Cancer

Association of alcohol intake over the lifetime with colorectal adenoma and colorectal cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract Background Alcohol drinking is associated with higher colorectal cancer (CRC) risk, but research on lifetime alcohol drinking is limited. The objective of the current study was to estimate the association of lifetime alcohol drinking with incident colorectal adenoma and cancer. Methods US adults enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial reported alcohol intake during four age periods. Average lifetime alcohol intake was calculated as average drinks per week from age 18 years until study baseline. Alcohol intake patterns were defined by past and current drinking frequency. Among 12,327 participants with a negative baseline screen, 812 had an adenoma on the second screen. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for incident adenoma. During 20 years of follow‐up, 1679 incident CRC cases occurred among 88,092 participants. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for CRC. Results Current drinkers with an average lifetime alcohol intake of 14 or more drinks per week, compared with one drink or less per week, had a higher risk of CRC (HR, 1.25; 95% CI, 1.01–1.53), especially rectal cancer (HR, 1.95; 95% CI, 1.17–3.28). Consistent heavy drinking versus light drinking was positively associated with CRC risk (HR, 1.91; 95% CI, 1.17–3.12). Compared with current drinkers averaging less than one drink per week, former drinkers had lower odds of nonadvanced adenoma (OR, 0.58; 95% CI, 0.39–0.84). Current drinkers averaging from seven to less than 14 drinks compared with less than one drink per week had a lower risk of CRC (HR, 0.79; 95% CI, 0.64–0.97), especially distal colon cancer (HR, 0.64; 95% CI, 0.42–1.00). Conclusions Consistent heavy alcohol intake and higher average lifetime alcohol drinking may increase CRC risk, whereas cessation may lower adenoma risk. Associations may differ by tumor site.

Association between racial residential segregation and screening uptake for colorectal and cervical cancer among Black and White patients in five US health care systems

AbstractBackgroundDespite increased recognition that structural racism contributes to poorer health outcomes for racial and ethnic minorities, there are knowledge gaps about how current patterns of racial residential segregation are associated with cancer screening uptake. The authors examined associations between Black residential segregation and screening for colorectal cancer (CRC) and cervical cancer among non‐Hispanic Black and non‐Hispanic White adults.MethodsThis was a retrospective study of CRC and cervical cancer screening‐eligible adults from five health care systems within the Population‐Based Research to Optimize the Screening Process (PROSPR II) Consortium (cohort entry, 2010–2012). Residential segregation was measured using site‐specific quartiles of the Black local isolation score (LIS). The outcome was receipt of CRC or cervical cancer screening within 3 years of cohort entry (2010–2015). Logistic regression was used to calculate associations between the LIS and screening completion, adjusting for patient‐level covariates.ResultsAmong CRC (n = 642,661) and cervical cancer (n = 163,340) screening‐eligible patients, 456,526 (71.0%) and 106,124 (65.0%), respectively, received screening. Across PROSPR sites, living in neighborhoods with higher LIS tended to be associated with lower odds of CRC screening (Kaiser Permanente Northern California: adjusted odds ratio [aOR] LIS trend in Black patients, 0.95 [p < .001]; aOR LIS trend in White patients, 0.98 [p < .001]; Kaiser Permanente Southern California: aOR LIS trend in Black patients, 0.98 [p = .026]; aOR LIS trend in White patients, 1.01 [p = .023]; Kaiser Permanente Washington: aOR LIS trend in White patients, 0.97 [p = .002]. However, for cervical cancer screening, associations with the LIS varied by site and race (Kaiser Permanente Washington: aOR LIS trend in White patients, 0.95 [p < .001]; Mass General Brigham: aOR LIS trend in Black patients, 1.12 [p < .001]; aOR LIS trend in White patients, 1.03 [p < .001]).ConclusionsAcross five diverse health care systems, the direction of the association between Black residential segregation and screening varied by PROSPR site, race, and screening type. Additional research, including studies that examine multiple dimensions of segregation and structural racism using intersectional approaches, are needed to further disentangle these relationships.

Optimizing treatment for platinum‐resistant ovarian clear cell carcinoma: Efficacy of gemcitabine and combination therapy with bevacizumab

AbstractBackgroundPlatinum‐resistant (PR) ovarian clear cell carcinoma (OCCC) is highly resistant to chemotherapy and has a poor prognosis. Both in‐vitro and clinical studies have suggested that gemcitabine (GEM) is particularly effective against OCCC. Moreover, a combination with bevacizumab (Bev) is expected to enhance the efficacy of chemotherapy.MethodsTo clarify these effects, the authors conducted a multicenter, retrospective cohort study of 130 patients who received treatment single‐agent chemotherapy, with or without Bev, for PR‐OCCC. The effects of loss of AT‐rich interaction domain 1A (ARID1A) protein expression also were assessed.ResultsPatients who received GEM as their first regimen achieved better overall survival (OS) than those who received other agents (median OS, 15.2 vs. 11.0 months; hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.41–0.96; p = .032). Bev combination therapies demonstrated a significantly improved time to treatment failure compared with chemotherapy alone (6.6 vs. 2.7 months; HR, 0.61; 95% CI, 0.41–0.87; p = .009) and showed a trend toward longer OS (23.3 vs. 9.8 months; HR, 0.62; 95% CI, 0.34–1.05; p = .085). ARID1A status did not affect OS in the overall group or in the group that received GEM as the first‐line regimen (p = .41 and p = .31, respectively).ConclusionsCollectively, the current findings suggest that GEM, particularly as a first‐line treatment, may improve the prognosis of patients with PR‐OCCC. Moreover, Bev combination therapy is a promising option for treating PR‐OCCC.

The human oral microbiome and risk of colorectal cancer within three prospective cohort studies in the United States

AbstractBackgroundOral microbes detected in feces have been associated with colorectal cancer (CRC) in cross‐sectional studies. This study investigated the prospective associations between the oral microbiome and incident CRC in the Agricultural Health Study (AHS), National Institutes of Health–AARP (NIH‐AARP) Diet and Health Study, and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.MethodsIndividuals with oral samples collected before incident CRC diagnoses were identified in the AHS (N = 331), NIH‐AARP (N = 249), and PLCO (N = 446) and compared with referent subcohorts (N = 3431). The V4 region of the 16S ribosomal RNA gene was sequenced from oral wash DNA, and the data were processed with QIIME2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall CRC and by anatomic subsite (i.e., proximal colon, distal colon, and rectum) were estimated with Cox proportional hazards models with adjustment for potential confounders by cohort and then meta‐analyzed.ResultsOverall, no associations were found between microbial characteristics and CRC risk. However, associations were observed with alpha and beta diversity indices and individual genera in analyses stratified by anatomic subsite. For instance, the presence of Olsenella was strongly positively associated with distal colon cancer risk (HR, 2.16; 95% CI, 1.59–2.95), whereas the presence of Prevotella 2 was positively associated with rectal cancer risk (HR, 1.68; 95% CI, 1.14–2.46).ConclusionsThis large study of the prospective association between the oral microbiome and CRC risk showed numerous site‐specific associations, including multiple associations with distal colon and rectal cancer risk.

New standard of care for platinum‐resistant ovarian cancer

Population‐specific validation and comparison of the performance of 77‐ and 313‐variant polygenic risk scores for breast cancer risk prediction

AbstractBackgroundThe polygenic risk score (PRS) allows the quantification of the polygenic effect of many low‐penetrance alleles on the risk of breast cancer (BC). This study aimed to evaluate the performance of two sets comprising 77 or 313 low‐penetrance loci (PRS77 and PRS313) in patients with BC in the Czech population.MethodsIn a retrospective case‐control study, variants were genotyped from both the PRS77 and PRS313 sets in 1329 patients with BC and 1324 noncancer controls, all women without germline pathogenic variants in BC predisposition genes. Odds ratios (ORs) were calculated according to the categorical PRS in individual deciles. Weighted Cox regression analysis was used to estimate the hazard ratio (HR) per standard deviation (SD) increase in PRS.ResultsThe distributions of standardized PRSs in patients and controls were significantly different (p < 2.2 × 10−16) with both sets. PRS313 outperformed PRS77 in categorical and continuous PRS analyses. For patients in the highest 2.5% of PRS313, the risk reached an OR of 3.05 (95% CI, 1.66–5.89; p = 1.76 × 10−4). The continuous risk was estimated as an HRper SD of 1.64 (95% CI, 1.49–1.81; p < 2.0 × 10−16), which resulted in an absolute risk of 21.03% at age 80 years for individuals in the 95th percentile of PRS313. Discordant categorization into PRS deciles was observed in 248 individuals (9.3%).ConclusionsBoth PRS77 and PRS313 are able to stratify individuals according to their BC risk in the Czech population. PRS313 shows better discriminatory ability. The results support the potential clinical utility of using PRS313 in individualized BC risk prediction.

Promising new treatment approaches for locally advanced cervical cancer

Absolute lung cancer risk increases among individuals with >15 quit‐years: Analyses to inform the update of the American Cancer Society lung cancer screening guidelines

AbstractBackgroundThis report quantifies counteracting effects of quit‐years and concomitant aging on lung cancer risk, especially on exceeding 15 quit‐years, when the US Preventive Services Task Force (USPSTF) recommends curtailing lung‐cancer screening.MethodsCox models were fitted to estimate absolute lung cancer risk among Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) and National Lung Screening Trial (NLST) participants who ever smoked. Absolute lung cancer risk and gainable years of life from screening for individuals aged 50 to 80 in the US‐representative National Health Interview Survey (NHIS) 2015–2018 who ever smoked were projected. Relaxing USPSTF recommendations to 20/25/30 quit‐years versus augmenting USPSTF criteria with individuals whose estimated gain in life expectancy from screening exceeded 16.2 days according to the Life Years From Screening‐CT (LYFS‐CT) prediction model was compared.ResultsAbsolute lung cancer risk increased by 8.7%/year (95% CI, 7.7%–9.7%; p < .001) as individuals aged beyond 15 quit‐years in the PLCO, with similar results in NHIS and NLST. For example, mean 5‐year lung cancer risk for those aged 65 years with 15 quit‐years = 1.47% (95% CI, 1.35%–1.59%) versus 1.76% (95% CI, 1.62%–1.90%) for those aged 70 years with 20 quit‐years in the PLCO. Removing the quit‐year criterion would make 4.9 million more people eligible and increase the proportion of preventable lung cancer deaths prevented (sensitivity) from 63.7% to 74.2%. Alternatively, augmentation using LYFS‐CT would make 1.7 million more people eligible while increasing the lung cancer death sensitivity to 74.0%.ConclusionsBecause of aging, absolute lung cancer risk increases beyond 15 quit‐years, which does not support exemption from screening or curtailing screening once it has been initiated. Compared with relaxing the USPSTF quit‐year criterion, augmentation using LYFS‐CT could prevent most of the deaths at substantially superior efficiency, while also preventing deaths among individuals who currently smoke with low intensity or long duration.

Primary results and characterization of patients with exceptional outcomes in a phase 1b study combining PARP and MEK inhibition, with or without anti–PD‐L1, for BRCA wild‐type, platinum‐sensitive, recurrent ovarian cancer

AbstractBackgroundThis phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD‐L1 inhibition, for BRCA wild‐type, platinum‐sensitive, recurrent ovarian cancer (PSROC).MethodsPatients with PSROC who had received one or two prior treatment lines were treated with 28‐day cycles of cobimetinib 60 mg daily (days 1–21) plus niraparib 200 mg daily (days 1–28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild‐type PSROC to receive either doublet or triplet therapy, stratified by genome‐wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum‐free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator‐determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super‐responders (complete response or those with progression‐free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized.ResultsThe ORR in patients who had BRCA wild‐type PSROC was 35% (95% confidence interval, 20%–53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%–44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post‐hoc analyses indicated more favorable ORR and PFS in the homologous recombination‐deficiency‐signature (HRDsig)‐positive subgroup than in the HRDsig‐negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively.ConclusionsChemotherapy‐free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild‐type, HRDsig‐positive or HRDsig‐negative PSROC harboring NF1 or MKNK1 mutations.

Somatic mutation profiles of clear cell endometrial tumors revealed by whole exome and targeted gene sequencing.

The molecular pathogenesis of clear cell endometrial cancer (CCEC), a tumor type with a relatively unfavorable prognosis, is not well defined. We searched exome-wide for novel somatically mutated genes in CCEC and assessed the mutational spectrum of known and candidate driver genes in a large cohort of cases. We conducted whole exome sequencing of paired tumor-normal DNAs from 16 cases of CCEC (12 CCECs and the CCEC components of 4 mixed histology tumors). Twenty-two genes-of-interest were Sanger-sequenced from another 47 cases of CCEC. Microsatellite instability (MSI) and microsatellite stability (MSS) were determined by genotyping 5 mononucleotide repeats. Two tumor exomes had relatively high mutational loads and MSI. The other 14 tumor exomes were MSS and had 236 validated nonsynonymous or splice junction somatic mutations among 222 protein-encoding genes. Among the 63 cases of CCEC in this study, we identified frequent somatic mutations in TP53 (39.7%), PIK3CA (23.8%), PIK3R1 (15.9%), ARID1A (15.9%), PPP2R1A (15.9%), SPOP (14.3%), and TAF1 (9.5%), as well as MSI (11.3%). Five of 8 mutations in TAF1, a gene with no known role in CCEC, localized to the putative histone acetyltransferase domain and included 2 recurrently mutated residues. Based on patterns of MSI and mutations in 7 genes, CCEC subsets molecularly resembled serous endometrial cancer (SEC) or endometrioid endometrial cancer (EEC). Our findings demonstrate molecular similarities between CCEC and SEC and EEC and implicate TAF1 as a novel candidate CCEC driver gene. Cancer 2017;123:3261-8. © 2017 American Cancer Society.

Clinical utility of comprehensive liquid molecular profiling in patients with advanced endometrial cancer

AbstractBackgroundMolecular characterization has significantly improved the management of advanced endometrial cancer (EC). It distinguishes four molecular subclasses associated with prognosis and personalized therapeutic strategies. This study assesses the clinical utility of cell‐free DNA (cfDNA) profiling in EC to identify targetable alterations.MethodsWomen with metastatic or recurrent EC were prospectively recruited within the framework of the STING trial (NCT04932525), during which cfDNA was analyzed. Genomic alterations were identified with the FoundationOne CDx assay. Each molecular report underwent review by a molecular tumor board. Alterations were categorized via the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT).ResultsA total of 61 patients were enrolled. The median age was 66.9 years, with 43% presenting frontline metastatic disease. All histologic subgroups were represented. Notably, 89% of patients yielded informative cfDNA analysis. Six tumors were classified with deficient mismatch repair/microsatellite instability (11%) and 37 as TP53 gene mutant (67%), and 12 had nonspecific molecular profiles (22%). Molecular classification based on liquid biopsy showed 87.5% accuracy in correlating with tissue results. Moreover, 65% of cases exhibited ≥1 actionable alteration, including 25% ESCAT I alterations and 13% ESCAT II alterations. Consequently, 16% of patients received a molecularly matched therapy, and presented with a 56% response rate and median progression‐free survival of 7.7 months.ConclusionscfDNA sequencing in EC is a feasible approach that produces informative results in 89% of cases and accurately categorizes patients into the main molecular subclasses. It also reveals multiple actionable alterations, which offers the potential for personalized therapeutic strategies.

