JAMA Oncology

Risk Model–Based Lung Cancer Screening and Racial and Ethnic Disparities in the US

ImportanceThe revised 2021 US Preventive Services Task Force (USPSTF) guidelines for lung cancer screening have been shown to reduce disparities in screening eligibility and performance between African American and White individuals vs the 2013 guidelines. However, potential disparities across other racial and ethnic groups in the US remain unknown. Risk model–based screening may reduce racial and ethnic disparities and improve screening performance, but neither validation of key risk prediction models nor their screening performance has been examined by race and ethnicity.ObjectiveTo validate and recalibrate the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012) model—a well-established risk prediction model based on a predominantly White population—across races and ethnicities in the US and evaluate racial and ethnic disparities and screening performance through risk-based screening using PLCOm2012 vs the USPSTF 2021 criteria.Design, Setting, and ParticipantsIn a population-based cohort design, the Multiethnic Cohort Study enrolled participants in 1993-1996, followed up through December 31, 2018. Data analysis was conducted from April 1, 2022, to May 19. 2023. A total of 105 261 adults with a smoking history were included.ExposuresThe 6-year lung cancer risk was calculated through recalibrated PLCOm2012 (ie, PLCOm2012-Update) and screening eligibility based on a 6-year risk threshold greater than or equal to 1.3%, yielding similar eligibility as the USPSTF 2021 guidelines.OutcomesPredictive accuracy, screening eligibility-incidence (E-I) ratio (ie, ratio of the number of eligible to incident cases), and screening performance (sensitivity, specificity, and number needed to screen to detect 1 lung cancer).ResultsOf 105 261 participants (60 011 [57.0%] men; mean [SD] age, 59.8 [8.7] years), consisting of 19 258 (18.3%) African American, 27 227 (25.9%) Japanese American, 21 383 (20.3%) Latino, 8368 (7.9%) Native Hawaiian/Other Pacific Islander, and 29 025 (27.6%) White individuals, 1464 (1.4%) developed lung cancer within 6 years from enrollment. The PLCOm2012-Update showed good predictive accuracy across races and ethnicities (area under the curve, 0.72-0.82). The USPSTF 2021 criteria yielded a large disparity among African American individuals, whose E-I ratio was 53% lower vs White individuals (E-I ratio: 9.5 vs 20.3; P < .001). Under the risk-based screening (PLCOm2012-Update 6-year risk ≥1.3%), the disparity between African American and White individuals was substantially reduced (E-I ratio: 15.9 vs 18.4; P < .001), with minimal disparities observed in persons of other minoritized groups, including Japanese American, Latino, and Native Hawaiian/Other Pacific Islander. Risk-based screening yielded superior overall and race and ethnicity–specific performance to the USPSTF 2021 criteria, with higher overall sensitivity (67.2% vs 57.7%) and lower number needed to screen (26 vs 30) at similar specificity (76.6%).ConclusionsThe findings of this cohort study suggest that risk-based lung cancer screening can reduce racial and ethnic disparities and improve screening performance across races and ethnicities vs the USPSTF 2021 criteria.

Remotely Delivered Cancer Genetic Testing in the Making Genetic Testing Accessible (MAGENTA) Trial

ImportanceRequiring personalized genetic counseling may introduce barriers to cancer risk assessment, but it is unknown whether omitting counseling could increase distress.ObjectiveTo assess whether omitting pretest and/or posttest genetic counseling would increase distress during remote testing.Design, Setting, and ParticipantsMaking Genetic Testing Accessible (MAGENTA) was a 4-arm, randomized noninferiority trial testing the effects of individualized pretest and/or posttest genetic counseling on participant distress 3 and 12 months posttest. Participants were recruited via social and traditional media, and enrollment occurred between April 27, 2017, and September 29, 2020. Participants were women aged 30 years or older, English-speaking, US residents, and had access to the internet and a health care professional. Previous cancer genetic testing or counseling was exclusionary. In the family history cohort, participants had a personal or family history of breast or ovarian cancer. In the familial pathogenic variant (PV) cohort, participants reported 1 biological relative with a PV in an actionable cancer susceptibility gene. Data analysis was performed between December 13, 2020, and May 31, 2023.InterventionParticipants completed baseline questionnaires, watched an educational video, and were randomized to 1 of 4 arms: the control arm with pretest and/or posttest genetic counseling, or 1 of 3 study arms without pretest and posttest counseling. Genetic counseling was provided by phone appointments and testing was done using home-delivered saliva kits.Main Outcomes and MeasuresThe primary outcome was participant distress measured by the Impact of Event Scale 3 months after receiving the results. Secondary outcomes included completion of testing, anxiety, depression, and decisional regret.ResultsA total of 3839 women (median age, 44 years [range 22-91 years]), most of whom were non-Hispanic White and college educated, were randomized, 3125 in the family history and 714 in the familial PV cohorts. In the primary analysis in the family history cohort, all experimental arms were noninferior for distress at 3 months. There were no statistically significant differences in anxiety, depression, or decisional regret at 3 months. The highest completion rates were seen in the 2 arms without pretest counseling.Conclusions and RelevanceIn the MAGENTA clinical trial, omitting individualized pretest counseling for all participants and posttest counseling for those without PV during remote genetic testing was not inferior with regard to posttest distress, providing an alternative care model for genetic risk assessment.Trial RegistrationClinicalTrials.gov Identifier: NCT02993068

Incidence of Cervical Cancer in Puerto Rico, 2001-2017

This cohort study examines recent trajectories in the incidence of cervical cancer in Puerto Rico by age and among birth cohorts.

What Is the Optimal Treatment for Vulnerable Older Women With Ovarian Cancer?

Adjuvant Chemoradiotherapy vs Radiotherapy Alone for Patients With Intermediate-Risk Cervical Cancer

ImportanceOptimal adjuvant treatment for patients with intermediate-risk cervical cancer remains controversial, and the benefit of adding chemotherapy to radiotherapy in this population is uncertain.ObjectiveTo evaluate whether adjuvant chemoradiotherapy is associated with improved overall survival compared with radiotherapy alone in patients with intermediate-risk cervical cancer. Secondary objectives included identifying clinical factors associated with the use of chemoradiotherapy.Design, Setting, and ParticipantsA cohort study was conducted at Commission on Cancer–accredited centers across the US using prospectively collected data from the National Cancer Database that focused on patients with a diagnosis of 2018 International Federation of Gynecology and Obstetrics stage IB cervical carcinoma (squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma) of intermediate risk who were undergoing adjuvant radiotherapy treatment after radical hysterectomy from January 2010 through December 2020. Missing variables were multiple imputed, and propensity score matching (1:1) was performed to balance baseline characteristics. A Kaplan-Meier analysis and proportional hazard models were used to compare the hazard of death between the groups.ExposureAdjuvant radiotherapy alone vs concurrent chemoradiotherapy.Main Outcome and MeasureThe primary outcome was time to death or last follow-up.ResultsA total of 1116 patients (mean [SD] age, 47 [12] years) were identified, of whom 486 (43.5%) received concurrent chemoradiotherapy. Chemotherapy was administered more frequently among those with adenocarcinoma or adenosquamous histology compared with squamous cell carcinoma (risk ratio [RR], 1.26; 95% CI, 1.10-1.44) and those with tumors larger than 4 cm (compared with tumors measuring 2-4 cm; RR, 1.31; 95% CI, 1.14-1.51). Propensity score matching yielded a cohort of 868 patients with balanced covariates. Patients who received chemoradiotherapy had similar overall survival (5- year survival, 87%) as those who received radiotherapy alone (5-year survival, 87%; hazard ratio, 0.85; 95% CI, 0.59-1.23; P = .38). There were no significant differences in survival associated with chemotherapy receipt among subgroups defined by tumor size, histology, presence of lymphovascular space invasion, surgical approach, or receipt of adjuvant brachytherapy.Conclusions and RelevanceThe results of this cohort study suggest that adding chemotherapy to radiotherapy was not associated with improved overall survival for patients with intermediate-risk cervical cancer.

Cervical Cancer Incidence in the US-Affiliated Pacific Islands

ImportanceThe World Health Organization has called for eliminating cervical cancer as a public health problem. Accurate and up-to-date estimates of population-based cervical cancer incidence are essential for monitoring progress toward elimination and informing local cancer control strategies, but these estimates are lacking for the US-Affiliated Pacific Islands (USAPI).ObjectiveTo calculate age-standardized incidence rates for cervical cancer in the 6 USAPI and compare these rates with rates in the US (50 states and the District of Columbia).Design, Setting, and ParticipantsThis cross-sectional study used population-based data from the Pacific Regional Central Cancer Registry for women aged 20 years or older who were diagnosed with invasive cervical cancer from January 1, 2007, to December 31, 2020. The registry comprises data on all cervical cancers from the USAPI, which include 3 US territories (American Samoa, Commonwealth of the Northern Mariana Islands, and Guam) and 3 freely associated states (Federated States of Micronesia [FSM], Republic of the Marshall Islands [RMI], and Republic of Palau). Data were analyzed from July 10, 2023, to November 28, 2023.Main Outcomes and MeasuresThe main outcome was age-standardized cervical cancer incidence rates, stratified by age, stage, and histologic code for the USAPI using population estimates from 3 different sources (US Census Bureau International Database, United Nations Population Division, and Pacific Data Hub). Rate ratios were calculated to compare incidence rates between the USAPI and the US.ResultsFrom 2007 to 2020, 409 cases of cervical cancer were diagnosed in the USAPI (median age at diagnosis, 46.0 years [25th-75th percentile, 39.0-55.0 years]), with an age-standardized incidence rate ranging from 21.7 (95% CI, 19.6-23.9) to 22.1 (95% CI, 20.0-24.4) per 100 000 women, depending on the population estimate. Incidence rates were highest in RMI, ranging from 58.1 (95% CI, 48.0-69.7) to 83.4 (95% CI, 68.3-101.0) per 100 000 women, followed by FSM, ranging from 28.7 (95% CI, 23.4-34.9) to 29.8 (95% CI, 24.3-36.3) per 100 000 women. Compared with the US, incidence rates were highest in RMI (rate ratio, 5.7 [95% CI, 4.7-6.8] to 8.2 [95% CI, 6.7-9.9]) and FSM (rate ratio; 2.8; 95% CI, 2.3-3.4). Of all cases in the USAPI, 213 (68.2%) were diagnosed at a late stage.Conclusions and RelevanceIn this cross-sectional study, cervical cancer remained a major public health issue in some USAPI, with RMI reporting the highest incidence rates. The findings suggest that improvements in human papillomavirus vaccination and cancer screening coverage through efforts tailored to the unique geographic, sociocultural, economic, and health care landscape of the USAPI may reduce the burden of cervical cancer.

Population-Based Incidence of Cervical Intraepithelial Neoplasia Across 14 Years of HPV Vaccination

This cohort study examines the incidence of cervical intraepithelial neoplasia during a period of increasing human papillomavirus (HPV) vaccination coverage from 2007 to 2020.

Vaccinia (Smallpox) for the Treatment of Ovarian Cancer—Turning an Old Foe Into a Friend?

Clinical Activity of Olvimulogene Nanivacirepvec–Primed Immunochemotherapy in Heavily Pretreated Patients With Platinum-Resistant or Platinum-Refractory Ovarian Cancer

ImportancePatients with platinum-resistant or platinum-refractory ovarian cancer (PRROC) have limited therapeutic options, representing a considerable unmet medical need.ObjectiveTo assess antitumor activity and safety of intraperitoneal (IP) olvimulogene nanivacirepvec (Olvi-Vec) virotherapy and platinum-based chemotherapy with or without bevacizumab in patients with PRROC.Design, Setting, and ParticipantsThis open-label, nonrandomized multisite phase 2 VIRO-15 clinical trial enrolled patients with PRROC with disease progression following their last prior line of therapy from September 2016 to September 2019. Data cutoff was on March 31, 2022, and data were analyzed between April 2022 and September 2022.InterventionsOlvi-Vec was administered via a temporary IP dialysis catheter as 2 consecutive daily doses (3 × 109 pfu/d) followed by platinum-doublet chemotherapy with or without bevacizumab.Main Outcomes and MeasuresPrimary outcomes were objective response rate (ORR) via Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) and cancer antigen 125 (CA-125) assay, and progression-free survival (PFS). Secondary outcomes included duration of response (DOR), disease control rate (DCR), safety, and overall survival (OS).ResultsTwenty-seven heavily pretreated patients with platinum-resistant (n = 14) or platinum-refractory (n = 13) ovarian cancer were enrolled. The median (range) age was 62 (35-78) years. The median (range) prior lines of therapy were 4 (2-9). All patients completed both Olvi-Vec infusions and chemotherapy. Median follow-up duration was 47.0 months (95% CI, 35.9 months to NA). Overall, ORR by RECIST 1.1 was 54% (95% CI, 33%-74%), with a DOR of 7.6 months (95% CI, 3.7-9.6 months). The DCR was 88% (21/24). The ORR by CA-125 was 85% (95% CI, 65%-96%). Median PFS by RECIST 1.1 was 11.0 months (95% CI, 6.7-13.0 months), and the PFS 6-month rate was 77%. Median PFS was 10.0 months (95% CI, 6.4-NA months) in the platinum-resistant group and 11.4 months (95% CI, 4.3-13.2 months) in the platinum-refractory group. The median OS was 15.7 months (95% CI, 12.3-23.8 months) in all patients, with a median OS of 18.5 months (95% CI, 11.3-23.8 months) in the platinum-resistant group and 14.7 months (95% CI, 10.8-33.6 months) in the platinum-refractory group. Most frequent treatment-related adverse events (TRAEs) (any grade, grade 3) were pyrexia (63.0%, 3.7%, respectively) and abdominal pain (51.9%, 7.4%, respectively). There were no grade 4 TRAEs, and no treatment-related discontinuations or deaths.Conclusions and RelevanceIn this phase 2 nonrandomized clinical trial, Olvi-Vec followed by platinum-based chemotherapy with or without bevacizumab as immunochemotherapy demonstrated promising ORR and PFS with a manageable safety profile in patients with PRROC. These hypothesis-generating results warrant further evaluation in a confirmatory phase 3 trial.Trial RegistrationClinicalTrials.gov Identifier: NCT02759588

Advances in Ovarian Cancer Care and Unmet Treatment Needs for Patients With Platinum Resistance

ImportancePlatinum-based chemotherapy has been the standard of care for ovarian cancer for the past 3 decades. Although most patients respond to platinum-based treatment, emergence of platinum resistance in recurrent ovarian cancer is inevitable during the disease course. Outcomes for patients with platinum-resistant ovarian cancer are poor, and options remain limited, highlighting a substantial unmet need for new treatment options.ObservationsThis review summarizes the current and evolving treatment landscape for platinum-resistant ovarian cancer with a focus on the development of novel compounds. Biologic and targeted therapies such as bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitors—originally approved in the platinum-resistant setting but since withdrawn—are now used in the up-front or platinum-sensitive setting, prolonging the duration of platinum sensitivity and delaying the use of nonplatinum options. The greater use of maintenance therapy and the emphasis on using platinum beyond first-line treatment has most likely been associated with a greater number of lines of platinum therapy before a patient is designated as having platinum-resistant ovarian cancer. In this contemporary setting, recent trials in platinum-resistant ovarian cancer have mostly had negative outcomes, with none having a clinically significant effect on progression-free or overall survival since the approval of bevacizumab in combination with chemotherapy. Nonetheless, a multitude of new therapies are under evaluation; preliminary results are encouraging. A focus on biomarker-directed treatment and patient selection may provide greater success in identifying novel therapies for treating platinum-resistant ovarian cancer.Conclusions and RelevanceAlthough many clinical trials in platinum-resistant ovarian cancer have had negative outcomes, these failures provide insights into how clinical trial design, biomarker-directed therapy, and patient selection could facilitate future successes in platinum-resistant ovarian cancer treatment.

