4.7%-25.2%) assigned to MIS underwent conversion to laparotomy. Surgeons achieved a complete gross resection rate in 42 of 48 evaluable patients (88%) assigned to MIS and in 39 of 47 patients (83%) assigned to laparotomy (difference, 4.5 [95% CI, −9.7 to 18.8] percentage points).Conclusions and RelevanceResults of this lead-in pilot study indicated the feasibility of the LANCE RCT to compare the oncological outcomes of MIS vs laparotomy.Trial RegistrationClinicalTrials.gov Identifier: NCT04575935

Race, Prevalence of POLE and POLD1 Alterations, and Survival Among Patients With Endometrial Cancer

ImportanceBlack patients with endometrial cancer (EC) in the United States have higher mortality than patients of other races with EC. The prevalence of POLE and POLD1 pathogenic alterations in patients of different races with EC are not well studied.ObjectiveTo explore the prevalence of and outcomes associated with POLE and POLD1 alterations in differential racial groups.Design, Setting, and ParticipantsThis retrospective cohort study incorporated the largest available data set of patients with EC, including American Association for Cancer Research Project GENIE (Genomics Evidence Neoplasia Information Exchange; 5087 participants), Memorial Sloan Kettering–Metastatic Events and Tropisms (1315 participants), and the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (517 participants), collected from 2015 to 2023, 2013 to 2021, and 2006 to 2012, respectively. The prevalence of and outcomes associated with POLE or POLD1 alterations in EC were evaluated across self-reported racial groups.ExposurePatients of different racial groups with EC and with or without POLE or POLD1 alterations.Main Outcomes and MeasuresThe main outcome was overall survival. Data on demographic characteristics, POLE and POLD1 alteration status, histologic subtype, tumor mutation burden, fraction of genome altered, and microsatellite instability score were collected.ResultsA total of 6919 EC cases were studied, of whom 444 (6.4%), 694 (10.0%), and 4869 (70.4%) patients were self-described as Asian, Black, and White, respectively. Within these large data sets, Black patients with EC exhibited a lower weighted average prevalence of pathogenic POLE alterations (0.5% [3 of 590 cases]) compared with Asian (6.1% [26 of 424]) or White (4.6% [204 of 4520]) patients. By contrast, the prevalence of POLD1 pathogenic alterations was 5.0% (21 cases), 3.2% (19 cases), and 5.6% (255 cases) in Asian, Black, and White patients with EC, respectively. Patients with POLD1 alterations had better outcomes regardless of race, histology, and TP53 alteration status. For a total of 241 clinically annotated Black patients with EC, a composite biomarker panel of either POLD1 or POLE alterations identified 7.1% (17 patients) with positive outcomes (1 event at 70 months follow up) in the small sample of available patients.Conclusions and RelevanceIn this retrospective clinicopathological study of patients of different racial groups with EC, a composite biomarker panel of either POLD1 or POLE alteration could potentially guide treatment de-escalation, which is especially relevant for Black patients.

Patient and Clinician Decision Support to Increase Genetic Counseling for Hereditary Breast and Ovarian Cancer Syndrome in Primary Care

To promote the identification of women carrying BRCA1/2 variants, the US Preventive Services Task Force recommends that primary care clinicians screen asymptomatic women for an increased risk of carrying a BRCA1/2 variant risk. To examine the effects of patient and clinician decision support about BRCA1/2 genetic testing compared with standard education alone. This clustered randomized clinical trial was conducted at an academic medical center including 67 clinicians (unit of randomization) and 187 patients. Patient eligibility criteria included women aged 21 to 75 years with no history of breast or ovarian cancer, no prior genetic counseling or testing for hereditary breast and ovarian cancer syndrome (HBOC), and meeting family history criteria for BRCA1/2 genetic testing. RealRisks decision aid for patients and the Breast Cancer Risk Navigation Tool decision support for clinicians. Patients scheduled a visit with their clinician within 6 months of enrollment. The primary end point was genetic counseling uptake at 6 months. Secondary outcomes were genetic testing uptake at 6 and 24 months, decision-making measures (perceived breast cancer risk, breast cancer worry, genetic testing knowledge, decision conflict) based upon patient surveys administered at baseline, 1 month, postclinic visit, and 6 months. From December 2018 to February 2020, 187 evaluable patients (101 in the intervention group, 86 in the control group) were enrolled (mean [SD] age: 40.7 [13.2] years; 88 Hispanic patients [46.6%]; 15 non-Hispanic Black patients [8.1%]; 72 non-Hispanic White patients [38.9%]; 35 patients [18.9%] with high school education or less) and 164 (87.8%) completed the trial. There was no significant difference in genetic counseling uptake at 6 months between the intervention group (20 patients [19.8%]) and control group (10 patients [11.6%]; difference, 8.2 percentage points; OR, 1.88 [95% CI, 0.82-4.30]; P = .14). Genetic testing uptake within 6 months was also statistically nonsignificant (13 patients [12.9%] in the intervention group vs 7 patients [8.1%] in the control group; P = .31). At 24 months, genetic testing uptake was 31 patients (30.7%) in intervention vs 18 patients (20.9%) in control (P = .14). Comparing decision-making measures between groups at baseline to 6 months, there were significant decreases in perceived breast cancer risk and in breast cancer worry (standard mean differences = -0.48 and -0.40, respectively). This randomized clinical trial did not find a significant increase in genetic counseling uptake among patients who received patient and clinician decision support vs those who received standard education, although more than one-third of the ethnically diverse women enrolled in the intervention underwent genetic counseling. These findings suggest that the main advantage for these high-risk women is the ability to opt for screening and preventive services to decrease their cancer risk. ClinicalTrials.gov Identifier: NCT03470402.

Reproductive Factors and Endometrial Cancer Risk Among Women

ImportanceDespite evidence of an association between reproductive factors and endometrial cancer risk, prospective studies have been conducted mainly in non-Asian countries.ObjectiveTo assess the association between reproductive factors, such as number of deliveries, age at menarche, or menopause, and endometrial cancer risk.Design, Setting, and ParticipantsThis cohort study used pooled individual data from 13 prospective cohort studies conducted between 1963 and 2014 in the Asia Cohort Consortium. Participants were Asian women. Data analysis was conducted from September 2019 to April 2023.ExposuresReproductive factors were assessed using a questionnaire in each cohort.Main Outcomes and MeasuresThe main outcome was time to incidence of endometrial cancer. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% CIs.ResultsA total of 1005 endometrial cancer cases were detected among 332 625 women (mean [SD] age, 54.3 [10.4] years) during a mean (SD) of 16.5 (6.4) years of follow-up. Increasing number of deliveries was associated with a decreased endometrial cancer risk in a dose-response manner (≥5 deliveries vs nulliparous [reference]: HR, 0.37; 95% CI, 0.26-0.53; P for trend &amp;amp;lt; .001). Compared with menarche at younger than 13 years, menarche at 17 years or older had an HR of 0.64 (95% CI, 0.48-0.86; P for trend &amp;amp;lt; .001). Late menopause (age ≥55 years) showed an HR of 2.84 (95% CI, 1.78-4.55; P for trend &amp;amp;lt; .001) compared with the youngest age category for menopause (&amp;amp;lt;45 years). Age at first delivery, hormone therapy, and breastfeeding were not associated with endometrial cancer risk.Conclusions and RelevanceThis large pooled study of individual participant data found that late menarche, early menopause, and a higher number of deliveries were significantly associated with a lower risk of endometrial cancer. These convincing results from Asian prospective studies add to the growing body of evidence for the association between reproductive factors and endometrial cancer.

Early-Life Factors and Early-Onset Endometrial Cancer Risk in the UK Biobank

This case-control study investigates UK Biobank data for 8 early-life factors and early-onset endometrial cancer risk among UK residents.

Association of Lower Extremity Lymphedema With Physical Functioning and Activities of Daily Living Among Older Survivors of Colorectal, Endometrial, and Ovarian Cancer

Lower extremity lymphedema (LEL) is associated with decreased physical functioning (PF) and activities of daily living (ADLs) limitations. However, the prevalence of LEL in older survivors of cancer is unknown. To examine LEL among older female survivors of colorectal, endometrial, or ovarian cancer and investigate the association of LEL with PF and ADLs. This secondary analysis of the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study was conducted using data from postmenopausal women enrolled at 40 US centers. Participants were women who had a prior diagnosis of endometrial, colorectal, or ovarian cancer and who had completed the WHI LILAC baseline and year 1 follow-up questionnaires as of September 2017. The 13-item Lower Extremity Lymphedema Screening Questionnaire in Women was used to determine LEL (ie, score ≥5). Validated surveys were used to assess PF and ADLs. Among 900 older women diagnosed with endometrial, colorectal, or ovarian cancer, the mean (SD) age was 78.5 (5.9) years and the mean (range) time since cancer diagnosis was 8.75 (1.42-20.23) years. Overall, 292 women (32.4%) reported LEL, with the highest LEL prevalence among survivors of ovarian cancer (38 of 104 women [36.5%]), followed by survivors of endometrial cancer (122 of 375 women [32.5%]) and colorectal cancer (132 of 421 women [31.4%]). Compared with women without LEL, women with LEL had a PF score that was lower by a mean (SE) 16.8 (1.7) points (P < .001) and higher odds of needing help with ADLs (odds ratio [OR], 2.45; 95% CI, 1.64-3.67). In the association of LEL with PF, the mean (SE) decrease in PF score was greatest among survivors of colorectal cancer (-21.8 [2.6]) compared with survivors of endometrial cancer (-13.3 [2.7]) and ovarian cancer (-12.8 [5.2]). Additionally, among survivors of colorectal cancer, LEL was associated with increased odds of needing help with ADLs (OR, 3.59; 95% CI, 1.94-6.66), while there was no such association among survivors of endometrial cancer or ovarian cancer. However, there were no interaction associations between LEL and cancer type for either outcome. Additionally, the overall mean (SE) difference in PF between women with and without LEL was greater among those aged 80 years and older (-19.4 [2.6] points) vs those aged 65 to 79 years (-14.9 [2.2] points). However, among survivors of colorectal cancer, the mean (SE) difference in PF score was greater among women aged 65 to 79 years (-22.9 [3.7] points) vs those aged 80 years or older (-20.8 [3.7] points) (P for 3-way interaction = .03). This study found that nearly one-third of older female survivors of colorectal, endometrial, or ovarian cancer experienced LEL and that LEL was associated with decreased PF and increased odds of needing help with ADLs. These findings suggest that clinicians may need to regularly assess LEL among older survivors of cancer and provide effective interventions to reduce LEL symptoms and improve PF for this population.

Trends in Primary Treatment and Median Survival Among Women With Advanced-Stage Epithelial Ovarian Cancer in the US From 2004 to 2016

This cohort study compares time trends in the use of neoadjuvant chemotherapy and survival rates among women with advanced-stage epithelial ovarian cancer.

Assessment of Prediagnostic Experiences of Black Women With Endometrial Cancer in the United States

Black women with endometrial cancer have a 90% higher mortality rate than white women with endometrial cancer. The advanced disease stage at which black women receive a diagnosis of endometrial cancer is a major factor in this disparity and is not explained by differences in health care access. To describe the prediagnostic experiences of symptoms and symptom disclosure among black women with endometrial cancer. This community-engaged qualitative study developed an interview guide to collect data during semistructured interviews among a sample of 15 black women with endometrial cancer in the United States. Interviews were conducted in person or via a secure conferencing platform. An exploratory and descriptive content analysis was performed using iterative rounds of inductive coding, case summaries, and coanalysis with community input to identify emergent themes. Data were collected from October 3, 2017, to April 15, 2019, and the descriptive content analysis was performed from October 11, 2017, to May 6, 2019. Beliefs, interpretations, and experiences of black women with endometrial cancer from symptom onset to diagnostic confirmation of cancer. Participants included 15 women who self-identified as black or African American and ranged in age from 31 to 72 years. Eight participants lived in the Puget Sound region of Washington, 2 participants lived in California, and 1 participant each lived in Alabama, Michigan, Louisiana, Georgia, and New York. Twelve participants were receiving adjuvant therapy during the study, which indicated that they were either in a high-risk group and/or had advanced-stage disease. Thirteen participants had health insurance at the time of symptom onset, and all participants had elected to receive cancer treatment. Participants described knowledge gaps and silence about menopause, misinterpretation of vaginal bleeding, and responses by first-line health care practitioners that were not aligned with the risk of endometrial cancer among black women in the United States. The responses of interviewed black women with endometrial cancer suggest that several mechanisms may be associated with a delay in care before diagnosis among this high-risk population and represent modifiable factors that may be useful in the development of targeted interventions to improve the rates of early diagnosis among black women with endometrial cancer.

HPV, Cytology, and Cotest Cervical Cancer Screening and the Risk of Precancer

Importance There is a global call to end cervical cancer, and various jurisdictions are still determining optimal strategies to accelerate elimination. Human papillomavirus (HPV)-negative testing confers lower risk of future precancer vs normal cytology; high-quality longitudinal data are needed comparing risk after a negative HPV test vs negative cotest (HPV and cytology). Objective To compare long-term risk of cervical precancer based on HPV, cytology, and cotest screening results. Design, Setting, and Participants This cohort study linked data from a randomized clinical trial to a comprehensive screening program in British Columbia. Participants were recruited between 2006 and 2012 and followed from trial exit to 10 years postexit. Eligible participants were women who completed trial exit cotesting. Data were analyzed between January and April 2025. Exposure HPV and cytology status from exit cotesting were considered, stratified by status of each test. Main Outcome and Measures Cumulative risk of precancer was calculated over follow-up using Kaplan-Meier techniques. Risk was compared among groups who tested HPV-negative with normal cytology, HPV-negative with abnormal cytology, HPV-positive with normal cytology, and HPV-positive with abnormal cytology. Additionally, risk among those who were HPV-negative (regardless of cytology result), with normal cytology (regardless of HPV results), or were cotest negative were compared in order to simulate outcomes in primary HPV screening, cytology, and cotest programs, respectively. Results In this cohort of 8078 women (median [IQR] age at exit screen, 49 [41-57] years; 1636 Asian [22.4%], 223 Indigenous [3.0%], 5568 White [76.1%]) who participated in a British Columbia–based cervical cancer screening trial, the HPV-positive with abnormal cytology group had the highest cumulative incidence risk (CIR) of cervical intraepithelial neoplasia grade 2 or higher at the end of follow-up (CIR, 43.47%; 95% CI, 23.45%-58.26%), followed by the HPV-positive and cytology-negative group (CIR, 22.21%; 95% CI, 11.49%-31.62%). The HPV-negative with abnormal cytology (CIR, 4.83%; 95% CI, 0%-10.03%) and the HPV-negative with normal cytology (CIR, 0.37%; 95% CI, 0.13%-0.60%) groups had significantly lower CIR at the end of follow-up. Less than 1% of the population was HPV-negative with abnormal cytology (69 of 8078 [0.85%]). Women who were HPV-negative regardless of cytology results (CIR, 0.41%; 95% CI, 0.17%-0.65%) had a similar risk as those who cotested negative (CIR, 0.37%; 95% CI, 0.13%-0.60%); both groups had lower risk than those with normal cytology results (regardless of HPV result) (CIR, 1.28%; 95% CI, 0.78%-1.78%) throughout follow-up. Conclusions and Relevance In this cohort study of cervical cancer screen testing approaches and risk of cervical precancer, after a negative HPV test (regardless of cytology results) risk of precancer remained acceptably low throughout long-term follow-up. This suggests that cotesting yielded limited benefits, while increasing costs, relative to primary HPV testing.

Cost-Effectiveness of Smoking Cessation Among Survivors of Cervical Intraepithelial Neoplasia or Cervical Cancer

Importance Evidence of cost-effectiveness is needed to demonstrate the value of smoking cessation behavioral interventions. Objective To evaluate the cost-effectiveness of motivation and problem-solving (MAPS) against standard treatment (ST) for smoking cessation among patients with a history of cervical intraepithelial neoplasia or cervical cancer. Design, Setting, and Participants In this economic evaluation, a cost-effectiveness analysis was conducted from the perspective of cancer centers using data collected in a randomized clinical trial conducted between February 2017 and January 2020 with follow-up until August 2021 that compared MAPS with ST. MAPS is a behavioral intervention that emphasizes smoking cessation and relapse prevention while addressing life events, stressors, and other individual concerns. The trial included up to 6 counseling sessions of MAPS delivered over 12 months. Data were analyzed from January 2024 to December 2025. Exposure Inclusion in a smoking cessation randomized clinical trial that compared MAPS with ST. Main Outcomes and Measures Deterministic and probabilistic cost-effectiveness analyses were conducted and findings were reported as incremental cost-effectiveness ratio and cost-effectiveness acceptability curve, respectively, for 7-day point prevalence abstinence at months 12 and 18. Results The analysis included 194 participants. Study participants had a mean (SD) age of 47.8 (10.8) years, had a mean (SD) smoking history of 29.1 (12.1) years, and smoked a mean (SD) of 15.5 (8.7) cigarettes per day. Mean costs were $522.74 (95% CI, $500.19 to $545.29) and $389.26 (95% CI, $362.67 to $415.84) per participant for MAPS (98 participants) and ST (96 participants), respectively. At month 12, abstinence rates were 26.5% and 12.5% for MAPS and ST, respectively. The deterministic analysis found that the incremental cost for MAPS vs ST was $921 per quit at month 12 and $7458 per quit at month 18. The probabilistic analysis found that at the societal willingness to pay of $10 000 per quit, the probability that MAPS is cost-effective at month 12 was nearly 100% but reduced to 52% at month 18. Subgroup analysis found a lower incremental cost-effectiveness ratio when comparing the high MAPS engagement subgroup with the ST group. The cost-effectiveness of MAPS (vs ST) was sustained at month 18 among the high MAPS engagement subgroup despite a decline in 7-day abstinence. Conclusions and Relevance In this cost-effectiveness analysis, there was robust evidence supporting the cost-effectiveness of MAPS (vs ST) at month 12 and moderate evidence at month 18 in terms of incremental cost per quit. The attenuation of intervention outcome over time was more pronounced among participants with less than 4 sessions of MAPS.

Cancer Screening Disparities Before and After the COVID-19 Pandemic

ImportanceBreast, cervical, and colorectal cancer–screening disparities existed prior to the COVID-19 pandemic, and it is unclear whether those have changed since the pandemic.ObjectiveTo assess whether changes in screening from before the pandemic to after the pandemic varied for immigrants and for people with limited income.Design, Setting, and ParticipantsThis population-based, cross-sectional study, using data from March 31, 2019, and March 31, 2022, included adults in Ontario, Canada, the country’s most populous province, with more than 14 million people, almost 30% of whom are immigrants. At both dates, the screening-eligible population for each cancer type was assessed.ExposuresNeighborhood income quintile, immigrant status, and primary care model type.Main Outcomes and MeasuresFor each cancer screening type, the main outcome was whether the screening-eligible population was up to date on screening (a binary outcome) on March 31, 2019, and March 31, 2022. Up to date on screening was defined as having had a mammogram in the previous 2 years, a Papanicolaou test in the previous 3 years, and a fecal test in the previous 2 years or a flexible sigmoidoscopy or colonoscopy in the previous 10 years.ResultsThe overall cohort on March 31, 2019, included 1 666 943 women (100%) eligible for breast screening (mean [SD] age, 59.9 [5.1] years), 3 918 225 women (100%) eligible for cervical screening (mean [SD] age, 45.5 [13.2] years), and 3 886 345 people eligible for colorectal screening (51.4% female; mean [SD] age, 61.8 [6.4] years). The proportion of people up to date on screening in Ontario decreased for breast, cervical, and colorectal cancers, with the largest decrease for breast screening (from 61.1% before the pandemic to 51.7% [difference, −9.4 percentage points]) and the smallest decrease for colorectal screening (from 65.9% to 62.0% [difference, −3.9 percentage points]). Preexisting disparities in screening for people living in low-income neighborhoods and for immigrants widened for breast screening and colorectal screening. For breast screening, compared with income quintile 5 (highest), the β estimate for income quintile 1 (lowest) was −1.16 (95% CI, −1.56 to −0.77); for immigrant vs nonimmigrant, the β estimate was −1.51 (95% CI, −1.84 to −1.18). For colorectal screening, compared with income quintile 5, the β estimate for quntile 1 was −1.29 (95% CI, 16 −1.53 to −1.06); for immigrant vs nonimmigrant, the β estimate was −1.41 (95% CI, −1.61 to −1.21). The lowest screening rates both before and after the COVID-19 pandemic were for people who had no identifiable family physician (eg, moving from 11.3% in 2019 to 9.6% in 2022 up to date for breast cancer). In addition, patients of interprofessional, team-based primary care models had significantly smaller reductions in β estimates for breast (2.14 [95% CI, 1.79 to 2.49]), cervical (1.72 [95% CI, 1.46 to 1.98]), and colorectal (2.15 [95% CI, 1.95 to 2.36]) postpandemic screening and higher uptake of screening in general compared with patients of other primary care models.Conclusions and RelevanceIn this cross-sectional study in Ontario that included 2 time points, widening disparities before compared with after the COVID-19 pandemic were found for breast cancer and colorectal cancer screening based on income and immigrant status, but smaller declines in disparities were found among patients of interprofessional, team-based primary care models than among their counterparts. Policy makers should investigate the value of prioritizing and investing in improving access to team-based primary care for people who are immigrants and/or with limited income.

National Outcomes of Increasing Cervical Cancer Screening in Federally Qualified Health Centers

Importance Federally qualified health centers (FQHCs) deliver health care to more than 30 million people across the US and often face structural constraints that affect their ability to provide cervical cancer screening (CCS). Objectives To estimate the number of underscreened individuals served by FQHCs and the outcomes of improving CCS in FQHCs to meet the Healthy People 2030 goal of 79.2%. Design, Setting, and Participants This cross-sectional analysis used data from the Uniform Data System reported in 2023 by 1352 FQHCs across the US, self-reported survey-weighted CCS prevalence from the National Health Interview Survey, and population size estimates from the US Census Bureau American Community Survey 2023. Participants were US adults served by FQHCs who were CCS eligible nested within the estimated 85 364 685 CCS-eligible individuals in the US population. Analyses were conducted between September 2024 and July 2025. Exposures Receipt of CCS at an FQHC. Main Outcomes and Measures Percentage of CCS-eligible individuals who were up to date on CCS. Results In 2023, a total of 7 757 211 CCS-eligible individuals were served by FQHCs, representing 9.1% (95% uncertainty interval [UI], 9.0%-9.2%) of the estimated 85 364 685 individuals in the CCS-eligible population. FQHCs served 35.9% (95% UI, 32.9%-39.6%) of the underscreened publicly insured population, 26.3% (95% UI, 23.1%-30.1%) of the underscreened rural population, 22.4% (95% UI, 20.9%-24.0%) of the underscreened population living at or below 200% of the poverty level, 19.5% (95% UI, 17.9%-21.4%) of the underscreened uninsured population, and 17.7% (95% UI, 16.7%-18.9%) of the underscreened racial or ethnic minority population. By region, FQHCs served 16.5% (95% UI, 14.6%-18.7%) of the underscreened population in the Northeast, 14.1% (95% UI, 12.7%-15.9%) in the Midwest, 13.5% (95% UI, 12.5%-14.7%) in the South, and 19.1% (95% UI, 17.3%-21.1%) in the West. Increasing CCS in FQHCs from the current estimate of 55.1% to the Healthy People 2030 goal of 79.2% would screen an additional 1 872 367 people and increase CCS among the aforementioned subgroups and regions by 2 to 6 percentage points. Conclusions and Relevance This cross-sectional study found that FQHCs served a large number of underscreened individuals from traditionally underscreened subgroups. These results suggest that improving CCS in FQHCs would result in a substantial increase in national CCS rates.