Study shows a decrease in cervical cancer but a rise in other human papillomavirus–related cancers

Reply to Worldwide trends in cervical cancer incidence and mortality

Olaparib as treatment for platinum‐sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency: Phase 2 LIGHT study final overall survival analysis

AbstractBackgroundLIGHT (oLaparib In HRD‐Grouped Tumor types; NCT02983799) prospectively evaluated olaparib treatment in patients with platinum‐sensitive relapsed ovarian cancer (PSROC) assigned to cohorts by known BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD‐positive non‐BRCAm, and HRD‐negative. At the primary analysis, olaparib treatment demonstrated activity across all cohorts, with greatest efficacy in terms of objective response rate and progression‐free survival observed in the g/sBRCAm cohorts. The authors report final overall survival (OS).MethodsIn this phase 2, open‐label, noncomparative study, patients with PSROC and one or more prior line of platinum‐based chemotherapy were assigned to cohorts by BRCAm and HRD status. OS was a secondary end point. Tumors were analyzed using Myriad BRACAnalysis CDx and MyChoice CDx assays; HRD‐positive tumors were defined using a genomic instability score of ≥42.ResultsOf 272 enrolled patients, 271 received olaparib and 270 met the inclusion criteria for the efficacy analysis. At data cutoff, 18‐month OS rates in the gBRCAm, sBRCAm, HRD‐positive non‐BRCAm, and HRD‐negative cohorts were 86.4%, 88.0%, 78.6%, and 59.6%, respectively. No new safety signals were observed. In a post hoc analysis, patients on treatment for >18 months were most frequently present in g/sBRCAm cohorts (31.0%).ConclusionsOlaparib treatment continued to demonstrate benefit across all cohorts. Consistent with the primary analysis, the highest OS rates were observed in the BRCAm cohorts, regardless of g/sBRCAm. In patients without a BRCAm, a higher OS rate was observed in the HRD‐positive non‐BRCAm than the HRD‐negative cohorts. These results highlight the importance of biomarker testing in this treatment setting.

Barriers and motivators to women’s cancer screening: A qualitative study of a sample of diverse women

AbstractIntroductionCancer is an enormous public health challenge in the United States and around the world. Early detection through screening can identify cancer when it is most treatable and can result in greater survival rates; however, racial and ethnic disparities in breast and cervical screening result in late diagnosis and a higher risk of poor outcomes and death for women of color.PurposeThe purpose of this study was to examine barriers that a diverse sample of women in Rhode Island face related to breast and cervical cancer screening, as well as motivators that encourage women to obtain screening services.Design and methodsWomen, most of whom self‐identified as Black or Hispanic, who were aged 40 years and older, were recruited to participate in focus groups via Zoom. The main topics of the discussions included thoughts, attitudes, beliefs, and prior experiences with screening.ResultsForty‐seven women from Rhode Island participated in a total of six focus groups. The following themes emerged: (1) fear, lack of knowledge, cultural beliefs, and the role of women as caretakers are personal barriers; (2) communication challenges, a shortage of primary care providers and negative health experiences are system barriers; and (3) family history of cancer, encouragement from providers, and clinic reminders are motivators that encourage women to get screened.ConclusionsResults suggest that communities must focus on eliminating barriers, promoting motivators, and expanding access to supportive screening services to reduce the number of cases and deaths due to breast and cervical cancer.

Trends and racial disparities in aggressive end‐of‐life care for a national sample of women with ovarian cancer

BACKGROUNDThe clinical landscape has moved toward less aggressive end‐of‐life care for women with ovarian cancer. However, whether there has been a decline in the use of aggressive end‐of‐life services is unknown. The authors evaluated current national trends and racial disparities in end‐of‐life care among women with ovarian cancer using the Surveillance, Epidemiology, and End Results‐Medicare–linked data set.METHODSIn total, 7756 Medicare beneficiaries aged >66 years with ovarian cancer who died between 2007 and 2016 were identified. The authors examined trends and racial disparities in late hospice or no hospice use, >1 emergency department (ED) visit, intensive care unit admission, >1 hospitalization, terminal hospitalization, chemotherapy, and invasive and/or life‐extending procedures using multivariable logistic regression.RESULTSThe median hospice length of stay did not change over time; however, women were increasingly admitted to the intensive care unit and had multiple ED visits in the last month of life (P < .001). Not enrolling in hospice at the end of life and terminal hospitalizations decreased over time (P < .001). Non‐White women were more likely to receive aggressive end‐of‐life care, particularly for hospital‐related utilization and life‐extending procedures, whereas non‐Hispanic Black women were more likely to have >1 ED visit (odds ratio, 2.04; 95% CI, 1.57‐2.64) or life‐extending procedures (odds ratio, 1.89; 95% CI, 1.45‐2.48) compared with non‐Hispanic White women.CONCLUSIONSDespite clinical guidelines and increasing emphasis on reducing aggressive end‐of‐life care, the use of aggressive end‐of‐life care for women with ovarian cancer persists, and care is most aggressive for non‐White women.

Significance of HIV status in cervical cancer patients receiving curative chemoradiation therapy, definitive radiation alone, or palliative radiation in Botswana

ABSTRACTBACKGROUNDCervical cancer associated with human papillomavirus has the highest cancer incidence and mortality for women in Botswana because of a high HIV prevalence and limited screening. This study investigates the significance of HIV on the overall survival (OS) of patients with locally advanced cervical cancer by various treatment categories (curative chemoradiation, definitive radiation [RT] alone, or palliative RT alone).METHODSThis study included patients diagnosed with cervical cancer between 2013 and 2020, prospectively enrolled in the Botswana Prospective Cancer Cohort. OS based on HIV status and completion of planned treatment regimen was estimated by the Kaplan–Meier method. Comparisons of 2‐year OS by HIV status was performed by the log‐rank test, univariate and multivariable Cox analyses adjusting for cancer stage, RT dose, number of chemotherapy cycles, and baseline hemoglobin levels.RESULTSOf 1131 patients diagnosed with stage IB‐IVB cervical cancer, 69.8% were women living with HIV (n = 789). For patients receiving curative chemoradiation, HIV status was not significantly associated with OS in unadjusted (p = .987) and adjusted (p = .578) analyses. For RT only treatment and definitive (high‐dose) RT alone, HIV status was significantly associated with OS in unadjusted analysis (HR = 1.77, p = .002; HR = 1.95, p = .014), but not in adjusted analysis (p = .227, p = .73). For patients receiving palliative (low‐dose) RT, HIV status was not associated with OS in unadjusted (p = .835) or adjusted analysis (p = .359).CONCLUSIONSIn Botswana, a resource‐limited setting, HIV status had no significant effect on 2‐year OS in patients with cervical cancer with well‐managed HIV receiving chemoradiation, RT alone, or palliative RT. This demonstrates that patients living with HIV receiving antiretroviral treatment can receive clinically appropriate treatment with no evidence that HIV may lead to poorer outcomes.

POLE mutations in endometrial carcinoma: Clinical and genomic landscape from a large prospective single‐center cohort

AbstractBackgroundTo date, 11 DNA polymerase epsilon (POLE) pathogenic variants have been declared “hotspot” mutations. Patients with endometrial cancer (EC) characterized by POLE hotspot mutations (POLEmut) have exceptional survival outcomes. Whereas international guidelines encourage deescalation of adjuvant treatment in early‐stage POLEmut EC, data regarding safety in POLEmut patients with unfavorable characteristics are still under investigation. On the other hand, the spread of comprehensive genome profiling programs has underscored the need to interpret POLE variants not considered to be hotspots.MethodsThis study provides a comprehensive analysis of 596 sequenced patients with EC. The genomic landscape of POLEmut EC was compared with cases harboring nonhotspot POLE mutations within the exonuclease domain. Additionally, the genomic characteristics of multiple classifiers, as well as those exhibiting unfavorable histopathological and clinical features, were examined.ResultsNo significant genomic differences were observed among patients with POLEmut EC when comparing multiple classifiers to not‐multiple classifiers or those with unfavorable clinical features. However, the tumor mutational burden differed in both comparisons, whereas the percentage of C>G mutations only differed in the comparison based on clinical features. Specific POLE mutations, even if not considered to be hotspots, have genomic features comparable to POLEmut.ConclusionsThe present findings confirm the absence of significant genomic differences among POLEmut patients regardless of multiple‐classifier status or association with high‐risk clinical features. Prognostic data will be essential to elucidate the clinical significance of POLE mutations not classified as hotspots that exhibit genomic characteristics similar to those in POLEmut patients.

Anticipation in families with MLH1‐associated Lynch syndrome

AbstractBackgroundLynch syndrome (LS) is an autosomal‐dominant, hereditary cancer predisposition syndrome caused by pathogenic variants (PVs) in one of the mismatch‐repair genes MLH1, MSH2/EPCAM, MSH6, or PMS2. Individuals who have MLH1 PVs have high lifetime risks of colorectal cancer (CRC) and endometrial cancer (EC). There is controversy regarding whether a younger age at diagnosis (or anticipation) occurs in MLH1‐associated LS. The objective of this study was to assess anticipation in families with MLH1‐associated LS by using statistical models while controlling for potential confounders.MethodsData from 31 families with MLH1 PVs were obtained from an academic registry. Wilcoxon signed‐rank tests on parent–child‐pairs as well as parametric Weibull and semiparametric Cox proportional hazards and Cox mixed‐effects models were used to calculate hazard ratios or to compare mean ages at CRC/EC diagnosis by generation. Models were also corrected for ascertainment bias and birth‐cohort effects.ResultsA trend toward younger ages at diagnosis of CRC/EC in successive generations, ranging from 3.2 to 15.7 years, was observed in MLH1 PV carrier families. A greater hazard for cancer in younger generations was not precluded by the inclusion of birth cohorts in the model. Individuals who had MLH1 variants with no Mlh1 activity were at a 78% greater hazard for CRC/EC than those who retained Mlh1 activity.ConclusionsThe current results demonstrated evidence in support of anticipation in families with MLH1‐associated LS across all statistical models. Mutational effects on Mlh1 activity influenced the hazard for CRC/EC. Screening based on the youngest age of cancer diagnosis in MLH1‐LS families is recommended.

Screening entire populations for breast and ovarian cancer could prevent millions of cases worldwide, study says

Research teams unite to develop an early detection test for ovarian cancer

Rucaparib is a safe and effective maintenance therapy for advanced pancreatic cancer

The Chicago Consensus on peritoneal surface malignancies: Management of ovarian neoplasms

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of ovarian neoplasms specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Further refining 2020 ESGO/ESTRO/ESP molecular risk classes in patients with early‐stage endometrial cancer: A propensity score–matched analysis

BackgroundThe integration of molecular features with clinicopathological findings in endometrial cancer classification seems to be able to significantly refine risk assessment. Nevertheless, clinical management remains challenging, and different therapeutic options are available for each class. Further prognostic characterization of the subgroups within each risk class could be helpful in the decision‐making process.MethodsThis study evaluated the role of the 2020 European Society of Gynaecological Oncology (ESGO)/European Society for Radiotherapy and Oncology (ESTRO)/European Society of Pathology (ESP) risk assessment system and the three prognostic profiles adopted in the PORTEC‐4a trial in predicting disease‐free and overall survival in a retrospective study cohort of patients with early‐stage endometrial cancer. Patients were selected according to a 1:2 propensity score matching analysis. Moreover, the sequencing of 29 genes was undertaken for tumor samples.ResultsThe study included 137 patients. No differences in disease‐free or overall survival at 5 years were observed among the 2020 ESGO/ESTRO/ESP risk classes without molecular features (p = .766 and p = .176, respectively). Once molecular features were integrated, the probability of overall survival was significantly different (p = .011). When the three prognostic profiles were applied, the probability of recurrence had a p value of .097, and significant differences were observed in overall survival (p = .004). Among patients experiencing recurrence, 17.6% showed mutations in BRCA1/2, RAD50, BRIP1, and XRCC2, whereas 22.5% had PD‐L1–positive expression and an MUTYH mutation.ConclusionsFurther stratification within each risk class according to the most relevant prognostic features could better define the prognosis of patients with early‐stage endometrial cancer. Nearly half of the patients who experienced recurrence showed a targetable molecular alteration for which dedicated trials should be encouraged.

Study finds that women with posttraumatic stress disorder have an increased risk of ovarian cancer

Mismatch repair and clinical response to immune checkpoint inhibitors in endometrial cancer

Lay Summary Endometrial cancer is common, and a subset recurs and requires additional treatment. Some of these are recognized as being susceptible to immune therapies and are said to have mismatch repair deficiency (dMMR). However, this clinical trial highlights which cases are more likely to respond well: those containing mutations in genes known as Lynch genes and also some with mutations in POLE/POLD1 (“ultra‐hypermutation” genes). In contrast, the majority of dMMR endometrial cancers have silencing or DNA methylation of one of these genes, MLH1, and do not seem to be as responsive to single‐agent immune therapy. The availability of combination therapies may be important to consider for these women.

Maximizing cancer prevention through genetic navigation for Lynch syndrome detection in women with newly diagnosed endometrial and nonserous/nonmucinous epithelial ovarian cancer

BackgroundDespite recommendations for reflex immunohistochemistry (IHC) for mismatch repair (MMR) proteins to identify Lynch syndrome (LS), the uptake of genetic assessment by those who meet referral criteria is low. The authors implemented a comprehensive genetic navigation program to increase the uptake of genetic testing for LS in patients with endometrial cancer (EC) or nonserous/nonmucinous ovarian cancer (OC).MethodsParticipants with newly diagnosed EC or OC were prospectively recruited from 3 cancer centers in Ontario, Canada. Family history questionnaires were used to assess LS‐specific family history. Reflex IHC for MMR proteins was performed with the inclusion of clinical directives in pathology reports. A trained genetic navigator initiated a genetic referral on behalf of the treating physician and facilitated genetic referrals to the closest genetics center.ResultsA total of 841 participants (642 with EC, 172 with OC, and 27 with synchronous EC/OC) consented to the study; 194 (23%) were MMR‐deficient by IHC. Overall, 170 women (20%) were eligible for a genetic assessment for LS: 35 on the basis of their family history alone, 24 on the basis of their family history and IHC, 82 on the basis of IHC alone, and 29 on the basis of clinical discretion. After adjustments for participants who died (n = 6), 149 of 164 patients (91%) completed a genetic assessment, and 111 were offered and completed genetic testing. Thirty‐four women (4.0% of the total cohort and 30.6% of those with genetic testing) were diagnosed with LS: 5 with mutL homolog 1 (MLH1), 9 with mutS homolog 2 (MSH2), 15 with mutS homolog 6 (MSH6), and 5 with PMS2.ConclusionsThe introduction of a navigated genetic program resulted in a high rate of genetic assessment (>90%) in patients with gynecologic cancer at risk for LS.

Ultrasensitive next‐generation sequencing–based detection of circulating human papillomavirus DNA for cervical cancer recurrence monitoring

Abstract Background Circulating cell‐free human papillomavirus (ccfHPV) DNA is a promising biomarker for cervical cancer monitoring. This study used next‐generation sequencing (NGS) to assess its prognostic and surveillance value. Methods The authors included 141 cervical cancer patients (International Federation of Gynecology and Obstetrics IA1–IVB) grouped by treatment: primary surgery ( n  = 50), primary surgery + adjuvant oncological ( n  = 22), and primary oncological treatment ( n  = 69). Plasma was collected pretreatment, at early follow‐up (first post‐treatment sample [FPS]), and during longer follow‐up. ccfHPV DNA was detected using an NGS‐based assay, enabling high sensitivity without prior knowledge of human papillomavirus (HPV) genotype. Associations between ccfHPV DNA status and recurrence were assessed using Cox proportional hazards models, and predictive accuracy was evaluated via sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results Pretreatment ccfHPV DNA positivity was detected in 8.0%, 36.4%, and 82.6% of patients across the groups, and ccfHPV DNA positivity was significantly associated with higher recurrence risk (adjusted hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.29–18.7; p  = .02). At FPS, ccfHPV DNA positivity strongly predicted recurrence (adjusted HR, 19.1; 95% CI, 7.27–50.2), with a PPV of 83% and NPV of 90% for recurrence within 50 months. Among patients who developed recurrence, ccfHPV DNA was detectable before clinical evidence of recurrence in 60.9% of cases with a mean lead time of 144 days. Conclusion ccfHPV DNA detected by NGS is a strong prognostic biomarker for residual disease or recurrence. Its strong performance, already at early follow‐up, supports its integration into individualized follow‐up strategies. Prospective multicenter studies should validate these findings and guide clinical implementation. Trial Registration The study was registered with ClinicalTrials.gov (identifiers: NCT03749720)

The BEV1L study: Do real‐world outcomes associated with the addition of bevacizumab to first‐line chemotherapy in patients with ovarian cancer reinforce clinical trial findings?