Substance Use Disorders Among US Adult Cancer Survivors

ImportanceSome individuals are predisposed to cancer based on their substance use history, and others may use substances to manage cancer-related symptoms. Yet the intersection of substance use disorder (SUD) and cancer is understudied. Because SUD may affect and be affected by cancer care, it is important to identify cancer populations with a high prevalence of SUD, with the goal of guiding attention and resources toward groups and settings where interventions may be needed.ObjectiveTo describe the cancer type–specific prevalence of SUD among adult cancer survivors.Design, Setting, and ParticipantsThis cross-sectional study used data from the annually administered National Survey on Drug Use and Health (NSDUH) for 2015 through 2020 to identify adults with a history of solid tumor cancer. Substance use disorder was defined as meeting at least 1 of 4 Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria for abuse or at least 3 of 6 criteria for dependence.Main Outcomes and MeasuresPer NSDUH guidelines, we made adjustments to analysis weights by dividing weights provided in the pooled NSDUH data sets by the number of years of combined data (eg, 6 for 2015-2020). The weighted prevalence and corresponding SEs (both expressed as percentages) of active SUD (ie, within the past 12 months) were calculated for respondents with any lifetime history of cancer and, in secondary analyses, respondents diagnosed with cancer within 12 months prior to taking the survey. Data were analyzed from July 2022 to June 2023.ResultsThis study included data from 6101 adult cancer survivors (56.91% were aged 65 years or older and 61.63% were female). Among lifetime cancer survivors, the prevalence of active SUD was 3.83% (SE, 0.32%). Substance use disorder was most prevalent in survivors of head and neck cancer (including mouth, tongue, lip, throat, and pharyngeal cancers; 9.36% [SE, 2.47%]), esophageal and gastric cancer (9.42% [SE, 5.51%]), cervical cancer (6.24% [SE, 1.41%]), and melanoma (6.20% [SE, 1.34%]). Alcohol use disorder was the most common SUD (2.78% [SE, 0.26%]) overall and in survivors of head and neck cancer, cervical cancer, and melanoma. In survivors of esophageal and gastric cancers, cannabis use disorder was the most prevalent SUD (9.42% [SE, 5.51%]). Among respondents diagnosed with cancer in the past 12 months, the overall prevalence of active SUD was similar to that in the lifetime cancer survivor cohort (3.81% [SE, 0.74%]). However, active SUD prevalence was higher in head and neck (18.73% [SE, 10.56%]) and cervical cancer survivors (15.70% [SE, 5.35%]). The distribution of specific SUDs was different compared with that in the lifetime cancer survivor cohort. For example, in recently diagnosed head and neck cancer survivors, sedative use disorder was the most common SUD (9.81% [SE, 9.17%]).Conclusions and RelevanceFindings of this study suggest that SUD prevalence is higher among survivors of certain types of cancer; this information could be used to identify cancer survivors who may benefit from integrated cancer and SUD care. Future efforts to understand and address the needs of adult cancer survivors with comorbid SUD should prioritize cancer populations in which SUD prevalence is high.

Debt, Bankruptcy, and Credit Scores After Cancer Diagnosis

Importance A cancer diagnosis is a major driver of financial burden for US households, yet longitudinal data on debt, bankruptcy, and credit scores after diagnosis are lacking. Objective To examine longitudinal changes in adverse financial outcomes for nearly all individuals diagnosed with cancer in Massachusetts over a 10-year period (2010-2019) compared with a Massachusetts control population. Design, Setting, and Participants This retrospective, population-based cohort study included individuals diagnosed with different cancers in Massachusetts over a 10-year period (2010-2019). Analysis was conducted between April 2024 and February 2025. Individuals with cancer were matched 1:1 with control individuals based on baseline demographic and socioeconomic factors. Using comprehensive financial data, a difference-in-differences design was then used to study debt, bankruptcy, and credit scores over time. Subanalyses across 9 major cancer types were performed to assess heterogeneity in adverse financial outcomes. Exposures Cancer diagnosis during the study period (2010-2019) was used as the primary exposure. Covariates included age, sex, marital status, education, occupation status, and income. In subgroup analyses, exposures were defined based on the cancer subpopulation (ie, bladder, breast, cervical, colorectal, liver, lung, ovarian, thyroid, and uterine cancer) over the same time period. Main Outcomes and Measures Financial outcomes included total debt, total debt in collections, medical debt in collections, credit scores, and bankruptcy rates. Results In a matched difference-in-differences analysis of 74 146 individuals with a cancer diagnosis and 74 146 control individuals (mean [SD] age, 57.2 [14.1] years; 81.2% female), increases in mean medical debt in collections of $15.45 (95% CI, $2.19-$28.71) at 6 years postdiagnosis were observed. There were no changes in mean total debt, total debt in collections, number of bankruptcies, or credit scores after diagnosis. In subgroup analysis, patients with colorectal cancer experienced an increase in mean total debt in collections of $155.55 (95% CI, $0.34-$310.76) at 6 years postdiagnosis, and patients with bladder cancer experienced an increase in mean total debt in collections of $375.77 (95% CI, $5.89-$745.65) at 5.5 years postdiagnosis. Conclusions and Relevance In this retrospective cohort study, modest amounts of medical debt in collections persisted for years after cancer diagnosis. Total debt in collections was present at higher amounts for certain cancer subpopulations. The persistence of adverse financial outcomes after cancer diagnosis, despite high rates of insurance coverage in Massachusetts, warrants further research and consideration of broader systemic reforms.

Estimation of Cancer Deaths Averted From Prevention, Screening, and Treatment Efforts, 1975-2020

ImportanceCancer mortality has decreased over time, but the contributions of different interventions across the cancer control continuum to averting cancer deaths have not been systematically evaluated across major cancer sites.ObjectiveTo quantify the contributions of prevention, screening (to remove precursors [interception] or early detection), and treatment to cumulative number of cancer deaths averted from 1975 to 2020 for breast, cervical, colorectal, lung, and prostate cancers.Design, Setting, and ParticipantsIn this model-based study using population-level cancer mortality data, outputs from published models developed by the Cancer Intervention and Surveillance Modeling Network were extended to quantify cancer deaths averted through 2020. Model inputs were based on national data on risk factors, cancer incidence, cancer survival, and mortality due to other causes, and dissemination and effects of prevention, screening (for interception and early detection), and treatment. Simulated or modeled data using parameters derived from multiple birth cohorts of the US population were used.InterventionsPrimary prevention via smoking reduction (lung), screening for interception (cervix and colorectal) or early detection (breast, cervix, colorectal, and prostate), and therapy (breast, colorectal, lung, and prostate).Main Outcomes and MeasuresThe estimated cumulative number of cancer deaths averted with interventions vs no advances.ResultsAn estimated 5.94 million cancer deaths were averted for breast, cervical, colorectal, lung, and prostate cancers combined. Cancer prevention and screening efforts averted 8 of 10 of these deaths (4.75 million averted deaths). The contribution of each intervention varied by cancer site. Screening accounted for 25% of breast cancer deaths averted. Averted cervical cancer deaths were nearly completely averted through screening and removal of cancer precursors as treatment advances were modest during the study period. Averted colorectal cancer deaths were averted because of screening and removal of precancerous polyps or early detection in 79% and treatment advances in 21%. Most lung cancer deaths were avoided by smoking reduction (98%) because screening uptake was low and treatment largely palliative before 2014. Screening contributed to 56% of averted prostate cancer deaths.Conclusions and RelevanceOver the past 45 years, cancer prevention and screening accounted for most cancer deaths averted for these causes; however, their contribution varied by cancer site according to these models using population-level cancer mortality data. Despite progress, efforts to reduce the US cancer burden will require increased dissemination of effective interventions and new technologies and discoveries.

Survival After Minimally Invasive vs Open Radical Hysterectomy for Early-Stage Cervical Cancer

Minimally invasive techniques are increasingly common in cancer surgery. A recent randomized clinical trial has brought into question the safety of minimally invasive radical hysterectomy for cervical cancer. To quantify the risk of recurrence and death associated with minimally invasive vs open radical hysterectomy for early-stage cervical cancer reported in observational studies optimized to control for confounding. Ovid MEDLINE, Ovid Embase, PubMed, Scopus, and Web of Science (inception to March 26, 2020) performed in an academic medical setting. In this systematic review and meta-analysis, observational studies were abstracted that used survival analyses to compare outcomes after minimally invasive (laparoscopic or robot-assisted) and open radical hysterectomy in patients with early-stage (International Federation of Gynecology and Obstetrics 2009 stage IA1-IIA) cervical cancer. Study quality was assessed with the Newcastle-Ottawa Scale and included studies with scores of at least 7 points that controlled for confounding by tumor size or stage. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist was used to abstract data independently by multiple observers. Random-effects models were used to pool associations and to analyze the association between surgical approach and oncologic outcomes. Risk of recurrence or death and risk of all-cause mortality. Forty-nine studies were identified, of which 15 were included in the meta-analysis. Of 9499 patients who underwent radical hysterectomy, 49% (n = 4684) received minimally invasive surgery; of these, 57% (n = 2675) received robot-assisted laparoscopy. There were 530 recurrences and 451 deaths reported. The pooled hazard of recurrence or death was 71% higher among patients who underwent minimally invasive radical hysterectomy compared with those who underwent open surgery (hazard ratio [HR], 1.71; 95% CI, 1.36-2.15; P < .001), and the hazard of death was 56% higher (HR, 1.56; 95% CI, 1.16-2.11; P = .004). Heterogeneity of associations was low to moderate. No association was found between the prevalence of robot-assisted surgery and the magnitude of association between minimally invasive radical hysterectomy and hazard of recurrence or death (2.0% increase in the HR for each 10-percentage point increase in prevalence of robot-assisted surgery [95% CI, -3.4% to 7.7%]) or all-cause mortality (3.7% increase in the HR for each 10-percentage point increase in prevalence of robot-assisted surgery [95% CI, -4.5% to 12.6%]). This systematic review and meta-analysis of observational studies found that among patients undergoing radical hysterectomy for early-stage cervical cancer, minimally invasive radical hysterectomy was associated with an elevated risk of recurrence and death compared with open surgery.

Association Between Overall Survival and the Tendency for Cancer Programs to Administer Neoadjuvant Chemotherapy for Patients With Advanced Ovarian Cancer

Randomized clinical trials have found that, in patients with advanced-stage epithelial ovarian cancer, neoadjuvant chemotherapy has similar long-term survival and improved perioperative outcomes compared with primary cytoreductive surgery. Despite this, considerable controversy remains about the appropriate use of neoadjuvant chemotherapy, and the proportion of patients who receive this treatment varies considerably among cancer programs in the US. To evaluate the association between high levels of neoadjuvant chemotherapy administration and overall survival in patients with advanced ovarian cancer. This difference-in-differences comparative effectiveness analysis leveraged differential adoption of neoadjuvant chemotherapy in Commission on Cancer-accredited cancer programs in the US and included women with a diagnosis of stage IIIC and IV epithelial ovarian cancer between January 2004 and December 2015 who were followed up through the end of 2018. The data were analyzed between September 2020 and January 2021. Treatment in a cancer program with high levels of neoadjuvant chemotherapy administration (more often than expected based on case mix) or in a program that continued to restrict its use after the 2010 publication of a clinical trial demonstrating the noninferiority of neoadjuvant chemotherapy compared with primary surgery for the treatment of patients with advanced ovarian cancer. Case mix-standardized median overall survival time and 1-year all-cause mortality assessed with a flexible parametric survival model. We identified 19 562 patients (mean [SD] age, 63.9 [12.6] years; 3.2% Asian, 8.0% Black, 4.8% Hispanic, 82.5% White individuals) who were treated in 332 cancer programs that increased use of neoadjuvant chemotherapy from 21.7% in 2004 to 2009 to 42.2% in 2010 to 2015 and 19 737 patients (mean [SD] age, 63.5 [12.6] years; 3.1% Asian, 7.7% Black, 6.5% Hispanic, 81.8% White individuals) who were treated in 332 programs that marginally increased use of neoadjuvant chemotherapy (20.1% to 22.5%) over these periods. The standardized median overall survival times improved by similar magnitudes in programs with high (from 31.6 [IQR, 12.3-70.1] to 37.9 [IQR, 17.0-84.9] months; 6.3-month difference; 95% CI, 4.2-8.3) and low (from 31.4 [IQR, 12.1-67.2] to 36.8 [IQR, 15.0-80.3] months; 5.4-month difference, 95% CI, 3.5-7.3) use of neoadjuvant chemotherapy after 2010 (difference-in-differences, 0.9 months; 95% CI, -1.9 to 3.7). One-year mortality declined more in programs with high (from 25.6% to 19.3%; risk difference, -5.2%; 95% CI, -6.4 to -4.1) than with low (from 24.9% to 21.8%; risk difference, -3.2%, 95% CI, -4.3 to -2.0) use of neoadjuvant chemotherapy (difference-in-differences, -2.1%; 95% CI, -3.7 to -0.5). In this comparative effectiveness research study, compared with cancer programs with low use of neoadjuvant chemotherapy, those with high use had similar improvements in median overall survival and larger declines in short-term mortality.