Geographic and Temporal Patterns of Screening for Breast, Cervical, and Colorectal Cancer in the US, 1997-2019

ImportanceDespite guidelines and recommendations, cancer screening remains low and variable across geographic and sociodemographic groups, contributing to persisting disparities.ObjectiveTo analyze geographic and temporal patterns of county-level cancer screening prevalence for breast, cervical, and colorectal cancer over a 22-year period in the US and examine sociodemographic factors associated with screening clusters.Design, Setting, and ParticipantsThis cross-sectional study used an ecological panel design using county-level screening prevalence as the unit of analysis. Data were collected from US mainland counties (ie, excluding Alaska, Hawaii, and Puerto Rico) from 1997 to 2019, with prevalence estimated over 3- to 5-year periods. Data were analyzed from 2024 to 2025.ExposuresCounty-level screening prevalence was estimated from the Behavioral Risk Factor Surveillance System and the National Health Interview Survey from 1997 to 2019. Socioeconomic and demographic characteristics were estimated from the 2000 US Census and linked with county and geographic clusters of screening.Main Outcomes and MeasuresSpatial autocorrelation analyses, including Global Moran I and bivariate local indicator of spatial autocorrelation, were conducted to assess geographic clustering of county-level cancer screening prevalence over time. A queen contiguity matrix defined neighboring counties, and permutation tests evaluated statistical significance.ResultsData from 3142 counties were assessed. Spatial analyses of mammography, Papanicolaou test, and colorectal cancer screening in the contiguous US from 1997 to 2019 revealed consistent geographic clustering, with high screening prevalence in the Northeast and lower prevalence in the Southwest. Spatial autocorrelation, measured by Global Moran I, declined over time. For example, the distribution of mammography screening became 83% more uniform in more recent years (eg, Moran I = 0.57 in 1997-1999 vs Moran I = 0.10 in 2017-2019). Similarly, Papanicolaou test screening became more uniform in more recent years (eg, Moran I = 0.44 in 1997-1999 vs Moran I = 0.07 in 2017-2019). Bivariate local indicator of spatial autocorrelation analyses identified clusters of persistently high and low screening, with sociodemographic characteristics associated with clusters that changed from low to high. For example, for both Papanicolaou test and mammography, areas that changed from low to high were more likely to be low socioeconomic status, suggesting improvements in disadvantaged areas in 2017 to 2019 vs 1997 to 1999. Disadvantaged areas were most likely to experienced persistently low screening, particularly for breast or colorectal cancer.Conclusion and RelevanceThese findings suggest that despite increasing screening overall, which led to reduced geographic variation in screening, local clusters of high and low screening persisted in the Northeast and Southwest US, respectively. Future studies could incorporate county-level health care access characteristics to explain why areas of low screening did not catch up to optimize cancer screening practices.

Disparities in Utilization of Uterine Fibroid Embolization

ImportanceUterine fibroid embolization (UFE) is a minimally invasive alternative to surgery. Understanding utilization patterns and disparities in access is important to ensure that patients can explore all treatment options.ObjectiveTo examine trends in the use of UFE vs hysterectomy and myomectomy for uterine fibroid management, with an emphasis on sociodemographic and institutional disparities.Design, Setting, and ParticipantsThis cross-sectional analysis used data from the 2016 to 2022 National Inpatient Sample obtained from the Healthcare Cost and Utilization Project, a population-based, multicenter inpatient dataset representing hospitals across the US. Adult patients with a diagnosis of uterine fibroids who underwent hysterectomy, myomectomy, or UFE were identified using International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes. Analysis was conducted in April 2025.ExposurePatient age, race, ethnicity, insurance, income quartile, rurality, year of procedure, and hospital characteristics.Main Outcomes and MeasuresThe primary outcome was undergoing UFE, modeled using multivariable logistic regression, with hysterectomy, myomectomy, or surgery overall as reference groups. The covariate reference categories were age younger than 30 years, White race, private insurance, 76th to 100th income percentile, central metropolitan residence, the year 2016, small hospitals, rural hospitals, and hospitals in the Pacific division. Results were reported as adjusted odds ratios (aORs) with 95% CIs.ResultsThe sample encompassed 271 885 encounters, including 199 625 hysterectomies (73.4%), 62 675 myomectomies (23.1%), and 9585 UFEs (3.5%). The median (IQR) patient age was 47 (43-52) years for those undergoing hysterectomy, 45 (40-49) years for those undergoing UFE, and 37 (33-41) years for those undergoing myomectomy. With regard to race and ethnicity, 105 780 patients (38.9%) were African American, 16 175 (5.9%) were Asian or Pacific Islander, 48 810 (18.0%) were Hispanic, 1050 (0.4%) were Native American, 86 425 were White (31.8%), and 13 645 (5.0%) were other races. Increasing age was associated with lower odds of undergoing UFE vs hysterectomy, and higher odds of undergoing UFE vs myomectomy. African American patients were more likely to undergo UFE than hysterectomy (aOR, 1.64; 95% CI, 1.44-1.87), but less likely to undergo UFE than myomectomy (aOR, 0.84; 95% CI, 0.73-0.97). Hispanic patients were less likely to undergo UFE than both surgical procedures (aOR, 0.83; 95% CI, 0.71-0.97). Patients with Medicaid (aOR, 1.58; 95% CI, 1.41-1.77), self-pay (aOR, 1.97; 95% CI, 1.60-2.42), and no-charge (aOR, 1.97; 95% CI, 1.24-3.12) coverage had higher odds of undergoing UFE vs both surgical procedures. Among Medicare patients, UFE was more likely than myomectomy among those aged 30 to 49 years, but less likely among those aged 50 years and older. Those in the lowest income quartile (0-25th percentile) had greater odds of undergoing UFE vs myomectomy (aOR, 1.22; 95% CI, 1.04-1.43). Rural patients were less likely to undergo UFE than hysterectomy (aOR, 0.53; 95% CI, 0.34-0.83), whereas urban hospitals were more likely to perform UFE than both surgical procedures (aOR, 7.13; 95% CI, 3.43-14.80).Conclusions and RelevanceIn this cross-sectional study, UFE was underutilized with significant disparities across socioeconomic factors. Further efforts are needed to equitably expand access to UFE across the country.

Disparities in Human Papillomavirus–Associated Cancer Incidence by Appalachian Residence

ImportancePoor socioeconomic conditions and corresponding health disparities have historically characterized the Appalachian region of the US. Low uptake of the human papillomavirus (HPV) vaccine and high rates of cervical cancer have been observed in the region; however, a comprehensive assessment of HPV-associated cancer in Appalachia has not been performed.ObjectiveTo compare the burden of HPV-associated cancer incidence between the Appalachian and non-Appalachian regions of the US.Design, Setting, and ParticipantsThis cross-sectional study of HPV-associated cancer incidence rates and trends used the US Cancer Statistics Incidence Analytic Database, covering 99% of the US population and 100% of the Appalachian region. Participants were individuals with an HPV-associated cancer diagnosis reported to a US cancer registry between January 1, 2004, and December 31, 2021. Human papillomavirus–associated cancers include squamous cell carcinomas of the oropharynx, anus, vulva, vagina or penis, or cervical carcinoma. Statistical analysis was performed in December 2024.ExposuresAge, sex, race and ethnicity, county of residence, urbanicity, and stage at diagnosis.Main Outcomes and MeasuresEstimated HPV-associated cancer incidence rates for 2017 to 2021 and annual incidence rate trends between 2004 and 2021. Calculated incidence rate ratios (IRRs) and differences in average annual percentage change by Appalachian residence. Additional comparisons were made between Appalachian regions.ResultsFrom 2017 to 2021, there were 23 649 cases of HPV-associated cancer diagnosed among Appalachian residents (12 929 females [54.7%]). The overall HPV-associated cancer incidence was 16% higher among Appalachian residents than non-Appalachian residents (IRR, 1.16; 95% CI, 1.14-1.18). Higher site-specific rates among Appalachian residents were noted for all HPV-associated cancer sites, except vaginal cancer and male anal cancer, with the greatest disparity occurring for vulvar cancer (IRR, 1.44; 95% CI, 1.38-1.51). Human papillomavirus–associated cancer incidence increased significantly faster in Appalachia vs non-Appalachia between 2004 and 2021 (average annual percentage change, 1.3% per year [95% CI, 1.0%-1.6% per year]; vs 0.7% per year [95% CI, 0.4%-1.0% per year]; P = .004), with the most marked trend difference occurring for penile cancer (2.1% faster per year in Appalachia; P = .003). Within Appalachia, the highest HPV-associated incidence rates per 100 000 persons were observed in the North Central (16.9 [95% CI, 16.2-17.6]) and Central (16.9 [95% CI, 16.1-17.7]) subregions.Conclusions and RelevanceThis cross-sectional study of HPV-associated cancer incidence found disproportionately high HPV-associated cancer rates among Appalachian residents compared with non-Appalachian residents. These findings highlight the need for targeted efforts to improve HPV vaccine uptake and encourage adherence to evidence-based screening guidelines for HPV-associated cancers in Appalachia.

Cervical Cancer Screening Rates Among Rural and Urban Females, From 2019 to 2022

ImportanceLittle nationally representative research has examined Papanicolaou testing rates from before the pandemic in 2019 through the COVID-19 pandemic in 2022. Papanicolaou testing rates among rural females are a concern as they have historically had lower screening rates than their urban counterparts.ObjectiveTo examine the receipt of a Papanicolaou test in the past year among US females overall and females residing in rural and urban areas in 2019, 2020, and 2022.Design, Setting, and ParticipantsThis repeated cross-sectional study used data from 3 years of the Health Information National Trends Survey (HINTS), a nationally representative survey that asks respondents about cancer screenings, sources of health information, and health and health care technologies. Study participants were females aged 21 to 65 years. Individuals who received a Papanicolaou test more than 1 to 3 years prior to a HINTS interview were excluded as they were likely not due for a Papanicolaou test.ExposuresSurvey year (2019, 2020, and 2022) and rural or urban residence were the main exposure variables.Main Outcomes and MeasuresSelf-reported receipt of a Papanicolaou test within the past year.ResultsAmong the 188 243 531 (weighted; 3706 unweighted) females included in the analysis, 12.5% lived in rural areas and 87.5% in urban areas. Participants had a mean (SE) age of 43.7 (0.27) years and were of Hispanic (18.8%), non-Hispanic Asian (5.2%), non-Hispanic Black (12.2%), non-Hispanic White (59.6%), or non-Hispanic other (4.1%) race and ethnicity. In 2022, unadjusted past-year Papanicolaou testing rates were significantly lower among rural vs urban residents (48.6% [95% CI, 39.2%-58.1%] vs 64.0% [95% CI, 60.0%-68.0%]; P &amp;amp;lt; .001). Adjusted odds of past-year Papanicolaou testing were lower in 2022 than 2019 (odds ratio, 0.70; 95% CI, 0.52-0.95; P = .02).Conclusions and RelevanceThis repeated cross-sectional study found that past-year Papanicolaou testing rates were lower in 2022 than 2019, pointing to a need to increase access to screenings to prevent an uptick in cervical cancer incidence. Rural-vs-urban differences in 2022 indicate a need to specifically target rural females.

Cervical Cancer Screening, HPV Vaccination, and Cervical Cancer Elimination

ImportanceTo accelerate cervical cancer elimination, it is essential to evaluate the combined impact of ongoing screening and human papillomavirus (HPV) vaccination efforts, as the disease remains a significant global public health concern.ObjectiveTo estimate how different cervical cancer screening strategies, along with HPV vaccination, affect the cervical cancer burden in South Korea.Design, Setting, and ParticipantsThis decision analytical model used a deterministic age-structured dynamic model to simulate HPV transmission and cervical cancer progression, considering sexual behavior and population structure, for the Korean population from 2024 to 2100. The study was conducted from April 2023 to September 2024.ExposuresCervical cancer screening using Papanicolaou (Pap) or HPV testing, with HPV vaccination.Main Outcomes and MeasuresThe cumulative number of incident cases of cervical cancer and deaths for the projected period are reported.ResultsThe study modeled more than 51 million Korean residents, with 25.88 million women (50.1%) and 10.05 million women aged 18 to 49 years. Among Pap test–based strategies, biennial screening for women aged 20 years and older was associated with the lowest number of cervical cancer cases (47 358) and deaths (34 242) by 2100, with as much as a 10% mortality reduction compared with other Pap test–based strategies. High-risk HPV (hrHPV) testing every 2 or 3 years was estimated to further reduce cases by as much as 27% and deaths by 13%. Depending on the screening strategy, cervical cancer elimination based on the World Health Organization definition (4 cases per 100 000 women) could occur as early as 2038 (with 2-year hrHPV testing starting at age 25 years or older) or as late as 2055 (5-year Pap testing for individuals aged 25 to 64 years). The current screening policy (Pap test every 2 years starting at age 20 years) was estimated to reach disease elimination by 2044. In an ideal scenario with 70% screening and 90% vaccination coverage from 2030, an additional 12% of cases and 7% of deaths could be prevented. Strategies using a 2-year interval for hrHPV testing could lead to the earliest cervical cancer elimination by 2034.Conclusions and RelevanceIn this decision analytical model, an ideal scenario with higher cervical cancer screening and HPV vaccination rates was associated with substantially reduced cervical cancer incidence and mortality and accelerated elimination in South Korea. Notably, hrHPV testing with 2- or 3-year screening intervals was estimated to achieve elimination as early as 2034.

Breast and Cervical Cancer Gaps in Displaced Lebanese Women in Syria

ImportanceBreast and cervical cancers are leading causes of cancer mortality in low-resource countries, yet awareness remains critically understudied among displaced populations in humanitarian crises. Lebanese women displaced to Syria represent a group navigating compounded vulnerabilities associated with conflict, displacement, and a collapsed health care system and may experience important gaps in cancer knowledge and access.ObjectiveTo evaluate knowledge of breast and cervical cancer risk factors and symptoms and screening for early cancer detection among displaced Lebanese women in Syria.Design, Setting, and ParticipantsThis cross-sectional study measured breast cancer, cervical cancer, and human papillomavirus (HPV) knowledge using a survey containing validated, Arabic-translated scales administered via structured interviews from November to December 2024. Lebanese women (aged ≥18 years) displaced to Syria and visiting outpatient health care facilities in Damascus were included. Women who were not Lebanese and with acute or severe physical or mental health conditions were excluded.ExposureBreast cancer and cervical cancer knowledge.Main Outcomes and MeasuresThe primary outcome was knowledge of cancer symptoms, risk factors, and screening practices. Analyses included Fisher exact test, Kruskal-Wallis test, Mann-Whitney U test, and Spearman rank correlation.ResultsAmong 378 displaced Lebanese women in Syria (median [IQR] age, 30 [23-39] years), 196 (51.9%) were married, 187 (49.5%) held a university degree, and 222 (58.7%) were unemployed. Only 85 participants (22.5%) had ever undergone breast imaging, 64 (16.9%) had undergone a Papanicolaou test, 274 (72.5%) rarely or never examined their breasts, and 135 (35.7%) ignored observed breast changes. Knowledge gaps were prominent, with 348 (92.1%) having a low awareness of HPV and only 4 (1.1%) correctly identifying age as an important risk factor for breast cancer. Higher educational attainment was significantly associated with improved screening rates and knowledge of breast and cervical cancer (χ23 = 11.661; P = .009), whereas financial status showed no association.Conclusions and RelevanceThese findings suggest that displaced women during humanitarian crises may face substantial breast and cervical cancer screening barriers, underscoring the need for crisis-responsive health care.

Diagnostic Timing and Ovarian Cancer Survival

Importance While earlier diagnosis improves outcomes for many cancers, studies report that earlier diagnosis does not improve ovarian cancer (OC) survival, discouraging investment in diagnostic improvements. One possible explanation is confounding due to the wait time paradox, in which patients with severe disease are diagnosed more quickly but have poorer outcomes, masking potential benefits of earlier diagnosis. Objective To visualize how nonlinear modeling of time to diagnosis alters observed associations with OC survival, with particular attention to the wait time paradox. Design, Setting, and Participants This cohort study used data from the North Carolina Central Cancer Registry with linked multipayer claims from Medicare, Medicaid, and private insurance. Participants included female patients diagnosed with OC from January 1, 2009, to December 31, 2019, in North Carolina. Follow-up was completed June 30, 2021. Data were analyzed from May 1, 2024, to November 1, 2025. Exposure Time to diagnosis, defined as the interval from the earliest symptom-related health care encounter to cancer diagnosis. Main Outcomes and Measures All-cause 5-year mortality. Results Among 2359 women included in the analysis (median age, 71 [IQR, 64-78] years), the median diagnostic interval was 33 (IQR, 10-149) days. Compared with all other quartiles, patients in the second-shortest quartile of the diagnostic interval were more likely to be diagnosed at localized (83 of 586 [14.2%] vs 180 of 1773 [10.2%]) or regional (134 of 586 [22.9%] vs 330 of 1773 [18.6%]) stages ( P  = .001) and had a median survival exceeding 5 years (lower 95% CI bound, 4.1 years), compared with median survivals of 2.5 years (95% CI, 2.0-3.1 years) in the shortest quartile and 2.9 years (95% CI, 2.5-3.8 years) in the longest quartile. When modeled using restricted cubic splines, the adjusted association between time to diagnosis and mortality was U-shaped; compared with a reference interval of 80 days, intervals of 10 and 360 days were associated with higher mortality (hazard ratios, 1.29 [95% CI, 1.09-1.53] and 1.13 [95% CI, 0.88-1.46], respectively). Conclusions and Relevance In this cohort study of patients with OC, very short diagnostic intervals were associated with poorer survival, consistent with residual confounding by the wait time paradox, while longer diagnostic intervals were also associated with worse outcomes. Conventional linear approaches may obscure this important confounding by severity in the association between diagnostic timing and survival, contributing to null findings in prior studies and potentially discouraging efforts to improve diagnosis of this difficult-to-detect disease.

Long-Term Survival in Patients With Low-Risk Cervical Cancer After Simple, Modified, or Radical Hysterectomy

ImportanceThree-year pelvic recurrence rate in women with low-risk cervical carcinoma was not inferior following simple hysterectomy (SH) vs modified radical hysterectomy (MRH) or radical hysterectomy (RH) in the Simple Hysterectomy and Pelvic Node Assessment randomized clinical trial, but the survival analysis of the trial was underpowered.ObjectiveTo evaluate long-term survival in low-risk cervical carcinoma following SH vs MRH or RH.Design, Setting, and ParticipantsThis cohort study included women undergoing SH, MRH or RH in US Commission on Cancer–accredited facilities participating in the National Cancer Database who received a diagnosis between January 2010 and December 2017 of International Federation of Gynecology and Obstetrics 2009 stage IA2 or IB1 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix (≤2 cm) and clinically negative lymph nodes.ExposureSH, MRH, or RH following diagnosis of stage IA2 or IB1 squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix.Main Outcomes and MeasuresSurvival was the primary end point, evaluated with and without propensity score balancing. Survival rates, survival distributions, adjusted hazard ratio (aHR) of death, and restricted mean survival times (RMST) were analyzed as of September 2024. Two multivariable models were fitted. Model 1 included the hysterectomy type and 9 baseline factors (age, comorbidity score, race and ethnicity, insurance status, treatment facility, stage, histologic subtype, tumor grade, and surgical approach). Model 2 included the model 1 variables plus 4 additional clinical factors (surgical margin, LVSI, pathologic LN metastasis, and adjuvant treatment).ResultsThis cohort study evaluated 2636 women (mean [SD] age, 45.4 [11.4] years; median [IQR] follow-up, 85 [64-110] months), including 982 with SH, 300 with MRH, 927 with traditional RH, and 427 with unspecified MRH or RH. Survival was similar following SH vs MRH or RH (7 year survival rate, 93.9%; 95% CI, 91.9%-95.4% vs 95.3%; 95% CI, 94.0%-96.3%%; P = .07) and SH vs MRH vs RH (7 year survival rate, 93.9%; 95% CI, 91.9%-95.4% vs 94.2%; 95% CI, 90.1%-96.7% vs 95.4%; 95% CI, 93.6%-96.6%; P = .15). Risk of death following either SH vs MRH or RH, SH vs RH, or MRH vs RH remained similar after adjusting for baseline covariates alone or baseline covariates plus clinical factors. Survival remained similar within subsets by age, comorbidity score, race and ethnicity, facility type, stage, histologic subtype, tumor grade, surgical approach, and year of diagnosis. Adjusted survival remained similar in patients with SH vs MRH or RH after propensity score balancing for baseline covariates (aHR, 1.19; 95% CI, 0.86-1.65; P = .31) with similar 3-year (98.3%; 95% CI, 97.2%-99.0% vs 97.6%; 95% CI, 96.6%-98.2%), 5-year (95.9%; 95% CI, 94.3%-97.1% vs 96.5%; 95% CI, 95.5%-97.3%), 7-year (94.5%; 95% CI, 92.5%-95.9% vs 95.1%; 95% CI, 93.7%-96.1%), and 10-year (89.8%; 95% CI, 86.3%-92.5% vs 91.7%; 95% CI, 89.4%-93.4%) survival rates. Sensitivity analysis for patients who received a diagnosis between 2010 and 2013 documented similar 10-year RMST following SH vs MRH or RH, SH vs RH, SH vs MRH, and MRH vs RH.Conclusions and RelevanceIn this cohort study, long-term survival was similar following SH vs MRH or RH, supporting the use of SH in select patients with low-risk early-stage cervical carcinoma.