In the BEV1L study, which used data from a US‐nationwide, electronic health record–derived, deidentified database of patients with epithelial ovarian cancer, the real‐world clinical benefit of adding bevacizumab to first‐line chemotherapy was limited to patients with high‐risk prognostic factors (defined as Stage IV disease or Stage III disease with visible residual disease or no evidence of surgery). These results are consistent with findings from the GOG‐0218 and ICON7 clinical trials.

Burden of female‐specific cancers in China from 1990 to 2021: A systematic analysis for the Global Burden of Disease Study 2021

AbstractBackgroundBreast cancer and reproductive system cancers remain significant public health threats for Chinese women. This study aimed to evaluate the latest epidemiological patterns and trends of four female‐specific cancers in China.MethodsThe year‐ and age‐specific estimates of the incidence, mortality, and disability‐adjusted life‐years (DALYs) associated with breast, cervical, ovarian, and uterine cancers in China from 1990 to 2021 were generated from the Global Burden of Disease, Injuries, and Risk Factors 2021 study. The epidemiological characteristics were analyzed with age–period–cohort models. A Bayesian age–period–cohort model was applied to forecast disease burden from 2022 to 2050.ResultsIn 2021, China reported 385.84 thousand (95% uncertainty interval [UI], 294.10–489.01 thousand) incident cases of female breast cancer, followed by cervical cancer (132.79 thousand [95% UI, 95.96–172.60 thousand]), uterine cancer (72.02 thousand [95% UI, 53.31–100.00 thousand]), and ovarian cancer (41.24 thousand [95% UI, 30.30–54.55 thousand]). Breast cancer ranked as the primary cause of cancer‐related deaths, followed by cervical cancer. The age‐specific incidence rate for breast, cervical, ovarian, and uterine cancers are projected to occur in the age groups 60–64 years, 55–59 years, 65–69 years, and 60–64 years, respectively. Breast, ovarian, and uterine cancer cases are projected to rise by 2050, which will exceed those recorded in 2021.ConclusionsVarious inequities have been identified across four types of cancers affecting women, which underscores the need for tailored national cancer control strategies. Emphasis should be placed on primary prevention and screening for breast and cervical cancers, whereas efforts for uterine and ovarian cancers should focus on implementing early diagnosis and treatment measures.Plain language summary This study examines the burdens and trends of breast, cervical, ovarian, and uterine cancers among Chinese women from 1990 to 2021. In 2021, breast cancer emerged as the most prevalent, followed by cervical, uterine, and ovarian cancers, with breast cancer also exhibiting the highest mortality rate. The age groups projected to exhibit the highest incidence rates for breast, cervical, ovarian, and uterine cancers are 60–64 years, 55–59 years, 65–69 years, and 60–64 years, respectively. Projections indicate that by 2050, the incidence of breast, ovarian, and uterine cancers will surpass 2021 levels, which underscores the necessity for targeted prevention, early detection, and treatment strategies.

Recent advances in gynecologic radiation oncology

AbstractSignificant advances have been made in the treatment of patients with gynecologic malignancies in the past few years. Integration of molecular testing in endometrial cancer now allows for more accurate risk stratification and personalized treatment recommendations for patients, with PORTEC‐4a investigating outcomes after treatment de‐escalation based on molecular subgroup. In several clinical trials, mismatch repair‐deficiency (MMR‐d) status has been proven to be a strong predictor for response to immunotherapy in the advanced/metastatic setting, and the role of immunotherapy in early‐stage endometrial cancer is now being investigated. For patients with locally advanced cervical cancer, results from INTERLACE demonstrate that induction chemotherapy is now a viable treatment option, and KEYNOTE A‐18 shows promise for the addition of concurrent and maintenance pembrolizumab to chemoradiation. Meanwhile, EMBRACE 1 and 2 have demonstrated the benefits of high‐quality image guided brachytherapy, providing patients with locally advanced cervical cancer excellent control with improved toxicity. For patients with vulvar cancer, GOG279 demonstrated that addition of multi‐agent chemotherapy with intensity modulated radiation therapy resulted in high rates of complete pathologic response, and GROINS‐V III is currently investigating the role of chemotherapy and nodal radiation for patients with macrometastases on sentinel lymph node biopsy. This work summarizes the findings of recent landmark trials in endometrial, cervical, and vulvar cancer and their implications for the radiation oncologist.

Cemiplimab shines for recurrent cervical cancer

Better HPV vaccination and cervical cancer screening needed

Preferences of BRCA mutation carriers for attributes of risk‐reducing surgical options for breast and ovarian cancer

Abstract Background Risk‐reducing surgeries are the most effective strategies for cancer prevention in patients with germline pathogenic variants in the BRCA1 / BRCA2 genes; these surgeries are associated with early menopause, loss of childbearing potential, and cosmetic effects. The authors assessed women's preferences for tradeoffs related to risk‐reducing surgical decision making. Methods Carriers of pathogenic mutations in BRCA1/BRCA2 aged 25–50 years without a personal history of breast, ovarian, peritoneal, or tubal cancer were recruited to complete one of four discrete choice surveys based on their age (younger than 40 years or 40 years and older) and BRCA mutation status (BRCA1 or BRCA2). Participants responded to a series of choices between a do‐nothing strategy and two profiles representing various effects of surgical options on menopause, childbearing potential (those younger than 40 years only), breast appearance, and 10‐year and lifetime risks of breast and ovarian cancer. A conditional logit model was used to quantify participants' choices as a function of surgical options and outcomes. Results In total, 298 participants completed the survey. Each cohort younger than <40 years more frequently chose profiles representing risk‐reducing salpingo‐oophorectomy (RRSO) at age 40 versus 30 years. The cohort aged 40 years and older with BRCA1 mutations favored RRSO at age 40 years but with a 56.6% choice probability of delayed RRSO after ages 35–40 years, as recommended by National Comprehensive Cancer Network guidelines. The cohort aged 40 and older with BRCA2 mutations favored RRSO at age 40, 45, or 50 years fairly equally, with a 33.0% choice probability of guideline‐nonconcordant RRSO timing. All cohorts favored mastectomy at younger ages and with reconstruction versus no mastectomy. Conclusions These findings demonstrate the heterogeneity of preferences and support individualized discussion of treatment goals relating to risk‐reducing surgical planning.

A trial of radiolabeled antibody yttrium‐90–FF‐21101 for the treatment of advanced ovarian and other cancers

AbstractBackgroundYttrium‐90 FF‐21101 (90Y–FF‐21101) is a radiopharmaceutical that targets P‐cadherin as a therapy against solid tumors. A previously reported, first‐in‐human study determined that a dose of 25 mCi/m2 was safe, and a patient with clear cell carcinoma of the ovary achieved a complete response. In this article, the authors report the results of 90Y–FF‐21101 treatment in an ovarian carcinoma expansion cohort and in patients with selected solid tumors who had known high P‐cadherin expression.MethodsThe trial was conducted as an open‐label study in patients with advanced/metastatic disease. Radiologic response and safety were evaluated in patients who received 25 mCi/m2 intravenously once every three cycles of 28 days until they developed progressive disease. Evaluation of the ovarian cohort was conducted in a Simon two‐stage manner to determine further enrollment.ResultsFifty‐seven patients (20 with ovarian carcinoma) were enrolled and treated. Patients who had ovarian and solid tumors had received a median of five and three prior therapies, respectively. No complete or partial responses were observed, so the trial was ended. The median progression‐free survival was 118 days for the ovarian cohort and 55 days for the solid‐tumor cohort. The most common treatment‐related adverse events were thrombocytopenia (40%) and neutropenia (54%). One patient each developed fatal veno‐occlusive disease and intracranial hemorrhage. Patients with higher P‐cadherin levels remained on the study longer.Conclusions90Y–FF‐21101 did not meet the predefined efficacy criteria, and adverse events were consistent with 90Y agents. These data may assist in the development of other P‐cadherin–directed therapies (ClinicalTrials.gov identifier NCT02454010).

Federal Cervical Cancer Collaborative: Improving cervical cancer prevention through vaccination, screening, and management in safety‐net settings of care

AbstractThe Federal Cervical Cancer Collaborative (FCCC) was established by the Health Resources and Services Administration Office of Women’s Health and its interagency partners within the U.S. Department of Health and Human Services. Its primary mission, aligned with the goals of the Cancer Moonshot (https://www.cancer.gov/research/key‐initiatives/moonshot‐cancer‐initiative/implementation/prevention‐early‐detection), is to accelerate control of cervical cancer within safety‐net settings of care. This interagency partnership works in close collaboration to reduce disparities in cervical cancer care, particularly among populations that are geographically isolated, economically challenged, and medically underserved. The FCCC bridges federal priorities of cancer research from the National Institutes of Health National Cancer Institute to health care delivery in Health Resources and Services Administration–supported and safety‐net settings of care. In this commentary, FCCC activities are discussed to improve cervical cancer prevention and control through vaccination, screening, and management of preinvasive cervical disease in safety‐net settings of care. These activities include the development and implementation of an evidence‐based, action‐oriented provider toolkit and federal opportunities report. The FCCC’s efforts to increase the readiness of safety‐net settings of care to implement the 2019 American Society for Colposcopy and Cervical Pathology Risk‐Based Management Consensus Guidelines for patients with abnormal cervical cancer screening results are discussed. Also described are the results from a survey of National Cancer Institute–designated cancer centers, designed to inform future efforts to strengthen referrals and care coordination with safety‐net settings of care.

Challenges in implementation of molecular classification in early stage endometrial cancer—An NRG Oncology cooperative group mixed‐methods study

AbstractBackgroundProfessional guidelines recommend molecular profiling for mismatch repair (MMR), p53, and polymerase epsilon (POLE) status in endometrial cancer (EC). However, adoption in the United States has not been documented, and barriers to the implementation of testing have not been described.MethodsIn this mixed‐methods study, implementation science frameworks were used to develop a quantitative survey. Gynecologic oncologists, medical oncologists, radiation oncologists, and pathologists affiliated with NRG Oncology programs were contacted through snowball sampling and were surveyed during 2022–2023. A subset of respondents was interviewed. Statistical and thematic analyses were performed.ResultsAt least 403 NRG Oncology‐affiliated providers were contacted for the survey, and 107 (26.6%) responded. Greater than 90% of respondents perceived POLE, MMR, and p53 status as important for clinical care. MMR and p53 tests were perceived as easy to obtain, but only 24.2% of respondents reported that POLE testing was moderately or very easy to obtain. Respondents from academic sites reported better access to molecular classification and perceived greater importance of molecular classification compared with respondents from community sites. In thematic analysis of 13 qualitative interviews, cost concerns were reported as large barriers to testing. Interviewees reported a desire for prospective data to guide treatment selection based on classification results.ConclusionsAlthough integrating molecular classification into standard pathologic reporting is recommended, and clinicians perceive molecular profiling in early stage EC as important, survey respondents noted significant implementation barriers. Implementation challenges that differ between community oncology and academic practice settings were identified. Strategies to improve equitable access to molecular classification of early stage EC are needed.

Factors contributing to differences in cervical cancer screening in rural and urban community health centers

AbstractIntroductionCommunity health centers (CHCs) provide historically marginalized populations with primary care, including cancer screening. Previous studies have reported that women living in rural areas are less likely to be up to date with cervical cancer screening than women living in urban areas. However, little is known about rural–urban differences in cervical cancer screening in CHCs and the contributing factors, and whether such differences changed during the COVID‐19 pandemic.MethodsUsing 8‐year pooled Uniform Data System (2014‐2021) data and Oaxaca‐Blinder decomposition, the extent to which CHC‐ and catchment area–level characteristics explained rural‐urban differences in up‐to‐date cervical cancer screening was estimated.ResultsUp‐to‐date cervical cancer screening was lower in rural CHCs than urban CHCs (38.2% vs 43.0% during 2014–2019), and this difference increased during the pandemic (43.5% vs 49.0%). The rural–urban difference in cervical cancer screening in 2014–2019 was mostly explained by differences in CHC‐level proportions of patients with limited English proficiency (55.9%) or income below the poverty level (12.3%) and females aged 21 to 64 years (9.8%), and catchment area–level’s unemployment (3.4%) and primary care physician density (3.2%). However, Medicaid (–48.5%) or no insurance (–19.6%) counterbalanced the differences between rural–urban CHCs. The contribution of these factors to rural–urban differences in cervical cancer screening generally increased in 2020–2021.ConclusionsRural–urban differences in cervical cancer screening were mostly explained by multiple CHC‐level and catchment area–level characteristics. The findings call for tailored interventions, such as providing resources and language services, to improve cancer screening utilization among uninsured, Medicaid, and patients with limited English proficiency in rural CHCs.

Biomarker‐driven phase 2 umbrella trial: Clinical efficacy of olaparib monotherapy and combination with ceralasertib (AZD6738) in small cell lung cancer

AbstractBackgroundBased on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)‐related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR‐targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated.MethodsAs part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum‐based regimens were allocated to the olaparib monotherapy arm and nonbiomarker‐selected patients were allocated to the olaparib and ceralasertib combination arm.ResultsIn the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression‐free survival was 1.3 months (95% CI, 1.2–NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression‐free survival was 2.8 months (95% CI, 1.8–5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm.ConclusionsTargeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.

Human epididymis protein 4 antigen‐autoantibody complexes complement cancer antigen 125 for detecting early‐stage ovarian cancer

BackgroundEarly detection of ovarian cancer could significantly improve patient outcomes. Cancer antigen 125 (CA 125) is elevated in sera from approximately 60% of patients with early‐stage (I/II) disease. Sensitivity might be improved through the combination of CA 125 with other biomarkers. Among potential biomarkers, antigen‐autoantibody (Ag‐AAb) complexes have received relatively little attention.MethodsLuminex‐based immunoassays were used to measure human epididymis protein 4 (HE4), anti‐HE4 autoantibody, and HE4 Ag‐AAb complexes in sera from patients with early‐ (n = 73) and late‐stage ovarian cancers (n = 49) at the time of diagnosis and from asymptomatic women with (n = 15) or without ovarian cancer (n = 212) enrolled in the Normal Risk Ovarian Cancer Screening Study.ResultsAt 98% specificity for healthy, asymptomatic women, 7% of patients with early‐stage (I/II) ovarian cancer and 4% of patients with late‐stage (III/IV) disease had elevated levels of HE4 autoantibody, whereas elevated levels of HE4 Ag‐AAb complexes were detected in sera from 38% of early‐stage cases and 31% of late‐stage cases. Complementarity was observed in receiver operating characteristic (ROC) curves between HE4 Ag‐AAb complexes and CA 125 levels in early‐stage ovarian cancer (P < .001). CA 125 detected 63% of cases, and a combination of CA 125 and HE4 Ag‐AAb complexes detected 81%. Complementarity was also observed in ROC curves for an independent validation set with 69 early‐stage patients (P = .039). HE4 Ag‐AAb complexes were detected in serial preclinical serum samples from women destined to develop ovarian cancer: they correlated with CA 125 but did not provide a lead time.ConclusionsHE4 Ag‐AAb complexes could complement CA 125 in detecting a higher fraction of early‐stage ovarian cancers.

Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models

BackgroundPoly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors.MethodsInduction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient‐derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line.ResultsFour PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ‐H2AX. Inhibition of autophagy also increased ROS and γ‐H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy.ConclusionsPARP inhibitor–induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild‐type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.

Increasing referral of at‐risk women for genetic counseling and BRCA testing using a screening tool in a community breast imaging center

BackgroundGenetic evaluation and testing for hereditary breast and ovarian cancer (HBOC) remain suboptimal. The authors evaluated the feasibility of using a screening tool at a breast imaging center to increase HBOC assessment referrals.MethodsA brief questionnaire based on the National Comprehensive Cancer Network HBOC genetic counseling referral guidelines was developed and added to the standard intake forms of patients undergoing mammography at a community breast imaging center from 2012 through 2015. Patients who met the criteria in the guidelines were referred for genetic counseling.ResultsA total of 34,851 patients were screened during the study period, and 1246 (4%) patients were found to be eligible for referral; 245 of these patients made a genetic counseling appointment, and 142 patients received genetic counseling. Forty patients (28%) had a personal history of breast cancer but were not previously tested. Following counseling, 105 patients were tested for BRCA1/2. Eight patients (8%) tested positive for a pathogenic mutation and nine (9%) had a variant of unknown significance. Although they tested negative, many patients met the criteria to add breast magnetic resonance imaging to their screening due to greater than 20% lifetime breast cancer risk based on their family cancer history. This study led to improved clinical risk management in 67% of the patients who underwent genetic counseling.ConclusionsThis study shows that large‐scale screening of patients for HBOC syndromes at time of breast imaging is practical and highly feasible. The screening tool identified women with actionable BRCA1/2 mutations and mutation‐negative but high‐risk women, leading to significant changes in their risk management; these women would otherwise have been missed.Lay Summary Hereditary breast and ovarian cancer (HBOC) caused by pathogenic mutations in breast cancer genes (BRCA1/BRCA2) increase an individual's lifetime risk of getting HBOC. Identifying these high‐risk individuals and using proven preventive clinical risk management strategies can significantly reduce their lifetime risk of HBOC. Using an innovative family cancer history questionnaire, 34,000 women were screened at a community breast imaging center, and genetic counseling and testing were provided to eligible women from the screening. Several women at high risk for HBOC were identified and this led to positive clinical risk management changes. These women would have been missed if not for intervention.

BRCA testing in unaffected young women in the United States, 2006‐2017

BackgroundThe discovery of the BRCA gene in the 1990s created an opportunity for individualized cancer prevention. BRCA testing in young women before cancer onset enables early detection of those with an increased cancer risk and creates an opportunity to offer lifesaving prophylactic procedures and medications. This study assessed trends in BRCA testing in women younger than 40 years without diagnosed breast or ovarian cancer (unaffected young women [UYW]) for cancer prevention between 2006 and 2017 in the United States.MethodsThis study included 93,278 adult women 18 to 65 years old with insurance claims for BRCA testing between 2006 and 2017 from the de‐identified Optum Clinformatics Data Mart database. The data contained medical claims and administrative information from privately insured individuals in the United States. The proportion of BRCA testing in UYW younger than 40 years among adult women aged 18 to 65 years who received BRCA testing was assessed.ResultsIn 2006, only 10.5% of the tests were performed in UYW. The proportion of BRCA tests performed in UYW increased significantly to 25.5% in 2017 (annual percentage change for the 2006‐2017 period, 6.9; 95% confidence interval, 6.4‐7.3; P < .001). The increased trend in the proportion of BRCA tests in UYW significantly differed by region of residence and family history of breast or ovarian cancer.ConclusionsOver the past decade, there was increased use of BRCA testing for cancer prevention. Additional efforts are needed to maximize the early detection of women with BRCA pathogenic variants so that these cancers may be prevented.

Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes

BackgroundPatients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC).MethodsInstitutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan‐Meier method.ResultsIn total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy‐seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty‐five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9‐34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19‐26 months). Seventy‐one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20‐52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24‐53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2).Conclusionsg/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.

Factors impacting the time to ovarian cancer diagnosis based on classic symptom presentation in the United States

BackgroundPatients with ovarian cancer often present with late‐stage disease and nonspecific symptoms, but little is known about factors affecting the time to diagnosis (TTD) in the United States.MethodsA retrospective, population‐based study of the Surveillance, Epidemiology, and End Results–Medicare database was conducted. It included women 66 years old or older with stage II to IV epithelial ovarian cancer with at least 1 code for abdominal/pelvic pain, bloating, difficulty eating, or urinary symptoms within 1 year of the cancer diagnosis. TTD was defined from the first claim with a prespecified symptom to the ovarian cancer diagnosis. Kruskal‐Wallis tests were used to assess for differences in TTD by group medians. Univariate and generalized linear models with a log‐link function evaluated TTD by covariables.ResultsFor the 13,872 women analyzed, the mean and median times to diagnosis were 2.9 and 1.1 months, respectively. The median TTD differed significantly by first symptom (P < .001), number of symptoms (P < .001), and first physician specialty seen (P < .001). In a multivariable analysis, TTD differed significantly according to race/ethnicity (P < .001), geographic region (P = .001), urban‐rural location (P = .031), emergency room presentation (P < .001), and number of specialties seen (P < .001). A shorter TTD was associated with a diagnosis in 2006‐2010 (relative risk [RR], 0.92; 95% confidence interval [CI], 0.87‐0.98) or 2011‐2015 (RR, 0.87; 95% CI, 0.81‐0.93) in comparison with 1992‐1999.ConclusionsThe time from a symptomatic presentation to care to a diagnosis of ovarian cancer is influenced by clinical and demographic variables. This study's findings reinforce the importance of educating all physicians on ovarian cancer symptoms to aid in diagnosis.Lay Summary Ovarian cancer is often diagnosed once disease has spread because the classic symptoms of ovarian cancer—abdominal or pelvic pain, bloating, difficulty eating, and urinary issues—can be mistaken for other problems. This study examined the time between when women with classic ovarian cancer symptoms went to a physician and when they received a cancer diagnosis in a large database population. The authors found that the time to diagnosis differed according to the type and number of symptoms and what type of physician a woman saw as well as factors such as race, geographic location, and year of diagnosis.

Uptake of cancer risk management strategies among women who undergo cascade genetic testing for breast cancer susceptibility genes

BackgroundUptake of cancer risk management based on inherited predispositions, which encompasses bilateral mastectomy (BLM), bilateral salpingo‐oophorectomy (BSO), and intensified screening, is the primary motivation for cascade testing for hereditary breast and ovarian cancer (HBOC). However, long‐term outcome data for cascade testers are lacking.MethodsMedical records were abstracted for all unaffected women with pathogenic variants in HBOC genes from 2 cancer hospitals (2013‐2019) with at least 1 year of follow‐up to compare the uptake of surgery and screening between cascade and noncascade testers.ResultsCascade testers (79.8%) were younger than noncascade testers (mean age, 37.6 vs 43.5 years; P = .002). Among women aged ≥40 years, 43% underwent BLM, and 71.6% underwent BSO, with no significant difference in uptake between cascade and noncascade testers. The mean time to BSO among cascade testers was shorter among women aged ≥40 years versus those aged <40 years (11.8 vs 31.9 months; P = .04); no such difference was observed among noncascade testers. Mammography and breast magnetic resonance imaging rates were low in the recorded 6 years for both groups after genetic counseling.ConclusionsManagement uptake among cascade testers is high with rates comparable to those for unaffected BRCA‐positive women. A large proportion of women act on cascade test results, and this represents a novel report of utilization of cancer management strategies.

An evaluation of memory and attention in BRCA mutation carriers using an online cognitive assessment tool

BackgroundThe objective of this study was to evaluate the impact of various surgical, hormonal, and lifestyle factors on memory and attention in women with a BRCA1 or BRCA2 mutation.MethodsBRCA mutation carriers enrolled in a longitudinal study were invited to complete an online brain health assessment tool designed to screen for cognitive deficits. Four measures of memory and executive attention were assessed individually, and an overall score was compiled adjusting for age. Exposures, including preventive surgery, hormone use, and lifestyle factors, were captured by questionnaire. Performance on each of the 5 subtasks was analyzed according to various exposures. Analysis of covariance was used to compare overall scores.ResultsIn total, 880 women completed the online cognitive assessment. The average age of the participants was 54 years (range, 23‐86 years). The mean overall test score was 54.4 (range, 0‐93). The individual subtask scores declined with age at test completion (P < .0001) and increased with level of education (P ≤ .01). Women who underwent a preventive oophorectomy had a significantly higher overall score compared with women who did not undergo this surgery (55.5 vs 50.5; P = .01). Reconstructive breast surgery was also associated with a higher overall score (56.5 vs 52.3; P = .005). Chemotherapy and hormone‐replacement therapy were not predictive of the overall score.ConclusionsThese findings are reassuring to high‐risk women who undergo early surgical menopause for their cancer predisposition. Further studies are needed to evaluate cognitive function over time when memory deficits become more prevalent.

Molecular and clinical predictors of improvement in progression‐free survival with maintenance PARP inhibitor therapy in women with platinum‐sensitive, recurrent ovarian cancer: A meta‐analysis

BACKGROUNDThe authors performed a meta‐analysis to better quantify the benefit of maintenance poly(ADP‐ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum‐sensitive, recurrent, high‐grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild‐type BRCA but homologous recombinant‐deficient (HRD), homologous recombinant‐proficient (HRP), and baseline clinical prognostic characteristics.METHODSRandomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression‐free survival were pooled across trials using the inverse variance weighted method.RESULTSFour trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23‐0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17‐0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12‐0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild‐type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31‐0.56); and, in those who had wild‐type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49‐0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab.CONCLUSIONSIn platinum‐sensitive, recurrent, high‐grade ovarian cancer, maintenance PARPi improves progression‐free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy.

SearcHPV: A novel approach to identify and assemble human papillomavirus–host genomic integration events in cancer

Background Human papillomavirus (HPV) is a well‐established driver of malignant transformation at a number of sites, including head and neck, cervical, vulvar, anorectal, and penile squamous cell carcinomas; however, the impact of HPV integration into the host human genome on this process remains largely unresolved. This is due to the technical challenge of identifying HPV integration sites, which includes limitations of existing informatics approaches to discovering viral‐host breakpoints from low‐read‐coverage sequencing data. Methods To overcome this limitation, the authors developed SearcHPV, a new HPV detection pipeline based on targeted capture technology, and applied the algorithm to targeted capture data. They performed an integrated analysis of SearcHPV‐defined breakpoints with genome‐wide linked‐read sequencing to identify potential HPV‐related structural variations. Results Through an analysis of HPV+ models, the authors showed that SearcHPV detected HPV‐host integration sites with a higher sensitivity and specificity than 2 other commonly used HPV detection callers. SearcHPV uncovered HPV integration sites adjacent to known cancer‐related genes, including TP63 , MYC , and TRAF2 , and near regions of large structural variation. The authors further validated the junction contig assembly feature of SearcHPV, which helped to accurately identify viral‐host junction breakpoint sequences. They found that viral integration occurred through a variety of DNA repair mechanisms, including nonhomologous end joining, alternative end joining, and microhomology‐mediated repair. Conclusions In summary, SearcHPV is a new optimized tool for the accurate detection of HPV‐human integration sites from targeted capture DNA sequencing data.

Biobehavioral factors predict an exosome biomarker of ovarian carcinoma disease progression

AbstractBackgroundBiobehavioral factors such as social isolation and depression have been associated with disease progression in ovarian and other cancers. Here, the authors developed a noninvasive, exosomal RNA profile for predicting ovarian cancer disease progression and subsequently tested whether it increased in association with biobehavioral risk factors.MethodsExosomes were isolated from plasma samples from 100 women taken before primary surgical resection or neoadjuvant (NACT) treatment of ovarian carcinoma and 6 and 12 months later. Biobehavioral measures were sampled at all time points. Plasma from 76 patients was allocated to discovery analyses in which morning presurgical/NACT exosomal RNA profiles were analyzed by elastic net machine learning to identify a biomarker predicting rapid (≤6 months) versus more extended disease‐free intervals following initial treatment. Samples from a second subgroup of 24 patients were analyzed by mixed‐effects linear models to determine whether the progression‐predictive biomarker varied longitudinally as a function of biobehavioral risk factors (social isolation and depressive symptoms).ResultsAn RNA‐based molecular signature was identified that discriminated between individuals who had disease progression in ≤6 months versus >6 months, independent of clinical variables (age, disease stage, and grade). In a second group of patients analyzed longitudinally, social isolation and depressive symptoms were associated with upregulated expression of the disease progression propensity biomarker, adjusting for covariates.ConclusionThese data identified a novel exosome‐derived biomarker indicating propensity of ovarian cancer progression that is sensitive to biobehavioral variables. This derived biomarker may be potentially useful for risk assessment, intervention targeting, and treatment monitoring.

Socially determined cervical cancer care navigation: An effective step toward health care equity and care optimization

BackgroundDespite being the standard of care for patients with locoregional cervical cancer, many patients do not complete all components of primary chemoradiotherapy (pCRT): external beam radiotherapy, chemosensitization, and brachytherapy. Incomplete or protracted pCRT is associated with worse survival. The authors implemented a socially determined cervical cancer care navigation program at a public safety‐net hospital to improve treatment adherence.MethodsPatients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IVA cervical cancer who underwent pCRT from 2012 to 2016 were prospectively enrolled into this navigation program spanning the medical, financial, and psychosocial aspects of care. This patient cohort was compared with a similar cohort of consecutive nonnavigated patients who were treated from 1998 to 2008. Patient characteristics, treatment data, and patient outcomes were collected. A database of navigation encounters was maintained prospectively.ResultsA total of 46 patients composed the navigated cohort and 85 patients composed the nonnavigated cohort. After implementation of the cervical cancer care navigation program, the percentage of patients receiving ≥5 cycles of weekly cisplatin increased from 74% to 93% (P < .01) and rates of the initiation of brachytherapy during external beam radiotherapy increased from 49% to 78% (P < .01). The median treatment time was reduced from 67 days in the nonnavigated patients to 55 days in the navigated patients (P < .01). Approximately 95% of navigated patients who completed pCRT did so within 63 days, compared with 52% of nonnavigated patients (P < .01). Treatment completion within 63 days was associated with significantly improved overall survival.ConclusionsSocially informed cervical cancer care navigation can significantly improve the timeliness of guideline‐based care, enhance access to resources for underserved minority patients receiving pCRT, and may improve overall patient outcomes.

How to reduce the impact of cervical cancer worldwide: Gaps and priority areas identified through the essential cancer and primary care packages: An analysis of effective interventions

BackgroundCervical cancer is a preventable cancer; therefore, countries should provide strategic, evidence‐based health services to reduce its incidence and impact on their populations. Two packages of health services that group together all the services related to cervical cancer, the Essential Cancer Package (9 interventions) and the Primary Care Package (5 interventions), are defined in this article with the aim of assessing the global status of the availability of health services and their coverage in 194 countries worldwide.MethodsThe study was based on the 2017 World Health Organization (WHO) Noncommunicable Disease Country Capacity Survey. Although the survey covered multiple noncommunicable diseases, this report examined only those results pertaining to cervical cancer in the 194 WHO member states divided by WHO region and World Bank income.ResultsOnly 21% of the countries reported providing all 9 interventions of the Essential Cancer Package, with the highest proportions being found in Europe (45.3%) and among high‐income countries (HICs; 54.3%). As for the Primary Care Package, only 19.1% of countries provided all 5 interventions, with the highest proportions being found in Europe (39.6%) and among HICs (45.5%).ConclusionsThe complete development and appropriate coverage of each service listed in both the Essential Cancer Package and the Primary Care Package are essential to reduce the impact of cervical cancer worldwide, and they should be integrated into all cancer control planning efforts.