Minimally Invasive Surgery and Risk of Capsule Rupture for Women With Early-Stage Ovarian Cancer

This cohort study examines the association between the use of minimally invasive surgery, capsule rupture, and survival among women with stage I epithelial ovarian cancer.

What Is the Optimal Treatment for Vulnerable Older Women With Ovarian Cancer?

What Is the Optimal Treatment for Vulnerable Older Women With Ovarian Cancer?—Reply

Association Between Breastfeeding and Ovarian Cancer Risk

Breastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent. To determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype. A pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019. Data on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies. Diagnosis of epithelial ovarian cancer. A total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02). Breastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.

BRCA Mutations and Homologous Recombination Repair Deficiency in Treatment With Niraparib Combined With Pembrolizumab—Reply

Clinical Activity and Safety of the Anti–Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients With Recurrent or Advanced Mismatch Repair–Deficient Endometrial Cancer

Deficient mismatch mutation repair mechanisms may sensitize endometrial cancers to anti-programmed death 1 (PD-1) therapies. Dostarlimab (TSR-042) is an investigational anti-PD-1 antibody that binds with high affinity to the PD-1 receptor. To assess the antitumor activity and safety of dostarlimab for patients with deficient mismatch repair endometrial cancer. This ongoing, open-label, single-group, multicenter study began part 1 on March 7, 2016, and began enrolling patients with deficient mismatch mutation repair endometrial cancer on May 8, 2017. Median follow-up was 11.2 months (range, 0.03 [ongoing] to 22.11 [ongoing] months; based on radiological assessments). Statistical analysis was performed July 8 to August 9, 2019. Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, treatment discontinuation, or withdrawal. The primary end point was objective response rate and duration of response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. As of the data cutoff, 104 women (median age, 64.0 years [range, 38-80 years]) with deficient mismatch mutation repair endometrial cancers were enrolled and treated with dostarlimab. Of these, 71 had measurable disease at baseline and at 6 months or more of follow-up and were included in the analysis. There was a confirmed response in 30 patients (objective response rate, 42.3%; 95% CI, 30.6%-54.6%); 9 patients (12.7%) had a confirmed complete response, and 21 patients (29.6%) had a confirmed partial response. Responses were durable; the median duration of response was not reached (median follow-up was 11.2 months). The estimated likelihood of maintaining a response was 96.4% at 6 months and 76.8% at 12 months. Anemia (3 of 104 [2.9%]), colitis (2 of 104 [1.9%]), and diarrhea (2 of 104 [1.9%]) were the most common grade 3 or higher treatment-related adverse events. In this nonrandomized trial, dostarlimab was associated with clinically meaningful and durable antitumor activity with an acceptable safety profile for patients with deficient mismatch mutation repair endometrial cancers after prior platinum-based chemotherapy. ClinicalTrials.gov identifier: NCT02715284.

Hyperthermic Intraperitoneal Chemotherapy for Ovarian and Colorectal Cancer

The peritoneal surface is a common site of disease in ovarian and colorectal cancer. Peritoneal metastases carry a poor prognosis, despite maximal therapeutic efforts, including surgical removal of tumor deposits and intravenous chemotherapy. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a single intraoperative procedure that delivers chemotherapy directly into the abdominal cavity, leading to high intracellular drug concentration at the peritoneal surface. This review describes the current knowledge regarding the mechanism of action, safety, and efficacy of HIPEC in the treatment of peritoneal metastases from epithelial ovarian and colorectal cancers and explores current knowledge gaps. Toxic effects of HIPEC are limited. Evidence from a randomized trial shows improved recurrence-free and overall survival after HIPEC in patients with ovarian cancer who are ineligible for primary cytoreductive surgery (CRS). The effect of HIPEC for patients with ovarian cancer undergoing primary CRS or CRS for recurrent disease has not yet been determined, and results of ongoing trials must be awaited. A recent study in patients with peritoneal metastases from colorectal cancer did not show a benefit of HIPEC when added to perioperative chemotherapy. Based on available evidence, various international guidelines include the option to add HIPEC to interval CRS for patients with stage III ovarian cancer. The role of HIPEC in colorectal cancer is less well defined. Future studies will need to tailor patient selection, timing, and optimal regimens of HIPEC to improve the effectiveness of this specialized treatment in ovarian, colorectal, and other tumor types.

Vulnerable Older Adults With Ovarian Cancer—Time to Stop Undertreating

Efficacy and Safety of First-line Single-Agent Carboplatin vs Carboplatin Plus Paclitaxel for Vulnerable Older Adult Women With Ovarian Cancer

Single-agent carboplatin is often proposed instead of a conventional carboplatin-paclitaxel doublet in vulnerable older patients with ovarian cancer. Such an approach could have a detrimental effect on outcomes for these patients. To compare the feasibility, efficacy, and safety of single-agent carboplatin every 3 weeks, weekly carboplatin-paclitaxel, or conventional every-3-weeks carboplatin-paclitaxel in vulnerable older patients with ovarian cancer. This international, open-label, 3-arm randomized clinical trial screened 447 women 70 years and older with newly diagnosed stage III/IV ovarian cancer by determining their Geriatric Vulnerability Score; 120 patients with a Geriatric Vulnerability Score of 3 or higher were stratified by country and surgical outcome. Enrollment took place at 48 academic centers in France, Italy, Finland, Denmark, Sweden, and Canada from December 11, 2013, to April 26, 2017. Final analysis database lock April 2019. Data analysis was performed from February 1 to December 31, 2019. Patients were randomized to receive 6 cycles of (1) carboplatin, area under the curve (AUC) 5 mg/mL·min, plus paclitaxel, 175 mg/m2, every 3 weeks; (2) single-agent carboplatin, AUC 5 mg/mL·min or AUC 6 mg/mL·min, every 3 weeks; or (3) weekly carboplatin, AUC 2 mg/mL·min, plus paclitaxel, 60 mg/m2, on days 1, 8, and 15 every 4 weeks. The primary outcome was treatment feasibility, defined as the ability to complete 6 chemotherapy cycles without disease progression, premature toxic effects-related treatment discontinuation, or death. A total of 120 women were randomized. The mean and median age was 80 (interquartile range, 76-83; range, 70-94) years; 43 (36%) had a Geriatric Vulnerability Score of 4 and 13 (11%) had a Geriatric Vulnerability Score of 5; 40 (33%) had stage IV disease. During its third meeting, the independent data monitoring committee's recommendation led to the termination of the trial because single-agent carboplatin was associated with significantly worse survival. Six cycles were completed in 26 of 40 (65%), 19 of 40 (48%), and 24 of 40 (60%) patients in the every-3-weeks combination, single-agent carboplatin, and weekly combination groups, respectively. Treatment-related adverse events were less common with the standard every-3-weeks combination (17 of 40 [43%]) than single-agent carboplatin or weekly combination therapy (both 23 of 40 [58%]). Treatment-related deaths occurred in 4 patients (2 of 40 [5%] in each combination group). This randomized clinical trial shows that compared with every-3-weeks or weekly carboplatin-paclitaxel regimens, single-agent carboplatin was less active with significantly worse survival outcomes in vulnerable older patients with ovarian cancer. ClinicalTrials.gov Identifier: NCT02001272.

Association of Risk-Reducing Salpingo-Oophorectomy With Breast Cancer Risk in Women With BRCA1 and BRCA2 Pathogenic Variants

Women with pathogenic variants in BRCA1 and BRCA2 are at high risk of developing breast and ovarian cancers. They usually undergo intensive cancer surveillance and may also consider surgical interventions, such as risk-reducing mastectomy or risk-reducing salpingo-oophorectomy (RRSO). Risk-reducing salpingo-oophorectomy has been shown to reduce ovarian cancer risk, but its association with breast cancer risk is less clear. To assess the association of RRSO with the risk of breast cancer in women with BRCA1 and BRCA2 pathogenic variants. This case series included families enrolled in the Breast Cancer Family Registry between 1996 and 2000 that carried an inherited pathogenic variant in BRCA1 (498 families) or BRCA2 (378 families). A survival analysis approach was used that was designed specifically to assess the time-varying association of RRSO with breast cancer risk and accounting for other potential biases. Data were analyzed from August 2019 to November 2020. Risk-reducing salpingo-oophorectomy. In all analyses, the primary end point was the time to a first primary breast cancer. A total of 876 families were evaluated, including 498 with BRCA1 (2650 individuals; mean [SD] event age, 55.8 [19.1] years; 437 White probands [87.8%]) and 378 with BRCA2 (1925 individuals; mean [SD] event age, 57.0 [18.6] years; 299 White probands [79.1%]). Risk-reducing salpingo-oophorectomy was associated with a reduced risk of breast cancer for BRCA1 and BRCA2 pathogenic variant carriers within 5 years after surgery (hazard ratios [HRs], 0.28 [95% CI, 0.10-0.63] and 0.19 [95% CI, 0.06-0.71], respectively), whereas the corresponding HRs were weaker after 5 years postsurgery (HRs, 0.64 [95% CI, 0.38-0.97] and 0.99 [95% CI; 0.84-1.00], respectively). For BRCA1 and BRCA2 pathogenic variant carriers who underwent RRSO at age 40 years, the cause-specific cumulative risk of breast cancer was 49.7% (95% CI, 40.0-60.3) and 52.7% (95% CI, 47.9-58.7) by age 70 years, respectively, compared with 61.0% (95% CI, 56.7-66.0) and 54.0% (95% CI, 49.3-60.1), respectively, for women without RRSO. Although the primary indication for RRSO is the prevention of ovarian cancer, it is also critical to assess its association with breast cancer risk in order to guide clinical decision-making about RRSO use and timing. The results of this case series suggest a reduced risk of breast cancer associated with RRSO in the immediate 5 years after surgery in women carrying BRCA1 and BRCA2 pathogenic variants, and a longer-term association with cumulative breast cancer risk in women carrying BRCA1 pathogenic variants.

Efficacy and Safety of Pembrolizumab in Combination With Bevacizumab and Oral Metronomic Cyclophosphamide in the Treatment of Recurrent Ovarian Cancer

Treatment options for recurrent ovarian cancer are of limited clinical benefit and adversely affect patient quality of life, representing an unmet need for tolerable effective therapies. To assess the efficacy and safety of a combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide in patients with recurrent platinum-sensitive, platinum-resistant, or refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer. This open-label, single-arm phase 2 cohort study enrolled patients from September 6, 2016, to June 27, 2018, at a single institution in the United States. Eligible patients had recurrent ovarian cancer, measurable disease per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST), and Eastern Cooperative Oncology Group performance status of 0 to 1. Data were analyzed from September 6, 2016, to February 20, 2020. Patients received intravenous pembrolizumab, 200 mg, and bevacizumab, 15 mg/kg, every 3 weeks and oral cyclophosphamide, 50 mg, once daily during the treatment cycle until disease progression, unacceptable toxic effects, or withdrawal of consent. Primary outcomes were objective response rate (ORR) and progression-free survival (PFS). Of the 40 women enrolled, 30 (75.0%) had platinum-resistant and 10 (25.0%) had platinum-sensitive ovarian cancer with a mean (SD) age of 62.2 (9.4) years. Three women (7.5%) had complete responses, 16 (40.0%) had partial responses, and 19 (47.5%) had stable disease in response to treatment based on irRECIST criteria, with an ORR of 47.5%, clinical benefit in 38 (95.0%), and durable response in 10 (25.0%). Median PFS was 10.0 (90% CI, 6.5-17.4) months. The most common grade 3 to 4 treatment-related adverse events were hypertension (6 [15.0%]) and lymphopenia (3 [7.5%]). The most frequently reported adverse events included fatigue (18 [45.0%]), diarrhea (13 [32.5%]), and hypertension (11 [27.5%]). In this phase 2 nonrandomized clinical trial, the combination of pembrolizumab with bevacizumab and oral cyclophosphamide was well tolerated and demonstrated clinical benefit in 95.0% and durable treatment responses (>12 months) in 25.0% of patients with recurrent ovarian cancer. This combination may represent a future treatment strategy for recurrent ovarian cancer. ClinicalTrials.gov Identifier: NCT02853318.

Human Papillomavirus Persistence and Association With Recurrent Cervical Intraepithelial Neoplasia After Cryotherapy vs Loop Electrosurgical Excision Procedure Among HIV-Positive Women

Persistence of cervical high-risk human papillomavirus (hrHPV) after treatment for cervical intraepithelial neoplasia grade 2 or higher (CIN2+) has not been compared between cryotherapy and loop electrosurgical excision procedure (LEEP) among HIV-positive women. To evaluate whether cryotherapy or LEEP is more effective at clearing hrHPV and whether persistent hrHPV is associated with CIN2+ recurrence among HIV-positive women. This is a secondary analysis of a randomized clinical trial conducted among women with HIV, hrHPV, and CIN2+ in Nairobi, Kenya. From June 2011 to September 2016, 354 HIV-positive women with CIN2+ disease had hrHPV cervical samples collected before and after treatment with cryotherapy or LEEP. Data were analyzed from September 2018 to January 2021. Women were randomized 1:1 to receive cryotherapy or LEEP and were followed up every 6 months for 24 months with hrHPV cervical swab and Papanicolaou test with confirmatory biopsy. The main outcomes of this analysis were hrHPV positivity defined as having 1 of 12 hrHPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) and disease recurrence defined as CIN grade 2 or higher as determined with cervical biopsy. A total of 354 HIV-positive women with CIN2+ were included in the study; mean (SD) age was 37 (8) years in the cryotherapy arm and 38 (9) years in the LEEP arm. Baseline hrHPV prevalence was 90% (160 of 177) in the cryotherapy arm and 94% (166 of 177) in the LEEP arm (P = .24), and the most common hrHPV types detected were 16 (87 of 326 [27%]), 58 (87 of 326 [27%]), 35 (86 of 326 [26%]), 52 (66 of 326 [20%]), and 18 (56 of 325 [17%]). Over 24 months, clearance of hrHPV was significantly higher among those who underwent LEEP compared with cryotherapy (hazard ratio, 1.40; 95% CI, 1.03-1.90; P = .03). In multivariable analysis, hrHPV type-specific persistence at 12-month follow-up was significantly associated with CIN2+ recurrence from 12 months to 24 months (adjusted hazard ratio, 4.70; 95% CI, 2.47-8.95; P < .001). Performance of hrHPV testing at 12 months for recurrent CIN2+ was 93% sensitivity, 46% specificity, 38% positive predictive value, and 95% negative predictive value. In this secondary analysis of a randomized clinical trial, HIV-positive women who received LEEP were more likely to clear hrHPV infection compared with those undergoing cryotherapy, reinforcing the efficacy of LEEP in this population. Persistent hrHPV was significantly associated with recurrent CIN2+, suggesting that LEEP's benefits may be related in part to its ability to clear hrHPV infection. Screening for hrHPV infection after treatment among HIV-positive women may be used to rule out recurrent CIN disease given its high sensitivity and negative predictive value. ClinicalTrials.gov Identifier: NCT01298596.