Cost-Effectiveness of Pembrolizumab With Chemoradiotherapy for Locally Advanced Cervical Cancer

ImportanceThe KEYNOTE-A18 trial demonstrated that adding concurrent and adjuvant pembrolizumab to chemoradiotherapy and brachytherapy significantly improved survival in patients with newly diagnosed, locally advanced cervical cancer. However, considering the annual global incidence of 660 000 cases of cervical cancer, including 13 820 in the US in 2024, incorporating this regimen into the standard of care could have substantial health care economic implications for both patients and the health care system.ObjectiveTo determine the cost-effectiveness of adding pembrolizumab to the first-line treatment of newly diagnosed, locally advanced cervical cancer.Design, Setting, and ParticipantsThis economic evaluation created a Markov model simulating 50-year outcomes to evaluate cost-effectiveness from the payer perspective for patients receiving either pembrolizumab or placebo in addition to chemoradiotherapy plus brachytherapy. Probabilities, including disease progression, survival, and treatment-related toxic effects, were derived from KEYNOTE-A18 clinical trial data in patients with newly diagnosed, locally advanced cervical cancer. Costs and health utilities were obtained from published literature; 1-way, 3-way, and probabilistic sensitivity analyses were used to assess model uncertainty. Data analyses were conducted from April to November 2024.ExposurePembrolizumab.Main Outcomes and MeasuresCosts, measured in 2024 US dollars, and effectiveness, measured in quality-adjusted life-years (QALYs) were used to calculate an incremental cost-effectiveness ratio (ICER). A willingness-to-pay threshold of $100 000 per QALY was chosen, below which pembrolizumab would be considered cost-effective.ResultsKEYNOTE-A18 enrolled 1060 patients (529 in pembrolizumab group, 531 in placebo group). The median age was 50 years. Pembrolizumab increased costs by $257 000 and effectiveness by 1.40 QALYs, yielding an incremental cost-effectiveness ratio of $183 400 per QALY. The addition of pembrolizumab became cost-effective if its monthly cost was decreased from $16 990 to $9190 (a 45.6% reduction) or its maximum duration of 24 months was decreased to 10 months. The model was insensitive to assumptions about treatment-related toxic effects, progression-free survival, and overall survival. Probabilistic sensitivity analysis indicated that at a willingness-to-pay threshold of $100 000 per QALY, the addition of pembrolizumab was cost-effective 37.3% of the time.Conclusions and RelevanceIn this economic evaluation of adding concurrent and adjuvant pembrolizumab to first-line treatment of newly diagnosed, locally advanced cervical cancer, this regimen was not cost-effective at current prices despite data demonstrating improved survival with this regimen.

Transportation Insecurity, Social Support, and Adherence to Cancer Screening

ImportanceTransportation insecurity and lack of social support are 2 understudied social determinants of health that contribute to excess morbidity, mortality, and acute health care utilization. However, whether and how these social determinants of health are associated with cancer screening has not been determined and has implications for preventive care.ObjectiveTo determine whether transportation insecurity or social support are associated with screening adherence for colorectal, breast, and cervical cancer.Design, Setting, and ParticipantsThis cohort study used data from the publicly available 2018 in-person National Health Interview Survey (NHIS) comprising a noninstitutionalized, civilian adult population of the United States. Participants included adults eligible for colorectal, breast, or cervical cancer screening who participated in the in-depth NHIS interview (1 selected per household). Data were acquired in December 2023 and analyzed through July 31, 2024.ExposuresTransportation insecurity, represented dichotomously as adults who reported that they have or have not delayed medical care in the past year due to transportation difficulties, and neighborhood social support, represented as factor scores derived from 4 Likert-type questions.Main Outcomes and MeasuresThe primary outcome was adherence to the US Preventive Services Task Force screening recommendations in place during 2018 for colorectal, breast, and cervical cancer.ResultsIn 2018, of 25 417 NHIS respondents (55% female), 660 (3%) reported delaying medical care because they did not have transportation. In fully adjusted models, transportation insecurity was associated with adherence to breast cancer screening (odds ratio [OR], 0.59 [95% CI, 0.40-0.86]) but not to colorectal (OR, 0.87 [95% CI, 0.65-1.15]) or cervical (OR, 0.73 [95% CI, 0.46-1.13) cancer screening. Social support was associated with colorectal (OR, 1.12 [95% CI, 1.06-1.17]) and breast (OR, 1.13 [95% CI, 1.05-1.22]) cancer screening but not with cervical cancer screening (OR, 1.01 [95% CI, 0.93-1.10]). There were no significant interactions between transportation insecurity and social support for any cancer screening.Conclusions and RelevanceThe presence of transportation insecurity was associated with a 41% reduction in the odds of breast cancer screening. Clinicians should consider screening for transportation needs at the time of mammography referral, as patients may be eligible for programs that can assist with medical transportation needs.

Cost-Effectiveness of 9-Valent HPV Vaccination for Patients Treated for High-Grade Cervical Intraepithelial Neoplasia in the UK

ImportancePatients who have been treated for high-grade cervical intraepithelial neoplasia (CIN grade ≥2) are at a high risk for subsequent CIN and other cancers and diseases related to human papillomavirus (HPV). HPV vaccination can reduce the risk of subsequent disease in patients surgically treated for grade 2 or greater CIN; however, there is no formal recommendation for prophylactic HPV vaccination in this high-risk population, and the cost-effectiveness is unknown.ObjectiveTo assess the incremental lifetime outcomes, costs, and cost-effectiveness of integrating peritreatment 9-valent HPV (9vHPV) vaccination in combination with posttreatment surveillance for the prevention of cervical cancer and other HPV-attributable diseases in patients surgically treated for grade 2 or greater CIN vs posttreatment surveillance alone from a UK payer perspective.Design, Setting, and ParticipantsThis economic evaluation used 3 independent Markov model structures. Model inputs for vaccine efficacy, utilities, and costs were obtained from published sources, and cervical cancer screening data were obtained from the National Health Service Cervical Screening Program. Costs were adjusted to 2022 to 2023 reference years. Data were analyzed from October 2022 to September 2023.ExposurePeritreatment vaccination with 9vHPV in combination with posttreatment surveillance compared with posttreatment surveillance alone.Main Outcomes and MeasuresClinical outcomes included grade 1, 2, or 3 CIN; cervical cancer; vaginal cancer; vulvar cancer; anal cancer; head and neck cancer; genital warts; and recurrent respiratory papillomatosis. Incremental cost-effectiveness ratios (ICERs) using a willingness-to-pay threshold (WTP) of £20 000 (US $26 200) per quality-adjusted life-year (QALY) were estimated. Deterministic sensitivity analysis and probabilistic sensitivity analysis were performed.ResultsVaccination with 9vHPV in conjunction with posttreatment surveillance was cost-effective, with a favorable ICER of £13 789.07 (US $18 064.68) per QALY gained (ie, below the WTP of £20 000 per QALY) vs posttreatment surveillance alone. The resulting ICER was £52 358.01 (US $68 588.99) per HPV-related cancer averted and £64 090 (US $83 958.18) per HPV-related cancer death averted. The ICER was most sensitive to discount rate, incidence of HPV infection, vaccine price, and age at initial treatment for grade 2 or greater CIN. Results of the probabilistic sensitivity analysis showed peritreatment 9vHPV vaccination was cost-effective at the WTP recommended by the UK’s Joint Committee on Vaccination and Immunisation (90% of iterations &amp;amp;lt;£30 000 [US $39 300] per QALY) in 100% of iterations.Conclusions and RelevanceThese findings suggest that peritreatment prophylactic 9vHPV vaccination is a cost-effective option for preventing subsequent HPV-attributable diseases in patients surgically treated for grade 2 or greater CIN.

Human Papillomavirus Vaccination and Human Papillomavirus–Related Cancer Rates

ImportanceTo inform the design and implementation of targeted interventions to reduce the future burden of human papillomavirus (HPV)–related cancers in Texas, it is necessary to examine the county and health service region (HSR) levels of (1) the proportion of children and teenagers aged 9 to 17 years who initiated and were up to date for HPV vaccination series and (2) HPV-related cancer incidence rates (IRs).ObjectiveTo evaluate temporal trends and geospatial patterns of HPV vaccination initiation and up-to-date status as well as HPV-related cancer rates at county and HSR levels in Texas.Design, Setting, and ParticipantsThis population-based cross-sectional study used data from the Texas Immunization Registry, the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program database, and Texas Department of State Health Services annual population counts from 2006 to 2022. The analysis of HPV vaccination rates was conducted among children and teenagers aged 9 to 17 years; the analysis of HPV-related cancer rates was conducted among adults aged 20 years and older. Data were extracted between June and July 2023 and statistical analysis was performed from February to April 2024.Main Outcomes and MeasuresHPV vaccination initiation and up-to-date status rates and HPV-related cancer IR at county and HSR levels.ResultsA total of 32 270 243 children and teenagers (65.8% female individuals and 34.2% male individuals) and 22 490 105 individuals aged 20 years and older (50.7% female individuals and 49.3% male individuals) were included. The mean 2021 to 2022 county-level HPV vaccination series initiation estimates ranged from 6.3% to 69.1% for female and from 7.0% to 77.6% for male children and teenagers aged 9 to 17 years. County-level vaccination up-to-date estimates were generally lower compared with those of initiation estimates and ranged from 1.6% to 30.4% for female and from 2.1% to 34.8% for male children and teenagers. The pattern of HPV vaccination rates stratified by sex were similar across counties and HSRs. The age-adjusted annual HPV-related cancer IR by county for years 2016 to 2020 ranged from 0 to 154.2 per 100 000 for female individuals and from 0 to 60.1 per 100 000 for male individuals. The counties located in North Texas, HSRs 2/3 and 4/5N, had lower HPV vaccination rates and higher IRs of HPV-related cancers for both female and male individuals compared with other regions.Conclusions and RelevanceIn this study, the incidence of HPV-related cancers varied widely across the counties and HSRs of Texas. More counties in North Texas, HSRs 2/3 and 4/5N, had higher IRs of HPV-related cancers and a lower proportion of HPV vaccination rates than counties in other regions. Designing and implementing targeted interventions to increase uptake and completion of HPV vaccination series across counties with low HPV vaccination rates may help to reduce future the burden of HPV-related cancers.

Pathologist-Read vs AI-Driven Assessment of Tumor-Infiltrating Lymphocytes in Melanoma

Importance Tumor-infiltrating lymphocytes (TILs) are a provocative biomarker in melanoma, influencing diagnosis, prognosis, and immunotherapy outcomes; however, traditional pathologist-read TIL assessment on hematoxylin and eosin–stained slides is prone to interobserver variability, leading to inconsistent clinical decisions. Therefore, development of newer TIL scoring approaches that produce more reliable and consistent readouts is important. Objective To evaluate the analytical and clinical validity of a machine learning algorithm for TIL quantification in melanoma compared with traditional pathologist-read methods. Design, Setting, and Participants This multioperator, global, multi-institutional prognostic study compared TIL scoring reproducibility between traditional pathologist-read methods and an artificial intelligence (AI)-driven approach. The study was conducted using retrospective cohorts of patients with melanoma between January 2022 and June 2023 across 45 institutions, with tissue evaluated by participants from academic, clinical, and research institutions. Participants were selected to ensure diverse expertise and professional backgrounds. Main Outcomes and Measures Intraclass correlation coefficient (ICC) values were calculated for the manual and AI-assisted arms using log-transformed data. Kendall W values were calculated for Clark scores (brisk = 3, nonbrisk = 2, and sparse = 1). Reliabilities of ICC and W values were classified as moderate (0.40-0.60), good (0.61-0.80), or excellent (&amp;amp;gt;0.80). AI TIL measurements were dichotomized using the 16.6 and median cutoffs. Univariable and multivariable Cox regression analyses assessed the prognostic value of TIL scores adjusted for clinicopathologic variables. Results There were 111 patients with melanoma in the independent testing cohort (median [range] age at diagnosis, 61.0 [25.0-87.0] years; 56 [50.5%] male) who contributed melanoma whole tissue sections. A total of 98 participants evaluated TILs on 60 hematoxylin and eosin–stained melanoma tissue sections. All 40 participants in the manual arm were pathologists, while the AI-assisted arm included 11 pathologists and 47 nonpathologists (scientists). The AI algorithm demonstrated superior reproducibility, with ICCs higher than 0.90 for all machine learning TIL variables, significantly outperforming manual assessments (ICC, 0.61 for AI-derived stromal TILs vs Kendall W , 0.44 for manual Clark TIL scoring). AI-based TIL scores showed prognostic associations with patient outcomes (n = 111) using the median cutoff approach with a hazard ratio (HR) of 0.45 (95% CI, 0.26-0.80; P  = .005), and using the cutoff of 16.6, with an HR of 0.56 (95% CI, 0.32-0.98; P  = .04). Conclusions and Relevance In this prognostic study of TIL quantification in melanoma, the AI algorithm demonstrated superior reproducibility and prognostic associations compared with traditional methods. Although the retrospective nature of the cohorts limits demonstration of clinical utility, the publicly available dataset and open-source AI tool offer a foundation for future validation and integration into melanoma management.

Closing the Cervical Cancer Screening Gap—Reaching Sexual and Gender Diverse Populations

Time-Dependent Changes in Risk of Progression During Use of Bevacizumab for Ovarian Cancer

ImportanceAlthough bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown.ObjectiveTo investigate time-dependent changes in the outcomes of bevacizumab therapy.Design, Setting, and ParticipantsThis cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed.ExposuresBevacizumab treatment vs placebo or no treatment.Main Outcomes and MeasuresRestricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups.ResultsIn the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P &amp;amp;lt; .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P &amp;amp;lt; .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P &amp;amp;lt; .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P &amp;amp;lt; .001; after, 0.71; 95% CI, 0.56-0.90; P &amp;amp;lt; .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P &amp;amp;lt; .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image–based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination–associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression.Conclusions and RelevanceIn ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome.

Effect of Exercise on Chemotherapy-Induced Peripheral Neuropathy Among Patients Treated for Ovarian Cancer

ImportanceChemotherapy-induced peripheral neuropathy (CIPN), one of the most common and severe adverse effects of chemotherapy, is associated with worse quality of life among survivors of ovarian cancer. Currently, there is no effective treatment for CIPN.ObjectiveTo evaluate the effect of a 6-month aerobic exercise intervention vs attention-control on CIPN among women treated for ovarian cancer in the Women’s Activity and Lifestyle Study in Connecticut (WALC) to provide evidence to inform the guidelines and recommendations for prevention or treatment of CIPN.Design, Setting, and ParticipantsThis prespecified secondary analysis evaluated the Women’s Activity and Lifestyle Study in Connecticut (WALC), a multicentered, open-label, population-based, phase 3 randomized clinical trial of an aerobic exercise intervention vs attention control for CIPN in patients who were diagnosed with ovarian cancer. Only WALC participants who received chemotherapy were included in this analysis. Participants were randomized 1:1 to either a 6-month aerobic exercise intervention or to attention control. All analyses were conducted between September 2022 and January 2023.InterventionsThe exercise intervention consisted of home-based moderate-intensity aerobic exercise facilitated by weekly telephone counseling from an American College of Sports Medicine/American Cancer Society–certified cancer exercise trainer. Attention control involved weekly health education telephone calls from a WALC staff member.Main Outcomes and MeasureChange in CIPN was the primary outcome in this secondary analysis. This outcome was represented by CIPN severity, which was self-measured by participants at baseline and 6 months using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity scale, with a score range of 0 to 44. A mixed-effects model was used to assess the 6-month change in CIPN between the exercise intervention and attention control arms.ResultsOf the 134 participants (all females; mean [SD] age, 57.5 [8.3] years) included in the analysis, 69 were in the exercise intervention arm and 65 were in the attention control arm. The mean (SD) time since diagnosis was 1.7 (1.0) years. The mean (SD) baseline CIPN scores were 8.1 (5.6) in the exercise intervention arm and 8.8 (7.9) in the attention control arm (P = .56). At 6 months, the self-reported CIPN score was reduced by 1.3 (95% CI, −2.3 to −0.2) points in the exercise intervention arm compared with an increase of 0.4 (95% CI, −0.8 to 1.5) points in the attention control arm. The between-group difference was −1.6 (95% CI, −3.1 to −0.2) points. The point estimate was larger among the 127 patients with CIPN symptoms at enrollment (−2.0; 95% CI, −3.6 to −0.5 points).Conclusions and RelevanceFindings of this secondary analysis of the WALC trial indicate that a 6-month aerobic exercise intervention vs attention control significantly improved self-reported CIPN among patients who were treated for ovarian cancer. While replication of the findings in other studies is warranted, incorporating referrals to exercise programs into standard oncology care could reduce CIPN symptoms and increase quality of life in patients with ovarian cancer.Trial RegistrationClinicalTrials.gov Identifier: NCT02107066

Cervical Cancer Screening via Visual Inspection With Acetic Acid and Lugol Iodine for Triage of HPV-Positive Women

ImportanceLimited evidence supports the performance of human papillomavirus (HPV) DNA testing as a primary screening method, followed by triage with visual inspection with acetic acid, in areas with limited health care resources, as suggested by the 2021 World Health Organization guidelines.ObjectiveTo evaluate the performance of visual inspection with acetic acid and Lugol iodine as a triage method for detecting cervical precancerous lesions among HPV-positive women in 1 visit.Design, Setting, and ParticipantsThis cohort study examined the implementation of a government-led cervical cancer screening program conducted from January 1, 2016, to December 31, 2020, in Ordos City, China. Female residents, aged 35 to 64 years, who understood the screening procedures and voluntarily participated were included in the study. Women were excluded if they reported never having had sexual intercourse, were pregnant, had a hysterectomy, or had ever undergone treatment for cervical lesions. Statistical analysis was conducted from December 2022 to December 2023.ExposuresThe program used the careHPV DNA assay as the primary screening method, and immediate triage was performed by visual inspection if HPV screening results were positive, with a 5-year screening interval. A colposcopy was performed for the women who had suspected cancer on visual inspection results or who were HPV positive and had abnormal visual inspection results, all in 1 visit.Main Outcomes and MeasuresThe rate of compliance with colposcopy and the detection rate of cervical intraepithelial neoplasia grade 2 or higher (CIN2+).ResultsThe study included 187 863 women (median age, 46 years [IQR, 40-52 years]) who participated in the program and had valid HPV test results. The overall prevalence of HPV positivity was 12.8% (24 070 of 187 863), and the adherence to triage with visual inspection among HPV-positive women was 93.9% (22 592 of 24 070). Among HPV-positive women, the rate of compliance with colposcopy was 65.6% (2714 of 4137), and the CIN2+ detection rate was 2.8% (643 of 22 592).Conclusions and RelevanceThe findings of this cohort study suggest that the implementation of HPV testing, visual inspection, and colposcopy within 1 visit may mitigate losses to follow-up, detect precancerous lesions, and hold significant implications for screening in comparable areas with limited health care resources.

Diagnostic Performance of Ultrasonography-Based Risk Models in Differentiating Between Benign and Malignant Ovarian Tumors in a US Cohort

ImportanceUltrasonography-based risk models can help nonexpert clinicians evaluate adnexal lesions and reduce surgical interventions for benign tumors. Yet, these models have limited uptake in the US, and studies comparing their diagnostic accuracy are lacking.ObjectiveTo evaluate, in a US cohort, the diagnostic performance of 3 ultrasonography-based risk models for differentiating between benign and malignant adnexal lesions: International Ovarian Tumor Analysis (IOTA) Simple Rules with inconclusive cases reclassified as malignant or reevaluated by an expert, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX), and Ovarian-Adnexal Reporting and Data System (O-RADS).Design, Setting, and ParticipantsThis retrospective diagnostic study was conducted at a single US academic medical center and included consecutive patients aged 18 to 89 years with adnexal masses that were managed surgically or conservatively between January 2017 and October 2022.ExposureEvaluation of adnexal lesions using the Simple Rules, ADNEX, and O-RADS.Main Outcomes and MeasuresThe main outcome was diagnostic performance, including area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. Surgery or follow-up were reference standards. Secondary analyses evaluated the models’ performances stratified by menopause status and race.ResultsThe cohort included 511 female patients with a 15.9% malignant tumor prevalence (81 patients). Mean (SD) ages of patients with benign and malignant adnexal lesions were 44.1 (14.4) and 52.5 (15.2) years, respectively, and 200 (39.1%) were postmenopausal. In the ROC analysis, the AUCs for discriminative performance of the ADNEX and O-RADS models were 0.96 (95% CI, 0.93-0.98) and 0.92 (95% CI, 0.90-0.95), respectively. After converting the ADNEX continuous individualized risk into the discrete ordinal categories of O-RADS, the ADNEX performance was reduced to an AUC of 0.93 (95% CI, 0.90-0.96), which was similar to that for O-RADS. The Simple Rules combined with expert reevaluation had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 91.9% specificity (95% CI, 88.9%-94.3%), and the Simple Rules combined with malignant classification had 93.8% sensitivity (95% CI, 86.2%-98.0%) and 88.1% specificity (95% CI, 84.7%-91.0%). At a 10% risk threshold, ADNEX had 91.4% sensitivity (95% CI, 83.0%-96.5%) and 86.3% specificity (95% CI, 82.7%-89.4%) and O-RADS had 98.8% sensitivity (95% CI, 93.3%-100%) and 74.4% specificity (95% CI, 70.0%-78.5%). The specificities of all models were significantly lower in the postmenopausal group. Subgroup analysis revealed high performances independent of race.Conclusions and RelevanceIn this diagnostic study of a US cohort, the Simple Rules, ADNEX, and O-RADS models performed well in differentiating between benign and malignant adnexal lesions; this outcome has been previously reported primarily in European populations. Risk stratification models can lead to more accurate and consistent evaluations of adnexal masses, especially when used by nonexpert clinicians, and may reduce unnecessary surgeries.

Analysis of Body Mass Index in Early and Middle Adulthood and Estimated Risk of Gastrointestinal Cancer

ImportanceIn a population with significantly increasing rates of individuals with overweight or obesity, understanding the association of obesity with long-term disease risk, such as cancer, is necessary to improve public health.ObjectiveTo investigate the association between body mass index (BMI) and gastrointestinal (GI) cancer risk (colorectal cancer [CRC] and noncolorectal GI cancer) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.Design, Setting, and ParticipantsThis retrospective cohort study was a secondary analysis of data from the PLCO Cancer Screening Trial. Participants aged 55 to 74 years were enrolled and randomized to the intervention (screening group) or control group at 10 screening centers between November 8, 1993, and July 2, 2001. The initial analysis of PLCO Cancer Screening Trial data occurred after 13 years of follow-up or December 31, 2009, whichever came first. Participants were reconsented in 2011 and either continued follow-up or refused additional follow-up. For those who reconsented, follow-up for incident cancers continued until December 31, 2014, or death, whichever occurred first. Data analysis for this secondary analysis was performed from April 2022 through November 2022.ExposuresBody mass index and aspirin use, defined as the frequency of use of aspirin or aspirin-containing substances in the last 12 months.Main Outcomes and MeasuresThe primary outcomes were the diagnoses of CRC and noncolorectal GI cancer. The association between BMI and cancer (CRC and noncolorectal GI cancer) was assessed using Cox proportional hazards regression modeling. The association between cancer risk and change in BMI was further analyzed at different ages, and an exploratory analysis was performed to evaluate GI cancer risk among aspirin users.ResultsThis analysis included 135 161 participants (median [range] age, 62 [55-78] years; 67 643 [50.0%] female). Overweight BMI in early adulthood (hazard ratio [HR], 1.23; 95% CI, 1.10-1.37) and overweight BMI in middle adulthood (HR, 1.23; 95% CI, 1.13-1.34) and later adulthood (HR, 1.21; 95% CI, 1.10-1.32) as well as obese BMI in middle adulthood (HR, 1.55; 95% CI, 1.38-1.75) and later adulthood (HR, 1.39; 95% CI, 1.25-1.54) were associated with increased risk of CRC. Similar results were observed for the association with overall GI and non-CRC GI risk and BMI in middle and later adulthood. Maintaining overweight or obese BMI or increasing BMI to overweight or obese in later adulthood was also associated with increased CRC risk. Aspirin use 3 or more times per week did not significantly modify this association.Conclusions and RelevanceIn this secondary analysis of the PLCO Cancer Screening Trial, overweight and obese BMI in early and middle adulthood was associated with an elevated risk of CRC and noncolorectal GI cancers. The results of the current study prompt further exploration into the mechanistic role of obese BMI in carcinogenesis.