Early posttherapy clearance of human papillomavirus and treatment response in cervical carcinoma

BackgroundAmong patients with cervical cancer, little is known about the significance of persistent human papillomavirus (HPV) expression after chemoradiation (CRT). This study evaluated associations between early posttreatment HPV clearance and patient outcomes with an added focus on the value of posttherapy positron emission tomography (PET) imaging.MethodsIncluded patients underwent pretreatment testing indicating a high‐risk HPV infection and posttreatment testing with a messenger RNA (mRNA)–based genital swab after CRT. Posttherapy responses were stratified on the basis of HPV mRNA detection into an early clearance (EC) group (no mRNA) and a persistent expression (PE) group (detectable mRNA) on the basis of an evaluation at a median of 6 weeks after therapy. The Kaplan‐Meier method was used to compare outcomes, and multivariable analysis was used to identify predictors of outcomes.ResultsSeventy‐two of the 97 eligible patients (74.2%) had EC. The mean follow‐up time was 25 months (range, 4‐56 months), and 2‐year pelvic control (76.9% vs 50.2%; P = .01) and overall survival (OS; 80.9% vs 52.2%; P < .01) were superior among EC patients. In the multivariable analysis, EC predicted for improved survival (hazard ratio [HR] for mortality, 0.46; 95% confidence interval [CI], 0.21‐0.96; P = .047), as did a complete response (CR) on posttherapy PET (HR for less than a CR on PET, 6.17; 95% CI, 2.58‐14.72; P < .01). In a subset analysis of patients with a posttherapy PET CR, HPV clearance retained prognostic significance (2‐year OS, 95.6% with EC vs 66.7% with PE; P = .04), whereas PE patients without a PET CR had the worst survival (35.9%; P < .01 for trend).ConclusionsEarly posttherapy clearance of HPV is associated with improved survival in cervical cancer. Evaluating HPV expression at this 6‐week time point provides prognostic information beyond posttherapy PET imaging and may aid in risk stratification and decisions for treatment escalation.

Comparison of the long‐term impact and clinical outcomes of fewer doses and standard doses of human papillomavirus vaccine in the United States: A database study

Background Human papillomavirus (HPV)–related disease remains a significant source of morbidity and mortality, and this underscores the need to increase HPV vaccination to reduce the burden of the disease. The objective of this study was to examine the association between the number of HPV vaccine doses and the risk of histologically confirmed preinvasive cervical disease and high‐grade cytology. Methods This retrospective matched cohort study used administrative data from Optum's Clinformatics DataMart Database to identify females aged 9 to 26 years who received 1 or more quadrivalent HPV vaccine doses between January 2006 and June 2015. Cases and controls were matched on region, age, sexually transmitted disease history, and pregnancy. All had a Papanicolaou test ≥1 year after the date of the matched case's final dose. Cox proportional hazards models were used to examine the association between the number of HPV vaccine doses and the incidence of preinvasive cervical disease and high‐grade cytology. The Kaplan‐Meier method was used to estimate the cumulative incidence rate at the 5‐year follow‐up. Results The study included 133,082 females (66,541 vaccinated and 66,541 unvaccinated) stratified by the number of HPV vaccine doses and the vaccine initiation age. Among those aged 15 to 19 years, the hazard ratio (HR) for high‐grade cytology for the 3‐dose group was 0.84 (95% confidence interval [CI], 0.73‐0.97), whereas the HRs for histologically confirmed preinvasive cervical disease for 1, 2, and 3 doses were 0.64 (95% CI, 0.47‐0.88), 0.72 (95% CI, 0.54‐0.95), and 0.66 (95% CI, 0.55‐0.80), respectively. Conclusions The receipt of 1, 2, or 3 doses of an HPV vaccine by females aged 15 to 19 years was associated with a lower incidence of preinvasive cervical disease in comparison with unvaccinated females, and this supports the use of any HPV vaccination in reducing the burden of the disease.

Geographic disparities in residential proximity to colorectal and cervical cancer care providers

BackgroundPersistent rural‐urban disparities for colorectal and cervical cancers raise concerns regarding access to treatment providers. To the authors knowledge, little is known regarding rural‐urban differences in residential proximity to cancer specialists.MethodsUsing the 2018 Physician Compare data concerning physician practice locations and the 2012 to 2016 American Community Survey, the current study estimated the driving distance from each residential zip code tabulation area (ZCTA) centroid to the nearest cancer provider of the following medical specialties involved in treating patients with colorectal and cervical cancer: medical oncology, radiation oncology, surgical oncology, general surgery, gynecological oncology, and colorectal surgery. Using population‐weighted multivariable logistic regression, the authors analyzed the associations between ZCTA‐level characteristics and driving distances >60 miles to each type of specialist. ZCTA‐level residential rurality was defined using rural‐urban commuting area codes.ResultsNearly 1 in 5 rural Americans lives >60 miles from a medical oncologist. Rural‐urban differences in travel distances to the nearest cancer care provider(s) increased substantially for cancer surgeons; greater than one‐half of rural residents were required to travel 60 miles to reach a gynecological oncologist, compared with 8 miles for their urban counterparts. Individuals residing within ZCTAs with a higher poverty rate, those of American Indian/Alaska Native ethnicity, and/or were located in the South and West regions were more likely than their counterparts to be >60 miles away from any of the aforementioned providers.ConclusionsThe substantial travel distances required for rural, low‐income residents to reach a cancer specialist should prompt a policy action to increase access to specialized cancer care for millions of rural residents.

Phase 1 trial of nelfinavir added to standard cisplatin chemotherapy with concurrent pelvic radiation for locally advanced cervical cancer

BackgroundNelfinavir (NFV), an HIV‐1 protease inhibitor, has been shown to sensitize cancer cells to chemoradiation (CRT). The objectives of this phase 1 trial were to evaluate safety and identify the recommended phase 2 dose of NFV added to concurrent CRT for locally advanced cervical cancer.MethodsTwo dose levels of NFV were evaluated: 875 mg orally twice daily (dose level 1 [DL1]) and 1250 mg twice daily (DL2). NFV was initiated 7 days before CRT and continued through CRT completion. Toxicity, radiographic responses, and pathologic responses were evaluated. Serial tumor biopsies (baseline, after NFV monotherapy, on NFV + CRT, and posttreatment) were evaluated by immunohistochemistry, NanoString, and reverse‐phase‐protein‐array analyses.ResultsNFV sensitized cervical cancer cells to radiation, increasing apoptosis and tumor suppression in vivo. Patients (n = 13) with International Federation of Gynecology and Obstetrics stage IIA through IVA squamous cell cervical carcinoma were enrolled, including 7 patients at DL1 and 6 patients at DL2. At DL1, expansion to 6 patients was required after a patient developed a dose‐limiting toxicity, whereas no dose‐limiting toxicities occurred at DL2. Therefore, DL2 was established as the recommended phase 2 dose. All patients at DL2 completed CRT, and 1 of 6 experienced grade 3 or 4 anemia, nausea, and diarrhea. One recurrence was noted at DL2, with disease outside the radiation field. Ten of 11 evaluable patients remained without evidence of disease at a median follow‐up of 50 months. NFV significantly decreased phosphorylated Akt levels in tumors. Cell cycle and cancer pathways also were reduced by NFV and CRT.ConclusionsNFV with CRT is well tolerated. The response rate is promising compared with historic controls in this patient population and warrants further investigation.

Worldwide trends in cervical cancer incidence and mortality

Cervical cancer prevention: Human papillomavirus testing as primary screening

Low‐ and middle‐income countries carry a high burden of preventable cervical cancer cases and deaths. Because human papillomavirus DNA‐based testing is increasingly becoming the preferred method of screening for cervical cancer prevention, this commentary discusses next steps and key considerations for its expansion.

Worldwide trends in cervical cancer incidence and mortality, with predictions for the next 15 years

BackgroundCervical cancer is 1 of the most common cancers in females worldwide. Understanding the most recent global patterns and temporal trends of cervical cancer burden might be helpful for its prevention and control.MethodsData on cervical cancer (International Classification of Diseases, Tenth Revision, code C53) incidence and mortality in 2018 were extracted from the GLOBOCAN 2018 database and further analyzed for their correlations with the Human Development Index. Temporal trends were analyzed using the annual percent change with joinpoint analysis among 31 countries with highly qualified data from the Cancer Incidence in Five Continents Plus and World Health Organization mortality databases. Future trends for the next 15 years were predicted using an open‐source age‐period‐cohort model.ResultsCervical cancer incidence and mortality rates were both negatively correlated with the Human Development Index (r = −0.56 for incidence, r = −0.69 for mortality; P < .001) in cross‐sectional analysis, and both remained stable in 12 countries or even decreased in 14 and 18 countries for incidence and mortality, respectively, during the most recent 10 data years. Similar findings were observed for the next 15 years.ConclusionsCervical cancer burden was correlated with socioeconomic development. An overwhelming majority of countries had stable or decreasing trends in incidence and mortality rates, especially in those with effective cervical cancer screening programs and human papillomavirus vaccination.Lay Summary The authors investigated the most up‐to‐date data from official databases released by the International Agency for Research on Cancer and found that cervical cancer incidence and mortality were negatively correlated with socioeconomic development. Among the 31 countries analyzed, most (26 countries were analyzed for incidence, and 30 were analyzed for mortality) had stable or even decreasing temporal trends over the most recent 10 years, especially in those with effective cervical cancer screening programs. In addition, the predicted trends for the next 15 years were basically consistent with the observed trends among most of the analyzed countries (19 countries for incidence and 26 countries for mortality).

The intersection of sexual orientation with race and ethnicity in cervical cancer screening

BackgroundCervical cancer screening is recommended for those with a cervix who are 21 to 65 years old, with specific timelines being dependent on individual risk. This study compared rates of ever undergoing Papanicolaou (Pap) testing at the intersection of self‐reported sexual minority (SM) status and race/ethnicity.MethodsData from the National Health Interview Survey (2015 and 2018) were used to examine cervical cancer screening disparities. Natal females without a history of hysterectomy who were 21 to 65 years old and had reported their sexual orientation and Pap testing history were included. Demographic and health characteristics were summarized with descriptive statistics. To adjust for differences in confounding variables between groups, propensity score–based inverse probability of treatment weighting (IPTW) was performed. IPTW‐adjusted multivariable logistic regression models estimated odds of ever undergoing a Pap test by sexual orientation alone and with race/ethnicity (non‐Hispanic White, non‐Hispanic Black, and Hispanic).ResultsSM persons (n = 877) had significantly reduced odds of ever undergoing Pap testing (odds ratio, 0.54; 95% confidence interval, 0.42‐0.70) in comparison with heterosexual persons (n = 17,760). When the intersection of sexual orientation and race/ethnicity was considered, non‐Hispanic White SM participants and Hispanic SM participants had reduced odds of ever undergoing Pap testing in comparison with non‐Hispanic White heterosexual participants. No significant differences were observed between non‐Hispanic White heterosexual participants and participants of non‐Hispanic Black SM or Hispanic heterosexual identities.ConclusionsSM participants were significantly less likely to have ever undergone a Pap test in comparison with heterosexual participants, with Hispanic SM participants having the lowest uptake. Future studies should further examine the roles of systemic discrimination and other key drivers of these disparities.

Cervical cancer elimination in Indian context: Moving from barriers to facilitators

AbstractIt has been 46 years since the launch of cancer control programs in India and yet the recent National Family Health Survey (fifth round, 2019–2021) has reported that just 1.9% of women aged 30–49 years have ever undergone cervical cancer screening. The cost of delayed diagnosis of cervical cancer and its treatment is overwhelming, and the rural population takes the worst hit. It is the need of the hour that the Indian health system and policymakers identify the barriers and facilitators for cervical cancer early detection and provide pragmatic solutions so that the targets of cervical cancer elimination can be achieved in a timely manner.

Overcoming disparities to improve cancer care: The story of cervical cancer

Lay summary Effective screening and vaccination programs can potentially eliminate cervical cancer in the future; however, to accomplish this goal, we have to be able to offer services to all girls and women. In particular, women who live in rural areas and women who have low socioeconomic status are at highest risk. Efforts are required to improve access to care at all levels for these women at risk.

Improving cervical cancer survival–A multifaceted strategy to sustain progress for this global problem

AbstractCervical cancer is associated with profound socioeconomic and racial disparities in incidence, mortality, morbidity, and years of life lost. The last standard‐of‐care treatment innovation for locally advanced cervical cancer occurred in 1999, when cisplatin chemotherapy was added to pelvic radiation therapy (chemoradiation therapy). Chemoradiation therapy is associated with a 30%–50% failure rate, and there is currently no cure for recurrent or metastatic disease. The enormity of the worldwide clinical problem of cervical cancer morbidity and mortality as well as the egregiously unchanged mortality rate over the last several decades are recognized by the National Institutes of Health as urgent priorities. This is reflected within the Office of Research on Women's Health effort to advance National Institutes of Health research on the health of women, as highlighted in a recent symposium. In the current review, the authors address the state of the science and opportunities to improve cervical cancer survival with an emphasis on improving access, using technology in innovative and widely implementable ways, and improving current understanding of cervical cancer biology.Lay summary Cervical cancer is associated with profound socioeconomic and racial disparities in incidence, mortality, morbidity, and years of life lost. In this review, the state of the science and opportunities to improve cervical cancer survival are presented with an emphasis on improving access, using technology in innovative and widely implementable ways, and improving current understanding of cervical cancer biology.

Analysis of human leukocyte antigen associations in human papillomavirus–positive and –negative head and neck cancer: Comparison with cervical cancer

BackgroundAlthough the majority of human papillomavirus (HPV) infections are cleared by the immune system, a small percentage of them progress to develop HPV‐driven cancers. Cervical cancer studies highlight that HPV persistence and cancer risk are associated with genetic factors, especially at the human leukocyte antigen (HLA) genes. This study was conducted to investigate such associations in head and neck cancer (HNC).MethodsIn all, 192 patients with HNC and 384 controls were genotyped with the Infinium Global Screening Array (Illumina, Inc). HLA variants were imputed with SNP2HLA, and an association analysis was performed by logistic regression.ResultsHPV‐positive HNCs were significantly associated with single‐nucleotide polymorphisms (SNPs) at DRB1_32660090 (P = 1.728 × 10–6) and DRB1_32660116 (P = 1.728 × 10–6) and with the amino acid variant DRB1_11_32660115 (P = 1.728 × 10–6). None of these associations were observed in the HPV‐negative cohort, and this suggested their specificity to convey risk for HPV‐associated HNCs. In general, associations observed for HPV‐negative HNC were relatively weak, and variants in the HLA‐DPA1 region were the strongest among them (P = 4.531 × 10–4). Several lead signals reported by previous HNC genome‐wide association studies, including SNPs rs3135001 (P = .012), rs1049055 (P = .012), and rs34518860 (P = .029) and allele HLA‐DQB1*06 (P = .009), were replicated in the current study. However, these associations were limited to the HPV‐positive HNC group. Several cervical cancer–associated HLA variants, including SNPs rs9272143 (P = .002) and rs9271858 (P = .002) and alleles HLA‐B‐1501 (P = .009) and HLA‐B‐15 (P = .015), were also exclusively associated with HPV‐positive HNC.ConclusionsHPV‐positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV‐positive HNC.Human papillomavirus (HPV)–positive head and neck cancer (HNC) risk is associated with distinct human leukocyte antigen variants, and some of them are shared by both cervical cancer and HPV‐positive HNC.Lay Summary Cervical cancer studies highlight that human papillomavirus (HPV)–driven cancer risk is linked with human leukocyte antigen (HLA) polymorphism. Hence, the current study was designed to investigate the HLA associations in HPV‐positive and HPV‐negative head and neck cancer (HNC) and compare these associations with cervical cancer. Several lead signals reported by previous HNC and cervical genome‐wide association studies were replicated in the current study. However, these associations were limited to the HPV‐positive HNC group, and this suggests that HPV‐positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV‐positive HNC.