Sequential Chemoradiotherapy vs Concurrent Chemoradiotherapy or Radiotherapy Alone in Adjuvant Treatment for Patients With Cervical Cancer

Sequential Chemoradiotherapy vs Concurrent Chemoradiotherapy or Radiotherapy Alone in Adjuvant Treatment for Patients With Cervical Cancer—Reply

Sequential Chemotherapy for Early-Stage, Post–Radical Hysterectomy Cervical Cancer

Effectiveness of Sequential Chemoradiation vs Concurrent Chemoradiation or Radiation Alone in Adjuvant Treatment After Hysterectomy for Cervical Cancer

There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. The primary end point was the rate of disease-free survival (DFS) at 3 years. A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. ClinicalTrials.gov Identifier: NCT00806117.

Effectiveness of High-risk Human Papillomavirus Testing for Cervical Cancer Screening in China

Evidence is needed regarding the introduction of high-risk human papillomavirus (hrHPV) testing into China's national cervical cancer screening program. To evaluate hrHPV testing as a new screening modality for the national program. This population-based, multicenter, open-label, randomized clinical trial took place across 20 primary health care centers in urban and rural areas across China. At least 3000 women aged 35 to 64 years per site were invited to participate, for a total of 60 732 women evaluated. At baseline, women were randomly assigned to cytology, hrHPV testing, or visual inspection with acetic acid and Lugol iodine (VIA/VILI) (rural only). Women who tested positive for hrHPV were randomized into cytology-triage, VIA/VILI-triage (rural only), or direct colposcopy arms. Regarding primary or triaging tests, women with cytological abnormalities or who tested positive with VIA/VILI were referred to colposcopy. After 24 months, combined screening of cytology, hrHPV testing, and VIA/VILI was performed, and all women with positive results were referred to colposcopy. The primary outcomes were cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+ yields. The secondary outcome was colposcopy referral rate. A total of 60 732 women were included in this study, with median (interquartile range) age of 47 (41-52) years. Among urban women, 8955 were randomized to cytology and 18 176 to hrHPV genotyping; among rural women, 11 136 were randomized to VIA/VILI, 7080 to cytology, and 15 385 to hrHPV testing. Participants who tested positive for hrHPV with direct colposcopy had higher risk ratios for disease yields at baseline (urban hrHPV vs cytology, CIN2+ 2.2 [95% CI, 1.6-3.2] and CIN3+ 2.0 [95% CI, 1.2-3.3]; rural hrHPV vs cytology, 2.6 [95% CI, 1.9-4.0] and 2.7 [95% CI, 2.0-3.6]; rural hrHPV vs VIA/VILI, 2.0 [95% CI, 1.6-2.3] and 2.3 [95% CI, 1.8-3.1]). At 24 months, baseline-negative women in the hrHPV arm had significantly lower risk ratios than those with cytology, or VIA/VILI for CIN2+ (0.3 [95% CI, 0.2-0.5], 0.3 [95% CI, 0.2-0.6]) and CIN3+ (0.3 [95% CI, 0.1-0.6], 0.4 [95% CI, 0.2-0.8]) in rural sites. The colposcopy referral rate for hrHPV-positive rural women was reduced to 2.8% by cytology triage, with significantly higher CIN2+ yields than cytology (2.1 [95% CI, 1.3-2.6]) or VIA/VILI arm (1.6 [95% CI, 1.03-2.1]). Genotyping for hrHPV with cytology triage significantly reduced the colposcopy referral rate compared with cytology (0.8 [95% CI, 0.7-0.9]) for urban women. In this randomized clinical trial, testing for hrHPV was an effective primary screening method in primary health care centers. Incorporating hrHPV testing (polymerase chain reaction-based for urban areas, hybrid capture-based for rural areas) into China's national screening program is reasonable. Chinese Clinical Trial Registry Identifier: ChiCTR1900022530.

Global Association of COVID-19 Pandemic Measures With Cancer Screening

ImportancePublic health services, including cancer screening tests, have been affected by the onset of the COVID-19 epidemic.ObjectiveTo investigate the pandemic’s association with cancer screening worldwide.Data SourcesIn this systematic review and meta-analysis, databases such as PubMed, ProQuest, and Scopus were searched comprehensively for articles published between January 1, 2020, and December 12, 2021.Study SelectionObservational studies and articles that reported data from cancer registries that compared the number of screening tests performed before and during the pandemic for breast, cervical, and colorectal cancer were included.Data Extraction and SynthesisTwo pairs of independent reviewers extracted data from the selected studies. The weighted average of the percentage variation was calculated between the 2 periods to assess the change in the number of cancer screening tests performed during the pandemic. Stratified analysis was performed by geographic area, period, and type of setting. The systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.Main Outcomes and MeasuresThe main outcome was the weighted average percentage variation in the number of screening tests performed between January and October 2020 compared with the previous period.ResultsThe review comprised 39 publications. There was an overall decrease of −46.7% (95% CI, −55.5% to −37.8%) for breast cancer screening, −44.9% (95% CI, −53.8% to −36.1%) for colorectal cancer screening, and −51.8% (95% CI, −64.7% to −38.9%) for cervical cancer screening during the pandemic. For all 3 cancers, a U-shaped temporal trend was identified; for colorectal cancer, a significant decrease was still apparent after May 2020 (in June to October, the decrease was −23.4% [95% CI, −44.4% to −2.4%]). Differences by geographic area and screening setting were also identified.Conclusions and RelevanceA summary estimate of the downscaling of cancer screening tests since the onset of the COVID-19 pandemic is provided in this systematic review and meta-analysis. This could be associated with an increase in the number of avoidable cancer deaths. Effective interventions are required to restore the capacity of screening services to the prepandemic level.

Association Between Neighborhood Socioeconomic Inequality and Cervical Cancer Incidence Rates in New York City

This cross-sectional study uses Agency for Healthcare Research and Quality data to compare incidence of cervical cancer in the lowest–socioeconomic status neighborhoods with that in higher–socioeconomic status neighborhoods of New York City from 2012 through 2016.

Baseline Fatigue and Severe Toxic Effects in Patients With Cancer Receiving Systemic Therapy

Importance Fatigue is a common symptom reported by patients with cancer, yet its role as a predictor of treatment-related toxic effects has not been well characterized. Understanding whether fatigue measured at treatment initiation may be associated with subsequent toxic effects could help guide individualized treatment planning and symptom monitoring. Objective To evaluate the association between baseline patient-reported fatigue and the risk of adverse events (AEs) in cancer treatment trials. Design, Setting, and Participants This cohort study and pooled analysis assessed baseline fatigue data from 17 SWOG phase 2 and 3 trials conducted from 1990 to 2022. Patients were enrolled across multiple cancer types and treatment settings. Data analysis was performed from March 1, 2023, to October 17, 2025. Exposures Baseline fatigue, classified on a 5-point Likert scale, analyzed as binary thresholds (eg, &amp;amp;lt;some vs ≥some fatigue) and across fatigue severity levels. Main Outcomes and Measures Adverse events were classified using the Common Terminology Criteria for Adverse Events (CTCAE), with multiple versions mapped to version 4. Symptomatic AEs followed the Patient-Reported Outcomes-CTCAE framework; laboratory-based or measurable toxic effects were considered objective (hematologic vs nonhematologic). Primary outcomes were grade 3 or higher (severe), grade 4 or higher (life-threatening), and grade 5 (fatal) AEs. Odds ratios (ORs) were estimated using generalized estimating equations. To account for confounding, the analysis was clustered by trial and adjusted for age, sex, race, and obesity. Results Among 7086 patients (mean [SD] age, 62.1 [15.2] years; 2107 females [29.7%] and 4979 males [70.3%]) with prostate, lung, colorectal, lymphoma, breast, melanoma, ovarian, or pancreatic cancer, 103 738 AEs were reported. At baseline, 2771 participants (39.1%) reported some or more fatigue. Proportions with maximum AEs rated grade 3 or higher, grade 4 or higher, and grade 5 were 3128 participants (44.1%), 1001 (14.1%), and 62 (0.9%), respectively. Compared with those reporting no or minimal fatigue, patients with some fatigue or more had higher risks of severe or worse toxic effects (odds ratio [OR], 2.09; 95% CI, 1.58-2.78; P  &amp;amp;lt; .001), life-threatening or fatal toxic effects (OR, 1.96; 95% CI, 1.36-2.82; P  &amp;amp;lt; .001), and fatal toxic effects (OR, 2.35; 95% CI, 1.07-5.19; P  = .03). A dose-response pattern was evident: patients reporting quite a lot or very much fatigue had an approximately 5-fold higher risk of fatal toxic effects (OR, 4.99; 95% CI, 1.84-13.51; P  = .002). Findings were consistent across symptomatic, hematologic, and nonhematologic AE categories. Conclusions and Relevance This cohort study found that baseline patient-reported fatigue was associated with an increased risk of cancer treatment−related toxic effects. Fatigue assessments at treatment initiation may serve as an early clinical marker of risk for toxic effects and may help inform personalized treatment strategies and symptom monitoring.

Prostate-Specific Antigen Levels Among Participants Receiving Annual Testing

Importance Repeating a prostate-specific antigen (PSA) test after an elevated measurement is a guideline-recommended component of the prebiopsy workup. However, it is unclear whether certain patients can be exempted from repeat PSA testing and proceed directly to further workup. Objective To determine yearly PSA variability and implications of repeating an elevated PSA in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Design, Setting, and Participants This retrospective multicenter cohort study used data from men aged 54 to 75 years participating in the screening arm of the randomized PLCO trial who received PSA testing annually over 6 years (between 1995 and 2006) without a prostate cancer diagnosis. Data were analyzed from February 10, 2023, to May 23, 2025. Main Outcomes and Measures The primary outcome was the proportion of PSA measurements above 1 of the 3 biopsy thresholds of interest (2.5, 3.0, and 4.0 ng/mL) that decreased below the threshold at the subsequent yearly measurement. Analyses were conducted at both the PSA test and patient levels. Results Among 11 176 eligible patients (median age 60 years, IQR, 57-65 years), 2700 patients were included at a threshold of 2.5 ng/mL, 1928 patients at 3.0 ng/mL, and 952 patients at 4.0 ng/mL at least once. Among PSA measurements greater than or equal to 2.5 ng/mL, 22% (95% CI, 21%-23%) decreased below 2.5 ng/mL the following year; rates were similar for thresholds of 3.0 ng/mL and 4.0 ng/mL. At the patient level, 54% (95% CI, 53%-56%) of men with at least 1 PSA greater than or equal to 2.5 ng/mL had a subsequent level below this threshold, with slightly greater rates for the higher thresholds. A predictive scoring system incorporating current and prior PSA levels showed that patients with PSA levels persistently above thresholds had a low (&amp;amp;lt;10%) probability of PSA decreasing below the threshold. Conclusions and Relevance In this study, significant intra-individual variability in PSA levels was observed in this large screening cohort, with many elevated values falling below the threshold at the next yearly measurement. These findings suggest the utility of guideline recommendations to confirm elevated PSA results in most patients before performing further diagnostic evaluation and that patients with a prior PSA score above a given biopsy threshold, and no recent PSA scores below that threshold, could proceed to further diagnostic evaluation without repeat testing.

GLP-1 Receptor Agonists and Cancer Risk in Adults With Obesity

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely prescribed for glycemic control in type 2 diabetes and have recently gained popularity for weight management. However, their long-term impact on cancer risk remains uncertain. Understanding this association is crucial for patient safety.ObjectiveTo compare the incidence of 14 cancers among adults with obesity prescribed GLP-1RAs vs nonusers.Design, Setting, and ParticipantsThis retrospective cohort study followed a target trial emulation design using 2014 to 2024 electronic health record data from OneFlorida+, a multicenter health research network that integrates real-world clinical data from diverse health care settings. Adults 18 years or older eligible for antiobesity medications without prior cancer history were included. Participants were categorized as GLP-1RA users or nonusers, matched 1:1 using propensity scores.ExposureIndividuals taking vs not taking GLP-1RAs.Main Outcomes and MeasuresThe primary outcomes were the incidence of 14 cancer types, including 13 obesity-associated cancers (liver, thyroid, pancreatic, bladder, colorectal, kidney, breast, endometrial, meningioma, upper gastrointestinal, ovarian, multiple myeloma, and prostate) and lung cancer.ResultsA total of 86 632 matched adults (mean [SD] age, 52.4 [14.5] years; 68.2% female) were included, comprising 43 317 GLP-1RA users and 43 315 otherwise eligible nonusers. The incidence rates of the 14 cancers were 13.6 vs 16.4 per 1000 person-years, respectively, indicating a significantly lower overall cancer risk among individuals taking GLP-1RAs (hazard ratio [HR], 0.83 [95% CI, 0.76-0.91]; P = .002) compared with nonusers. In particular, taking GLP-1RAs was associated with a reduced risk of endometrial cancer (HR, 0.75 [95% CI, 0.57-0.99]; P = .05), ovarian cancer (HR, 0.53 [95% CI, 0.29-0.96]; P = .04), and meningioma (HR, 0.69 [95% CI, 0.48-0.97]; P = .05). However, GLP-1RAs were associated with a marginally nonsignificant increased risk of kidney cancer (HR, 1.38 [95% CI, 0.99-1.93]; P = .04).Conclusions and RelevanceThis retrospective cohort study found that taking GLP-1RAs was associated with a reduced overall risk of cancer, including lower risks of endometrial, ovarian, and meningioma cancers, among patients with obesity or overweight. However, taking GLP-1RAs may be associated with an increased risk of kidney cancer, highlighting the need for longer-term follow-up to clarify the underlying mechanisms and clinical implications of these findings.