Factor Analysis of Health Care Access With Ovarian Cancer Surgery and Gynecologic Oncologist Consultation

ImportancePoor health care access (HCA) is associated with racial and ethnic disparities in ovarian cancer (OC) survival.ObjectiveTo generate composite scores representing health care affordability, availability, and accessibility via factor analysis and to evaluate the association between each score and key indicators of guideline-adherent care.Design, Setting, and ParticipantsThis retrospective cohort study used data from patients with OC diagnosed between 2008 and 2015 in the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The SEER Medicare database uses cancer registry data and linked Medicare claims from 12 US states. Included patients were Hispanic, non-Hispanic Black, and non-Hispanic White individuals aged 65 years or older diagnosed from 2008 to 2015 with first or second primary OC of any histologic type (International Classification of Diseases for Oncology, 3rd Edition [ICD-O-3] code C569). Data were analyzed from June 2020 to June 2022.ExposuresThe SEER-Medicare data set was linked with publicly available data sets to obtain 35 variables representing health care affordability, availability, and accessibility. A composite score was created for each dimension using confirmatory factor analysis followed by a promax (oblique) rotation on multiple component variables.Main Outcomes and MeasuresThe main outcomes were consultation with a gynecologic oncologist for OC and receipt of OC-related surgery in the 2 months prior to or 6 months after diagnosis.ResultsThe cohort included 8987 patients, with a mean (SD) age of 76.8 (7.3) years and 612 Black patients (6.8%), 553 Hispanic patients (6.2%), and 7822 White patients (87.0%). Black patients (adjusted odds ratio [aOR], 0.75; 95% CI, 0.62-0.91) and Hispanic patients (aOR, 0.81; 95% CI, 0.67-0.99) were less likely to consult a gynecologic oncologist compared with White patients, and Black patients were less likely to receive surgery after adjusting for demographic and clinical characteristics (aOR, 0.76; 95% CI, 0.62-0.94). HCA availability and affordability were each associated with gynecologic oncologist consultation (availability: aOR, 1.16; 95% CI, 1.09-1.24; affordability: aOR, 1.13; 95% CI, 1.07-1.20), while affordability was associated with receipt of OC surgery (aOR, 1.08; 95% CI, 1.01-1.15). In models mutually adjusted for availability, affordability, and accessibility, Black patients remained less likely to consult a gynecologic oncologist (aOR, 0.80; 95% CI, 0.66-0.97) and receive surgery (aOR, 0.80; 95% CI, 0.65-0.99).Conclusions and RelevanceIn this cohort study of Hispanic, non-Hispanic Black, and non-Hispanic White patients with OC, HCA affordability and availability were significantly associated with receiving surgery and consulting a gynecologic oncologist. However, these dimensions did not fully explain racial and ethnic disparities.

Utilization of Primary Cytoreductive Surgery for Advanced-Stage Ovarian Cancer

This cohort study examines changes in surgical approach for patients with stage III and IV epithelial ovarian cancer from 2010 to 2021.

Biomarker Testing Approaches, Treatment Selection, and Cost of Care Among Adults With Advanced Cancer

ImportanceClinical guidelines recommend biomarker testing to identify patients eligible for targeted therapy. However, evidence suggests that biomarker testing rates are below guideline recommendations, which has been associated with worsened clinical outcomes, including overall survival.ObjectivesTo identify patients with newly diagnosed advanced cancer receiving comprehensive genomic profiling (CGP), non-CGP, or no biomarker testing and to explore the change in rates of testing over time and compare targeted therapy rates and health care costs during first-line therapy.Design, Setting, and ParticipantsThis retrospective cohort study used the deidentified Optum Labs Data Warehouse, a claims database of longitudinal health information on commercial health plan and Medicare Advantage enrollees, to identify patients diagnosed with advanced cancer between January 1, 2018, and January 1, 2022. The study included 26 311 adults with newly diagnosed advanced cancer (breast, colorectal, gastric, non–small cell lung, ovarian, and pancreatic) and continuous enrollment in a commercial or Medicare Advantage health plan for 12 months before and 6 months after their first advanced cancer diagnosis. Data were analyzed between February 1, 2023, and March 31, 2024.ExposureBiomarker testing.Main Outcomes and MeasuresEvidence of biomarker testing, the receipt of targeted therapy during first-line therapy, and per-patient, per-month (PPPM) costs during first-line therapy.ResultsAmong 26 311 patients (mean [SD] age, 68 [11] years; 62% female; 70% Medicare Advantage enrollees), molecular testing rates were suboptimal (35% had evidence of molecular testing), but testing rates increased across time for most cancer types (from 32% in 2018 to 39% in 2021-2022). Patients with non–small cell lung cancer and colorectal cancer with CGP testing were more likely to receive targeted therapy (odds ratio [OR], 1.57; 95% CI, 1.31-1.90; P &amp;amp;lt; .001) compared with patients who received non-CGP testing (OR, 2.34; 95% CI, 1.58-3.47; P &amp;amp;lt; .001). Costs among patients with CGP testing were not statistically different from those with non-CGP testing (cost ratios of 1.03; 95% CI, 0.91-1.17 [P = .63] for breast cancer, 0.98; 95% CI, 0.89-1.09 [P = .71] for colorectal cancer, 1.10; 95% CI, 0.87-1.40 [P = .42] for gastric cancer, 1.06; 95% CI, 1.00-1.13 [P = .054] for non–small cell lung, 0.94; 95% CI, 0.76-1.15 [P = .55] for ovarian cancer, and 1.00; 95% CI, 0.83-1.21 [P = .98] for pancreatic cancer).Conclusions and RelevanceIn this cohort study, although increasing over time, biomarker testing rates were suboptimal despite guideline recommendations and increasing insurance coverage for testing. Given the potential benefits of CGP testing, such as increasing rates of targeted therapy without increased treatment-related costs, increasing CGP testing may improve outcomes.

Association of Prediagnostic Frailty, Change in Frailty Status, and Mortality After Cancer Diagnosis in the Women’s Health Initiative

Understanding changes in frailty in relation to cancer diagnosis can inform optimal selection of cancer treatments and survivorship care. To investigate associations of prediagnostic frailty and change in frailty status with mortality after a cancer diagnosis. This multicenter, prospective cohort study included 7257 community-dwelling, postmenopausal women in the United States who had frailty assessed at the Women's Health Initiative (WHI) enrollment (1993-1998) and the 3-year visit who were subsequently diagnosed as having invasive cancer. The data were analyzed from January 7, 2019, to June, 8, 2020. Frailty scores were defined from validated questionnaire items conceptually aligned with the Fried frailty phenotype, including at least 3 of the following characteristics: self-reported unintentional weight loss, exhaustion, low physical activity, and muscle weakness or impaired walking. Physical function components of the frailty score were updated a median of 10 (range, 1-18) times. Using multivariable-adjusted Cox proportional hazards models, this study examined associations of prediagnostic frailty (at the 3-year visit, before cancer diagnosis) and prediagnostic changes in frailty (from enrollment to the 3-year visit) with mortality. Women were followed up beginning from cancer diagnosis for mortality outcomes through March 2018. In linear mixed-effects models with frailty scores as a function of time since cancer diagnosis, this study evaluated whether the time slope, ie, the rate of change in frailty score, increased after cancer diagnosis. This study included 7257 women in the WHI cohort who completed frailty assessments at enrollment and the 3-year WHI visit before cancer diagnosis and subsequently developed cancer. Cancer cases included 2644 breast cancers (36%), 822 lung cancers (11%), 691 colorectal cancers (10%), 445 endometrial cancers (6%), and 286 ovarian cancers (4%). At the 3-year visit, prior to cancer diagnosis, the mean (SD) age was 63 (7) years, and 1161 of 7257 (16%) of participating women met criteria for frailty; 2129 of 7257 (29%) were prefrail, and 3967 of 7257 (55%) were nonfrail. Over a median follow-up of 5.8 years after cancer diagnosis (range, 1 day to 19.9 years), 3056 women died. After multivariable adjustment, women who were frail (vs nonfrail) before cancer diagnosis had an increased risk of mortality after cancer diagnosis (hazard ratio [HR], 1.40; 95% CI, 1.26-1.55; P for trend <.001). Sustained frailty (21% [1537 of 7257] of women) or worsening frailty (22% [1578 of 7257]) vs being consistently nonfrail (45% [3266 of 7257]) before cancer diagnosis increased the risk of mortality after cancer diagnosis (HR, 1.25; 95% CI, 1.14-1.38 and 1.22; 95% CI, 1.11-1.34, respectively; P for trend <.001). In linear mixed-effects models, the rate of increase in physical frailty over time was statistically significantly higher after cancer diagnosis. Sustained and worsening frailty before cancer diagnosis was associated with an increased risk of mortality after cancer diagnosis in postmenopausal women. Furthermore, the rate of decline in physical function accelerated after cancer diagnosis. Frailty assessment could provide valuable information and perhaps prompt interventions to reduce and preempt worsening of physical frailty after cancer diagnosis.

County-Level Trends in Cervical Cancer Incidence, Stage at Diagnosis, and Mortality in Kentucky

This cross-sectional study evaluates recent trends in rates of cervical cancer incidence and incidence-based mortality among women in Appalachian and non-Appalachian Kentucky counties.

Use of Virus Genotypes in Machine Learning Diagnostic Prediction Models for Cervical Cancer in Women With High-Risk Human Papillomavirus Infection

ImportanceHigh-risk human papillomavirus (hrHPV) is recognized as an etiologic agent for cervical cancer, and hrHPV DNA testing is recommended as the preferred method of cervical cancer screening in recent World Health Organization guidelines. Cervical cancer prediction models may be useful for screening and monitoring, particularly in low-resource settings with unavailable cytological and colposcopic examination results, but previous studies did not include women infected with hrHPV.ObjectivesTo develop and validate a cervical cancer prediction model that includes women positive for hrHPV infection and examine whether the inclusion of HPV genotypes improves the cervical cancer prediction ability.Design, Setting, and ParticipantsThis diagnostic study included diagnostic data from 314 587 women collected from 136 primary care centers in China between January 15, 2017, and February 28, 2018. The data set was separated geographically into data from 100 primary care centers in 6 districts for model development (training data set) and 36 centers in 3 districts for model validation. A total of 24 391 women identified with positive hrHPV test results in the cervical cancer screening program were included in the study. Data were analyzed from January 1, 2022, to July 14, 2022.Main Outcomes and MeasuresCervical intraepithelial neoplasia grade 3 or worse (CIN3+) was the primary outcome, and cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was the secondary outcome. The ability of the prediction models to discriminate CIN3+ and CIN2+ was evaluated using the area under the receiver operating characteristic curve (AUROC), sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio. The calibration and clinical utility of the models were assessed using calibration plots and decision curves, respectively.ResultsAfter excluding women without screening outcomes, the study included 21 720 women (median [IQR] age, 50 [44-55] years). Of 14 553 women in the training data set, 349 (2.4%) received a diagnosis of CIN3+ and 673 (4.6%) of CIN2+. Of 7167 women in the validation set, 167 (2.3%) received a diagnosis of CIN3+ and 228 (3.2%) of CIN2+. Including HPV genotype in the model improved the AUROC by 35.9% for CIN3+ and 41.7% for CIN2+. With HPV genotype, epidemiological factors, and pelvic examination as predictors, the stacking model had an AUROC of 0.87 (95% CI, 0.84-0.90) for predicting CIN3+. The sensitivity was 80.1%, specificity was 83.4%, positive likelihood ratio was 4.83, and negative likelihood ratio was 0.24. The model for predicting CIN2+ had an AUROC of 0.85 (95% CI, 0.82-0.88), with a sensitivity of 80.4%, specificity of 81.0%, positive likelihood ratio of 4.23, and negative likelihood ratio of 0.24. The decision curve analysis indicated that the stacking model provided a superior standardized net benefit when the threshold probability for clinical decision was lower than 23% for CIN3+ and lower than 17% for CIN2+.Conclusions and RelevanceThis diagnostic study found that inclusion of HPV genotypes markedly improved the ability of a stacking model to predict cervical cancer among women who tested positive for hrHPV infection. This prediction model may be an important tool for screening and monitoring cervical cancer, particularly in low-resource settings.

Cervical Cancer Screening in Women With Physical Disabilities

ImportanceCervical cancer screening is a crucial public health intervention, but screening disparities exist for women with physical disabilities (WWPD).ObjectiveTo explore the experiences of WWPD with both traditional speculum examination–based screening and at-home self-sampling for cervical cancer screening.Design, Setting, and ParticipantsThis qualitative study enrolled 56 WWPD to test self-sampling kits, provide feedback via a survey, and participate in a qualitative interview. An interprofessional team conducted semistructured interviews with 16 key informants and 40 pilot participants for 56 WWPD from November 1, 2021, through April 30, 2023. All completed a self-administered quantitative survey. Key informants’ experiences with 4 self-sampling devices helped determine which 2 self-sampling kits would be offered to participants in a pilot study.Main Outcomes and MeasuresA coding scheme was developed to represent inductive codes generated through preliminary coding and deductive codes representing domains from the Theoretical Domains Framework. This coding scheme was used to conduct a 2-pass thematic analysis.ResultsOf the 56 WWPD (mean [SD] age, 45.4 [9.1] years) who participated in the study, 28 (50.0%) were up to date with cervical cancer screening. Participants described accessibility barriers and clinician ableism that made speculum-based in-office examinations difficult, leading some participants to delay or avoid screening. In contrast, participants described self-screening as more comfortable and convenient, regardless of whether they prefer future speculum-based screening. Their responses also allowed for the exploration of how screening preferences may impact future screening behavior.Conclusions and RelevanceInterviews with WWPD suggested that access to self-sampling screening options would be more comfortable for cervical cancer screening participation. Understanding participants’ experiences with self-sampling devices generates insights into improving screening experiences for WWPD.

Cost-effectiveness of Maintenance Therapy Based on Molecular Classification Following Treatment of Primary Epithelial Ovarian Cancer in the United States

There are large randomized clinical trials-SOLO-1 (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy [December 2018]), PRIMA (A Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy [September 2019]), and PAOLA-1 (Platine, Avastin and Olaparib in 1st Line [December 2019])-reporting positive efficacy results for maintenance regimens for women with primary, advanced epithelial ovarian cancer. The findings resulted in approval by the US Food and Drug Administration of the treatments studied as of May 2020. However, there are pressing economic considerations given the many eligible patients and substantial associated costs. To evaluate the cost-effectiveness of maintenance strategies for patients with (1) a BRCA variant, (2) homologous recombination deficiency without a BRCA variant, or (3) homologous recombination proficiency. In this economic evaluation of the US health care sector using simulated patients with primary epithelial ovarian cancer, 3 decision trees were developed, one for each molecular signature. The maintenance strategies evaluated were olaparib (SOLO-1), olaparib-bevacizumab (PAOLA-1), bevacizumab (PAOLA-1), and niraparib (PRIMA). Base case 1 assessed olaparib, olaparib-bevacizumab, bevacizumab, and niraparib vs observation of a patient with a BRCA variant. Base case 2 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination deficiency without a BRCA variant. Base case 3 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination proficiency. The time horizon was 24 months. Costs were estimated from Medicare claims, wholesale acquisition prices, and published sources. Probabilistic sensitivity analyses with microsimulation were then conducted to account for uncertainty and assess model stability. One-way sensitivity analyses were also performed. The study was performed from January through June 2020. Incremental cost-effectiveness ratios (ICERs) in US dollars per progression-free life-year saved (PF-LYS). Assuming a willingness-to-pay threshold of $100 000/PF-LYS, none of the drugs could be considered cost-effective compared with observation. In the case of a patient with a BRCA variant, olaparib was the most cost-effective (ICER, $186 777/PF-LYS). The third-party payer price per month of olaparib would need to be reduced from approximately $17 000 to $9000 to be considered cost-effective. Olaparib-bevacizumab was the most cost-effective in the case of a patient with homologous recombination deficiency without a BRCA variant (ICER, $629 347/PF-LYS), and bevacizumab was the most cost-effective in the case of patient with homologous recombination proficiency (ICER, $557 865/PF-LYS). Even at a price of $0 per month, niraparib could not be considered cost-effective as a maintenance strategy for patients with homologous recombination proficiency. The findings of this study suggest that, at current costs, maintenance therapy for primary ovarian cancer is not cost-effective, regardless of molecular signature. For certain therapies, lowering the drug price alone may not make them cost-effective.

Are We Ready for Hyperthermic Intraperitoneal Chemotherapy in the Upfront Treatment of Ovarian Cancer?

Detection of TP53 Clonal Variants in Papanicolaou Test Samples Collected up to 6 Years Prior to High-Grade Serous Epithelial Ovarian Cancer Diagnosis

The low 5-year survival rate of women with high-grade serous epithelial ovarian cancer (HGS-EOC) is related to its late diagnosis; thus, improvement in diagnosis constitutes a crucial step to increase the curability of this disease. To determine whether the presence of the clonal pathogenic TP53 variant detected in matched primary tumor biopsies can be identified in DNA purified from Papanicolaou test samples collected from women with HGS-EOC years before the diagnosis. This cohort study was conducted among a single-center cohort of women with histologically confirmed diagnosis of HGS-EOC recruited at San Gerardo Hospital, Monza, Italy, from October 15, 2015, to January 4, 2019. Serial dilutions of DNA derived from tumor samples and DNA extracted from healthy women's Papanicolaou test samples were analyzed to define the sensitivity and specificity of droplet digital polymerase chain reaction assays designed to detect the TP53 variants identified in tumors. All available brush-based Papanicolaou test slides performed up to 6 years before diagnosis were investigated at the Mario Negri Institute, Milano, Italy. Data were analyzed from October 2018 to December 2019. The presence of tumor pathogenic TP53 variants was assessed by the droplet digital polymerase chain reaction approach in DNA purified from Papanicolaou test samples obtained from the same patients before diagnosis during cervical cancer screenings. Among 17 included patients (median [interquartile range] age at diagnosis, 60 [53-69] years), Papanicolaou tests withdrawn before diagnosis presented tumor-matched TP53 variants in 11 patients (64%). In 2 patients for whom longitudinal Papanicolaou tests were available, including 1 patient with Papanicolaou tests from 25 and 49 months before diagnosis and 1 patient with Papanicolaou tests from 27 and 68 months before diagnosis, the TP53 clonal variant was detected at all time points. These findings suggest that noninvasive early molecular diagnosis of HGS-EOC is potentially achievable through detection of TP53 clonal variants in the DNA purified from Papanicolaou tests performed during cervical cancer screening.

Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History

Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening. To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care. This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019. Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist. Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome. Among 49 738 participants (mean [SD] age, 57 [8] years; 27 144 female [55%]), 441 (0.9%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3%) for familial hypercholesterolemia, 235 (0.5%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4%) vs 4663 of 49 607 noncarriers (9.4%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6%) vs 2080 of 27 028 female noncarriers (7.7%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4%) vs 929 of 49 662 noncarriers (1.9%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3% for carriers of familial hypercholesterolemia, 41.1% for hereditary breast and ovarian cancer syndrome, and 38.3% for Lynch syndrome. Across the 3 conditions, 39.7% (175 of 441) of the carriers reported a family history of disease vs 23.2% (34 517 of 148 772) of noncarriers. The findings suggest that approximately 1% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.

Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer

The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R2) model. Criteria for PFS surrogacy required R2 ≥ 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external validation, 14 of the 16 hazard ratios for OS in the published reports fell within the 95% prediction interval from PFS. This large meta-analysis of individual patient data did not establish PFS as a surrogate end point for OS in first-line treatment of advanced ovarian cancer, but the analysis was limited by the narrow range of treatment effects observed or by poststudy treatment. These results suggest that if PFS is chosen as a primary end point, OS must be measured as a secondary end point.

Female Reproductive Cancers and the Sex Gap in Survival

IMPORTANCE On average, females live longer than males. Research on sex differences in longevity has traditionally focused on higher mortality among males; however, the contribution of female reproductive cancers to survival gaps between females and males remains insufficiently quantified. OBJECTIVE To assess the female-to-male survival gaps by estimating the contribution of age, birth cohort, and cause of death to sex differences in survival, with a particular emphasis on female reproductive cancers—breast and gynecological cancers—in long-term longevity disparities. DESIGN, SETTING, AND PARTICIPANTS This cohort study used population-level mortality data from 20 countries with complete records from 1955 to 2020 from the Human Mortality and World Health Organization Mortality Databases. Data were analyzed from January 2023 to September 2025. EXPOSURE Geographic location (Australia, Austria, Belgium, Canada, Denmark, Finland, France, Hungary, Ireland, Italy, Japan, the Netherlands, New Zealand, Norway, Portugal, Spain, Sweden, Switzerland, the UK, and the US). MAIN OUTCOME AND MEASURES The primary outcome was the truncated cross-sectional average length of life (TCAL), which incorporates historical mortality information for all birth cohorts alive at a given time. For each country, the sex gap in survival—measured as the difference in TCAL between females and males—was calculated, decomposed, and presented graphically by birth cohort, age, and calendar year. RESULTS The analysis encompassed 264.4 million deaths from all causes (119.1 million female [45.1%]; 145.2 million male [54.9%]), including 11.5 million deaths from female reproductive cancers. The sex gap in TCALs ranged from 8.31 (95% CI, 8.28-8.34) years in Hungary to 4.22 (95% CI, 4.20-4.25) years in the Netherlands. Across all countries, females had a survival advantage for major causes of death, except for neoplasms at reproductive ages. In most populations, females aged between 35 and 60 years experienced a consistent cross-cohort excess in cancer mortality compared with males, mainly due to breast cancer and, to a lesser extent, gynecological cancers. Eliminating female reproductive cancers would increase the survival of females and expand the sex gap in TCALs by an estimated mean of 0.77 (95% CI, 0.75-0.78) years, ranging from 0.96 (95% CI, 0.92-1.00) years in Ireland to 0.51 (95% CI, 0.50-0.52) years in Japan. CONCLUSIONS AND RELEVANCE In this population-level cohort study of 20 low-mortality countries, females aged 35 to 60 years experienced disadvantage in cancer mortality compared with males—a consistent pattern observed across birth cohorts and over time. These findings underscore the ongoing need for action on the prevention, early detection, and treatment of early-onset female reproductive cancers.