Associations of lifetime exposure to fine particulate matter (PM 2.5 ) and its constituents with increased risk and earlier occurrence of 14 site‐specific cancers

Abstract Background Evidence is limited concerning whether and to what extent fine particulate matter pollution (particulate matter with an aerodynamic diameter less than 2.5 μm [PM 2.5 ]) is linked to the risk and the time to occurrence of site‐specific cancers along with the key constituents of PM 2.5 and the sensitive exposure window. Methods By using data from 277,446 participants in the UK Biobank, the authors estimated exposures to PM 2.5 and its 15 constituents during each participant's lifetime and at different life stages using a bilinear interpolation method. The incidence and time to occurrence of 14 cancers were ascertained. Cox proportional hazard models and accelerated failure time models were applied to investigate the associations between air pollutants and incidence risk and occurrence time of 14 cancers. Results During a mean follow‐up of 11.15 years, 25,820 patients with incident cancer were identified. Lifetime exposure to PM 2.5 and to its constituents was associated with an increased incidence risk of 12 of 14 cancers, with hazard ratios and 95% confidence intervals ranging from 1.04 (95% confidence interval, 1.01–1.07) for breast cancer to 1.18 (95% confidence interval, 1.10–1.27) for esophageal cancer. The constituents chloride ion, ammonium, nitrate, and sodium demonstrated the most pronounced effects. The middle‐aged and elderly life stage (individuals aged 45 years and older) comprised the sensitive exposure window. The time to occurrence of cancers was earlier by from 0.05 years (ovarian cancer) to 1.95 years (esophageal cancer) because of overexposure to PM 2.5 levels greater than 5 μg/m 3 . Conclusions Lifetime exposure to PM 2.5 and its constituents might increase the risk and accelerate the onset of various cancers. Combustion‐sourced and agriculture‐sourced components mainly account for this influence, with the middle‐aged and elderly life stage (aged 45 years and older) a sensitive exposure window.

The relationship between cardiometabolic abnormalities and mortality in the Women’s Health Initiative: A comparison of associations among women with cancer to women without cancer

AbstractBackgroundPrior studies of participants with breast and other obesity‐associated cancers in the Women’s Health Initiative (WHI) showed worse mortality and cardiovascular disease (CVD) outcomes for individuals with a higher number of cardiometabolic risk factors at study entry. The purpose of this analysis is to compare the relationship between cardiometabolic abnormalities and mortality among women with and without cancer in the WHI.MethodsWomen with one of five early‐stage obesity‐associated cancers (breast, colorectal, endometrial, ovarian, and non‐Hodgkin lymphoma) and controls without any new or prior history of cancer were selected from the WHI‐Life and Longevity after Cancer ancillary study. Cardiometabolic abnormalities included high waist circumference (≥88 cm), hypertension (>130/85 mm Hg), and self‐reported history of diabetes and/or elevated cholesterol. Multivariable Cox proportional hazards models (all‐cause mortality) and Fine‐Gray models (CVD and non‐CVD mortality) were used to evaluate the association between cardiometabolic risk factors and survival outcomes for the cancer and noncancer cohorts.ResultsA total of 7491 and 35,508 women were studied in the cancer and noncancer cohorts, respectively. Adjusted analyses showed that increased number of cardiometabolic abnormalities was associated with increased short‐term risk of all‐cause mortality, with the association being stronger among the noncancer “controls” compared to the cancer cohort (interaction p value = .02). Associations were similar between cancer cases and controls in competing risk models for CVD and non‐CVD mortality.ConclusionPreexisting cardiovascular abnormalities are an important predictor of adverse health outcomes among women with and without cancer in the WHI.

The missing data: A review of gender and sex disparities in research

AbstractThis article highlights the gender data gaps in clinical trial inclusion and funding, with a particular focus on gynecologic oncology. Female patients have historically been excluded from clinical trials across all medical domains. Despite recent improvements, female patients remain underrepresented in key diseases, including several cancer types, despite experiencing increased burden of disease. Lack of representation is particularly stark for patients in racial, ethnic, and gender minoritized populations, including in gynecologic cancer trials. Furthermore, female health conditions receive disproportionately small amounts of funding relative to their disease burden. Despite their high lethality, gynecologic cancers, including ovarian, cervical, and uterine malignancies, rank among the lowest funded cancer sites from the National Cancer Institute. Likewise, there is significant bias against female investigators with regard to funding, publication, and academic advancement, which affects the prioritization of women’s health. In combination, gender disparities at multiple steps along the research pathway from investigator and disease funding to trial inclusion to publication and dissemination of research perpetuate a significant data gap in the diagnosis, treatment, and prevention of diseases affecting female patients, including gynecologic cancers. Strategies to improve this gender gap and prioritize women’s health funding include increasing female representation in clinical trials with a specific focus on inclusion of patients from historically marginalized backgrounds, considering disease burden–based funding policies, and prioritizing female academic leadership opportunities.

Comorbid conditions and survival among Black women with ovarian cancer

AbstractBackgroundBlack women with epithelial ovarian cancer (EOC) have worse survival and a higher burden of comorbid conditions compared with other racial groups. This study examines the association of comorbid conditions and medication use for these conditions with survival among Black women with EOC.MethodsIn a prospective study of 592 Black women with EOC, the Charlson comorbidity index (CCI) based on self‐reported data, three cardiometabolic comorbidities (type 2 diabetes, hypertension, and hyperlipidemia), and medication use for each cardiometabolic comorbidity were evaluated. Cox proportional hazards regression models were used to examine the association of comorbid conditions and related medication use with all‐cause mortality while adjusting for relevant covariates overall and by histotype (high‐grade serous [HGS]/carcinosarcoma vs. non‐HGS/carcinosarcoma) and stage (I/II vs. III/IV).ResultsA CCI of ≥2 was observed in 42% of the cohort, and 21%, 67%, and 34% of women had a history of type 2 diabetes, hypertension, and hyperlipidemia, respectively. After adjusting for prognostic factors, a CCI ≥2 (vs. 0; hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.04–1.71) and type 2 diabetes (HR, 1.42; 95% CI, 1.10–1.84) were associated with an increased risk of mortality. The increased risk of mortality for type 2 diabetes was present specifically among women with HGS/carcinosarcoma (HR, 1.47; 95% CI, 1.10–1.97) and among women with stage III/IV disease (HR, 1.47; 95% CI, 1.10–1.98). The authors did not find evidence that hypertension, hyperlipidemia, or medication use for the cardiometabolic comorbidities meaningfully impacted survival.ConclusionComorbid conditions, especially type 2 diabetes, had a significant adverse impact on survival among Black women with EOC.

Fertility preservation before and after cancer treatment in children, adolescents, and young adults

AbstractFertility is a top concern for many survivors of cancer diagnosed as children, adolescents and young adults (CAYA). Fertility preservation (FP) treatments are effective, evidence‐based interventions to support their family building goals. Fertility discussions are a part of quality oncology care throughout the cancer care continuum. For nearly 2 decades, clinical guidelines recommend counseling patients about the possibility of infertility promptly at diagnosis and offering FP options and referrals as indicated. Multiple guidelines now recommend post‐treatment counseling. Infertility risks differ by cancer treatments and age, rendering risk stratification a central part of FP care. To support FP decision‐making, online tools for female risk estimation are available. At diagnosis, females can engage in mature oocyte/embryo cryopreservation, ovarian tissue cryopreservation, ovarian suppression with GnRH agonists, in vitro oocyte maturation, and/or conservative management for gynecologic cancers. Post‐treatment, several populations may consider undergoing oocyte/embryo cryopreservation. Male survivors’ standard of care FP treatments center on sperm cryopreservation before cancer treatment and do not have the same post‐treatment indication for additional gamete cryopreservation. In practice, FP care requires systemized processes to routinely screen for FP needs, bridge oncology referrals to fertility, offer timely fertility consultations and access to FP treatments, and support financial navigation. Sixteen US states passed laws requiring health insurers to provide insurance benefits for FP treatments, but variation among the laws and downstream implementation are barriers to accessing FP treatments. To preserve the reproductive futures of CAYA survivors, research is needed to improve risk stratification, FP options, and delivery of FP care.

Survival difference between secondary and de novo acute myeloid leukemia by age, antecedent cancer types, and chemotherapy receipt

AbstractBackgroundThis study compared the survival of persons with secondary acute myeloid leukemia (sAML) to those with de novo AML (dnAML) by age at AML diagnosis, chemotherapy receipt, and cancer type preceding sAML diagnosis.MethodsData from Surveillance, Epidemiology, and End Results 17 Registries were used, which included 47,704 individuals diagnosed with AML between 2001 and 2018. Multivariable Cox proportional hazards regression was used to compare AML‐specific survival between sAML and dnAML. Trends in 5‐year age‐standardized relative survival were examined via the Joinpoint survival model.ResultsOverall, individuals with sAML had an 8% higher risk of dying from AML (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.05–1.11) compared to those with dnAML. Disparities widened with younger age at diagnosis, particularly in those who received chemotherapy for AML (HR, 1.14; 95% CI, 1.10–1.19). In persons aged 20–64 years and who received chemotherapy, HRs were greatest for those with antecedent myelodysplastic syndrome (HR, 2.04; 95% CI, 1.83–2.28), ovarian cancer (HR, 1.91; 95% CI, 1.19–3.08), head and neck cancer (HR, 1.55; 95% CI, 1.02–2.36), leukemia (HR, 1.45; 95% CI, 1.12–1.89), and non‐Hodgkin lymphoma (HR, 1.42; 95% CI, 1.20–1.69). Among those aged ≥65 years and who received chemotherapy, HRs were highest for those with antecedent cervical cancer (HR, 2.42; 95% CI, 1.15–5.10) and myelodysplastic syndrome (HR, 1.28; 95% CI, 1.19–1.38). The 5‐year relative survival improved 0.3% per year for sAML slower than 0.86% per year for dnAML. Consequently, the survival gap widened from 7.2% (95% CI, 5.4%–9.0%) during the period 2001–2003 to 14.3% (95% CI, 12.8%–15.8%) during the period 2012–2014.ConclusionsSignificant survival disparities exist between sAML and dnAML on the basis of age at diagnosis, chemotherapy receipt, and antecedent cancer, which highlights opportunities to improve outcomes among those diagnosed with sAML.

Top advances of the year: Ovarian cancer

AbstractAlthough cure rates remain low and effective screening strategies are elusive, the recent advances in systemic therapies over the past year highlighted in this review have prolonged survival for women with ovarian cancer. In 2022, the first antibody–drug conjugate for platinum‐resistant ovarian cancer received accelerated US Food and Drug Administration (FDA) approval. Confirmatory studies examining the efficacy of mirvetuximab and other antibody–drug conjugates are underway. In the upfront setting, the first data establishing an overall survival benefit from poly(ADP‐ribose) polymerase inhibitor maintenance was demonstrated after a 7‐year follow‐up period. In contrast, long‐term updates from poly(ADP‐ribose) polymerase inhibitor trials in the noncurative setting reported survival detriments, and the FDA withdrew the respective indications. Several trials attempted to improve upon the standard of care for platinum‐sensitive ovarian carcinoma and those with rare ovarian cancer histologies (carcinosarcoma, clear cell carcinoma) but failed to demonstrate a clinically or statistically meaningful benefit. This leaves the open question of how to further optimize systemic therapy for advanced ovarian carcinoma to improve long‐term survival and cure rates.

Phase 1/2 trial of avelumab combined with utomilumab (4‐1BB agonist), PF‐04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies

AbstractBackgroundImmune checkpoint blockade has shown mixed results in advanced/recurrent gynecologic malignancies. Efficacy may be improved through costimulation with OX40 and 4‐1BB agonists. The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4‐1BB agonist), PF‐04518600 (an OX40 agonist), and radiotherapy in patients with recurrent gynecologic malignancies.MethodsThe primary end point in this six‐arm, phase 1/2 trial was safety of the combination regimens. Secondary end points included the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors and immune‐related Response Evaluation Criteria in Solid Tumors, the disease control rate (DCR), the duration of response, progression‐free survival, and overall survival.ResultsForty patients were included (35% with cervical cancer, 30% with endometrial cancer, and 35% with ovarian cancer). Most patients (n = 33; 83%) were enrolled in arms A–C (no radiation). Among 35 patients who were evaluable for efficacy, the ORR was 2.9%, and the DCR was 37.1%, with a median duration of stable disease of 5.4 months (interquartile range, 4.1–7.3 months). Patients with cervical cancer in arm A (avelumab and utomilumab; n = 9 evaluable patients) achieved an ORR of 11% and a DCR of 78%. The median progression‐free survival was 2.1 months (95% CI, 1.8–3.5 months), and overall survival was 9.4 months (95% CI, 5.6–11.9 months). No dose‐limiting toxicities or grade 3–5 immune‐related adverse events were observed.ConclusionsThe findings from this trial highlight that, in heavily pretreated patients with gynecologic cancer, even multidrug regimens targeting multiple immunologic pathways, although safe, did not produce significant responses. A DCR of 78% in patients with cervical cancer who received avelumab and utomilumab indicates that further research on this combination in select patients may be warranted.

Cell‐free DNA in recurrent and metastatic endometrial cancer: The future is now? Promises and potential pitfalls

Blanc‐Durand and colleagues present a prospective analysis of cell‐free DNA in patients with recurrent, advanced, or metastatic endometrial cancer, which offers insights into its potential application in molecular classification and the evolving targeted therapy landscape of this disease. More research is needed to validate cell‐free DNA's clinical utility but its potential to guide therapy and improve patient outcomes warrants ongoing exploration.

Top advances of the year: Immunotherapy in endometrial cancer

AbstractIn the past year, notable advances were achieved toward improving oncological outcomes in patients with advanced and recurrent endometrial cancer because of reporting of high‐level results of several phase 3 clinical trial combining an immune checkpoint inhibitor with chemotherapy in the first‐line setting. For the first time, patients with recurrent or advanced endometrial cancer have options for treatment that are superior to traditional chemotherapy alone. What remains to be determined is population specificity of these recommendations. All four major studies were in agreement that patients with endometrial cancer with deficient mismatch repair markedly benefited from addition of an immune checkpoint inhibitor for progression‐free survival; some showed preliminary results demonstrating a potential overall survival. Molecular characterization details are needed to determine if and which patients with tumors that are mismatch proficient should receive this new combination approach.Plain Language Summary Combining an immune checkpoint inhibitor with chemotherapy in the first‐line setting treatment of patients with advanced endometrial cancer improved progression‐free survival, especially in patients with mismatch repair deficiency. Improving patient selection with potential biomarkers of sensitivity and biomarkers of resistance is key in developing the next clinical trials and will assist in directing therapy to the correct patients and minimize toxicity.