Nivolumab and Ipilimumab Combination Treatment in Advanced Ovarian and Endometrial Clear Cell Cancers

ImportanceGynecological clear cell cancers (CCCs) are aggressive malignant neoplasms with low response rate to chemotherapy. The treatment of patients with metastatic disease remains an area of significant unmet need.ObjectiveTo evaluate the efficacy of combined anti–programmed cell death 1 protein (PD-1)/cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) blockade using nivolumab and ipilimumab in advanced gynecological CCCs.Design, Setting, and ParticipantsThe MoST-CIRCUIT prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced selected rare cancers. Patients with advanced clear cell ovarian cancer (CCOC)/clear cell endometrial cancer (CCEC) with a maximum of 1 course of prior systemic therapy were enrolled from August 2021 to February 2024 across 17 Australian and New Zealand sites.InterventionsPatients received nivolumab, 3 mg/kg, and ipilimumab, 1 mg/kg, every 3 weeks for 4 doses followed by nivolumab, 480 mg, every 4 weeks for 96 weeks until disease progression or the development of unacceptable toxic effects.Main Outcomes and MeasuresCoprimary end points were objective response rate (ORR) and 6-month progression-free survival (PFS) as assessed by RECIST version 1.1 criteria, with the secondary end points being median overall survival, PFS, and treatment-related toxic effects.ResultsOf 28 included patients, the median (range) age was 55 (34-77) years. A total of 24 had CCOC and 4 had CCEC; 19 (68%) had a previous course of therapy. Overall ORR was 54% (95% CI, 35-71), with 3 (12%) with complete response and 12 (42%) with partial response; the ORR was 55% (95% CI, 35-73) in the CCOC group and 50% (95% CI, 9-91) in the CCEC group. The median duration of response has not been reached, with all responses ongoing. The 6-month PFS was 58% (95% CI, 39-74), and the median overall survival has not been reached. A total of 9 patients (35%) experienced a grade 3 or 4 immune-related adverse event, and a grade 5 myocarditis occurred in 1 patient.Conclusions and RelevanceIn this nonrandomized clinical trial, immunotherapy using combined anti–PD-1/CTLA-4 blockade demonstrated encouraging activity with a high rate of durable responses in patients with advanced gynecological CCCs. This regimen should be further investigated in this patient population with unmet medical need.Trial RegistrationClinicalTrials.gov Identifier: NCT04969887

Incidence and Risk Factors of Interval and Screen-Detected Breast Cancer

ImportanceMammographic screening is the only proven method for early detection and mortality reduction of breast cancer (BC). However, many patients are missed at prior screening; thus, they receive their diagnosis between the interval of screening rounds, called interval cancer (IntCa). Some IntCas are fast growing between screening rounds.ObjectiveTo investigate the incidence and proportion of IntCa and screen-detected breast cancer (ScrCa) and identify factors associated with IntCa.Design, Setting, and ParticipantsThis population-based cohort study was conducted from January 1989 to March 2020, with follow-up until 2020 and a mean (SD) follow-up of 13 (8.3) years. The statistical analysis was performed from February 2023 to June 2024. It included cancer-free women (N = 527 144) residing in Stockholm, Sweden, who were invited to undergo mammography screening (aged 40-74 years) during 1989 to 2020. An additional cohort of women were included who were participating in the Karolinska Mammography Project for Risk Prediction of Breast Cancer study and had mammography data available.ExposuresFamily cancer history (defined from the Swedish Multi-Generation Register and Cancer Register), mammographic density, and various demographic, reproductive, and other factors (multiple Swedish registers).Main Outcomes and MeasuresIncidence of ScrCa and IntCa (defined from the Swedish Cancer Register in conjunction with individual screening histories).ResultsA total of 29 049 women (5.5%) received a diagnosis of BC, of whom 10 631 (2.0%) had ScrCa and 4369 (0.8%) IntCa. ScrCa and IntCa incidences increased during the period. The proportion of IntCa among screened patients with BC was around 30%, which decreased with older age. Factors associated with increased risk of IntCa included older age at first childbirth, higher education level, hormone replacement therapy, and higher mammographic density. Risk estimates of family cancer history on IntCa were family history of BC (hazard ratio [HR], 1.85; 95% CI, 1.72-1.99), family history of IntCa (HR, 2.92; 95% CI, 2.39-3.55), and hereditary breast and ovarian cancers (HR, 1.45; 95% CI, 1.36-1.54), with risk further elevated with the number of relatives who received a diagnosis when younger than the median age. Women with IntCa were more likely to have estrogen receptor (ER)–negative cancers than women with ScrCa (22% vs 11%), and having family history of ER-negative BC was associated with 3-fold risk for ER-negative IntCa.Conclusions and RelevanceThe results of this cohort study suggest that IntCa rates have not decreased with age-based screening, and implementing risk-based screening considering IntCa-specific risk factors is necessary for improving outcomes.

Bintrafusp Alfa for Recurrent or Metastatic Cervical Cancer After Platinum Failure

ImportanceCervical cancer is a common and lethal cancer worldwide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor β receptor II (or transforming growth factor β trap) fused via a flexible linker to the C-terminus of each heavy chain of an immunoglobulin G1 antibody blocking programmed cell death 1 ligand 1.ObjectiveTo evaluate the safety and response rates of bintrafusp alfa in patients with recurrent or metastatic cervical cancer.Design, Setting, and ParticipantsThis phase 2 nonrandomized controlled trial evaluated bintrafusp alfa monotherapy in patients with recurrent or metastatic cervical cancer with disease progression during or after platinum-based chemotherapy. Data were collected from March 2020 to February 2022.InterventionPatients received bintrafusp alfa, 1200 mg, intravenously once every 2 weeks.Main Outcomes and MeasuresThe primary end point was confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee.ResultsAt data cutoff, 146 of 203 screened patients received 1 or more doses of bintrafusp alfa; of these, the median (range) age was 53 (24-79) years. The study met its primary end point of a 95% CI above the objective response rate benchmark of 15%, with a confirmed objective response rate of 21.9% (95% CI, 15.5-29.5) per the independent review committee. Of these patients, 19 (59.4%) had a durable response of 6 months or more. At data cutoff, responses were ongoing in 13 of 32 responders (40.6%). The most common treatment-related adverse events were anemia (25 [17.1%]), rash (21 [14.4%]), hypothyroidism (15 [10.3%]), and pruritus (15 [10.3%]). Any-cause adverse events of special interest included anemia (82[56.2%]), bleeding events (81 [55.5%]), and immune-related adverse events (49 [33.6%]).Conclusions and RelevanceThis phase 2 nonrandomized controlled trial of bintrafusp alfa met its primary end point, which may support the potential of a bispecific therapy targeting transforming growth factor β and programmed cell death 1 ligand 1 in patients with recurrent or metastatic cervical cancer.Trial RegistrationClinicalTrials.gov Identifier: NCT04246489

Association of Salpingectomy With Delayed Oophorectomy Versus Salpingo-oophorectomy With Quality of Life in BRCA1/2 Pathogenic Variant Carriers

Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause. To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant. A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible. Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications. Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes. A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P < .001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P < .001) compared with RRS. Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy. ClinicalTrials.gov Identifier: NCT02321228.

Postoperative Hypofractionated Intensity-Modulated Radiotherapy With Concurrent Chemotherapy in Cervical Cancer

ImportanceProspective data assessing the safety of hypofractionated (40 Gy in 16 fractions) radiotherapy (RT) among patients who receive postoperative concurrent chemoradiotherapy for cervical cancer are lacking.ObjectiveTo evaluate the acute toxic effects of hypofractionated pelvic intensity-modulated radiotherapy (IMRT) with concurrent chemotherapy among women with cervical cancer who underwent radical hysterectomy.Design, Setting, and ParticipantsThe POHIM-CCRT (Postoperative Hypofractionated Intensity-Modulated Radiation Therapy With Concurrent Chemotherapy in Cervical Cancer) study was designed as a multicenter, phase 2 nonrandomized controlled trial that accrued and followed up patients from June 1, 2017, to February 28, 2023. In total, 84 patients were enrolled from 5 institutions affiliated with the Korean Radiation Oncology Group. Eligible patients experienced lymph node metastasis, parametrial invasion, or positive resection margins after radical hysterectomy for treatment of confirmed cervical cancer.InterventionPostoperative pelvic radiation using hypofractionated IMRT with 40 Gy in 16 fractions to the whole pelvis combined with concurrent chemotherapy.Main Outcomes and MeasuresThe primary end point was incidence of acute grade 3 or higher gastrointestinal tract, genitourinary, and hematologic toxic effects (based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) in the evaluable population during RT or within 3 months after RT completion.ResultsOf 84 patients enrolled, 5 dropped out prior to RT, and data from 79 patients were analyzed. The patients’ median (IQR) age was 48 (42-58) years, and the median (IQR) tumor size was 3.7 (2.7-4.5) cm. Of these patients, 31 (39.7%) had lymph node metastasis, 4 (5.1%) had positive resection margins, and 43 (54.4%) had parametrial invasion. Grade 3 or higher acute toxic effects occurred in 2 patients (2.5% [90% CI, 0%-4.8%]). After a median (IQR) follow-up of 43.0 (21.1-59.0) months, the 3-year disease-free survival rate was 79.3%, and the overall survival rate was 98.0%.ConclusionsFindings from this nonrandomized control trial indicated that postoperative pelvic irradiation combined with concurrent chemotherapy using hypofractionated IMRT with 40 Gy in 16 fractions was safe and well-tolerated in women with cervical cancer. Studies assessing long-term toxic effects and oncological outcomes with longer follow-up periods are needed.Trial RegistrationClinicalTrials.gov Identifier: NCT03239613

Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma

ImportancePatients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity.ObjectiveTo evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC.Design, Setting, and ParticipantsThis phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022.InterventionsPatients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo.Main Outcomes and MeasuresThe primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life.ResultsA total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (weekly paclitaxel plus vistusertib) vs 36.7% (weekly paclitaxel plus placebo), and there was no difference in quality of life.Conclusions and RelevanceIn this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel.Trial Registrationisrctn.org Identifier: ISRCTN16426935

Pembrolizumab or Placebo Plus Chemotherapy With or Without Bevacizumab for Persistent, Recurrent, or Metastatic Cervical Cancer

ImportanceThe KEYNOTE-826 randomized clinical trial showed statistically significant and clinically meaningful survival benefits with the addition of pembrolizumab to chemotherapy with or without bevacizumab in patients with persistent, recurrent, or metastatic cervical cancer. Treatment effects in patient subgroups of the study population are unknown.ObjectiveTo assess efficacy outcomes in patient subgroups of KEYNOTE-826.Design, Setting, and ParticipantsExploratory subgroup analyses were conducted in a global, phase 3, randomized, double-blind, placebo-controlled clinical trial. Participants included women with persistent, recurrent, or metastatic adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma of the cervix that had not been treated with systemic chemotherapy and was not amenable to curative treatment. This subanalysis was conducted from November 20, 2018, to May 3, 2021.InterventionsPembrolizumab, 200 mg, every 3 weeks or placebo for up to 35 cycles plus chemotherapy (paclitaxel, 175 mg/m2, plus cisplatin, 50 mg/m2, or carboplatin AUC 5 [area under the free carboplatin plasma concentration vs time curve]) with or without bevacizumab, 15 mg/kg.Main Outcomes and MeasuresOverall survival (OS) and progression-free survival (PFS) by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 in subgroups defined by use of bevacizumab (yes or no), choice of platinum (carboplatin or cisplatin), prior chemoradiotherapy (CRT) exposure only (yes or no), and histologic type (squamous or nonsquamous) in patients with programmed cell death ligand 1–positive tumors (defined as a combined positive score [CPS] ≥1) and in the intention-to-treat population.ResultsA total of 617 patients (median age, 51 years; range, 22-82 years) were enrolled in the trial. In the CPS greater than or equal to 1 population, hazard ratios (HRs) for OS favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.62; 95% CI, 0.45-0.87) and without bevacizumab (HR, 0.67; 95% CI, 0.47-0.96), use of carboplatin (HR, 0.65; 95% CI, 0.50-0.85) and cisplatin (HR, 0.53; 95% CI, 0.27-1.04), with prior CRT only (HR, 0.56; 95% CI, 0.39-0.81) and without prior CRT only (HR, 0.72; 95% CI, 0.52-1.00), and squamous (HR, 0.60; 95% CI, 0.46-0.79) and nonsquamous (HR, 0.70; 95% CI, 0.41-1.20) histologic type. In the intention-to-treat population, HRs for OS also favored the pembrolizumab group in all subgroups: with bevacizumab (HR, 0.63; 95% CI, 0.47-0.87) and without bevacizumab (HR, 0.74; 95% CI, 0.53-1.04), use of carboplatin (HR, 0.69; 95% CI, 0.54-0.89) or cisplatin (HR, 0.59; 95% CI, 0.32-1.09), with prior CRT only (HR, 0.64; 95% CI, 0.45-0.91) and without prior CRT only (HR, 0.71; 95% CI, 0.53-0.97), and squamous (HR, 0.61; 95% CI, 0.47-0.80) and nonsquamous (HR, 0.76; 95% CI, 0.47-1.23) histologic type. Similar to OS, the addition of pembrolizumab prolonged PFS across all subgroups in the CPS greater than or equal to 1 and intention-to-treat populations.Conclusions and RelevanceThe findings of this trial suggest that adding pembrolizumab to chemotherapy with or without bevacizumab improved OS across subgroups of patients with persistent, recurrent, or metastatic cervical cancer.Trial RegistrationClinicalTrials.gov Identifier: NCT03635567

Quadrivalent Human Papillomavirus Vaccine and High-Grade Vulvovaginal Lesions

Importance Human papillomavirus (HPV) vaccination has been associated with reduced risk of high-grade cervical lesions. However, evidence on its association with high-grade vulvovaginal lesions remains scarce. Objective To evaluate the association between quadrivalent HPV vaccination and high-grade vulvovaginal lesions and assess the population-level incidence reduction among birth cohorts eligible for various vaccination programs. Design, Setting, and Participants This population-based cohort study included women who were born between 1985 and 1998 and resided in Sweden between 2006 and 2022. Eligible participants had not previously received an HPV vaccination and did not have high-grade vulvovaginal lesions. Data were analyzed from February to October 2025. Exposure HPV vaccination status was treated as a time-varying exposure, and birth cohorts corresponded to different vaccination programs: 1985 to 1988 (opportunistic vaccination program), 1989 to 1992 (subsidized vaccination), and 1993 to 1998 (catch-up vaccination). Main Outcome and Measures The main outcome was incidence of high-grade vulvovaginal lesions, including cancers. Poisson regression models were used to estimate incidence rate ratios with 95% CIs. Results Among 778 943 women, a total of 256 353 (32.9%) received at least 1 dose of the quadrivalent HPV vaccine. The median (IQR) follow-up duration was 17.0 (17.0-17.0) years for unvaccinated women, 12.2 (10.6-13.4) years for those vaccinated between ages 10 and 16 years, and 10.8 (9.3-13.5) years for those vaccinated at 17 years or older. During follow-up, 98 cases of high-grade vulvovaginal lesions were found in vaccinated women, and 547 cases were found in unvaccinated women. Compared with unvaccinated women, the fully adjusted incidence rate ratio of high-grade vulvovaginal lesions was 0.63 (95% CI, 0.50-0.81) in vaccinated women. Stratified by age at vaccination, the incidence rate ratios for those vaccinated at 10 to 16 years and 17 years or older were 0.45 (95% CI, 0.32-0.65) and 0.80 (95% CI, 0.61-1.06), respectively. Compared with women born between 1985 and 1988, the incidence rate ratios for those born in 1989 to 1992 and 1993 to 1998 were 0.81 (95% CI, 0.67-0.97) and 0.62 (95% CI, 0.49-0.80), respectively. Conclusions and Relevance In this cohort study, vaccinated women had a lower incidence of high-grade vulvovaginal lesions compared with unvaccinated women, with a greater incidence reduction for those vaccinated at younger ages (before 17 years of age). Population-level incidence reduction was observed in cohorts vaccinated through subsidized or catch-up programs. These findings support that scaling up coverage of HPV vaccination at younger ages may help prevent high-grade vulvovaginal lesions.

Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer

ImportanceAbout 25% of all triple-negative breast cancers (TNBCs) and 10% to 20% of high-grade serous ovarian cancers (HGSOCs) harbor BRCA1 promoter methylation. While constitutional BRCA1 promoter methylation has been observed in normal tissues of some individuals, the potential role of normal tissue methylation as a risk factor for incident TNBC or HGSOC is unknown.ObjectiveTo assess the potential association between white blood cell BRCA1 promoter methylation and subsequent risk of incident TNBC and HGSOC.Design, Setting, and ParticipantsThis case-control study included women who were participating in the Women’s Health Initiative study who had not received a diagnosis of either breast or ovarian cancer before study entrance. A total of 637 women developing incident TNBC and 511 women developing incident HGSOC were matched with cancer-free controls (1841 and 2982, respectively) in a nested case-control design. Cancers were confirmed after central medical record review. Blood samples, which were collected at entry, were analyzed for BRCA1 promoter methylation by massive parallel sequencing. The study was performed in the Mohn Cancer Research Laboratory (Bergen, Norway) between 2019 and 2022.Main Outcomes and MeasuresAssociations between BRCA1 methylation and incident TNBC and incident HGSOC were analyzed by Cox proportional hazards regression.ResultsOf 2478 cases and controls in the TNBC group and 3493 cases and controls in the HGSOC group, respectively, 7 (0.3%) and 3 (0.1%) were American Indian or Alaska Native, 46 (1.9%) and 30 (0.9%) were Asian, 1 (0.04%) and 1 (0.03%) was Native Hawaiian or Pacific Islander, 326 (13.2%) and 125 (3.6%) were Black or African, 56 (2.3%) and 116 (3.3%) were Hispanic, 2046 (82.6%) and 3257 (93.2%) were White, and 35 (1.4%) and 35 (1.0%) were multiracial. Median (range) age at entry was 62 (50-79) years, with a median interval to diagnosis of 9 (TNBC) and 10 (HGSOC) years. Methylated BRCA1 alleles were present in 194 controls (5.5%). Methylation was associated with risk of incident TNBC (12.4% methylated; HR, 2.35; 95% CI, 1.70-3.23; P &amp;amp;lt; .001) and incident HGSOC (9.4% methylated; HR, 1.93; 95% CI, 1.36-2.73; P &amp;amp;lt; .001). Restricting analyses to individuals with more than 5 years between sampling and cancer diagnosis yielded similar results (TNBC: HR, 2.52; 95% CI, 1.75-3.63; P &amp;amp;lt; .001; HGSOC: HR, 1.82; 95% CI, 1.22-2.72; P = .003). Across individuals, methylation was not haplotype-specific, arguing against an underlying cis-acting factor. Within individuals, BRCA1 methylation was observed on the same allele, indicating clonal expansion from a single methylation event. There was no association found between BRCA1 methylation and germline pathogenic variant status.Conclusions and RelevanceThe results of this case-control suggest that constitutional normal tissue BRCA1 promoter methylation is significantly associated with risk of incident TNBC and HGSOC, with potential implications for prediction of these cancers. These findings warrant further research to determine if constitutional methylation of tumor suppressor genes are pancancer risk factors.

Effect of Apatinib Plus Pegylated Liposomal Doxorubicin vs Pegylated Liposomal Doxorubicin Alone on Platinum-Resistant Recurrent Ovarian Cancer

There are substantial unmet therapeutic needs in patients with platinum-resistant recurrent ovarian cancer (PROC), and novel therapeutic strategies should be explored. To evaluate the efficacy and safety of treatment with apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) plus pegylated liposomal doxorubicin (PLD) for PROC. The APPROVE trial was performed as an open-label, randomized clinical trial at 11 hospitals in China between March 22, 2018, and November 16, 2020. Patients with histologically confirmed ovarian cancer who had experienced disease progression during or within 6 months of discontinuing any prior line of treatment with platinum-based chemotherapy were eligible. This primary analysis was based on data that were current as of January 28, 2021. Patients received PLD alone (40 mg/m2, intravenously, every 4 weeks, for up to 6 cycles) or PLD plus apatinib (250 mg, orally, daily). The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, in the intent-to-treat population. In total, 152 female patients were randomized, with 78 (51.3%) in the apatinib plus PLD group (median age, 54 years; range, 22-76 years) and 74 (48.7%) in the PLD group (median age, 56 years; range, 33-72 years). The median follow-up duration was 8.7 months (IQR, 4.7-14.1 months). The median PFS was 5.8 months (95% CI, 3.8-8.8) for treatment with apatinib plus PLD vs 3.3 months (95% CI, 2.1-3.8) for PLD (hazard ratio, 0.44; 95% CI, 0.28-0.71; P < .001). The median overall survival was 23.0 months (95% CI, 18.9 to not reached) with treatment with apatinib plus PLD vs 14.4 months (95% CI, 12.1-23.4) with PLD (hazard ratio, 0.66; 95% CI, 0.40-1.09). The most frequent grade 3 or higher treatment-emergent adverse events were decreased neutrophil counts (11 [14.9%] in the apatinib plus PLD group vs 6 [8.3%] in the PLD group), hypertension (6 [8.1%] vs none), and decreased white blood cell count (5 [6.8%] vs 3 [4.2%]). Two patients receiving treatment with apatinib plus PLD experienced grade 2 fistulas. This randomized clinical trial found that treatment with apatinib plus PLD showed promising efficacy and manageable toxic effects in patients with PROC and may be a new alternative treatment option in this setting. Clinicaltrials.gov Identifier: NCT04348032.

Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer

ImportanceAlthough the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration–approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC.ObjectiveTo assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC.Design, Settings, and ParticipantsThis investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies.InterventionsTalazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects.Main Outcomes and MeasuresStatistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity.ResultsThirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit.Conclusions and RelevanceThe results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer.Trial RegistrationClinicalTrials.gov Identifier: NCT02912572

Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer

ImportanceThe efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease.ObjectiveTo evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted).Design, Setting, and ParticipantsThis multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months.InterventionsPatients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of &amp;amp;lt;77 kg and/or platelet count of &amp;amp;lt;150 ×103/μL [to convert to ×109/μL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy.Main Outcomes and MeasurementsThe primary end point was blinded, independent central review–assessed PFS in the intention-to-treat population.ResultsA total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P &amp;amp;lt; .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events.Conclusion and RelevanceThis randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting.Trial RegistrationClinicalTrials.gov Identifier: NCT03709316

Hormonal Contraceptive Formulations and Breast Cancer Risk in Adolescents and Premenopausal Women

Importance Hormonal contraceptives are widely used but how breast cancer risk differs by hormonal content remains unclear. Objective To estimate the difference in breast cancer risk associated with different hormonal contraceptive formulations. Design, Setting, and Participants This Swedish nationwide, population-based cohort study was conducted using linked national registers. All adolescent girls and women aged 13 to 49 years residing in Sweden as of January 1, 2006, with no history of breast cancer, ovarian cancer, cervical cancer, uterine cancer, bilateral oophorectomy, or infertility treatment were included and followed up from 2006 to 2019. Individuals were censored on meeting an exclusion criterion, reaching age 50 years, or study end, whichever occurred first. Data were analyzed from November 2023 to August 2025. Exposure Ever use and duration of use of hormonal contraceptives, categorized by hormone formulations and route of administration. Main Outcomes and Measures Time-dependent Cox regression was used to estimate hazard ratios (HRs) with 95% CIs for incident cases of in situ and invasive breast cancer. Results Among 2 095 130 adolescent girls and women (median [IQR] age at diagnosis, 45 [41-48] years) who were followed up for 21 020 846 person-years, 16 385 breast cancer cases occurred. Ever use of any hormonal contraceptive was associated with increased breast cancer risk (HR, 1.24; 95% CI, 1.20-1.28), corresponding to 1 additional case per 7752 (95% CI, 5350-14 070) users, with both combined (HR, 1.12; 95% CI, 1.07-1.17) and progestin-only formulations (HR, 1.21; 95% CI, 1.17-1.25) being associated. Higher risk was associated with oral desogestrel-only formulations (HR, 1.18; 95% CI, 1.13-1.23) and oral desogestrel-combined formulations (HR, 1.19; 95% CI, 1.08-1.31), as well as implants containing etonogestrel, desogestrel’s active metabolite (HR, 1.22; 95% CI, 1.11-1.35), compared to levonorgestrel-containing combined pills (HR, 1.09; 95% CI, 1.03-1.15) and levonorgestrel, 52 mg, intrauterine system (HR, 1.13; 95% CI, 1.09-1.18). No statistically significant increased risk was observed for medroxyprogesterone acetate injection, etonogestrel vaginal ring, or combined oral drospirenone, despite having many users. Conclusions and Relevance Findings of this cohort study highlight that breast cancer risk varies substantially by progestin content in hormonal contraceptives, providing valuable insights to support more informed contraceptive prescription.

Pembrolizumab in Patients With Advanced Clear Cell Gynecological Cancer

ImportanceAdvanced clear cell gynecological cancers (CCGCs) have a poor prognosis, with response rates to second-line chemotherapy less than 8%. Preliminary clinical activity with programmed cell death 1 protein (PD-1) inhibitors reported in CCGC merits further investigation.ObjectiveTo assess the clinical benefit of pembrolizumab in patients with previously treated advanced CCGC.Design, Setting, and ParticipantsThe PEACOCC trial is a single-arm multicenter phase 2 trial conducted at 5 UK centers investigating the clinical benefit and safety of pembrolizumab. PD-1 inhibitor–naive patients with histologically confirmed advanced CCGC, radiological disease progression following 1 or more prior courses of chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1 were included. Patients were enrolled from March 2019 to October 2021, with data collected until July 2024.InterventionsPembrolizumab, 200 mg, intravenously every 21 days up to 2 years until progression, discontinuation due to toxic effects, or patient/clinician decision. Up to 1 year of retreatment on diseases progression, if stable disease, partial response, or complete response at 2 years.Main Outcomes and MeasuresThe primary end point was progression-free survival (PFS) rate at 12 weeks using Response Evaluation Criteria in Solid Tumors version 1.1 to detect a 12-week PFS rate of 33% or greater and exclude a PFS rate of less than 15%, with 90% power and 1-sided 5% significance level. Secondary end points included objective response rate, duration of response, PFS, overall survival, safety, and quality of life.ResultsA total of 48 patients were eligible. The median (range) age was 58.5 (32-77) years, and 26 (54%) had an ECOG PS score of 0 and 22 (46%) had an ECOG PS score of 1; 41 (85%) had ovarian, 6 (13%) had endometrial, and 1 (2%) had cervical advanced CCGC. The median (range) courses prior therapy was 3 (1-6); 19 patients (40%) received prior anti-angiogenic therapy, and 19 (40%) had a platinum-free interval of more than 12 months. Grade 3 treatment-related adverse events were observed in 9 patients (19%), and no patients had grade 4 or 5 adverse events. A total of 45 of 46 patients (98%) had mismatch repair–proficient tumors. The 12-week PFS rate was 42% (95% CI, 28-57), and the best objective response rate was 25% (95% CI, 14-40), with 12 partial responses. After a median follow-up of 46.9 months (95% CI, 43.4-55.0), the median PFS was 2.7 months (95% CI, 1.3-5.4), and the median overall survival was 14.8 months (95% CI, 6.7-28.2).Conclusions and RelevanceThe PEACOCC trial showed clinical benefit with pembrolizumab in patients with previously treated advanced CCGC, of whom all except 1 had MMR-proficient disease. Clinical outcomes were durable with an overall tolerable safety profile, justifying further evaluation of pembrolizumab monotherapy for advanced CCGC in a randomized clinical trial.Trial RegistrationClinicalTrials.gov Identifier: NCT03425565

An Analysis of Contemporary Oncology Randomized Clinical Trials From Low/Middle-Income vs High-Income Countries

The burden of cancer falls disproportionally on low-middle-income countries (LMICs). It is not well known how novel therapies are tested in current clinical trials and the extent to which they match global disease burden. To describe the design, results, and publication of oncology randomized clinical trials (RCTs) and examine the extent to which trials match global disease burden and how trial methods and results differ across economic settings. In this retrospective cohort study, a literature search identified all phase 3 RCTs evaluating anticancer therapies published from 2014 to 2017. Randomized clinical trials were classified based on World Bank economic classification. Descriptive statistics were used to compare RCT design and results from high-income countries (HICs) and low/middle-income countries (LMICs). Statistical analysis was conducted in January 2020. Differences in the design, results, and output of RCTs between HICs and LMICs. The study cohort included 694 RCTs: 636 (92%) led by HICs and 58 (8%) led by LMICs. A total of 601 RCTs (87%) tested systemic therapy and 88 RCTs (13%) tested radiotherapy or surgery. The proportion of RCTs relative to global deaths was higher for breast cancer (121 RCTs [17%] and 7% of deaths) but lower for gastroesophageal cancer (38 RCTs [6%] and 14% of deaths), liver cancer (14 RCTs [2%] and 8% of deaths), pancreas cancer (14 RCTs [2%] and 5% of deaths), and cervical cancer (9 RCTs [1%] and 3% of deaths). Randomized clinical trials in HICs were more likely than those in LMICs to be funded by industry (464 [73%] vs 24 [41%]; P < .001). Studies in LMICs were smaller than those in HICs (median, 219 [interquartile range, 137-363] vs 474 [interquartile range, 262-743] participants; P < .001) and more likely to meet their primary end points (39 of 58 [67%] vs 286 of 636 [45%]; P = .001). The observed median effect size among superiority trials was larger in LMICs compared with HICs (hazard ratio, 0.62 [interquartile range, 0.54-0.76] vs 0.84 [interquartile range, 0.67-0.97]; P < .001). Studies from LMICs were published in journals with lower median impact factors than studies from HICs (7 [interquartile range, 4-21] vs 21 [interquartile range, 7-34]; P < .001). Publication bias persisted when adjusted for whether a trial was positive or negative (median impact factor: LMIC negative trial, 5 [interquartile range, 4-6] vs HIC negative trial, 18 [interquartile range, 6-26]; LMIC positive trial, 9 [interquartile range, 5-25] vs HIC positive trial, 25 [interquartile range, 10-48]; P < .001). This study suggests that oncology RCTs are conducted predominantly by HICs and do not match the global burden of cancer. Randomized clinical trials from LMICs are more likely to identify effective therapies and have a larger effect size than RCTs from HICs. This study suggests that there is a funding and publication bias against RCTs led by LMICs. Policy makers, research funders, and journals need to address this issue with a range of measures including building capacity and capability in RCTs.

Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib

A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors. To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment. This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment. Enrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates. Among 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs. The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.

Cost-effectiveness of Leveraging Social Determinants of Health to Improve Breast, Cervical, and Colorectal Cancer Screening

Screening for breast, cervical, and colorectal cancers in the United States has remained below the Healthy People 2020 goals, with evidence indicating that persistent screening disparities still exist. The US Department of Health and Human Services has emphasized cross-sectoral collaboration in aligning social determinants of health with public health and medical services. Examining the economics of intervening through these novel methods in the realm of cancer screening can inform program planners, health care providers, implementers, and policy makers. To conduct a systematic review of economic evaluations of interventions leveraging social determinants of health to improve screening for breast, cervical, and colorectal cancer to guide implementation. A systematic literature search for economic evidence was performed in MEDLINE, Embase, PsycINFO, Cochrane Library, Global Health, Scopus, Academic Search Complete, Business Source Complete, EconLit, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ERIC (Education Resources Information Center), and Sociological Abstracts from January 1, 2004, to November 25, 2019. Included studies intervened on social determinants of health to improve breast, cervical, and colorectal cancer screening in the United States and reported intervention cost, incremental cost per additional person screened, and/or incremental cost per quality-adjusted life-year (QALY). Risk of bias was assessed along with qualitative assessment of quality to ensure complete reporting of economic measures, data sources, and analytic methods. In addition, included studies with modeled outcomes had to define structural elements and sources for input parameters, distinguish between programmatic and literature-derived data, and assess uncertainty. Thirty unique articles with 94 706 real and 4.21 million simulated participants satisfied our inclusion criteria and were included in the analysis. The median intervention cost per participant was $123.87 (interquartile interval [IQI], $24.44-$313.19; 34 estimates). The median incremental cost per additional person screened was $250.37 (IQI, $44.67-$609.38; 17 estimates). Studies that modeled final economic outcomes had a median incremental cost per person of $122.96 (IQI, $46.96-$124.80; 5 estimates), a median incremental screening rate of 15% (IQI, 14%-20%; 5 estimates), and a median incremental QALY per person of 0.04 years (IQI, 0.006-0.06 year; 5 estimates). The median incremental cost per QALY gained of $3120.00 (IQI, $782.59-$33 600.00; 5 estimates) was lower than $50 000, an established, conservative threshold of cost-effectiveness. Interventions focused on social determinants of health to improve breast, cervical, and colorectal cancer screening appear to be cost-effective for underserved, vulnerable populations in the United States. The increased screening rates were associated with earlier diagnosis and treatment and in improved health outcomes with significant gains in QALYs. These findings represent the latest economic evidence to guide implementation of these interventions, which serve the dual purpose of enhancing health equity and economic efficiency.

Minimally Invasive Surgery for Gynecologic Cancers—A Cautionary Tale

Sequential Ipilimumab After Chemoradiotherapy in Curative-Intent Treatment of Patients With Node-Positive Cervical Cancer

Despite standard chemoradiotherapy (CRT), most women with lymph node (LN)-positive cervical cancer experience disease recurrence. Immunotherapy is being investigated in the up-front treatment setting. To assess the safety of sequential immunotherapy after CRT and to investigate human papillomavirus (HPV) genotype and HLA allele status on survival and programmed cell death 1 (PD-1) expression before and after CRT and sequential immunotherapy. This prospective phase 1 trial conducted in 29 Gynecology Oncology Cooperative Group member institutions enrolled participants from December 18, 2012, to August 31, 2016, with a 14.8-month median follow-up and translational end points. Thirty-four women with International Federation of Gynecology and Obstetrics stage IB2 to IVA cervical cancer with positive pelvic LNs, para-aortic LNs, or both were enrolled; 13 did not receive ipilimumab and were excluded from the analysis. Data were analyzed from January 21 to April 4, 2018. Treatment consisted of 6 weekly doses of cisplatin, 40 mg/m2, concurrent with radiotherapy. After completion of chemotherapy, sequential ipilimumab was given every 21 days for 4 doses. Two dosage levels of ipilimumab, 3 mg/kg and 10 mg/kg, were studied to identify the maximum tolerated dose. The primary end point was safety, and the secondary end points were overall survival and progression-free survival. Exploratory end points included HPV genotype, HLA allele status, and PD-1 expression measured in peripheral blood. The median age of the 32 participants included in the intent-to-treat analysis was 50 (range, 26-61) years, and 22 patients (69%) were white. Of the 21 patients who received ipilimumab, all had positive pelvic LN, and 6 (29%) had positive para-aortic LNs. All patients completed CRT, and of the 21 patients who received at least 2 cycles of ipilimumab, 18 (86%) completed 4 cycles of ipilimumab, and 3 (14%) completed 2 cycles. The maximum tolerated dose was 10 mg/kg. Two of the 21 patients (9.5%) who received ipilimumab had self-limiting grade 3 toxic effects (lipase increase; dermatitis). The 12-month overall survival was 90%, and progression-free survival was 81%. Human papillomavirus genotype and HLA subtype were not associated with progression-free survival or overall survival. T cells expressing PD-1 increased after CRT, and levels were sustained with ipilimumab. This study's findings suggest that the use of immunotherapy after CRT for curative-intent treatment of patients with cervical cancer is tolerable and effective. The results indicated that PD-1 was upregulated after CRT and sustained with sequential ipilimumab therapy. These immune findings may help guide future therapies to harness the activated T-cell phenotype in patients with node-positive cervical cancer.

High-risk Human Papillomavirus Testing for Cervical Cancer Screening—Reply

High-risk Human Papillomavirus Testing for Cervical Cancer Screening

Modeling Strategies to Optimize Cancer Screening in USPSTF Guideline–Noncompliant Women

In 2018, only half of US women obtained all evidence-based cancer screenings. This proportion may have declined during the COVID-19 pandemic because of social distancing, high-risk factors, and fear. To evaluate optimal screening strategies in women who obtain some, but not all, US Preventive Services Task Force (USPSTF)-recommended cancer screenings. This modeling study was conducted from January 31, 2017, to July 20, 2020, and used 4 validated mathematical models from the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network using data from 20 million simulated women born in 1965 in the US. Forty-five screening strategies were modeled that combined breast, cervical, colorectal, and/or lung cancer (LC) screenings; restricted to 1, 2, 3 or 4 screenings per year; or all eligible screenings once every 5 years. Modeled life-years gained from restricted cancer screenings as a fraction of those attainable from full compliance with USPSTF recommendations (maximum benefits). Results were stratified by LC screening eligibility (LC-eligible/ineligible). We repeated the analysis with 2018 adherence rates, evaluating the increase in adherence required for restricted screenings to have the same population benefit as USPSTF recommendations. This modeling study of 20 million simulated US women found that it was possible to reduce screening intensity to 1 carefully chosen test per year in women who were ineligible for LC screening and 2 tests per year in eligible women while maintaining 94% or more of the maximum benefits. Highly ranked strategies screened for various cancers, but less often than recommended by the USPSTF. For example, among LC-ineligible women who obtained just 1 screening per year, the optimal strategy frequently delayed breast and cervical cancer screenings by 1 year and skipped 3 mammograms entirely. Among LC-eligible women, LC screening was essential; strategies omitting it provided 25% or less of the maximum benefits. The top-ranked strategy restricted to 2 screenings per year was annual LC screening and alternating fecal immunochemical test with mammography (skipping mammograms when due for cervical cancer screening, 97% of maximum benefits). If adherence in a population of LC-eligible women obtaining 2 screenings per year were to increase by 1% to 2% (depending on the screening test), this model suggests that it would achieve the same benefit as USPSTF recommendations at 2018 adherence rates. This modeling study of 45 cancer screening strategies suggests that women who are noncompliant with cancer screening guidelines may be able to reduce USPSTF-recommended screening intensity with minimal reduction in overall benefits.

Oral Microbiome and Subsequent Risk of Head and Neck Squamous Cell Cancer

ImportanceThe oral microbiota may be involved in development of head and neck squamous cell cancer (HNSCC), yet current evidence is largely limited to bacterial 16S amplicon sequencing or small retrospective case-control studies.ObjectiveTo test whether oral bacterial and fungal microbiomes are associated with subsequent risk of HNSCC development.Design, Setting, and ParticipantsProspective nested case-control study among participants providing oral samples in 3 epidemiological cohorts, the American Cancer Society Cancer Prevention Study II Nutrition Cohort, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and the Southern Community Cohort Study. Two hundred thirty-six patients who prospectively developed HNSCC were identified during a mean (SD) of 5.1 (3.6) years of follow-up. Control participants who remained HNSCC free were selected by 2:1 frequency matching on cohort, age, sex, race and ethnicity, and time since oral sample collection. Data analysis was conducted in 2023.ExposuresCharacterization of the oral bacterial microbiome using whole-genome shotgun sequencing and the oral fungal microbiome using internal transcribed spacer sequencing. Association of bacterial and fungal taxa with HNSCC was assessed by analysis of compositions of microbiomes with bias correction. Association with red and orange oral pathogen complexes was tested by logistic regression. A microbial risk score for HNSCC risk was calculated from risk-associated microbiota.Main Outcomes and MeasuresThe primary outcome was HNSCC incidence.ResultsThe study included 236 HNSCC case participants with a mean (SD) age of 60.9 (9.5) years and 24.6% women during a mean of 5.1 (3.6) years of follow-up, and 485 matched control participants. Overall microbiome diversity at baseline was not related to subsequent HNSCC risk; however 13 oral bacterial species were found to be differentially associated with development of HNSCC. The species included the newly identified Prevotella salivae, Streptococcus sanguinis, and Leptotrichia species, as well as several species belonging to beta and gamma Proteobacteria. The red/orange periodontal pathogen complex was moderately associated with HNSCC risk (odds ratio, 1.06 per 1 SD; 95% CI, 1.00-1.12). A 1-SD increase in microbial risk score (created based on 22 bacteria) was associated with a 50% increase in HNSCC risk (multivariate odds ratio, 1.50; 95% CI, 1.21-1.85). No fungal taxa associated with HNSCC risk were identified.Conclusions and RelevanceThis case-control study yielded compelling evidence that oral bacteria are a risk factor for HNSCC development. The identified bacteria and bacterial complexes hold promise, along with other risk factors, to identify high-risk individuals for personalized prevention of HNSCC.

Breast Cancer Index in Premenopausal Women With Early-Stage Hormone Receptor–Positive Breast Cancer

ImportanceAdjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor–positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking.ObjectiveTo assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer.Design, Setting, and ParticipantsThis prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])–high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022.Main Outcomes and MeasuresPrimary end points were breast cancer–free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses.ResultsTumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, −0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, −1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively.Conclusions and RelevanceIn this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

BRCA1, BRCA2, and Associated Cancer Risks and Management for Male Patients

ImportanceHalf of all carriers of inherited cancer-predisposing variants in BRCA1 and BRCA2 are male, but the implications for their health are underrecognized compared to female individuals. Germline variants in BRCA1 and BRCA2 (also known as pathogenic or likely pathogenic variants, referred to here as BRCA1/2 PVs) are well known to significantly increase the risk of breast and ovarian cancers in female carriers, and knowledge of BRCA1/2 PVs informs established cancer screening and options for risk reduction. While risks to male carriers of BRCA1/2 PVs are less characterized, there is convincing evidence of increased risk for prostate cancer, pancreatic cancer, and breast cancer in males. There has also been a rapid expansion of US Food and Drug Administration–approved targeted cancer therapies, including poly ADP ribose polymerase (PARP) inhibitors, for breast, pancreatic, and prostate cancers associated with BRCA1/2 PVs.ObservationsThis narrative review summarized the data that inform cancer risks, targeted cancer therapy options, and guidelines for early cancer detection. It also highlighted areas of emerging research and clinical trial opportunities for male BRCA1/2 PV carriers. These developments, along with the continued relevance to family cancer risk and reproductive options, have informed changes to guideline recommendations for genetic testing and strengthened the case for increased genetic testing for males.Conclusions and RelevanceDespite increasing clinical actionability for male carriers of BRCA1/2 PVs, far fewer males than female individuals undergo cancer genetic testing. Oncologists, internists, and primary care clinicians should be vigilant about offering appropriate genetic testing to males. Identifying more male carriers of BRCA1/2 PVs will maximize opportunities for cancer early detection, targeted risk management, and cancer treatment for males, along with facilitating opportunities for risk reduction and prevention in their family members, thereby decreasing the burden of hereditary cancer.