Cervical Cancer Screening Among Medicaid Patients During Natural Disasters and the COVID-19 Pandemic in Puerto Rico, 2016 to 2020

This cohort study examines rates of cervical cancer screening in Puerto Rico among women with Medicaid health coverage following the 2017 hurricanes, earthquakes in late 2019-2020, and the 2020 COVID-19 lockdown.

Resignation in Working Women With Breast and Gynecologic Cancers

ImportanceDiagnosis of breast and gynecologic cancers may hamper employment; little is known about who is at greater risk of resignation.ObjectiveTo examine whether a breast or gynecologic cancer diagnosis is associated with resignation in working women and to identify high-risk subpopulations.Design, Setting, and ParticipantsThis matched cohort study included women aged 15 to 58 years insured by the Japan Health Insurance Association. From April 2017 to March 2023, women newly diagnosed with breast, cervical, uterine, or ovarian cancer were identified and matched in a 1:10 ratio to working women without these cancers.ExposureCancer diagnosis was based on International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10).Main Outcomes and MeasuresThe primary outcome was all-cause resignation, and the secondary outcome was a composite of resignation and death, both assessed during a 2-year follow-up. Stratified Cox proportional-hazards models were applied, with multiple imputation and covariate adjustments. Subgroup analyses by prespecified covariates assessed effect size moderation and interactions between exposure and these covariates.ResultsThe study included 99 964 women with cancer, including 59 452 women with breast cancer (median [IQR] age, 48 [44-53] years), 14 713 women with cervical cancer (median [IQR] age, 46 [39-51] years), 16 933 women with uterine cancer (median [IQR] age, 49 [44-53 years]), and 8866 women with ovarian cancer (median age [IQR] age, 47 [40-52] years), as well as 999 640 matched controls (594 520 for the breast cancer cohort, 147 130 for the cervical cancer cohort, 169 330 for the uterine cancer cohort, and 88 660 for the ovarian cancer cohort). Most women with cancer were working in the medical, health care, or welfare sector (32 123 women [32.1%]). During follow-up, resignation rates were significantly higher for women with cancer vs controls (breast cancer: 10 820 women [18.2%] vs 97 892 women [16.5%]; hazard ratio [HR], 1.18; 95% CI, 1.16-1.20; cervical cancer: 3296 women [22.4%] vs 27 476 women [18.7%]; HR, 1.31; 95% CI, 1.26-1.36; uterine cancer: 3161 women [18.7%] vs 27 786 women [16.4%]; HR, 1.24; 95% CI, 1.19-1.29; ovarian cancer: 2004 women [22.6%] vs 15 847 women [17.9%]; HR, 1.44; 95% CI, 1.37-1.51). Regarding the composite outcome of resignation and death, there was an increased risk for all cohorts, ranging from an HR of 1.25 (95% CI, 1.22-1.27) for breast cancer to 1.81 (95% CI, 1.73-1.89) for ovarian cancer. Among all 4 cancer cohorts, resignation risk was higher among women with older age, lower income, and a history of depression.Conclusions and RelevanceIn this cohort study using a nationwide health claims database in Japan, breast and gynecologic cancers were associated with a higher resignation risk, especially among those with older age, lower income, and depression history. These findings suggest that developing targeted support interventions may benefit women at high resignation risk after a cancer diagnosis.

Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer

Tailoring therapeutic regimens to individual patients with ovarian cancer is informed by severity of disease using a variety of clinicopathologic indicators. Although DNA repair variations are increasingly used for therapy selection in ovarian cancer, molecular features are not widely used for general assessment of patient prognosis and disease severity. To distill a highly dynamic characteristic, signature of copy number variations (CNV), into a risk score that could be easily validated analytically or repurposed for use given existing US Food and Drug Administration (FDA)-approved multigene assays. This genetic association study used the Cancer Genome Atlas Ovarian Cancer database to assess for genome-wide survival associations agnostic to gene function. Regions enriched for significant associations were compared to associations from scrambled data. CNV associations were condensed into a risk score, which was internally validated using bootstrapping. The participants were patients with serous ovarian cancer (stages I-IV) diagnosed from 1992 to 2013. Statistical analysis was performed from April to July 2020. Overall survival (OS). Among 564 patients with serous ovarian cancer, the mean (SD) age was 59.7 (11.5) years; 34 (6%) identified as Black or African American. A total of 13 genome regions, comprising 14 alterations, were identified as significantly risk associated. Composite risk score was independent of total CNV burden, total mutational burden, BRCA status, and open-source genome-wide DNA repair deficiency signatures. Binned terciles yielded high-, standard-, and low-risk groups with respective median OS estimates of 2.9 (95% CI, 2.3-3.2) years, 4.1 (95% CI, 3.7-4.8) years, and 5.7 (95% CI, 4.7-7.4) years, respectively (P < .001). Associated 5-year survival estimates in each tercile were 15% (95% CI, 10%-22%), 36% (95% CI, 29%-46%), and 53% (95% CI, 45%-62%). The risk score had more discriminatory ability to prognosticate OS than age, clinical stage, grade, and race combined, and was strongly additive to significant clinical features (P < .001). Simulated adaptation of FDA-approved assays showed similar performance. Gene ontology analyses of identified regions showed an enrichment for regulatory miRNAs and protein kinase regulators. This study found that a CNV-based risk score is independent to and stronger than current or near-future ovarian cancer genomic biomarkers to prognosticate OS. CNV regions identified were not strongly associated with canonical ovarian cancer biological pathways, identifying candidates for future mechanistic investigations. External validation of the CNV risk score, especially in concert with more extensive clinical features, could be pursued via existing FDA-approved assays.

Gene Sequencing for Pathogenic Variants Among Adults With Breast and Ovarian Cancer in the Caribbean

Rates of breast and ovarian cancer are high in the Caribbean; however, to date, few published data quantify the prevalence of inherited cancer in the Caribbean population. To determine whether deleterious variants in genes that characterize the hereditary breast and ovarian cancer syndrome are associated with the development of breast and ovarian cancer in the English- and Creole-speaking Caribbean populations. This multisite genetic association study used data from germline genetic test results between June 2010 and June 2018 in the Bahamas, Cayman Islands, Barbados, Dominica, Jamaica, Haiti, and Trinidad and Tobago. Next-generation sequencing on a panel of 30 genes and multiplex ligation-dependent probe amplification (BRCA1 and BRCA2) were performed. Medical records were reviewed at time of study enrollment. Women and men diagnosed with breast and ovarian cancer with at least 1 grandparent born in the participating study sites were included; 1018 individuals were eligible and consented to participate in this study. Data were analyzed from November 4, 2019, to May 6, 2020. Breast and/or ovarian cancer diagnosis. Rate of inherited breast and ovarian cancer syndrome and spectrum and types of variants. Of 1018 participants, 999 (98.1%) had breast cancer (mean [SD] age, 46.6 [10.8] years) and 21 (2.1%) had ovarian cancer (mean [SD] age, 47.6 [13.5] years). Three individuals declined to have their results reported. A total of 144 of 1015 (14.2%) had a pathogenic or likely pathogenic (P/LP) variant in a hereditary breast and ovarian cancer syndrome gene. A total of 64% of variant carriers had P/LP variant in BRCA1, 23% in BRCA2, 9% in PALB2 and 4% in RAD51C, CHEK2, ATM, STK11 and NBN. The mean (SD) age of variant carriers was 40.7 (9.2) compared with 47.5 (10.7) years in noncarriers. Individuals in the Bahamas had the highest proportion of hereditary breast and ovarian cancer (23%), followed by Barbados (17.9%), Trinidad (12%), Dominica (8.8%), Haiti (6.7%), Cayman Islands (6.3%), and Jamaica (4.9%). In Caribbean-born women and men with breast cancer, having a first- or second-degree family member with breast cancer was associated with having any BRCA1 or BRCA2 germline variant (odds ratio, 1.58; 95% CI, 1.24-2.01; P < .001). A BRCA1 vs BRCA2 variant was more strongly associated with triple negative breast cancer (odds ratio, 6.33; 95% CI, 2.05-19.54; P = .001). In this study, among Caribbean-born individuals with breast and ovarian cancer, 1 in 7 had hereditary breast and ovarian cancer. The proportion of hereditary breast and ovarian cancer varied by island and ranged from 23% in the Bahamas to 4.9% in Jamaica. Each island had a distinctive set of variants.

Number Needed to Treat in Trials of Targeted Therapies for Advanced Ovarian Cancer

This comparative effectiveness study assesses the numbers needed to treat in targeted trials of agents for newly diagnosed ovarian cancer.

Assessment of US Preventive Services Task Force Guideline–Concordant Cervical Cancer Screening Rates and Reasons for Underscreening by Age, Race and Ethnicity, Sexual Orientation, Rurality, and Insurance, 2005 to 2019

Cervical cancer screening rates are suboptimal in the US. Population-based assessment of reasons for not receiving screening is needed, particularly among women from historically underserved demographic groups. To estimate changes in US Preventive Service Task Force guideline-concordant cervical cancer screening over time and assess the reasons women do not receive up-to-date screening by sociodemographic factors. This pooled population-based cross-sectional study used data from the US National Health Interview Survey from 2005 and 2019. A total of 20 557 women (weighted, 113.1 million women) aged 21 to 65 years without previous hysterectomy were included. Analyses were conducted from March 30 to August 19, 2021. Sociodemographic factors, including age, race and ethnicity, sexual orientation, rurality of residence, and health insurance type. Primary outcomes were US Preventive Services Task Force guideline-concordant cervical cancer screening rates and self-reported primary reasons for not receiving up-to-date screening. For 2005, up-to-date screening was defined as screening every 3 years for women aged 21 to 65 years. For 2019, up-to-date screening was defined as screening every 3 years with a Papanicolaou test alone for women aged 21 to 29 years and screening every 3 years with a Papanicolaou test alone or every 5 years with high-risk human papillomavirus testing or cotesting for women aged 30 to 65 years. Population estimation included sampling weights. Among 20 557 women (weighted, 113.1 million women) included in the study, most were aged 30 to 65 years (16 219 women; weighted, 86.3 million women [76.3%]) and had private insurance (13 571 women; weighted, 75.8 million women [67.0%]). With regard to race and ethnicity, 997 women (weighted, 6.9 million women [6.1%]) were Asian, 3821 women (weighted, 19.5 million women [17.2%]) were Hispanic, 2862 women (weighted, 14.8 million women [13.1%]) were non-Hispanic Black, 12 423 women (weighted, 69.0 million women [61.0%]) were non-Hispanic White, and 453 women (weighted, 3.0 million women [2.7%]) were of other races and/or ethnicities (including Alaska Native and American Indian [weighted, 955 000 women (0.8%)] and other single and multiple races or ethnicities [weighted, 2.0 million women (1.8%)]). In 2019, women aged 21 to 29 years had a significantly higher rate of overdue screening (29.1%) vs women aged 30 to 65 years (21.1%; P < .001). In both age groups, the proportion of women without up-to-date screening increased significantly from 2005 to 2019 (from 14.4% to 23.0%; P < .001). Significantly higher rates of overdue screening were found among those of Asian vs non-Hispanic White race and ethnicity (31.4% vs 20.1%; P = .01), those identifying as LGBQ+ (gender identity was not assessed because of a small sample) vs heterosexual (32.0% vs 22.2%; P < .001), those living in rural vs urban areas (26.2% vs 22.6%; P = .04), and those without insurance vs those with private insurance (41.7% vs 18.1%; P < .001). The most common reason for not receiving timely screening across all groups was lack of knowledge, ranging from 47.2% of women identifying as LGBQ+ to 64.4% of women with Hispanic ethnicity. Previous receipt of a human papillomavirus vaccine was not a primary reason for not having up-to-date screening (<1% of responses). From 2005 to 2019, among women aged 30 to 65 years, lack of access decreased significantly as a primary reason for not receiving screening (from 21.8% to 9.7%), whereas lack of knowledge (from 45.2% to 54.8%) and not receiving recommendations from health care professionals (from 5.9% to 12.0%) increased significantly. This cross-sectional study found that cervical cancer screening that was concordant with US Preventive Services Task Force guidelines decreased in the US between 2005 and 2019, with lack of knowledge reported as the biggest barrier to receiving timely screening. Campaigns addressing patient knowledge and provider communication may help to improve screening rates, and cultural adaptation of interventions is needed to reduce existing disparities.

Effect of Patient Characteristics on Uptake of Screening Using a Mailed Human Papillomavirus Self-sampling Kit

ImportanceMailing human papillomavirus (HPV) self-sampling kits increases cervical cancer screening participation, but effects may differ across subpopulations. Subpopulation data can inform US health care system implementation.ObjectiveTo identify patient characteristics that modify effectiveness of a mailed kit intervention at increasing screening.Design, Setting, and ParticipantsThis was a secondary analysis of data from the Home-Based Options to Make Cervical Cancer Screening Easy (HOME) randomized clinical trial conducted from 2014 to 2018 at Kaiser Permanente Washington. Data analysis was performed from March 2018 to May 2022. Individuals aged 30 to 64 years with female sex, health plan enrollment longer than 3 years and 5 months, a current primary care clinician, and no Papanicolaou test within the prior 3 years and 5 months were identified through electronic medical records and randomized (1:1) to the control or intervention group.InterventionsThe control group received usual care Papanicolaou screening reminders and outreach. The intervention group received usual care plus an unsolicited mailed HPV self-sampling kit.Main Outcomes and MeasuresScreening uptake was captured within 6 months after randomization. Baseline patient characteristics (age, race, ethnicity, travel time to clinic, income, body mass index, tobacco use, health plan enrollment duration, time since last Papanicolaou test, mammography, comorbidities, and colorectal cancer screening adherence) were extracted from the electronic medical record.ResultsOf 19 734 individuals (mean [SD] age, 50.1 [9.5] years; 14 129 [71.6%] White), 9843 were randomized to the intervention group, and 9891 were randomized to the control group. Screening uptake was 26.3% (2592 of 9843 individuals) in the intervention group vs 17.4% (1719 of 9891 individuals) in the control group (relative risk [RR], 1.51; 95% CI, 1.43-1.60). Although absolute differences in uptake by group varied little by screening history, relative effects were greater with longer vs shorter time since last Papanicolaou test (no prior Papanicolaou test: RRs, 1.85-3.25; ≥10 years: RR, 2.78; 5-10 years: RRs, 1.69-1.86; &amp;amp;lt;5 years: RRs 1.29-1.37). Relative effects were greater in participants overdue (RR, 2.03; 95% CI, 1.73-2.38) vs up-to-date with mammography (RR, 1.53; 95% CI, 1.41-1.67), although absolute difference was greater in the up-to-date group. Differences by age were not significant, with RRs of 1.33 to 1.48 across 5-year age groups in participants 30 to 54, vs 1.60 (95% CI, 1.40-1.82) in participants 55 to 59 and 1.77 (95% CI, 1.56-2.01) in participants 60 to 64 years. Among those mailed kits, there were differences in kit use vs in-clinic screening by age, race, plan enrollment duration, underscreening duration, and colorectal cancer screening adherence.Conclusions and RelevanceIn this secondary analysis of a randomized clinical trial, clinically important improvements in screening uptake were observed for all subgroups. Differences in magnitude of intervention effect and kit use highlighted opportunities to optimize HPV self-sampling for priority groups.Trial RegistrationClinicalTrials.gov Identifier:NCT02005510

Leisure-Time Physical Activity and Cancer Mortality Among Cancer Survivors

Importance There is insufficient evidence to determine whether physical activity lengthens survival among people with a history of cancers less commonly studied for such benefit. Objective To examine the associations between physical activity assessed after a cancer diagnosis with cancer mortality and, secondarily, changes in physical activity before vs after diagnosis with cancer mortality among people previously diagnosed with 1 of 7 cancers. Design, Setting, and Participants This study used a pooled dataset of 6 cohorts (Cancer Prevention Study-II Nutrition Cohort, Health Professionals Follow-Up Study, National Institutes of Health–AARP Diet and Health Study, Nurses’ Health Study, Nurses’ Health Study II, and Women’s Health Study). Participants were survivors of bladder, endometrial, kidney, lung, oral cavity, ovarian, or rectal cancer who had completed surveys and had repeated measures of leisure-time physical activity. Baseline data were collected from 1976 through 1997. The mean (SD) follow-up was 10.9 (7.0) years. Data were analyzed from June 2023 to March 2024. Exposures Leisure-time moderate to vigorous physical activity (MVPA) before and after cancer diagnosis. Main Outcomes and Measures Association of MVPA in categories of metabolic equivalents of task hours per week (MET-h/wk) measured before and a mean (SD) of 2.8 (1.5) years after cancer diagnosis with cancer mortality. Results This pooled analysis included 17 141 cancer survivors (mean [SD] age, 67 [8] years; 60% female). Engagement in low amounts of MVPA (&amp;amp;gt;0 to &amp;amp;lt;7.5 vs 0 MET-h/wk) was associated with lower risk of cancer mortality among survivors who had been diagnosed with bladder (hazard ratio [HR], 0.67 [95% CI, 0.50-0.91]), endometrial (HR, 0.62 [95% CI, 0.45-0.87]), and lung cancer (HR, 0.56 [95% CI, 0.43-0.75]). Doubling the recommended MVPA guideline or more (eg, &amp;amp;gt;15 vs 0 MET-h/wk) was associated with lower risk of cancer mortality among oral (HR, 0.39 [95% CI, 0.15-0.99] for &amp;amp;gt;22.5 to 30.0 MET-h/wk) and rectal (HR, 0.57 [95% CI, 0.33-0.97] for &amp;amp;gt;15.0 to 22.5 MET-h/wk) cancer survivors. Point estimates were less than 1 for cancer mortality among kidney cancer survivors (HR, 0.51 [95% CI, 0.22-1.18] for &amp;amp;gt;15.0 to 22.5 MET-h/wk), although the confidence interval included the null. Compared with survivors who did not meet the MVPA guidelines before or after diagnosis, lung (HR, 0.58 [95% CI, 0.47-0.71]) and rectal (HR, 0.51 [95% CI, 0.32-0.83]) cancer survivors who met guidelines after diagnosis had a lower risk of cancer mortality, even if they were inactive before their diagnosis. Conclusions and Relevance In this analysis of 6 pooled cohorts, higher levels of MVPA after a cancer diagnosis were associated with lower risk of cancer mortality among people previously diagnosed with 1 of 7 cancers not commonly studied for their association with MVPA. Findings suggest that it is important for health care professionals to promote physical activity for longevity and overall health among people living with and beyond cancer.

County-Level Social Vulnerability and Breast, Cervical, and Colorectal Cancer Screening Rates in the US, 2018

ImportanceArea-level factors have been identified as important social determinants of health (SDoH) that impact many health-related outcomes. Less is known about how the social vulnerability index (SVI), as a scalable composite score, can multidimensionally explain the population-based cancer screening program uptake at a county level.ObjectiveTo examine the geographic variation of US Preventive Services Task Force (USPSTF)–recommended breast, cervical, and colorectal cancer screening rates and the association between county-level SVI and the 3 screening rates.Design, Setting, and ParticipantsThis population-based cross-sectional study used county-level information from the Centers for Disease Control and Prevention’s PLACES and SVI data sets from 2018 for 3141 US counties. Analyses were conducted from October 2021 to February 2022.ExposuresSocial vulnerability index score categorized in quintiles.Main Outcomes and MeasuresThe main outcome was county-level rates of USPSTF guideline-concordant, up-to-date breast, cervical, and colorectal screenings. Odds ratios were calculated for each cancer screening by SVI quintile as unadjusted (only accounting for eligible population per county) or adjusted for urban-rural status, percentage of uninsured adults, and primary care physician rate per 100 000 residents.ResultsAcross 3141 counties, county-level cancer screening rates showed regional disparities ranging from 54.0% to 81.8% for breast cancer screening, from 69.9% to 89.7% for cervical cancer screening, and from 39.8% to 74.4% for colorectal cancer screening. The multivariable regression model showed that a higher SVI was significantly associated with lower odds of cancer screening, with the lowest odds in the highest SVI quintile. When comparing the highest quintile of SVI (SVI-Q5) with the lowest quintile of SVI (SVI-Q1), the unadjusted odds ratio was 0.86 (95% posterior credible interval [CrI], 0.84-0.87) for breast cancer screening, 0.80 (95% CrI, 0.79-0.81) for cervical cancer screening, and 0.72 (95% CrI, 0.71-0.73) for colorectal cancer screening. When fully adjusted, the odds ratio was 0.92 (95% CrI, 0.90-0.93) for breast cancer screening, 0.87 (95% CrI, 0.86-0.88) for cervical cancer screening, and 0.86 (95% CrI, 0.85-0.88) for colorectal cancer screening, showing slightly attenuated associations.Conclusions and RelevanceIn this cross-sectional study, regional disparities were found in cancer screening rates at a county level. Quantifying how SVI associates with each cancer screening rate could provide insight into the design and focus of future interventions targeting cancer prevention disparities.