Top advances of the year: Uterine cancer

AbstractEndometrial cancer continues to be the only gynecologic malignancy with a rising incidence and mortality, with both regional and global implications. Combination carboplatin and paclitaxel has been the recognized chemotherapy backbone for the treatment of advanced‐stage or recurrent disease, with modest clinical outcomes. Over the last year, significant advances were achieved in improving oncologic outcomes by capitalizing on the molecular characterization of this heterogenous disease. These advances include incorporation of immunotherapy, identification of effective hormonal approaches, the evolution of antibody drug conjugates, and utilization of alternate targeted therapies.Plain Language Summary The molecular characterization of endometrial cancer has been critical in informing novel treatment strategies. Over the past year, significant gains have been made via the incorporation of immunotherapy, hormonal combinations as well as antibody drug conjugates.

A tale of two pathways: Review of immune checkpoint inhibitors in DNA mismatch repair‐deficient and microsatellite instability‐high endometrial cancers

AbstractThe DNA mismatch repair (MMR) pathway is critical for correcting DNA mismatches generated during DNA replication. MMR‐deficiency (MMR‐D) leads to microsatellite instability (MSI) associated with an increased mutation rate, driving cancer development. This is particularly relevant in endometrial cancer (EC) as 25%–30% of tumors are of MMR‐D/MSI‐high (MSI‐H) phenotype. Comprehensive assessment using immunohistochemistry (IHC) and sequencing‐based techniques are necessary to fully evaluate ECs given the importance of molecular subtyping in staging and prognosis. This also influences treatment selection as clinical trials have demonstrated survival benefits for immune checkpoint inhibitors (ICIs) alone and in combination with chemotherapy for MMR‐D/MSI‐H EC patients in various treatment settings. As a portion of MMR‐D/MSI‐H ECs are driven by Lynch syndrome, an inherited cancer predisposition syndrome that is also associated with colorectal cancer, this molecular subtype also prompts germline assessment that can affect at‐risk family members. Additionally, heterogeneity in the tumor immune microenvironment and tumor mutation burden (TMB) have been described by MMR mechanism, meaning MLH1 promoter hypermethylation versus germline/somatic MMR gene mutation, and this may affect response to ICI therapies. Variations by ancestry in prevalence and mechanism of MMR‐D/MSI‐H tumors have also been reported and may influence health disparities given observed differences in tumors of Black compared to White patients which may affect ICI eligibility. These observations highlight the need for additional prospective studies to evaluate the nuances regarding MMR‐D heterogeneity as well as markers of resistance to inform future trials of combination therapies to further improve outcomes for patients with EC.

NRG‐GY012: Randomized phase 2 study comparing olaparib, cediranib, and the combination of cediranib/olaparib in women with recurrent, persistent, or metastatic endometrial cancer

AbstractPurposeThis paper reports the efficacy of the poly (ADP‐ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer.MethodsThis was open‐label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28‐day cycles until progression or unacceptable toxicity. The primary end point was progression‐free survival in the intention‐to‐treat population. Homologous repair deficiency was explored using the BROCA‐GO sequencing panel.ResultsA total of 120 patients were enrolled and all were included in the intention‐to‐treat analysis. Median age was 66 (range, 41–86) years and 47 (39.2%) had serous histology. Median progression‐free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91‐2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43–1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA‐GO panel results were not associated with response.ConclusionThe combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity.

Pathogenic germline variants in patients with endometrial cancer of diverse ancestry

AbstractBackgroundRacial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry‐based variations in germline pathogenic variants (gPVs) is unknown.MethodsGermline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor‐normal Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets sequencing from January 1, 2015 through June 30, 2021. Self‐reported race/ethnicity and Ashkenazi Jewish ancestry data classified patients into groups. Genetic ancestry was inferred from Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets. Rates of gPV and genetic counseling were compared by ancestry.ResultsAmong 1625 patients with EC, 216 (13%) had gPVs; 15 had >1 gPV. Rates of gPV varied by self‐reported ancestry (Ashkenazi Jewish, 40/202 [20%]; Asian, 15/124 [12%]; Black/African American (AA), 12/171 [7.0%]; Hispanic, 15/124 [12%]; non‐Hispanic (NH) White, 129/927 [14%]; missing, 5/77 [6.5%]; p = .009], with similar findings by genetic ancestry (p < .001). We observed a lower likelihood of gPVs in patients of Black/AA (odds ratio [OR], 0.44; 95% CI, 0.22–0.81) and African (AFR) ancestry (OR, 0.42; 95% CI, 0.18–0.85) and a higher likelihood in patients of Ashkenazi Jewish genetic ancestry (OR, 1.62; 95% CI; 1.11–2.34) compared with patients of non‐Hispanic White/European ancestry, even after adjustment for age and molecular subtype. Somatic landscape influenced gPVs with lower rates of microsatellite instability‐high tumors in patients of Black/AA and AFR ancestry. Among those with newly identified gPVs (n = 114), 102 (89%) were seen for genetic counseling, with lowest rates among Black/AA (75%) and AFR patients (67%).ConclusionsIn those with EC, gPV and genetic counseling varied by ancestry, with lowest rates among Black/AA and AFR patients, potentially contributing to disparities in outcomes given implications for treatment and cancer prevention.Plain Language Summary Black women with endometrial cancer do worse than White women, and there are many reasons for this disparity. Certain genetic changes from birth (mutations) can increase the risk of cancer, and it is unknown if rates of these changes are different between different ancestry groups. Genetic mutations in 1625 diverse women with endometrial cancer were studied and the lowest rates of mutations and genetic counseling were found in Black and African ancestry women. This could affect their treatment options as well as their families and may make disparities worse.

Characterization of mismatch‐repair/microsatellite instability‐discordant endometrial cancers

AbstractBackgroundMismatch‐repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity.MethodsSix hundred sixty‐six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut‐L homolog 1 (MLH1) methylation. Select samples underwent whole‐transcriptome analysis and next‐generation sequencing. MMR expression of metastatic/recurrent sites was evaluated.ResultsMSI testing identified 27.3% of cases as MSI‐high (n = 182), MMR IHC identified 25.1% cases as MMR‐deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut‐S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6‐associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR‐deficient cases and 9% in MMR‐proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial–mesenchymal transition.ConclusionsSubclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR‐deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker‐directed therapy.Plain Language Summary Endometrial cancer is the most common gynecologic cancer, and 20%–40% of tumors have a defect in DNA proofreading known as mismatch‐repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR‐deficient cells may drive tumor behavior and the risk of spreading cancer.

Endometrial cancer risk and trends among distinct African descent populations

AbstractBackgroundEndometrial cancer (EC) is the fourth most common cancer among Black women in the United States, a population disproportionately affected by aggressive nonendometrioid subtypes (e.g., serous, carcinosarcoma). To examine EC vulnerability among a wider spectrum of African descent populations, a comparison between Black women residing in different countries, rather than in the United States alone, is needed.MethodsThe authors analyzed 34,789 EC cases from Florida (FL) (2005–2018), Martinique (2005–2018), and Guadeloupe (2008–2018) based on cancer registry data. Age‐adjusted incidence rates, incidence rate ratios (IRRs), and annual percent changes (APC) in trends were estimated for Black populations residing in the United States (non‐Hispanic Blacks [NHB]) and Caribbean. The US non‐Hispanic White (NHW) population was used as a reference.ResultsCaribbean Black women had the lowest rates for endometrioid and nonendometrioid subtypes. Nonendometrioid types were most common among US (FL) NHBs (9.2 per 100,000), 2.6 times greater than NHWs (IRR, 2.60; 95% confidence interval [CI], 2.44–2.76). For endometrioid EC, rates increased 1.8% (95% CI, 0.1–3.5) yearly from 2005 to 2018 for US (FL) NHBs and 1.2% (95% CI, 0.9–1.6) for US (FL) NHWs whereas no change was observed for Caribbean Blacks. For nonendometroid carcinomas, rates increased 5.6% (95% CI, 4.0–7.2) among US (FL) NHB, 4.4% (95% CI, 0.3–8.6) for Caribbean Black, and 3.9% for US (FL) NHW women (95% CI, 2.4–5.5).ConclusionsLower rates of nonendometrioid EC among Caribbean Black women suggest that vulnerability for these aggressive tumor subtypes may not currently be an overarching African ancestry disparity. Most importantly, there is an alarmingly increasing trend in nonendometrioid across all populations studied, which warrants further surveillance and etiological research for this particular subtype.Plain Language Summary We analyze population‐based incidence rates and trends of endometrial cancer (EC) for African descent populations residing in different countries (i.e., United States, Martinique, Guadeloupe) to examine whether EC vulnerability among Black women is socio‐environmental or more ancestry‐specific in nature. The increased EC risk was not uniform across all Black women since the Caribbean had the lowest rates (for endometrioid and nonendometrioid histology subtypes). Regardless, from 2005 to 2018, there was an increasing trajectory of nonendometrioid EC for all groups, regardless of race.

Impact of obesity and white adipose tissue inflammation on the omental microenvironment in endometrial cancer

BackgroundA complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC.MethodsAdipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown‐like structures. Circulating levels of metabolic syndrome–associated and inflammatory markers were quantified. RNA‐sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state‐of‐the‐art bioinformatics methods.ResultsWAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p < .05). WAT inflammation was associated with greater body mass index (p < .001) and higher circulating levels of leptin, high‐sensitivity C‐reactive protein, and interleukin‐6, as well as lower levels of adiponectin and sex hormone–binding globulin (p < .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro‐neoplastic–related gene expression in inflamed omental adipose tissue.ConclusionsWAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.

Real‐life data on treatment and outcomes in advanced ovarian cancer: An observational, multinational cohort study (RESPONSE trial)

BackgroundThis study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high‐grade serous or endometrioid ovarian cancer (OC).MethodsThis observational study collected real‐world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III–IV) high‐grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for ≥20 months.ResultsOf the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician‐assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first‐line chemotherapy after surgery. After ≥20 months of follow‐up, 32.9% of the patients were disease‐free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42–0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression‐free survival (HR, 0.60; 95% CI, 0.41–0.84; p < .01).ConclusionsWomen with advanced high‐grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real‐world population.Lay summary Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high‐grade serous or endometrioid OC could potentially be eligible for first‐line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first‐line PARPi maintenance treatment.

Molecular classification in endometrial cancer: Opportunities for precision oncology in a changing landscape

Lay summary Endometrial carcinoma (EC) classification and risk stratification have undergone a global transformation in the last decade, shifting from a reliance on poorly reproducible histomorphological parameters such as grade and histotype, toward a molecular classification that is consistent and biologically informative. Molecular classification enables reliable categorization of ECs, provides prognostic information, and is now beginning to drive clinical management, including surgery and adjuvant therapy. Within this framework, we now have the ability to further refine both the prognostic and predictive value of molecular classification. As we move toward the routine implementation of this classification system as a stratification tool for research, clinical trials, and patient care, it is imperative that access to these tests be equitable. Furthermore, continued education will be critical for patients and providers to understand the value that this molecular information provides.

A phase 2 evaluation of pembrolizumab for recurrent Lynch‐like versus sporadic endometrial cancers with microsatellite instability

BackgroundMicrosatellite instability–high (MSI‐H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI‐H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793).MethodsPatients with measurable MSI‐H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression‐free survival (PFS) and overall survival (OS).ResultsTwenty‐five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch‐like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch‐like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867‐5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411‐798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch‐like patients but only 44% in sporadic patients (P = .024). The 3‐year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively.ConclusionsThis study suggests prognostic significance of Lynch‐like cancers versus sporadic MSI‐H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI‐H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI‐H ECs. Oligoprogression in MSI‐H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI‐H/dMMR EC subtypes treated with ICIs are warranted.

FBXW7, L1CAM, and TGM2 in endometrial cancer

Reply to Survival analysis and treatment effects in patients with endometrial cancer and POLE mutations

Survival analysis and treatment effects in patients with endometrial cancer and POLE mutations

Evaluation of treatment effects in patients with endometrial cancer and POLE mutations: An individual patient data meta‐analysis

BACKGROUNDEndometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE‐mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment.METHODSA PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta‐Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one‐stage meta‐analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC).RESULTSThree hundred fifty‐nine women with POLE‐mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47‐7.58; log‐rank P < .01). Except for stage (P < .01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease‐specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5‐14.2 years). Adjuvant treatment was not associated with outcome.CONCLUSIONSClinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de‐escalating treatment for these patients.LAY SUMMARY Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE‐mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.

Guideline‐adherent treatment, sociodemographic disparities, and cause‐specific survival for endometrial carcinomas

BACKGROUNDAdherence to National Comprehensive Cancer Network guidelines have been adopted as the standard of care for various cancers and have been cited to have survival benefits. Few studies have examined the association of adherent treatment and endometrial cancer survival among various racial/ethnic groups and socioeconomic statuses.METHODSBetween January 1, 2006 and December 31, 2015, 83,673 women diagnosed with endometrial carcinomas were identified from the Surveillance, Epidemiology, and End Results database. Descriptive statistics of demographic and clinical characteristics were performed. Cox‐proportional hazards models were used to examine the effect on cause‐specific survival for adherence to guidelines across racial/ethnic and socioeconomic groups.RESULTSWithin our sample, 59.5% were treated according to guidelines. Nonadherence to treatment guidelines was significantly associated with decreased survival compared with adherent care (adjusted hazard ratio [HR], 1.59; 95% CI, 1.52‐1.67). Being of Black (adjusted HR, 1.41; 95% CI, 1.32‐1.51) or Native Hawaiian/Pacific Islander (adjusted HR, 1.44; 95% CI, 1.19‐1.73) race/ethnicity compared with White women was significantly associated with worse survival. Being of Asian race/ethnicity (adjusted HR, 0.86, 95% CI, 0.78‐0.94) was significantly associated with improved survival compared with White women. Lower neighborhood socioeconomic status was associated with a negative effect on survival relative to women in the highest socioeconomic status category.CONCLUSIONSFindings from this study suggest treatment adherence is an independent predictor of improved survival; however, improved survival was not observed equally among all racial/ethnic and socioeconomic status groups.LAY SUMMARY The National Comprehensive Cancer Network (NCCN) has developed guidelines for physicians to follow in treating various cancers. Within this study of 83,673 women with endometrial cancer, 59.5% of women were treated according to the NCCN guidelines. The findings suggest following NCCN guidelines for treatment of endometrial cancer improves survival. Black or Native Hawaiian/Pacific Islander race and lower neighborhood socioeconomic status has worse survival rates compared with other groups, indicating the importance of exploring other factors that may shape treatment across racial/ethnic and socioeconomic status groups.