A Case of Gastric Thickening and a Large Ovarian Mass

A 35-year-old female patient with hypothyroidism and Ehler-Danlos syndrome presents with fatigue, abdominal distension, and dyspnea. What is your diagnosis?

Tumor-Infiltrating Lymphocytes in Patients With Stage I Triple-Negative Breast Cancer Untreated With Chemotherapy

ImportanceThe absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking.ObjectiveTo examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs.Design, Setting, and ParticipantsThis cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023.Main Outcomes and MeasuresThe primary end point was breast cancer–specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin–stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients.ResultsOf a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater.Conclusions and RelevanceResults of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.

Ovarian Cancer Isn’t Just a White Woman’s Disease

This Viewpoint highlights the need for recognition that ovarian cancer affects women from racial and ethnic minority groups worldwide and that the rates of ovarian cancer are increasing in those populations while decreasing among White women.

Bilateral Oophorectomy and All-Cause Mortality in Women With BRCA1 and BRCA2 Sequence Variations

ImportancePreventive bilateral salpingo-oophorectomy is offered to women at high risk of ovarian cancer who carry a pathogenic variant in BRCA1 or BRCA2; however, the association of oophorectomy with all-cause mortality has not been clearly defined.ObjectiveTo evaluate the association between bilateral oophorectomy and all-cause mortality among women with a BRCA1 or BRCA2 sequence variation.Design, Setting, and ParticipantsIn this international, longitudinal cohort study of women with BRCA sequence variations, information on bilateral oophorectomy was obtained via biennial questionnaire. Participants were women with a BRCA1 or BRCA2 sequence variation, no prior history of cancer, and at least 1 follow-up questionnaire completed. Women were followed up from age 35 to 75 years for incident cancers and deaths. Cox proportional hazards regression was used to estimate the hazard ratios (HRs) and 95% CIs for all-cause mortality associated with a bilateral oophorectomy (time dependent). Data analysis was performed from January 1 to June 1, 2023.ExposuresSelf-reported bilateral oophorectomy (with or without salpingectomy).Main Outcomes and MeasuresAll-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.ResultsThere were 4332 women (mean age, 42.6 years) enrolled in the cohort, of whom 2932 (67.8%) chose to undergo a preventive oophorectomy at a mean (range) age of 45.4 (23.0-77.0) years. After a mean follow-up of 9.0 years, 851 women had developed cancer and 228 had died; 57 died of ovarian or fallopian tube cancer, 58 died of breast cancer, 16 died of peritoneal cancer, and 97 died of other causes. The age-adjusted HR for all-cause mortality associated with oophorectomy was 0.32 (95% CI, 0.24-0.42; P &amp;amp;lt; .001). The age-adjusted HR was 0.28 (95% CI, 0.20-0.38; P &amp;amp;lt; .001) and 0.43 (95% CI, 0.22-0.90; P = .03) for women with BRCA1 and BRCA2 sequence variations, respectively. For women with BRCA1 sequence variations, the estimated cumulative all-cause mortality to age 75 years for women who had an oophorectomy at age 35 years was 25%, compared to 62% for women who did not have an oophorectomy. For women with BRCA2 sequence variations, the estimated cumulative all-cause mortality to age 75 years was 14% for women who had an oophorectomy at age 35 years compared to 28% for women who did not have an oophorectomy.Conclusions and RelevanceIn this cohort study among women with a BRCA1 or BRCA2 sequence variation, oophorectomy was associated with a significant reduction in all-cause mortality.

Endometrial Thickness as Diagnostic Triage for Endometrial Cancer Among Black Individuals

ImportancePoor performance of the transvaginal ultrasonography triage strategy has been suggested as a contributor to racial disparity between Black individuals and White individuals in endometrial cancer (EC) stage at diagnosis in population-level simulation analyses.ObjectivesTo examine the false-negative probability using ultrasonography-measured endometrial thickness (ET) thresholds as triage for EC diagnosis among Black individuals and assess whether known risk factors of EC modify ET triage performance.Design, Setting, and ParticipantsThis retrospective diagnostic study of merged abstracted electronic health record data and secondary administrative data (January 1, 2014, to December 31, 2020) from the Guidelines for Transvaginal Ultrasound in the Detection of Early Endometrial Cancer sample assessed Black individuals who underwent hysterectomy in a 10-hospital academic-affiliated health care system and affiliated outpatient practices. Data analysis was performed from January 31, 2023, to November 30, 2023.ExposurePelvic ultrasonography within 24 months before hysterectomy.Main Outcome and MeasuresUltrasonography performed before hysterectomy as well as demographic and clinical data on symptom presentation, endometrial characterization, and final EC diagnosis were abstracted. Endometrial thickness thresholds were examined for accuracy in ruling out EC diagnosis by using sensitivity, specificity, and negative predictive value. False-negative probability was defined as 1 − sensitivity. Accuracy measures were stratified by risk factors for EC and by factors hypothesized to influence ET measurement quality.ResultsA total of 1494 individuals with a uterus (median [IQR] age, 46.1 [41.1-54.0] years) comprised the sample, and 210 had EC. Fibroids (1167 [78.1%]), vaginal bleeding (1067 [71.4%]), and pelvic pain (857 [57.4%]) were the most common presenting diagnoses within 30 days of ultrasonography. Applying the less than 5-mm ET threshold, there was an 11.4% probability that someone with EC would be classified as not having EC (n = 24). At the 4-mm (cumulative) threshold, the probability was 9.5%, and at 3 mm, it was 3.8%. False-negative probability at the 5-mm threshold was similar among EC risk factor groups: postmenopausal bleeding (12.4%; 95% CI, 7.8%-18.5%), body mass index greater than 40 (9.3%; 95% CI, 3.1%-20.3%); and age 50 years or older (12.8%; 95% CI, 8.4%-18.5%). False-negative probability was also similar among those with fibroids on ultrasonography (11.8%; 95% CI, 6.9%-18.4%) but higher in the setting of reported partial ET visibility (26.1%; 95% CI, 10.2%-48.4%) and pelvic pain (14.5%; 95% CI, 7.7%-23.9%).Conclusion and RelevanceThese findings suggest that the transvaginal ultrasonography triage strategy is not reliable among Black adults at risk for EC. In the presence of postmenopausal bleeding, tissue sampling is strongly recommended.

Patterns of Undertreatment and Overtreatment in Adjuvant Radiotherapy for Early-Stage Endometrial Cancer Based on Molecular Classification

The quality improvement study examines the use of risk-adaptive adjuvant radiotherapy in women with non–mismatch repair deficiency endometrial cancer.

Survival After Fertility-Preserving Hormonal Therapy vs Hysterectomy for Early-Stage Endometrial Cancer

ImportanceAs the number of young women with early-stage endometrial cancer is increasing, there is growing interest in use of progesterone-based therapy to allow fertility preservation.ObjectiveTo ascertain the long-term survival of premenopausal women with clinical stage I endometrial cancer treated primarily with fertility-preserving hormonal therapy compared with hysterectomy.Design, Setting, and ParticipantsThis cohort study used data from the National Cancer Database to identify female patients aged 18 to 49 years with clinical stage I, grade 1 to 2, endometrioid endometrial cancer diagnosed from 2004 through 2020. In addition, trends in and factors associated with the use of fertility-preserving hormonal therapy were examined. Propensity score matching was used to compare survival among patients treated primarily with fertility-preserving hormonal therapy and those treated with hysterectomy. Data were analyzed from November 2023 to January 2024.ExposuresPrimary treatment was defined as hysterectomy or fertility-preserving hormonal therapy based on days from diagnosis to operation or fertility-preserving hormonal therapy.Main Outcomes and MeasuresTime to all-cause mortality was measured in months from cancer diagnosis to death or last follow-up at 2-year, 5-year, and 10-year intervals.ResultsA total of 15 849 women, including 14 662 (92.5%) treated with primary hysterectomy (mean [IQR] age, 44 [39-47] years]) and 1187 (7.5%) who received primary hormonal therapy (mean [IQR] age, 34 [30-38] years) were identified. The use of hormonal treatment increased from 5.2% in 2004 to 13.8% in 2020 (P &amp;amp;lt; .001). After propensity score matching, 5-year survival was 98.5% (95% CI, 97.3%-99.2%) for primary hysterectomy and 96.8% (95% CI, 95.3%-97.8%) for primary hormonal therapy (hazard ratio [HR] = 1.84; 95% CI, 1.06-3.21). Among patients younger than 40 years, there was no difference in survival between hysterectomy and hormonal therapy (HR = 1.00; 95% CI, 0.50-2.00). However, for patients aged 40 to 49 years, fertility-preserving hormonal therapy was associated with a significantly increased risk of death (HR = 4.94; 95% CI, 1.89-12.91).Conclusions and RelevanceThis study found that the use of fertility-preserving hormonal therapy among reproductive age patients with early-stage endometrial cancer has increased over time. While overall survival in patients with hormonal therapy is shorter than with hysterectomy, survival for patients younger than 40 years of age is comparable after primary treatment with fertility-preserving hormonal therapy or hysterectomy.

Is Appendiceal Cancer a Lynch Syndrome–Associated Cancer?

Is Appendiceal Cancer a Lynch Syndrome–Associated Cancer?—Reply

Safety and Efficacy of the mTOR Inhibitor, Vistusertib, Combined With Anastrozole in Patients With Hormone Receptor−Positive Recurrent or Metastatic Endometrial Cancer

Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives hormonal resistance, thus supporting the rationale of combining mTOR inhibitor with endocrine therapy. To evaluate the safety and efficacy of vistusertib in combination with anastrozole in the treatment of women with hormone receptor-positive recurrent or metastatic endometrial cancer. The VICTORIA study was a multicenter, open-label, randomized clinical trial that accrued 75 patients with hormone receptor-positive recurrent or metastatic endometrial cancer from 12 cancer centers in France in April 2016 to October 2019. After a safety run-in period, a Simon 2-stage design was used. Data analyses were performed from December 11, 2020, to March 11, 2021. Patients were randomized in a 2:1 ratio to oral vistusertib (125 mg twice daily 2 days per week) and oral anastrozole (1 mg daily) in the combination vistusertib with anastrozole arm (V+A arm) or oral anastrozole alone (A arm). The primary end point was serious adverse events for the safety run-in period and progression-free rate at 8 weeks (8wk-PFR)-assessed with a blinded independent central review in phase 2. The secondary end points were objective response rate, duration of response, progression-free survival (PFS), overall survival, and incidence of adverse events. Of the 75 patients who were randomized, 73 (median [range] age, 69.5 [37-88] y; all female) were treated: V+A arm, 49 patients; A arm, 24 patients. In the V+A arm, the 8wk-PFR was 67.3% (unilateral 95% CI, 54.7%) and in the A arm, 39.1% (unilateral 95% CI, 22.2%). No significant serious adverse events were reported during the safety run-in period (n = 6 in V+A arm). The overall response rate was 24.5% (95% CI, 13.3%-38.9%) in the V+A arm vs 17.4% (95% CI, 5.0%-38.8%) in the A arm. With a median follow-up of 27.7 months, median PFS was 5.2 (95% CI, 3.4-8.9) in the V+A arm and 1.9 (95% CI, 1.6-8.9) months in the A arm. Fatigue, lymphopenia, hyperglycemia, and diarrhea were the most common (grade ≥2) adverse events associated with vistusertib. This multicenter, open-label, phase 1/2 randomized clinical trial demonstrated that adding vistusertib to anastrozole improved 8wk-PFR, overall response rate, and PFS for patients with endometrial cancer and had manageable adverse events. Identification of molecular subgroups would allow for more precise selection of patients who may be most likely to experience favorable outcomes. ClinicalTrials.gov Identifier: NCT02730923.

A Race-Conscious Analysis of the Use of Transvaginal Ultrasonography in the Evaluation of Postmenopausal Bleeding

Estimated Performance of Transvaginal Ultrasonography for Evaluation of Postmenopausal Bleeding in a Simulated Cohort of Black and White Women in the US

Black women in the US with endometrial cancer (EC) are more likely to be diagnosed with advanced-stage disease independent of insured status and histologic type. The most common way of diagnosing EC at early stages is through screening of people with postmenopausal bleeding to detect endometrial thickness (ET). This approach may disproportionately underperform in Black women secondary to a higher prevalence of fibroids and nonendometrioid EC in this population, both of which affect the quality of ET measurement. To compare the performance of recommended transvaginal ultrasonography (TVUS) ET thresholds as a screening method to prompt endometrial biopsy by race in a simulated cohort of symptomatic women. In a simulated retrospective cohort study, based on data from Surveillance, Epidemiology, and End Results (SEER) national cancer registry 2012-2016; the US census; and published estimates of ET distribution and fibroid prevalence, diagnostic test characteristics of the 3-mm or more, 4-mm or more, and 5-mm or more ET thresholds for biopsy to capture EC diagnoses were calculated. The simulated cohort was constructed from February 2, 2020 (date of access to SEER data), to August 31, 2020. Analysis occurred from September 30, 2020, to March 30, 2021, including the primary analysis and the sensitivity calculations. The main outcome measured was accuracy of the TVUS ET threshold to accurately identify cases of EC, measured by sensitivity, negative predictive value, and area under the curve (AUC). A total of 367 073 simulated Black and White women with postmenopausal bleeding were evaluated, including 36 708 with EC. Among Black women, the currently recommended 4-mm or greater ET threshold prompted biopsy for fewer than half of EC cases (sensitivity, 47.5%; 95% CI, 46.0%-49.0%); of women referred for biopsy, 13.1% were EC cases (positive predictive value, 13.1%; 95% CI, 12.5%-13.6%). The AUC for the 4-mm or more threshold was 0.57 (95% CI, 0.56-0.57). In contrast, among the White women, the 4-mm or more threshold led to biopsy for most with EC (sensitivity, 87.9%; 95% CI, 87.6%-88.3%). Of those referred for biopsy, 14.6% had EC (positive predictive value, 14.6%; 95% CI, 14.4%-14.7%); AUC was 0.73 (95% CI, 0.73-0.74). The same variations held for the 3-mm or more and 5-mm or more ET thresholds: sensitivity, positive predictive value, and AUC were consistently lower for Black women than White women. The findings of this simulated cohort study suggest that use of ET as measured by TVUS to determine the need for EC diagnostic testing in symptomatic women may exacerbate racial disparities in EC stage at diagnosis. In simulated data, TVUS ET screening missed almost 5 times more cases of EC among Black women vs White women owing to the greater prevalence of fibroids and nonendometrioid histologic type in Black women.