Outcomes of Anastrozole, Letrozole, and Exemestane in Patients With Postmenopausal Breast Cancer

Importance Third-generation aromatase inhibitors (AIs)—anastrozole, letrozole, and exemestane—are standard adjuvant endocrine therapy for women with postmenopausal hormone receptor (HR)–positive early-stage breast cancer. However, little is known about their comparative effectiveness in clinical settings. Objective To compare adjuvant anastrozole, letrozole, and exemestane in terms of disease-free survival (DFS) and overall survival (OS) in women with postmenopausal HR-positive early-stage breast cancer. Design, Setting, and Participants This comparative effectiveness study conducted in France emulated a target trial using national medicoadministrative data. The patient cohort was derived from the updated French Early Breast Cancer Cohort and consisted of women aged 50 to 75 years with early-stage breast cancer who were diagnosed between January 1, 2011, and December 31, 2020, and followed up through December 31, 2021. All women initiated adjuvant AI therapy without ovarian suppression. Data analysis was performed from November 2024 to May 2025. Exposures Upfront adjuvant anastrozole, letrozole, and exemestane, evaluated under natural persistence and under a hypothetical intervention ensuring perfect persistence for 5 years. Main Outcomes and Measures The primary end points were DFS and OS. Both DFS and OS were estimated using adjusted Kaplan-Meier curves. Results Among 148 436 women (median [IQR] age, 64 [59-69] years) included in the analyses, 38.5% initiated anastrozole, 52.9% initiated letrozole, and 8.5% initiated exemestane. After a median (IQR) follow-up of 63 (34-94) months, the 8-year DFS under natural persistence was estimated to be lower for the exemestane group (79.1%; 95% CI, 78.1%-80.0%) compared with the anastrozole (81.0%; 95% CI, 80.6%-81.5%) and letrozole (81.1%; 95% CI, 80.7%-81.5%) groups. Similarly, the 8-year OS was 88.8% (95% CI, 88.0%-89.6%) for the exemestane group compared with 90.5% (95% CI, 90.2%-90.8%) for the anastrozole group and 89.9% (95% CI, 89.6%-90.2%) for the letrozole group. Patients who initiated exemestane were also more likely to discontinue treatment within 5 years of therapy than their counterparts taking the other AIs (39.3% [95% CI, 38.3%-40.3%] in the exemestane group vs 35.1% [95% CI, 34.7%-35.6%] in the anastrozole group and 35.0% [95% CI, 34.6%-35.4%] in the letrozole group). However, the lower DFS and OS observed for exemestane compared with letrozole and anastrozole persisted under perfect persistence. Conclusions and Relevance The findings of this comparative effectiveness study using a target trial emulation framework suggest that adjuvant endocrine therapy with exemestane may result in slightly lower DFS and OS compared with anastrozole and letrozole in patients with postmenopausal HR-positive early-stage breast cancer. The findings favor anastrozole or letrozole as initial treatment and highlight the need for future studies to inform AI selection.

Changes in Cancer Screening in the US During the COVID-19 Pandemic

Health care was disrupted in the US during the first quarter of 2020 with the emergence of the COVID-19 pandemic. Early reports in selected samples suggested that cancer screening services decreased greatly, but population-based estimates of cancer screening prevalence during 2020 have not yet been reported. To examine changes in breast cancer (BC), cervical cancer (CC), and colorectal cancer (CRC) screening prevalence with contemporary national, population-based Behavioral Risk Factor Surveillance System (BRFSS) data. This survey study included respondents from the 2014, 2016, 2018, and 2020 BRFSS surveys who were eligible for BC (women aged 50-74 years), CC (women aged 25-64 years), and CRC (women and men aged 50-75 years) screening. Data analysis was performed from September 2021 to February 2022. Calendar year. Self-reported receipt of a recent (defined as in the past year) BC, CC, and CRC screening test. Adjusted prevalence ratios (aPRs) comparing 2020 vs 2018 prevalence and 95% CIs were computed. In total, 479 248 individuals were included in the analyses of BC screening, 301 453 individuals were included in CC screening, and 854 210 individuals were included in CRC screening, In 2020, among respondents aged 50 to 75 years, 14 815 (11.4%) were Black, 12 081 (12.6%) were Hispanic, 156 198 (67.3%) were White, and 79 234 (29.9%) graduated from college (all percentages are weighted). After 4 years (2014-2018) of nearly steady prevalence, past-year BC screening decreased by 6% between 2018 and 2020 (from 61.6% in 2018 to 57.8% in 2020; aPR, 0.94; 95% CI, 0.92-0.96), and CC screening decreased by 11% (from 58.3% in 2018 to 51.9% in 2020; aPR, 0.89; 95% CI, 0.87-0.91). The magnitude of these decreases was greater in people with lower educational attainment and Hispanic persons. CRC screening prevalence remained steady; past-year stool testing increased by 7% (aPR, 1.07; 95% CI, 1.02-1.12), offsetting a 16% decrease in colonoscopy (aPR, 0.84; 95% CI, 0.82-0.88) between 2018 and 2020. In this survey study, stool testing increased and counterbalanced a decrease in colonoscopy during 2020, and BC and CC screening modestly decreased. How these findings might be associated with outcomes is not yet known, but they will be important to monitor, especially in populations with lower socioeconomic status, who experienced greater screening decreases during the COVID-19 pandemic.

Test Performance of Cervical Cytology Among Adults With vs Without Human Papillomavirus Vaccination

Current US cervical cancer screening guidelines do not differ by human papillomavirus (HPV) vaccination status. However, as the positive predictive value (PPV) of a screening test decreases, the risk of a false-positive result increases. To evaluate whether HPV vaccination is associated with decreased PPV for abnormal cervical cytology. This retrospective cohort study conducted via electronic medical record review included eligible patients aged 21 to 35 years who had at least 1 cervical cytology result within a single health system between January 2015 and December 2018. The health system comprises a partnership between an academic health center and a private not-for-profit health center. Patients with abnormal screening cytology and no diagnostic test results were omitted from analysis. Data were analyzed from December 2019 to November 2021. HPV vaccination, defined as receiving at least 1 dose of HPV vaccine. Subgroup analyses were performed for those completing all vaccination doses per Advisory Committee on Immunization Practices guidelines and by age at vaccination initiation, dichotomized as younger than 21 years vs 21 years or older. PPV of abnormal cervical cytology for risk of cervical intraepithelial neoplasia (CIN) 2 or more severe diagnosis. A total of 46 988 patients (mean [SD] age, 28.7 [4.5] years; 3058 [6.5%] Asian; 4159 [8.9%] Black or African American; 35 446 [75.4%] White) were included; 15 494 (33.0%) were at least partially vaccinated, and 4289 (9.1%) had abnormal cytology results during the study period. Among the individuals with abnormal cytology, the PPV for CIN 2 or more severe diagnosis was lower among vaccinated individuals (17.4%; 95% CI, 16.4%-18.4%) than unvaccinated individuals (21.3%; 95% CI, 20.4%-22.3%). Among vaccinated individuals, PPV was significantly lower among those completing vaccination (15.9%; 95% CI, 14.9%-17.0%) than those with incomplete vaccination (22.4%; 95% CI, 20.0%-25.0%), especially among those initiating vaccination when younger than 21 years (11.9%; 95% CI, 10.9%-12.9%) vs those initiating at age 21 years or older (30.7%; 95% CI, 27.3%-34.4%). Among a population with relatively low HPV vaccine coverage, the PPV of cervical cytology for CIN 2 or more severe diagnosis was significantly lower among vaccinated individuals. PPV will likely further decrease in the future as a population with higher HPV vaccination coverage ages into screening. Confirmation of these results will call for changes in screening strategies, particularly for completely vaccinated individuals who initiated vaccination when younger than 21 years.

Reproductive Shifts and Ovarian Cancer Risk in Women Aged 40 Years or Older

Importance Reproductive factors are associated with ovarian cancer risk, but their influence may differ across menopausal status and birth cohorts. Objective To examine the associations between reproductive factors and ovarian cancer risk stratified by menopausal status and birth cohort. Design, Setting, and Participants This nationwide population-based cohort study obtained data from the National Health Insurance Service (NHIS), a single-payer system covering 97% of the population in South Korea. Women aged 40 years or older who underwent NHIS health screening in 2009 and had reproductive, clinical, and other data were included and followed up until ovarian cancer diagnosis, death, or December 31, 2022. Data were analyzed in March 2025. Exposures Age at menarche, parity, breastfeeding duration, oral contraceptive use, age at menopause, total reproductive span, and hormone replacement therapy use. Main Outcomes and Measures Incident ovarian cancer identified from NHIS claims with International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes C56, C57, and C48 and confirmed through the Rare/Intractable Disease Registry (code V193). Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% CIs. Results A total of 2 285 774 women (932 637 [40.8%] premenopausal, 1 353 137 [59.2%] postmenopausal; mean [SD] age, 54.9 [10.85] years) were included in the final analytic cohort. The mean (SD) follow-up duration overall was 10.7 (2.99) years, and 10 729 ovarian cancer cases were identified during follow-up. Early menarche (aged ≤12 vs &amp;amp;gt;16 years) was associated with higher ovarian cancer risk in both premenopausal women (HR, 1.37; 95% CI, 1.16-1.61) and postmenopausal women (HR, 1.24; 95% CI, 1.00-1.54). Parity of 2 or more births was associated with lower risk in both groups (HR, 0.68 [95% CI, 0.58-0.79] and 0.71 [95% CI, 0.60-0.85]). Breastfeeding for 12 months or longer and oral contraceptive use for 1 year or longer were associated with lower risk in premenopausal women but not postmenopausal women (HR, 0.86 [95% CI, 0.77-0.96] and 0.75 [95% CI, 0.61-0.93]). Among postmenopausal women, later menopause (at age ≥55 years; HR, 1.36 [95% CI, 1.11-1.66]), longer reproductive span (≥40 years; HR, 1.21 [95% CI, 1.09-1.34]), and hormone replacement therapy use for 2 to 5 years (HR, 1.20 [95% CI, 1.07-1.34]) were associated with higher risk. Parity-related risk reduction was attenuated in the 1960s birth cohort (HR, 1.07; 95% CI, 0.52-2.19; P for interaction = .36). Conclusions and Relevance This cohort study found that reproductive factors were associated with ovarian cancer risk, with distinct patterns across menopausal status and birth cohorts. These findings highlight the need for tailored prevention strategies in aging, low-fertility populations.

Physician Peer Influence on Salpingectomy Uptake for Tubal Sterilization and Ovarian Cancer Prevention

Importance Prophylactic removal of the fallopian tubes (opportunistic salpingectomy) in lieu of conventional methods of tubal sterilization helps reduce ovarian cancer risk. Objective To examine how peer influence among physicians is associated with opportunistic salpingectomy uptake at the time of postpartum and interval sterilizations. Design, Setting, and Participants This retrospective cohort study used insurance claims data from the Blue Cross Blue Shield Axis database. Participants were patients aged 18 to 49 years who underwent a tubal sterilization after childbirth (postpartum sterilization) or unrelated to pregnancy (interval sterilization) from January 2020 to December 2022 and whose operating surgeon did not perform opportunistic salpingectomy at baseline (2017-2019). Exposures Applying a Louvain clustering methodology, physician patient-sharing networks were constructed based on their billing of the same patients in claims data at baseline (2017-2019). For surgeons who did not use opportunistic salpingectomy at baseline, the rate of opportunistic salpingectomy use among peer physicians in the same network at baseline was measured. Main Outcomes and Measures Opportunistic salpingectomy was defined as removal of both (or the remaining side of) fallopian tubes with preservation of the ovaries. Results The overall sample included 4520 patients undergoing postpartum sterilization and 3376 patients undergoing interval sterilization in 2020 to 2022, with 4173 (92.3%) of the postpartum sterilization sample involving a cesarean delivery. Most patients in these 2 samples (3520 patients [77.9%] and 2599 patients [77.0%], respectively) were aged 30 to 49 years. In the postpartum sterilization sample, having peer physicians in the highest (vs lowest) quartile of baseline opportunistic salpingectomy rate was associated with higher odds of receiving opportunistic salpingectomy for postpartum sterilization (13.6% vs 5.6%; adjusted odds ratio [aOR], 2.17; 95% CI, 1.20-3.92; P  &amp;amp;lt; .001). In the interval sterilization sample, having peer physicians in the highest (vs lowest) quartile of baseline opportunistic salpingectomy rate was also associated with higher odds of receiving opportunistic salpingectomy for interval sterilization (42.3% vs 19.3%; aOR, 4.16; 95% CI, 1.98-8.77; P  &amp;amp;lt; .001). Conclusions and Relevance In this retrospective cohort study of postpartum and interval sterilizations, surgeons who previously shared patients with other physicians with high rates of opportunistic salpingectomy use were more likely to adopt opportunistic salpingectomy in their own subsequent practice. These results suggest physician peer influence in salpingectomy uptake.

Disparities in Survival and Comorbidity Burden Between Asian and Native Hawaiian and Other Pacific Islander Patients With Cancer

ImportanceImproper aggregation of Native Hawaiian and other Pacific Islander individuals with Asian individuals can mask Native Hawaiian and other Pacific Islander patient outcomes. A comprehensive assessment of cancer disparities comparing Asian with Native Hawaiian and other Pacific Islander populations is lacking.ObjectiveTo compare comorbidity burden and survival among East Asian, Native Hawaiian and other Pacific Islander, South Asian, and Southeast Asian individuals with non-Hispanic White individuals with cancer.Design, Setting, and ParticipantsThis retrospective cohort study used a national hospital-based oncology database enriched with Native Hawaiian and other Pacific Islander and Asian populations. Asian, Native Hawaiian and other Pacific Islander, and White individuals diagnosed with the most common cancers who received treatment from January 1, 2004, to December 31, 2017, were included. Patients younger than 18 years, without pathologic confirmation of cancer, or with metastatic disease were excluded. Data were analyzed from January to May 2022.Main Outcomes and MeasuresThe primary end points were comorbidity burden by Charlson-Deyo Comorbidity Index and overall survival (OS).ResultsIn total, 5 955 550 patients were assessed, including 60 047 East Asian, 11 512 Native Hawaiian and other Pacific Islander, 25 966 South Asian, 42 815 Southeast Asian, and 5 815 210 White patients. The median (IQR) age was 65 (56-74) years, median (IQR) follow-up was 58 (30-96) months, and 3 384 960 (57%) were women. Patients were predominantly from metropolitan areas (4 834 457 patients [84%]) and the Southern United States (1 987 506 patients [34%]), with above median education (3 576 460 patients [65%]), and without comorbidities (4 603 386 patients [77%]). Cancers included breast (1 895 351 patients [32%]), prostate (948 583 patients [16%]), kidney or bladder (689 187 patients [12%]), lung (665 622 patients [11%]), colorectal (659 165 patients [11%]), melanoma (459 904 patients [8%]), endometrial (307 401 patients [5%]), lymphoma (245 003 patients [4%]), and oral cavity (85 334 patients [1%]) malignant neoplasms. Native Hawaiian and other Pacific Islander patients had the highest comorbidity burden (adjusted odds ratio [aOR], 1.70; 95% CI, 1.47-1.94) compared with Asian and White groups. Asian patients had superior OS compared with White patients for most cancers; only Southeast Asian patients with lymphoma had inferior survival (adjusted hazard ratio [aHR], 1.26; 95% CI, 1.16-1.37). In contrast, Native Hawaiian and other Pacific Islander patients demonstrated inferior OS compared with Asian and White patients for oral cavity cancer (aHR, 1.56; 95% CI, 1.14-2.13), lymphoma (aHR, 1.35; 95% CI, 1.11-1.63), endometrial cancer (aHR, 1.30; 95% CI, 1.12-1.50), prostate cancer (aHR, 1.29; 95% CI, 1.14-1.46), and breast cancer (aHR, 1.09; 95% CI, 1.00-1.18). No cancers among Native Hawaiian and other Pacific Islander patients had superior OS compared with White patients.Conclusions and RelevanceIn this cohort study, compared with White patients with the most common cancers, Asian patients had superior survival outcomes while Native Hawaiian and other Pacific Islander patients had inferior survival outcomes. Native Hawaiian and other Pacific Islander patients had significantly greater comorbidity burden compared with Asian and White patients, but this alone did not explain the poor survival outcomes. These results support the disaggregation of these groups in cancer studies.

Estimands for Clinical Effectiveness of Risk-Reducing Early Salpingectomy in Women With High Risk of Ovarian Cancer

ImportanceRisk-reducing early-salpingectomy (RRES) and delayed oophorectomy (DO) is a novel 2-stage alternative prevention strategy to risk-reducing salpingo-oophorectomy (RRSO) that avoids detrimental consequences of premature menopause. However, direct data on the clinical effectiveness for ovarian cancer (OC) risk reduction are lacking.ObjectiveTo explore how to define clinical effectiveness from prospective cohort studies using the estimand framework and sample size requirements.Design, Setting, and ParticipantsIn this comparative effectiveness research study, estimand and analysis options were considered to evaluate the clinical effectiveness of RRES with DO by extending the UK PROTECTOR cohort study, a multicenter, prospective, observational, national cohort study (N = 1250 recruited from January 1, 2019, to December 31, 2024) evaluating RRES and DO for OC surgical prevention. Eligibility criteria for participants were broadly premenopausal women 30 years or older at increased OC risk due to BRCA1/BRCA2 pathogenic variants. Participants could choose RRES, RRSO, or no surgery at entry. Sample-size requirements to extend recruitment used initial data (eg, age and BRCA1/BRCA2 distribution) from PROTECTOR (analysis undertaken from January 1, 2024, to December 31, 2025).Main Outcomes and MeasuresIncidence of OC after (not at) RRES and before or at DO in women with normal histologic analysis findings at surgery. The proportion of cancers prevented was estimated as the completement of the observed (O) to expected (E; assuming no preventive effect of surgery) number of cancers detected (1 – O/E).ResultsInitial data were obtained from 889 women in PROTECTOR (overall mean [SD] age, 39 [4.9] years), with 255 (28.7%) choosing RRSO (mean [SD] age, 42 [4.4] years), 405 (45.5%) choosing RRES (mean [SD] age, 38 [4.4] years), and 229 (25.7%) choosing no surgery (mean [SD], 38 [4.6] years). The preferred estimand outcome was OC incidence after surgery (RRES or RRSO) with a “while on intervention” strategy to account for intercurrent events. The primary target measure was the proportion of cancers prevented for RRES vs no surgery with superiority testing. A secondary target measure was noninferiority of RRES vs RRSO. An estimated 1150 RRES participants with 8 to 10 years of follow-up would provide approximately 92% power to show that 20% or more of cancers are prevented using a 1-sample binomial test of the O:E risk (external reference) at the 5% level under a range of assumptions and at least the same power for a noninferiority margin for the proportion of cancers prevented by RRES of those prevented by RRSO. Estimands based on incidence ratios had an infeasible sample size.Conclusions and RelevanceFor this comparative effectiveness study of UK BRCA carriers, the recommended estimand differed from other ongoing clinical-effectiveness studies of RRES and DO. Advantages include direct use of expected risk at baseline (unknown at design stage), easier interpretation across cohorts than absolute risk differences, and providing a feasible recruitment target for PROTECTOR to evaluate clinical effectiveness.

Comorbidity in Midlife and Cancer Outcomes

ImportanceComorbidities in midlife are common but how these conditions are associated with cancer outcomes is poorly understood.ObjectiveTo investigate the association between different comorbidities and risk of incident cancer and cancer mortality.Design, Setting, and ParticipantsThis cohort study is a secondary analysis of the prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial conducted at 10 PLCO screening centers across the US. Participants included adults aged 55 to 74 years without a history of cancer enrolled between 1993 and 2001. Statistical analysis was performed from June 2023 to December 2024.ExposuresSelf-reported history of 12 comorbid conditions classified into 5 distinct classifications guided by World Health Organization categorization.Main Outcome and MeasuresOutcomes included risk of all cancers combined, risk of 19 individual cancer types, and cancer mortality. Multivariable Cox proportional hazards models were used to estimate the association between comorbidity classifications and cancer outcomes.ResultsAmong 128 999 participants included in the analysis, 330 (0.3%) were American Indian, 5414 (4.2%) were Asian or Pacific Islander, 6704 (5.2%) were non-Hispanic Black, and 114 073 (88.4%) were non-Hispanic White; 64 171 (49.7%) were male; and the median (IQR) age was 62 (58-66) years. After a median (IQR) follow-up of 20 (19-22) years, the risk of any incident cancer was significantly higher for individuals with a history of respiratory (hazard ratio [HR], 1.07 [95% CI, 1.02-1.12]) and cardiovascular conditions (HR, 1.02 [95% CI, 1.00-1.05]). History of each comorbid condition evaluated was significantly associated with incidence of at least 1 cancer type. The strongest association was between history of liver conditions and risk of liver cancer (HR, 5.57 [95% CI, 4.03-7.71]), whereas metabolic conditions (obesity or type 2 diabetes) were significantly associated with higher risk of 9 cancer types and lower risk of 4 cancer types. Respiratory (HR, 1.19 [95% CI, 1.11-1.28]), cardiovascular (HR, 1.08 [95% CI, 1.04-1.13]), and metabolic (HR, 1.09 [95% CI, 1.05-1.14]) conditions were positively associated with a higher hazard of cancer death.Conclusions and RelevanceIn this cohort study of 128 999 adults without a history of cancer, comorbidities in midlife were associated with the overall risk of cancer and more strongly associated with risk of multiple individual cancer types, with the direction of association differing across cancer types. These results may inform clinical management of patients at risk for cancer.

Cancer Antigen 125 Levels at Time of Ovarian Cancer Diagnosis by Race and Ethnicity

ImportanceInternational guidelines use cancer antigen (CA) 125 thresholds to recommend which patients with pelvic masses should undergo evaluation by gynecologic oncologists for ovarian cancer. However, CA-125 thresholds were developed from White populations. If CA-125 levels differ among patient populations, current guidelines may contribute to delayed ovarian cancer diagnoses among women of other races and ethnicities than White.ObjectiveTo examine CA-125 levels at ovarian cancer diagnosis by patient race and ethnicity and associations of elevated CA-125 levels with timely treatment.Design, Setting, and ParticipantsThis retrospective cohort study included all patients with ovarian cancer diagnosed between January 1, 2004, and December 31, 2020, using the US National Cancer Database. The data analysis was performed between November 1, 2023, and July 10, 2024.ExposurePatient race and ethnicity as identified in the National Cancer Database.Main Outcome and MeasuresCancer antigen 125 level was defined as elevated or borderline and negative or normal. Multivariable logistic regression models were used to examine the association of patient race and ethnicity with CA-125 level overall and for epithelial and high-grade serous cancers. Generalized linear models were used to examine the association of CA-125 level with days from diagnosis to chemotherapy start for patients with stage II to IV ovarian cancer.ResultsOf the 250 749 patients with ovarian cancer diagnosed between 2004 and 2020 (median [IQR] age, 62.0 [52.0-73.0] years; 0.4% American Indian, 3.7% Asian, 8.6% Black, 85.2% White, and 2.0% other or unknown race and 6.7% Hispanic, 88.8% non-Hispanic, and 4.6% of unknown ethnicity), 212 477 had measured CA-125 levels, and 88.2% had an elevated CA-125 level at diagnosis. Patients with American Indian, Asian, or Black race were less likely to have an elevated CA-125 level at ovarian cancer diagnosis than White patients. In multivariable analyses adjusted for stage, comorbidities, and menopausal status, Black patients had lower odds of elevated CA-125 levels (adjusted odds ratio [AOR], 0.77; 95% CI, 0.74-0.81) compared with White patients, as did American Indian patients (AOR, 0.77; 95% CI, 0.62-0.94). Among patients with high-grade serous ovarian cancer only, Black patients had a lower odds of having an elevated CA-125 level at diagnosis (AOR, 0.81; 95% CI, 0.73-0.91). Patients with stage II to IV ovarian cancer with false-negative CA-125 findings at diagnosis had 9.38 days longer (95% CI, 8.43-10.34 days) to chemotherapy start compared with patients with an elevated CA-125 level.Conclusions and RelevanceIn this cohort study of patients with ovarian cancer, American Indian and Black patients were 23% less likely to have an elevated CA-125 level at diagnosis. Current CA-125 thresholds may miss racially and ethnically diverse patients with ovarian cancer. Work is needed to develop inclusive CA-125 thresholds and diagnostic guidelines and not compound disparities in ovarian cancer diagnosis and treatment.

Salpingectomy and the Risk of Ovarian Cancer in Ontario

ImportanceA body of pathological and clinical evidence supports the position that the fallopian tube is the site of origin for a large proportion of high-grade serous ovarian cancers. Consequently, salpingectomy is now considered for permanent contraception (in lieu of tubal ligation) or ovarian cancer prevention (performed opportunistically at the time of surgical procedures for benign gynecologic conditions).ObjectiveTo evaluate the association between salpingectomy and the risk of invasive epithelial ovarian, fallopian tube, and peritoneal cancer.Design, Setting, and ParticipantsThis population-based retrospective cohort study included all women aged 18 to 80 years who were eligible for health care services in Ontario, Canada. Participants were identified using administrative health databases from Ontario between January 1, 1992, and December 31, 2019. A total of 131 516 women were included in the primary (matched) analysis. Women were followed up until December 31, 2021.ExposuresSalpingectomy (with and without hysterectomy) vs no pelvic procedure (control condition) among women in the general population.Main Outcomes and MeasuresWomen with a unilateral or bilateral salpingectomy in Ontario between April 1, 1992, and December 31, 2019, were matched 1:3 to women with no pelvic procedure from the general population. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% CIs for ovarian, fallopian tube, and peritoneal cancer combined.ResultsAmong 131 516 women (mean [SD] age, 42.2 [7.6] years), 32 879 underwent a unilateral or bilateral salpingectomy, and 98 637 did not undergo a pelvic procedure. After a mean (range) follow-up of 7.4 (0-29.2) years in the salpingectomy group and 7.5 (0-29.2) years in the nonsurgical control group, there were 31 incident cancers (0.09%) and 117 incident cancers (0.12%), respectively (HR, 0.82; 95% CI, 0.55-1.21). The HR for cancer incidence was 0.87 (95% CI, 0.53-1.44) when comparing those with salpingectomy vs those with hysterectomy alone.Conclusions and RelevanceIn this cohort study, no association was found between salpingectomy and the risk of ovarian cancer; however, this observation was based on few incident cases and a relatively short follow-up time. Studies with additional years of follow-up are necessary to define the true level of potential risk reduction with salpingectomy, although longer follow-up will also be a challenge unless collaborative efforts that pool data are undertaken.

Genetic Alterations, Therapy Response, and Survival Among Patients With Triple-Negative Breast Cancer

ImportanceSubgroup definitions for possible deescalation of neoadjuvant cancer treatment are urgently needed in clinical practice.ObjectiveTo investigate the effect of BRCA1 and/or BRCA2 tumor pathogenic variants (tPVs) by comparing 2 deescalated neoadjuvant regimens (nab-paclitaxel plus either carboplatin or gemcitabine) on pathologic complete response (pCR), invasive disease–free survival (IDFS), and overall survival (OS) of patients with early-stage triple-negative breast cancer (TNBC).Design, Setting, and ParticipantsThis was a preplanned secondary analysis of a phase 2 prospective randomized clinical trial (ADAPT-TN) conducted by the West German Study Group (WSG) at 45 sites in Germany between June 2013 and February 2015. The trial enrolled patients with noninflammatory early-stage TNBC (clinical tumor size ≥1 cm; estrogen receptor and progesterone receptor expression &amp;amp;lt;1%; and ERBB2 negative). DNA samples from pretreatment biopsies were obtained. Genetic analysis was performed between January 2018 and March 2020. Final data analyses took place in September 2023.ExposurePatients were randomized to 12 weeks of treatment with nab-paclitaxel plus either carboplatin or gemcitabine; omission of otherwise mandatory anthracycline-containing chemotherapy was allowed in the case of pCR. tPVs in 20 cancer-associated genes, including BRCA1 and BRCA2, were analyzed using a customized gene panel.Main Outcomes and MeasuresThe prevalence of BRCA1 and/or BRCA2 tPVs and their effect on pCR rate, IDFS, and OS were evaluated using logistic and Cox proportional hazards regression.ResultsOf the 307 patients with DNA samples from pretreatment biopsies available, tumor next-generation sequencing analyses were successful for 266 patients. The 266 patients included in this analysis were female, with a median age of 51 years (range, 26-76 years). A total of 162 patients (60.9%) had a clinical tumor size of 2 cm or greater, and 70 (26.3%) had clinical node-positive disease. BRCA1 and/or BRCA2 tPVs were detected in 42 patients (15.8%). The highest pCR rate among patients with BRCA1 and/or BRCA2 tPVs was seen in the nab-paclitaxel plus carboplatin group (9 of 14 patients [64.3%]) compared with the nab-paclitaxel plus gemcitabine group (10 of 28 [35.7%]) (odds ratio, 3.24 [95% CI, 0.85-12.36]; P = .08); the highest numeric 5-year IDFS and OS rates (84.4% and 92.9%, respectively) were seen in the nab-paclitaxel plus carboplatin group.Conclusions and RelevanceIn this secondary analysis of the WSG-ADAPT-TN randomized clinical trial on tPVs, deescalated nab-paclitaxel plus carboplatin was superior to nab-paclitaxel plus gemcitabine, particularly in patients with BRCA1 and/or BRCA2 tPVs. These findings suggest that BRCA1 and/or BRCA2 tPV status could be a candidate marker for a deescalation strategy in early-stage TNBC; however, prospective validation of survival outcomes in larger cohorts with differentiation between germline and somatic pathogenic variants is necessary.Trial RegistrationClinicalTrials.gov Identifier: NCT01815242

Timing of Palliative Care, End-of-Life Quality Indicators, and Health Resource Utilization

ImportanceDespite research supporting the benefits of early palliative care, timely initiation by gynecologic oncology patients is reportedly low, which may limit the effectiveness of palliative care.ObjectiveTo investigate the association of the timing of palliative care initiation with the aggressiveness of end-of-life care using established quality indicators among patients with ovarian cancer.Design, Setting, and ParticipantsThis population-based retrospective cohort study of ovarian cancer decedents used linked administrative health care data to identify palliative care provision across all health care sectors and health care professionals (specialist and nonspecialist) and end-of-life quality indicators in Ontario, Canada, from 2006 to 2018. Data analyses were performed July 12, 2024.Main Outcomes and MeasuresThe primary outcome was the associations between the timing of palliative care and end-of-life quality indicators, including emergency department use, hospital or intensive care unit admission in the last 30 days of life, chemotherapy in last 14 days of life, death in the hospital, and a composite measure of aggressive care. Late palliative care was defined as 3 months or less prior to death.ResultsThere were 8297 ovarian cancer decedents. Their mean (SD) age at death was 69.6 (13.1) years, and their mean (SD) oncologic survival was 2.8 (3.9) years. Among 3958 patients with known cancer stage, 3495 (88.3%) presented with stage III or IV disease. One-third of patients (2667 [32.1%]) received late palliative care in the final 3 months of life. Results of multivariable regression analysis indicated that any palliative care initiated earlier than 3 months before death was associated with lower rates of aggressive end-of-life care (odds ratio [OR], 0.47 [95% CI, 0.37-0.60]), death in hospital (OR, 0.54 [95% CI, 0.45-0.65]), and intensive care unit admission (OR, 0.46 [95% CI, 0.27-0.76]). Specialist palliative consultation from 3 months up to 6 monts before death was associated with decreased likelihood of late chemotherapy (OR, 0.46 [95% CI, 0.24-0.88]).ConclusionsFindings from this cohort study suggested that early palliative care may be associated with less-aggressive end-of-life care than late palliative care. Implementation strategies for early palliative care initiation are needed to optimize care quality and health resource utilization at the end of life.

Red Blood Cell Transfusion Practices for Patients With Cervical Cancer Undergoing Radiotherapy

Packed red blood cell (PRBC) transfusions are used to treat anemia in patients with cervical cancer undergoing radiotherapy (RT) owing to concerns of hypoxia-induced radioresistance. In the absence of high-quality evidence informing transfusion practices for patients receiving external beam RT (EBRT) and brachytherapy, various arbitrary hemoglobin target levels are used worldwide. To develop consensus statements to guide PRBC transfusion practices in patients with cervical cancer receiving curative-intent RT with EBRT and brachytherapy. This international Delphi consensus study was completed between November 1, 2019, and July 31, 2020. A total of 63 international clinical experts in gynecologic radiation oncology were invited; 39 (62%) accepted and consented to participate. Consensus building was achieved using a 3-round anonymous Delphi consensus method. Participants rated their agreement or disagreement with statements using a 5-point Likert scale. An a priori threshold of 75% or more was required for consensus. The preplanned primary outcome of this study was to assess hemoglobin transfusion thresholds and targets for both EBRT and brachytherapy by expert consensus. Response rates of 100% (39 of 39), 92% (36 of 39), and 97% (35 of 36) were achieved for the first, second, and third rounds of surveys, respectively. Twenty-three experts (59%) practiced in Canada, 11 (28%) in the United States, 3 (8%) in South America, 1 (3%) in Europe, and 1 (3%) in Asia. Consensus was reached for 44 of 103 statements (43%), which were combined to form the final 27-statement consensus guideline. No specific hemoglobin transfusion threshold was agreed on by consensus for EBRT or brachytherapy. By consensus (89% [31 of 35]), a hemoglobin transfusion target for patients who receive a PRBC transfusion should be 9 g/dL or more and less than 12 g/dL. This study presents the first international expert consensus guideline informing PRBC transfusion practices for patients with cervical cancer undergoing EBRT and brachytherapy. A minimum hemoglobin transfusion target of 9 g/dL was endorsed to balance tumor radiosensitivity with appropriate use of a scarce resource. Randomized clinical trials are required to evaluate the optimal transfusion threshold and target that maximize clinical benefit in this patient population.

Uptake and Outcomes of Neoadjuvant Chemotherapy Among US Patients With Less Common Epithelial Ovarian Carcinomas

ImportanceRandomized clinical trials examining the effectiveness of neoadjuvant chemotherapy (NACT) for advanced ovarian cancer predominantly included patients with high-grade serous carcinomas. The use and outcomes of NACT in less common epithelial carcinomas are understudied.ObjectiveTo investigate the uptake and survival outcomes in treatment with NACT for less common histologic subtypes of epithelial ovarian cancer.Design, Setting, and ParticipantsA retrospective cohort study and systematic literature review with meta-analysis was conducted using the National Cancer Database from 2006 to 2017 and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program from 2006 to 2019. Data analysis was performed from July 2022 to April 2023. The evaluation included patients with stage III to IV ovarian cancer with clear cell, mucinous, or low-grade serous histologic subtypes who received multimodal treatment with surgery and chemotherapy.ExposuresExposure assignment per the sequence of treatment: primary debulking surgery (PDS) followed by chemotherapy (PDS group) or NACT followed by interval surgery (NACT group).Main Outcomes and MeasuresTemporal trends and characteristics of NACT use were assessed using multivariable analysis, and overall survival (OS) was assessed with the inverse probability of treatment weighting propensity score.ResultsA total of 3880 patients were examined in the National Cancer Database including 1829 women (median age, 56 [IQR, 49-63] years) with clear cell, 1156 women (median age, 53 [IQR, 42-64] years) with low-grade serous, and 895 women (median age, 57 [IQR, 48-66] years) with mucinous carcinomas. NACT use increased in patients with clear cell (from 10.2% to 16.2%, 58.8% relative increase; P &amp;amp;lt; .001 for trend) or low-grade serous (from 7.7% to 14.2%, 84.4% relative increase; P = .007 for trend) carcinoma during the study period. This association remained consistent in multivariable analysis. NACT use also increased, but nonsignificantly, in mucinous carcinomas (from 8.6% to 13.9%, 61.6% relative increase; P = .07 for trend). Across the 3 histologic subtypes, older age and stage IV disease were independently associated with NACT use. In a propensity score–weighted model, the NACT and PDS groups had comparable OS for clear cell (4-year rates, 31.4% vs 37.7%; hazard ratio [HR], 1.12; 95% CI, 0.95-1.33) and mucinous (27.0% vs 26.7%; HR, 0.90; 95% CI, 0.68-1.19) carcinomas. For patients with low-grade serous carcinoma, NACT was associated with decreased OS compared with PDS (4-year rates, 56.4% vs 81.0%; HR, 2.12; 95% CI, 1.55-2.90). Increasing NACT use and histologic subtype–specific survival association were also found in the Surveillance, Epidemiology, and End Results Program cohort (n = 1447). A meta-analysis of 4 studies, including the current study, observed similar OS associations for clear cell (HR, 1.13; 95% CI, 0.96-1.34; 2 studies), mucinous (HR, 0.93; 95% CI, 0.71-1.21; 2 studies), and low-grade serous (HR, 2.11; 95% CI, 1.63-2.74; 3 studies) carcinomas.Conclusions and RelevanceDespite the lack of data on outcomes of NACT among patients with less common carcinomas, this study noted that NACT use for advanced disease has gradually increased in the US. Primary chemotherapy for advanced-stage, low-grade serous ovarian cancer may be associated with worse survival compared with PDS.

Personalized Decision-Making in Risk-Reducing Surgery of the Ovaries

Importance Premenopausal women at familial or hereditary risk of ovarian cancer must weigh the risks and benefits of risk-reducing surgery. How they navigate this decision is not well understood. Objective To assess the factors that motivate women to seek risk-reducing surgery for ovarian cancer. Design, Setting, and Participants A discrete choice experiment enrolled premenopausal women seeking genetic testing for ovarian cancer risk at 2 tertiary-level cancer centers between August 2019 and January 2022. The experiment was conducted twice, once just prior to pretest counseling and again approximately 2 months later, after receiving results of genetic testing. Data analysis was conducted between June 2022 through January 2026. Main Outcomes and Measures Conjoint analysis to assess factors influencing cancer-prevention decisions in women with risk of familial and hereditary ovarian cancer. Conjoint analysis was used to investigate which attributes were the most salient for women when considering treatment scenarios, with demographic and clinical data as modifiers. Participants were asked to choose between sets of randomly permuted scenarios specifying type of treatment, risk and age of ovarian cancer, risk of heart disease and osteoporosis, and features of menopause. Results The participants included 355 women (median age, 37 years [range, 21-55 years]): 10.4% were Black, 7.6% were Hispanic, 85.1% were White, and 79.2% were college graduates. Family history of breast cancer was reported by 45.1%, ovarian cancer by 13.0%, and 11.3% had a personal history of breast cancer. Women preferred risk-reducing salpingo-oophorectomy (RRSO) to risk-reducing salpingectomy (RRS) or observation (odds ratio [OR], 1.24; 95% CI, 1.10-1.39). Differences in osteoporosis (OR, 0.83; 95% CI, 0.78-0.89) and heart disease (OR, 0.78; 95% CI, 0.73-0.84) risks affected choices. Preferences favored natural menopause (OR, 1.21; 95% CI, 1.11-1.33) and milder menopausal symptoms (OR, 0.66; 95% CI, 0.61-0.70). Family history of ovarian cancer increased preference for RRSO (OR, 1.26; 95% CI, 1.05-1.52), with a reduced effect in older women. Personal breast cancer history, ancestry, and genetic test results were not significant factors. Conclusions and Relevance This survey study using conjoint analysis highlights the ability of women to weigh competing risks in reducing ovarian cancer. Counseling models that address decision complexity and incorporate personalized guidance are likely to improve the decision-making process.

Evaluation of Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy for Stage III Epithelial Ovarian Cancer

Interval cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) showed promising oncologic outcomes for patients with advanced ovarian cancer, but a large-scale, multicenter study to evaluate the efficacy of HIPEC combined with primary cytoreductive surgery (PCS) has yet to be conducted. To compare survival outcomes between PCS with HIPEC vs PCS alone for patients with stage III epithelial ovarian cancer. This cohort study was conducted from January 2010 to May 2017 at 5 high-volume institutions in China. A total of 584 patients with stage III primary epithelial ovarian cancer were treated with either PCS alone or PCS with HIPEC. The median (interquartile range) follow-up period was 42.2 (33.3-51.0) months. Data analysis was conducted from August to December 2019. PCS with HIPEC vs PCS alone. Primary outcomes were median survival time and 3-year overall survival. The inverse probability of treatment weighting (IPTW) method, based on propensity score, was used to control for confounding factors. From a total of 789 patients with stage III epithelial ovarian cancer, 584 patients (74.0%; mean [SD] age, 55.0 [10.5] years) were ultimately included for IPTW in this study. Of the 584 patients, 425 (72.8%) underwent PCS with HIPEC and 159 (27.2%) underwent PCS alone. After IPTW adjustment, the median survival time was 49.8 (95% CI, 45.2-60.2) months for patients undergoing PCS with HIPEC and 34.0 (95% CI, 28.9-41.5) months for patients undergoing PCS alone, and the 3-year overall survival rate was 60.3% (95% CI, 55.3%-65.0%) for patients undergoing PCS with HIPEC and 49.5% (95% CI, 41.0%-57.4%) for patients undergoing PCS alone (weighted hazard ratio, 0.64; 95% CI, 0.50-0.82; P < .001). Further stratified into complete and incomplete surgery subgroups, patients in the PCS with HIPEC group had significantly better survival than those in the PCS group, except for the 3-year overall survival rate in the incomplete subgroup. Among those who underwent complete surgical procedures and comparing those who received PCS with HIPEC vs those who received PCS alone, the median survival time was 53.9 (95% CI, 46.6-63.7) months vs 42.3 (95% CI, 31.1-59.3) months (P = .02), and the 3-year overall survival rate was 65.9% (95% CI, 60.1%-71.2%) vs 55.4% (95% CI, 44.7%-64.8%) (P = .04); meanwhile, among patients who underwent incomplete surgical procedures and comparing those who received PCS with HIPEC vs those who received PCS alone, the median survival time was 29.2 (95% CI, 22.3-45.5) months vs 19.9 (95% CI, 11.6-39.1) months (P = .03), and the 3-year OS rate was 44.3% (95% CI, 34.6%-53.4%) vs 36.7% (95% CI, 23.4%-50.1%) (P = .19). The treatment was well tolerated in both groups. In this study, the PCS with HIPEC treatment approach was associated with better long-term survival. When complete PCS is possible, this approach could be a valuable therapy for patients with stage III epithelial ovarian cancer.

Feasibility and Accuracy of Menstrual Blood Testing for High-risk Human Papillomavirus Detection With Capture Sequencing

High-risk human papillomavirus (hrHPV) persistent infection is the major etiology of cervical precancer and cancer. Noninvasive self-sampling HPV testing is a promising alternative cervical cancer screening for avoiding stigma and improving patient willingness to participate. To investigate the feasibility and accuracy of menstrual blood (MB) hrHPV capture sequencing in hrHPV detection. This cohort study collected 137 sanitary pads from 120 women who were premenopausal and had hrHPV as detected by cervical HPV GenoArray testing. Patients were recruited from September 1, 2020, to April 1, 2021, at Central Hospital of Wuhan, China. Target capture sequencing was performed to determine hrHPV genotypes in MB. Sanger sequencing was performed as the criterion standard for detecting hrHPV genotypes among enrolled women. Data were analyzed from April 1 through June 1, 2021. Complete concordance, incomplete concordance, and discordance of MB hrHPV capture sequencing and conventional HPV testing were defined according to genotype overlapping levels. Concordance of the 2 detection methods and comparative power of MB hrHPV capture sequencing during different menstrual cycle days (MCDs) were the main outcomes. A total of 120 enrolled women with hrHPV (mean [SD; range] age, 33.9 [6.9; 20.0 -52.0] years) provided 137 sanitary pads. The overall concordance rate of MB hrHPV capture sequencing and cervical HPV testing was 92.7% (95% CI, 88.3%-97.1%), with a κ value of 0.763 (P < .001). Among 24 samples with incomplete concordance or discordant results, 11 samples with additional hrHPV genotypes (45.8%), 5 true-negative samples (20.8%), and the correct hrHPV genotypes of 2 samples (8.3%) were correctly identified by MB hrHPV capture sequencing. MB hrHPV detection of hrHPV was equivalent on different MCDs, with an MB hrHPV-positive rate of 27 of 28 patients (96.4%) for MCD 1, 52 of 57 patients (91.2%) for MCD 2, 27 of 28 patients for MCD 3, 4 of 4 patients (100%) for MCD 4, and 3 of 3 patients (100%) for MCD 5 (P = .76). The sensitivity of the MB hrHPV capture sequencing was 97.7% (95% CI, 95.0%-100%). These findings suggest that MB hrHPV capture sequencing is a feasible and accurate self-collected approach for cervical cancer screening. This study found that this method is associated with superior performance in identification of HPV genotypes and true-negative events compared with cervical HPV testing.

Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors

ImportanceMismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti–programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor.ObjectiveTo assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors.Design, Setting, And ParticipantsThe GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability–high (MSI-H) or polymerase epsilon (POLE)–altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months.InterventionsPatients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal.Main Outcomes and MeasuresThe primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1.ResultsThe efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified.Conclusions And RelevanceIn this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need.Trial RegistrationClinicalTrials.gov Identifier: NCT02715284

Classification of High-Grade Serous Ovarian Cancer Using Tumor Morphologic Characteristics

ImportanceDespite similar histologic appearance among high-grade serous ovarian cancers (HGSOCs), clinical observations suggest vast differences in gross appearance. There is currently no systematic framework by which to classify HGSOCs according to their gross morphologic characteristics.ObjectiveTo develop and characterize a gross morphologic classification system for HGSOC.Design, Setting, and ParticipantsThis cohort study included patients with suspected advanced-stage ovarian cancer who presented between April 1, 2013, and August 5, 2016, to the University of Texas MD Anderson Cancer Center, a large referral center. Patients underwent laparoscopic assessment of disease burden before treatment and received a histopathologic diagnosis of HGSOC. Researchers assigning morphologic subtype and performing molecular analyses were blinded to clinical outcomes. Data analysis was performed between April 2020 and November 2021.ExposuresGross tumor morphologic characteristics.Main Outcomes and MeasuresClinical outcomes and multiomic profiles of representative tumor samples of type I or type II morphologic subtypes were compared.ResultsOf 112 women (mean [SD] age 62.7 [9.7] years) included in the study, most patients (84% [94]) exhibited a predominant morphologic subtype and many (63% [71]) had a uniform morphologic subtype at all involved sites. Compared with those with uniform type I morphologic subtype, patients with uniform type II morphologic subtype were more likely to have a favorable Fagotti score (83% [19 of 23] vs 46% [22 of 48]; P = .004) and thus to be triaged to primary tumor reductive surgery. Similarly, patients with uniform type II morphologic subtype also had significantly higher mean (SD) estimated blood loss (639 [559; 95% CI, 391-887] mL vs 415 [527; 95% CI, 253-577] mL; P = .006) and longer mean (SD) operative time (408 [130; 95% CI, 350-466] minutes vs 333 [113; 95% CI, 298-367] minutes; P = .03) during tumor reductive surgery. Type I tumors had enrichment of epithelial-mesenchymal transition (false discovery rate [FDR] q-value, 3.10 × 10−24), hypoxia (FDR q-value, 1.52 × 10−5), and angiogenesis pathways (FDR q-value, 2.11 × 10−2), whereas type II tumors had enrichment of pathways related to MYC signaling (FDR q-value, 2.04 × 10−9) and cell cycle progression (FDR q-value, 1.10 × 10−5) by integrated proteomic and transcriptomic analysis. Abundances of metabolites and lipids also differed between the 2 morphologic subtypes.Conclusions and RelevanceThis study identified 2 novel, gross morphologic subtypes of HGSOC, each with unique clinical features and molecular signatures. The findings may have implications for triaging patients to surgery or chemotherapy, identifying outcomes, and developing tailored therapeutic strategies.

Use of Germline BRCA Testing in Patients With Ovarian Cancer and Commercial Insurance

This cross-sectional study evaluates changes in the rate of germline BRCA testing among patients with ovarian cancer between 2008 and 2018 and analyzes factors associated with testing rates.

Oncological Outcomes After Okabayashi-Kobayashi Radical Hysterectomy for Early and Locally Advanced Cervical Cancer

The role of surgery in early-stage cervical cancer has been established, but it is controversial in locally advanced cervical cancer. To determine whether a radical hysterectomy method with extended removal of paracervical tissue for locally advanced cervical cancer is associated with satisfactory oncological outcomes. This retrospective cohort study was conducted from January 1, 2002, to December 31, 2011, and participants were patients with cervical cancer at a single tertiary center in Northern Japan. The median follow-up period was 106 months, and none of the patients were lost to follow-up at less than 60 months. Data analyses were performed from July 1, 2017, to December 31, 2018. Patients underwent radical hysterectomy using the Okabayashi-Kobayashi method. Bilateral nerve preservation was used for stage IB1/IB2 disease and unilateral nerve preservation for stage IIA/IIB if disease extension outside the uterine cervix was 1-sided. Chemotherapy was used as the choice of adjuvant treatment for patients with an intermediate or high risk of recurrence, while some patients chose or were assigned to radiotherapy. Primary outcomes were the 5-year local control rate and 5-year overall survival rate along with risk factor analysis. Of 121 consecutive patients, 76 (62.8%) had early-stage cervical cancer in 2008 International Federation of Gynecology and Obstetrics stages IB1 and IIA1 and 45 (37.2%) had locally advanced cervical cancer in stages IB2, IIA2, and IIB. The median (range) age was 42 (26-68) years. Adjuvant radiotherapy was used in 2 patients (3%) with early-stage cervical cancer and 3 (7%) of those with locally advanced cervical cancer. The 5-year local control rates for early-stage cervical cancer and locally advanced cervical cancer were 99% and 87%, respectively. The 5-year overall survival rates for early-stage cervical cancer and locally advanced cervical cancer were 95% and 82%, respectively. Cox regression analysis showed that lymph node metastasis and histology of adeno(squamous)carcinoma were independent risk factors for the overall survival of patients with cervical cancer treated with radical hysterectomy. The nerve-sparing Okabayashi-Kobayashi radical hysterectomy for locally advanced cervical cancer may provide survival not inferior to radical hysterectomy or radiotherapy in published literature. The applicability of radical hysterectomy with adjuvant chemotherapy for locally advanced cervical cancer needs to be validated by prospective comparative trials.

Effect of an Intervention in General Practice to Increase the Participation of Immigrants in Cervical Cancer Screening

Immigrant women have lower participation in cervical cancer screening (CCS) programs. At the same time, some groups of immigrants have higher prevalence of cervical cancer. Targeted interventions are therefore necessary. To determine whether an intervention among general practitioners (GPs) could influence immigrant women's participation in the Norwegian CCS program. Cluster-randomized clinical trial using the 20 subdistricts of the Bergen, Norway, municipality as clusters. The clusters were matched in 10 pairs according to the number of immigrant women living in them and randomized thereafter. The intervention was implemented between January and June 2017 among urban, primary care, general practices in Bergen. Follow-up ended in January 2018. General practices belonging to the control areas continued treatment as usual. A total of 10 360 women who attended 73 general practices in the 20 subdistricts were included as participants. The intervention consisted of 3 elements: an educational session for GPs at lunch describing the importance of CCS among immigrants and giving advice about how to invite them to participate, a mouse pad as a reminder, and a poster placed in waiting rooms. In the educational session, we elaborated the need for GPs to ask every immigrant woman about CCS, regardless of their reason for contacting their GP. The main outcome, screening status of immigrant women by January 1, 2018, was obtained from the Norwegian Cancer Registry. The effect of the intervention was measured as odds ratio (OR) for CCS status as of January 1, 2018, for the intervention group vs the control group, with 3 levels of adjustments: baseline CCS status at January 1, 2017 (model 1), additional adjustment for women's age, marital status, income level, and region of origin (model 2), and further adjustment for the GP's sex, age, and region of origin (model 3). Two subgroup analyses, screening status at baseline and women's country of origin, were conducted to assess whether these factors had any influence on the effect of the intervention. Data were analyzed as intention to treat. A total of 10 360 immigrant women, 5227 (50.4%; mean [SD] age, 44.0 [12.0] years) in the intervention group and 5133 (49.6%; mean [SD] age, 44.5 [11.6] years) in the control group, belonging to 39 general practices in the intervention area and 34 in the control area, were included in the study. The proportion of immigrant women screened increased by 2.6% in the intervention group and 0.6% in the control group. After adjustment for screening status at baseline, women in the intervention group were more likely to have participated in CCS (OR, 1.24 [95% CI, 1.11-1.38]). This statistically significant effect remained unchanged after adjustment for women's characteristics (OR, 1.24 [95% CI, 1.11-1.38]) and was reduced, but still significant, after further adjustment for GP characteristics (OR, 1.19 [95% CI, 1.06-1.34]). In subgroup analyses, the intervention particularly increased participation among women who were not previously screened at baseline (OR, 1.35 [95% CI, 1.16-1.56]), and those from Poland, Pakistan, and Somalia (OR, 1.74 [95% CI, 1.17-2.61]) when adjusting for baseline screening status. Our intervention targeting general practices significantly increased CCS participation among immigrants, although the absolute effect size of 2% in the fully adjusted model was small. Engaging other primary health professionals such as midwives to perform CCS could further contribute to increasing participation. ClinicalTrials.gov Identifier: NCT03155581.

Overuse of Cervical Cancer Screening Tests Among Women With Average Risk in the United States From 2013 to 2014

While cervical cancer screening with cytologic and human papillomavirus (HPV) testing has reduced mortality from cervical cancer, overuse of these tests is associated with downstream psychological and medical consequences, as well as significant costs. Guidelines now recommend less frequent testing, although adherence to these recommendations is uncertain. To determine the frequency of overuse of cervical cancer screening tests. This cohort study included 2 299 177 women aged 30 to 65 years recorded in the MarketScan database who underwent cervical cancer screening with cervical cytologic testing, cotesting, or primary HPV testing in 2013 through 2014. Women were followed-up for 3 years, and use of repeat testing during this period was noted. Clinical and demographic characteristics associated with overuse of screening and the association between screening and performance of routine gynecologic examinations were recorded. Data were analyzed from June 15 to September 15, 2020. Cumulative performance of overuse of cervical cancer screening with repeat cytologic or HPV testing within 36 months of the index screening test. A total of 2 299 177 women with a median (interquartile range) age of 47 (39-54) years were identified. Initial cervical cancer screening consisted of cytologic testing alone in 1 286 179 women (55.9%), cotesting in 991 583 women (43.1%) and HPV testing in 21 415 women (0.9%). The cumulative incidence of repeat cervical cancer screening was 17.7% (95% CI, 17.6%-17.7%) at 12 months, 51.1% (95% CI, 51.0%-51.2%) at 24 months and 65.8% (65.7%-65.8%) at 36 months. Repeat screening was less common in older women (32 198 women [60.2%] aged 60-64 years vs 194 665 women [67.8%] aged 30-39 years; P < .001), women with medical comorbidities (125 197 women [64.1%] with ≥2 comorbidities vs 423 012 women [64.7%] with no comorbidities; P < .001), women screened in 2014 (176 734 women [53.4%] in 2014 vs 555 767 women [69.4%] in 2013; P < .001), and those screened with cotesting (277 032 women [56.9%] for cotesting vs 450 438 [71.2%] for cytologic testing; P < .001). In contrast, overuse of testing was more common in the Northeastern US (143 916 women [68.1%] in the Northeast vs 81 552 women [51.6%] in the West; P < .001), in women with more frequent outpatient visits (238 510 women [71.1%] with ≥6 visits vs 279 412 [58.7%] with ≤2 visits; P < .001). Women with a sexually transmitted infection after their index testing were also more likely to undergo repeat testing (adjusted odds ratio, 1.42 [95% CI, 1.21-1.68]). Women who did not undergo repeat screening were significantly less likely to undergo a gynecological exam after the index screening test: during year 2 of follow-up, 657 749 women (96.7%) who underwent repeating screening had a gynecological examination compared with 203 566 women (26.2%) who did not undergo a gynecological examination. These findings suggest that among commercially insured women with average risk, cervical cancer screening tests were frequently overused.

Evaluation of Cervical Cancer Screening Uptake and Adherence Among Women Without Human Papillomavirus Vaccination in the US

This cross-sectional study compares uptake rates of cervical cancer screening and adherence among US women who were vaccinated for human papillomavirus vs those who were not vaccinated.

Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes

ImportanceThirteen human malignant neoplasms have been identified as obesity-associated cancers (OACs), ie, the presence of excess body fat is associated with increased risk of developing cancer and worse prognosis in patients with these specific tumors. The glucagon-like peptide receptor agonist (GLP-1RA) class of pharmaceuticals are effective agents for the treatment of type 2 diabetes (T2D) and for achieving weight loss, but the association of GLP-1RAs with the incident risk of 13 OACs is unclear.ObjectiveTo compare the incident risk of each of the 13 OACs in patients with T2D who were prescribed GLP-1RAs vs insulins or metformin.Design, Setting, and ParticipantsThis retrospective cohort study was based on a nationwide multicenter database of electronic health records (EHRs) of 113 million US patients. The study population included 1 651 452 patients with T2D who had no prior diagnosis of OACs and were prescribed GLP-1RAs, insulins, or metformin during March 2005 to November 2018. Data analysis was conducted on April 26, 2024.ExposuresPrescription of GLP-1RAs, insulins, or metformin.Main Outcomes and MeasuresIncident (first-time) diagnosis of each of the 13 OACs occurring during a 15-year follow-up after the exposure was examined using Cox proportional hazard and Kaplan-Meier survival analyses with censoring applied. Hazard ratios (HRs), cumulative incidences, and 95% CIs were calculated. All models were adjusted for confounders at baseline by propensity-score matching baseline covariates.ResultsIn the study population of 1 651 452 patients with T2D (mean [SD] age, 59.8 [15.1] years; 827 873 [50.1%] male and 775 687 [47.0%] female participants; 5780 [0.4%] American Indian or Alaska Native, 65 893 [4.0%] Asian, 281 242 [17.0%] Black, 13 707 [0.8%] Native Hawaiian or Other Pacific Islander, and 1 000 780 [60.6%] White participants), GLP-1RAs compared with insulin were associated with a significant risk reduction in 10 of 13 OACs, including in gallbladder cancer (HR, 0.35; 95% CI, 0.15-0.83), meningioma (HR, 0.37; 95% CI, 0.18-0.74), pancreatic cancer (HR, 0.41; 95% CI, 0.33-0.50), hepatocellular carcinoma (HR, 0.47; 95% CI, 0.36-0.61), ovarian cancer (HR, 0.52; 95% CI, 0.03-0.74), colorectal cancer (HR, 0.54; 95% CI, 0.46-0.64), multiple myeloma (HR, 0.59; 95% CI, 0.44-0.77), esophageal cancer (HR, 0.60; 95% CI, 0.42-0.86), endometrial cancer (HR, 0.74; 95% CI, 0.60-0.91), and kidney cancer (HR, 0.76; 95% CI, 0.64-0.91). Although not statistically significant, the HR for stomach cancer was less than 1 among patients who took GLP-1RAs compared with those who took insulin (HR, 0.73; 95% CI, 0.51-1.03). GLP-1RAs were not associated with a reduced risk of postmenopausal breast cancer or thyroid cancer. Of those cancers that showed a decreased risk among patients taking GLP-1RAs compared with those taking insulin, HRs for patients taking GLP-1RAs vs those taking metformin for colorectal and gallbladder cancer were less than 1, but the risk reduction was not statistically significant. Compared with metformin, GLP-1RAs were not associated with a decreased risk of any cancers, but were associated with an increased risk of kidney cancer (HR, 1.54; 95% CI, 1.27-1.87).Conclusions and RelevanceIn this study, GLP-1RAs were associated with lower risks of specific types of OACs compared with insulins or metformin in patients with T2D. These findings provide preliminary evidence of the potential benefit of GLP-1RAs for cancer prevention in high-risk populations and support further preclinical and clinical studies for the prevention of certain OACs.

Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer

ImportancePathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed.ObjectiveTo estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs.Design, Setting, and ParticipantsIn this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed.ExposuresCSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention.Main Outcomes and MeasuresThe incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated.ResultsIn the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were −£1942/QALY (−$2680/QALY), −£89/QALY (−$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs.Conclusions and RelevanceIn this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

Racial and Ethnic Disparities in Clinical Trial Enrollment Among Women With Gynecologic Cancer

ImportanceRacial and ethnic disparities in clinical trial enrollment are unjust and hinder development of new cancer treatments.ObjectiveTo examine the association of race and ethnicity with clinical trial enrollment among women with endometrial, ovarian, or cervical cancer.Design, Setting, and ParticipantsThis retrospective cohort study used data from the National Cancer Database, a hospital-based cancer registry, and the Surveillance, Epidemiology, and End Results Program (SEER), a population-based cancer registry. Population-based race and ethnicity–specific proportions for each cancer site were derived from SEER. Participants included women with an endometrial, ovarian, or cervical cancer diagnosed from 2004 to 2019. Analyses were performed from February 2 to June 14, 2023.ExposureRace and ethnicity were categorized as American Indian/Alaska Native, Asian, Black, Hispanic (any race), Native Hawaiian/Pacific Islander, White, and other (not defined in the National Cancer Database).Main Outcomes and MeasuresThe primary outcomes were the odds of clinical trial enrollment and representation in clinical trials compared with the US population. Multivariable-adjusted logistic regression was used to estimate odds ratios (ORs) and 95% CIs for associations of race and ethnicity with clinical trial enrollment within the National Cancer Database sample. Participation-to-prevalence ratios (PPRs) according to diagnosis period (2004-2011 vs 2012-2019) were calculated by dividing the race and ethnicity–specific percentage of clinical trial participants in the study sample by the percentage of racial and ethnic groups in SEER.ResultsAmong 562 592 patients with gynecologic cancer (mean [SD] age at diagnosis, 62.9 [11.3] years), 1903 were American Indian/Alaska Native, 18 680 were Asian, 56 421 were Black, 38 145 were Hispanic, 1453 were Native Hawaiian/Pacific Islander, 442 869 were White, and 3121 were other race and ethnicity. Only 548 (&amp;amp;lt;1%) were enrolled in clinical trials. Compared with White women, clinical trial enrollment was lower for Asian (OR, 0.44; 95% CI, 0.25-0.78), Black (OR, 0.70; 95% CI, 0.50-0.99), and Hispanic (OR, 0.53; 95% CI, 0.33-0.83) women. Compared with the US population, White women were adequately or overrepresented for all cancer types (PPRs ≥1.1), Black women were adequately or overrepresented for endometrial and cervical cancers (PPRs ≥1.1) but underrepresented for ovarian cancer (PPR ≤0.6), and Asian and Hispanic women were underrepresented among all 3 cancer types (PPRs ≤0.6).Conclusions and RelevanceIn this cohort of patients with gynecologic cancer, clinical trial enrollment was lower among certain minoritized racial and ethnic groups. Continued efforts are needed to address disparate clinical trial enrollment among underrepresented groups.

Development, Implementation, and Evaluation of a Distance Learning and Telementoring Program for Cervical Cancer Prevention in Cameroon

ImportanceAlthough Africa has the highest burden of cervical cancer in the world, educational resources to achieve the 90-70-90 targets set by the World Health Organization in its strategy to eliminate cervical cancer are lacking in the region.ObjectivesTo adapt, implement, and evaluate the Project Extension for Community Health Care Outcomes (ECHO), an innovative learning tool, to build capacity of clinicians to better incorporate new evidence-based guidelines into cervical cancer control policies and clinical practices.Design, Setting, and ParticipantsThis cross-sectional study assessed knowledge and practices of clinicians and support staff regarding cervical cancer prevention and control and compared them among respondents who had attended Project ECHO sessions (prior ECHO attendees) with those who had not but were planning on attending in the near future (newcomers) as part of the Cameroon Cervical Cancer Prevention Project ECHO. Satisfaction of prior ECHO attendees was also evaluated. Data were analyzed from January to March 2022.Main Outcomes and MeasuresMain outcomes were practices and knowledge regarding cervical cancer education and prevention and preinvasive management procedures compared among prior ECHO attendees and newcomers.ResultsOf the 75 participants (mean [SD] age, 36.4 [10.0] years; 65.7% [95% CI, 54.3%-77.1%] women) enrolled in this study, 41 (54.7%; 95% CI, 43.1%-66.2%) were prior ECHO attendees, and most were clinicians (55 respondents [78.6%; 95% CI, 68.7%-88.4%]). Overall, 50% (95% CI, 37.8%-62.2%) of respondents reported performing cervical cancer screening with visual inspection of the cervix after application of acetic acid (VIA) and/or visual inspection of the cervix after application of Lugol’s iodine (VILI), 46.3% (95% CI, 34.0%-58.5%) of respondents reported performing human papillomavirus (HPV) testing, and 30.3% (95% CI, 18.9%-41.7%) of respondents reported performing cervical cytological examination in their practices, Approximately one-fourth of respondents reported performing cryotherapy (25.4% [95% CI, 14.7%-36.1%]), thermal ablation (27.3% [95% CI, 16.2%-38.3%]) or loop electrosurgical excisional procedure (LEEP, 25.0% [95% CI, 14.4%-35.6%]) for treatment of preinvasive disease. The clinical use of many of these screening and treatment tools was significantly higher among prior ECHO attendees compared with newcomers (VIA/VILI: 63.2% [95% CI, 47.4%-78.9%] vs 33.3% [95% CI, 16.0%-50.6%]; P = .03; cryotherapy: 40.5% [95% CI, 24.3%-56.8%] vs 6.7% [95% CI, 0.0%-15.8%]; P = .002; thermal ablation: 43.2% [95% CI, 26.9%-59.6%] vs 6.9% [95% CI, 0.0%-16.4%]; P = .002). Knowledge about cervical cancer education, prevention, and management procedures was satisfactory in 36.1% (95% CI, 23.7%-48.5%) of respondents; this proportion was significantly higher among prior ECHO attendees (53.8% [95% CI, 37.7%-69.9%]) compared with newcomers (4.5% [95% CI, 0.0%-13.5%]; P &amp;amp;lt; .001). Approximately two-thirds of participants (68.8% [95% CI, 51.8%-85.8%]) reported that they had applied knowledge learned in our ECHO sessions to patient care in their practice or adopted best-practice care through their participation in this ECHO program.Conclusions and RelevanceThese findings suggest that the Project ECHO e-learning and telementoring program was associated with improved skills for clinicians and support staff and enhanced quality of care for patients. In the COVID-19 era and beyond, reinforced efforts to strengthen cervical cancer knowledge and best practices through distance learning and collaboration are needed.

Risk of Endometrial Polyps, Hyperplasia, Carcinoma, and Uterine Cancer After Tamoxifen Treatment in Premenopausal Women With Breast Cancer

ImportanceThe association of tamoxifen use with the risk of uterine diseases, such as endometrial cancer, in premenopausal women with breast cancer remains controversial. However, many studies have reported an increased risk of uterine disease among postmenopausal tamoxifen users.ObjectiveTo investigate the association of tamoxifen use with the risk of endometrial cancer and other uterine diseases in premenopausal women with breast cancer.Design, Setting, and ParticipantsA nationwide, population-based, retrospective longitudinal cohort study with an 18-year study period was conducted using data obtained from the Korean National Health Insurance Service. Participants included premenopausal women aged 20 to 50 years with breast cancer diagnoses between January 2003 and December 2018. Data were analyzed from April to December 2021.ExposuresTamoxifen treatment.Main Outcomes and MeasuresThe incidence of uterine diseases, including endometrial cancer, hyperplasia, polyps, and other uterine cancers, was identified in the study cohort using insurance claim codes. The incidence of uterine diseases per 1000 person-years was compared between women receiving tamoxifen and those not treated with adjuvant hormone therapy. Multivariable Cox proportional hazard regression analysis was performed to determine the risk of each uterine disease.ResultsAmong 78 320 female participants with a mean (SD) age of 42.1 (6.1) years, 34 637 (44.2%) were categorized into the tamoxifen group and 43 683 (55.8%) were categorized into the control group. Among tamoxifen users, during the mean (SD) follow-up duration of 6.13 (4.15) years, the incidence of newly diagnosed endometrial polyps was 20.13 cases per 1000 person-years, that of endometrial hyperplasia was 13.49 cases per 1000 person-years, that of endometrial cancer was 2.01 cases per 1000 person-years, and that of other uterine cancers was 0.45 cases per 1000 person-years. The risk of endometrial cancer was higher in the tamoxifen group than in the control group (hazard ratio, 3.77; 95% CI, 3.04-4.66) after adjusting for age, body mass index, history of diabetes, hypertension, dyslipidemia, polycystic ovary syndrome, gonadotropin-releasing hormone agonist treatment, and trastuzumab treatment.Conclusions and RelevanceIn this longitudinal cohort study, premenopausal Korean women with breast cancer who received tamoxifen as adjuvant hormone therapy had a significantly increased risk of endometrial hyperplasia, polyps, carcinoma, and other uterine cancers compared with those who were not treated with adjuvant hormone therapy. These findings suggest that clinicians should consider the risk of uterine disease among tamoxifen users, including premenopausal women.