Cardiometabolic risk factors and survival after cancer in the Women's Health Initiative

BackgroundCardiometabolic abnormalities are a leading cause of death among women, including women with cancer.MethodsThis study examined the association between prediagnosis cardiovascular health and total and cause‐specific mortality among 12,076 postmenopausal women who developed local‐ or regional‐stage invasive cancer in the Women's Health Initiative (WHI). Cardiovascular risk factors included waist circumference, hypertension, high cholesterol, and type 2 diabetes. Obesity‐related cancers included breast cancer, colorectal cancer, endometrial cancer, kidney cancer, pancreatic cancer, ovarian cancer, stomach cancer, liver cancer, and non‐Hodgkin lymphoma. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for important predictors of survival.ResultsAfter a median follow‐up of 10.0 years from the date of the cancer diagnosis, there were 3607 total deaths, with 1546 (43%) due to cancer. Most participants (62.9%) had 1 or 2 cardiometabolic risk factors, and 8.1% had 3 or 4. In adjusted models, women with 3 to 4 risk factors (vs none) had a higher risk of all‐cause mortality (HR, 1.99; 95% CI, 1.73‐2.30), death due to cardiovascular disease (CVD) (HR, 4.01; 95% CI, 2.88‐5.57), cancer‐specific mortality (HR, 1.37; 95% CI, 1.1‐1.72), and other‐cause mortality (HR, 2.14; 95% CI, 1.70‐2.69). A higher waist circumference was associated with greater all‐cause mortality (HR, 1.17; 95% CI, 1.06‐1.30) and cancer‐specific mortality (HR, 1.22; 95% CI, 1.04‐1.42).ConclusionsAmong postmenopausal women diagnosed with cancer in the WHI, cardiometabolic risk factors before the cancer diagnosis were associated with greater all‐cause, CVD, cancer‐specific, and other‐cause mortality. These results raise hypotheses regarding potential clinical intervention strategies targeting cardiometabolic abnormalities that require future prospective studies for confirmation.Lay Summary This study uses information from the Women's Health Initiative (WHI) to find out whether cardiac risk factors are related to a greater risk of dying among older women with cancer. The WHI is the largest study of medical problems faced by older women in this country. The results show that women who have 3 or 4 risk factors are more likely to die of any cause, heart disease, or cancer in comparison with women with no risk factors. It is concluded that interventions to help to lower the burden of cardiac risk factors can have an important impact on survivorship among women with cancer.

Patterns and predictors of cancer‐related fatigue in ovarian and endometrial cancers: 1‐year longitudinal study

BackgroundFatigue is a common and distressing symptom for patients with gynecologic cancers. Few studies have empirically examined whether it spontaneously resolves. This study was aimed at identifying longitudinal patterns of fatigue and predictors of clinically significant fatigue 1 year after treatment completion.MethodsThis was a prospective cohort study of women with newly diagnosed ovarian (n = 81) or endometrial cancer (n = 181) that did not progress or recur within 1 year of treatment completion. Symptoms of fatigue, depression, and anxiety were assessed after surgery and 6 and 12 months after treatment completion with the Fatigue Assessment Scale and the Hospital Anxiety and Depression Scale. Patients' fatigue scores over time were classified (scores of 22‐50, clinically significant; scores of 10‐21, not clinically significant). Logistic regression models were fit to examine associations between fatigue and patient characteristics.ResultsAmong 262 participants, 48% reported clinically significant fatigue after surgery. One year later, 39% reported fatigue. There were 6 patterns over time: always low (37%), always high (25%), high then resolves (18%), new onset (10%), fluctuating (6%), and incidental (5%). Patients with fatigue after surgery were more likely to report fatigue at 12 months in comparison with others (odds ratio [OR], 6.08; 95% confidence interval [CI], 2.82‐13.11; P < .001). Patients with depressive symptoms also had higher odds of fatigue (OR, 3.36; 95% CI, 1.08‐10.65; P = .039), although only one‐third of fatigued patients reported depressive symptoms.ConclusionNearly half of women with gynecologic cancers had clinically significant fatigue after surgery, whereas 44% and 39% had fatigue 6 months and 1 year later; this suggests that spontaneous regression of symptoms is relatively rare. Women who reported fatigue, depressive symptoms, or 2 or more medical comorbidities had higher odds of reporting fatigue 1 year later. Future studies should test scalable interventions to improve fatigue in women with gynecologic cancers.

Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma

Background Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression. Methods Next‐generation sequencing was performed on archived endometrial biopsy specimens from a retrospective cohort of women with endometrial hyperplasia. Cases were considered to be either progressing if the patient subsequently developed EMC or resolving if the patient had a subsequent negative tissue sampling or no cancer during medium‐term follow‐up (32 patients: 15 progressing and 17 resolving). Somatic mutations in endometrial hyperplasia were assessed for enrichment in progressing cases versus resolving cases, with an emphasis on genes commonly mutated in EMC. Results Several mutations were more common in progressing hyperplasia than resolving hyperplasia, although significant overlap was observed between progressing and resolving cases. Mutations included those in PTEN , PIK3CA , and FGFR2 , genes commonly mutated in EMC. Mutations in ARID1A and MYC were seen only in progressing hyperplasia, although these were uncommon; this limited diagnostic sensitivity. Progressing hyperplasia demonstrated an accumulation of mutations in oncogenic signaling pathways similarly to endometrial carcinoma. Conclusions Because of mutational differences between progressing and nonprogressing hyperplasia, mutational analysis may predict the risk of progression from endometrial hyperplasia to EMC.

Pelvic fractures and changes in bone mineral density after radiotherapy for cervical, endometrial, and vaginal cancer: A prospective study of 239 women

Background Advances in radiotherapy (RT) have led to improved oncologic outcomes for women with gynecologic cancers; however, the long‐term effects and survivorship implications need further evaluation. The purpose of this study was to determine the incidence of pelvic fractures and changes in bone mineral density (BMD) after pelvic RT. Methods Two hundred thirty‐nine women who had pelvic RT for cervical, endometrial, or vaginal cancer between 2008 and 2015 were prospectively studied. BMD scans and biomarkers of bone turnover were obtained at the baseline and 3 months, 1 year, and 2 years after RT. Imaging studies were assessed for pelvic fractures for up to 5 years. Patients with osteopenia, osteoporosis, or pelvic fractures at any point were referred to the endocrinology service for evaluation and treatment. Results The median age at diagnosis was 51 years; 132 patients (56%) were menopausal. The primary diagnoses were cervical (63.6%), endometrial (30.5%), and vaginal cancer (5.9%). Sixteen patients (7.8%; 95% confidence interval, 4.5%‐12.4%) had pelvic fractures with actuarial rates of 3.6%, 12.7%, and 15.7% at 1, 2, and 3 years, respectively. Fractures were associated with baseline osteoporosis ( P  < .001), higher baseline bone‐specific alkaline phosphatase ( P  < .001), and older age ( P  = .007). The proportion of patients with osteopenia/osteoporosis increased from 50% at the baseline to 58%, 59%, and 70% at 3 months, 1 year, and 2 years, respectively. Conclusions A high proportion of women had significant decreases in BMD after pelvic RT, with 7.8% diagnosed with a pelvic fracture. BMD screening and pharmacologic intervention should be strongly considered for these high‐risk women.

Pooled performance of urinary human papillomavirus (HPV) testing for the presence of cervical HPV

Abstract Background Human papillomavirus (HPV) testing is the preferred method for cervical cancer screening. Noninvasive urinary HPV testing offers an attractive alternative to improve screening coverage among underscreened populations. However, few studies have assessed its performance in detecting cervical HPV via systematic review and meta‐analysis. Methods This study systematically searched PubMed, Embase, Web of Science Core Collection, and the Cochrane Library from inception until September 2023. The aim was to assess the performance of urinary HPV testing for detecting cervical HPV against two distinct reference standards: cervical HPV infection and histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) or grade 3 or worse (CIN3+). The study also pooled results of vaginal self‐sampling and participants' attitudes toward urine sampling. This study was registered in PROSPERO (CRD42023462218). Results A total of 2292 records were initially retrieved, and four previous reviews were examined. The meta‐analysis was conducted in two primary parts on the basis of the reference standard. First, with cervical HPV infection as the reference standard, the analysis included 65 studies (17,766 individuals). Compared to cervical samples, urine samples had a lower detection rate for high‐risk HPV (46% vs. 53%; p  = .110), with a pooled sensitivity of 76% (95% CI, 72%–80%) and specificity of 90% (95% CI, 87%–92%). Second, with CIN2+ as the reference standard, the analysis included 31 studies (15,054 individuals). In a direct comparison with paired data from 28 of these studies, urine samples demonstrated lower sensitivity than cervical samples (79% [95% CI, 72%–84%] vs. 93% [95% CI, 89%–96%]) but slightly higher specificity (58% [95% CI, 50%–65%] vs. 50% [95% CI, 42%–58%]). Additionally, with CIN2+ as the reference standard, this analysis of 21 studies (8974 individuals) showed that vaginal self‐samples had higher sensitivity (89% vs. 79%) but lower specificity (43% vs. 49%) compared to urine samples. Similar results were observed for CIN3+. Questionnaires or interviews conducted in 13 studies with 2426 participants revealed a greater preference for urine sampling. Conclusions Urinary HPV testing exhibits lower sensitivity than both cervical professional sampling and vaginal self‐sampling. Although its noninvasive nature supports its potential utility as a complementary strategy in resource‐limited or culturally conservative populations, it is not currently suitable for general population screening where standard methods are available because of its suboptimal performance and lack of standardized protocols for sampling and testing. Furthermore, standardization of sampling and testing protocols is required before routine implementation.

Cervical cancer elimination in India: Repurposing diagnostics, vaccination, and accelerating policy for the 2030 target

Abstract Cervical cancer remains one of the most significant yet preventable causes of cancer‐related mortality among women in India. Current estimates indicate that the country reports approximately 127,000 new cases and nearly 80,000 deaths annually, accounting for about one fifth of the global burden. Despite advances in vaccination, screening, and molecular diagnostics, coverage remains critically low: fewer than 2% of women undergo screening, and less than 1% have received a human papillomavirus (HPV) vaccine. The introduction of the indigenous quadrivalent vaccine Cervavac in 2023 has provided renewed momentum; however, limitations in infrastructure, public awareness, and stratic barrier to implementation continue to hinder progress toward achieving the World Health Organization's 2030 elimination targets. This opinion article highlights the epidemiological landscape, diagnostic and programmatic barriers, and emphasis to repurpose India's vast coronavirus disease‐era reverse transcriptase‐polymerase chain reaction network for HPV molecular testing. Integrating HPV vaccination into the Universal Immunization Program and incorporating the HPV Nucleic Acid Amplification Test (NAAT) into the National Essential Diagnostics List (NEDL) are critical steps for accelerating India's pathway to cervical cancer elimination by 2030.

Factors associated with an inconclusive result from commercial homologous recombination deficiency testing in ovarian cancer

AbstractIntroductionHomologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP‐ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result.MethodsGIS was retrieved for patients at their institution with epithelial ovarian cancer without germline/somatic BRCA1/2 deleterious alterations who underwent HRD testing from April 2020–August 2023. Clinical data were abstracted from the medical record.ResultsOf 477 HRD test results identified, 57 (12%) were inconclusive. High‐grade serous ovarian cancers had higher GIS than other histologic types (median 29 vs. 21, p < .001). Most HRD cases were of high‐grade serous histology; no cases with clear cell or endometrioid histology were HRD‐positive. On univariate analysis, interval versus primary cytoreductive surgery, other specimen sources versus surgical specimens, and chemotherapy exposure were risk factors for inconclusive HRD testing. On multivariable analysis, chemotherapy exposure, and tissue source were associated with an inconclusive test result, with surgical specimens more likely to yield a conclusive result than other sources (biopsy, cytology, other). Age, stage, self‐reported race, and histology were not associated with an inconclusive result.ConclusionsSurgical tissue was more likely to yield a conclusive HRD test result versus other sources of epithelial ovarian cancer tissue acquisition. When feasible, laparoscopic biopsy before initiation of neoadjuvant chemotherapy may increase the likelihood of obtaining interpretable HRD test results.

Association of mental health treatment receipt with cancer screening among US adults with a history of anxiety or depression

Adults with a history of depression or anxiety who lacked mental health treatment in the past year were significantly less likely to be up‐to‐date with breast, cervical, and colorectal cancer than those who received treatment. Concerted efforts to increase mental health treatment receipt among adults with mental illness may reduce disparities in cancer screening and related outcomes in this population.

Randomized phase 2 trial of tremelimumab and durvalumab in combination versus sequentially in recurrent platinum‐resistant ovarian cancer

AbstractBackgroundSingle‐agent immune checkpoint inhibitors (ICIs) have demonstrated limited responses in recurrent ovarian cancer; however, 30%–40% of patients achieve stable disease. The primary objective was to estimate progression‐free survival (PFS) after sequential versus combination cytotoxic T‐lymphocyte antigen 4 and programmed death ligand 1 ICIs in patients with platinum‐resistant high‐grade serous ovarian cancer (HGSOC).MethodsPatients were randomized to a sequential arm (tremelimumab followed by durvalumab on progression) or a combination arm (tremelimumab plus durvalumab, followed by durvalumab) via a Bayesian adaptive design that made it more likely for patients to be randomized to the more effective arm. The primary end point was immune‐related PFS (irPFS).ResultsSixty‐one subjects were randomized to sequential (n = 38) or combination therapy (n = 23). Thirteen patients (34.2%) in the sequential arm received durvalumab. There was no difference in PFS in the sequential arm (1.84 months; 95% CI, 1.77–2.17 months) compared with the combination arm (1.87 months; 95% CI, 1.77–2.43 months) (p = .402). In the sequential arm, no responses were observed, although 12 patients (31.6%) demonstrated stable disease. In the combination arm, two patients (8.7%) had partial response, whereas one patient (4.4%) had stable disease. Adverse events were consistent with those previously reported for ICIs. Patient‐reported outcomes were similar in both arms.ConclusionsThere was no difference in irPFS for combination tremelimumab plus durvalumab compared to tremelimumab alone (administered as part of a sequential treatment strategy) in a heavily pretreated population of patients with platinum‐resistant HGSOC. Response rates were comparable to prior reports, although the combination regimen did not add significant benefit, as has been previously described.

National organized screening programs for breast, colorectal, and cervical cancer reduce socioeconomic disparities, but it is not enough

Reply to “National organized screening programs for breast, colorectal, and cervical cancer reduce socioeconomic disparities, but it is not enough”

The highs and lows of serous ovarian cancer

AbstractLow‐grade serous ovarian cancer was initially described as a distinct type of rare epithelial ovarian cancer 20 years ago; however, only recently have physicians begun to leverage the understanding of the clinical behavior and molecular profile of this disease for treatment. The use of routine next‐generation sequencing has allowed a deeper understanding of the molecular drivers of this disease and shown how molecular alterations in mitogen‐activated protein kinase pathway genes such as KRAS and BRAF can affect overall prognosis and disease behavior. The use of targeted therapies, including MEK inhibitors, BRAF kinase inhibitors, and other investigational targeted therapies are changing the way this disease is viewed and treated. In addition, endocrine therapy can provide prolonged disease stability with generally mild toxicity, as well as promising response rates in recent studies examining combination therapy with CDK 4/6 inhibitors in the upfront and recurrent setting. Once seen merely as a chemo‐resistant form of ovarian cancer, recent studies have worked to harness the unique features of low‐grade serous ovarian cancer to provide individualized treatment options for patients with this disease.

Prospective evaluation of the tolerability and efficacy of niraparib dosing based on baseline body weight and platelet count: Results from the PRIMA/ENGOT‐OV26/GOG‐3012 trial

AbstractBackgroundThe PRIMA/ENGOT‐OV26/GOG‐3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first‐line maintenance therapy in patients with newly diagnosed advanced ovarian cancer.MethodsIn the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first‐line platinum‐based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg once daily. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg once daily in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/µL, and 300 mg once daily in all other patients. Efficacy and safety outcomes were assessed by starting dose.ResultsOverall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46–0.76] vs. ISD HR, 0.69 [95% CI, 0.48–0.98]) and the homologous recombination–deficient (FSD HR, 0.44 [95% CI, 0.30–0.64] vs. ISD HR, 0.39 [95% CI, 0.22–0.72]) populations. In patients with low body weight/platelet count, rates of grades ≥3 and 4 hematologic treatment‐emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD.ConclusionsIn PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.

Functional estrogen receptor signal transduction pathway activity and antihormonal therapy response in low‐grade ovarian carcinoma

AbstractBackgroundAdvanced low‐grade ovarian carcinoma (LGOC) is difficult to treat. In several studies, high estrogen receptor (ER) protein expression was observed in patients with LGOC, which suggests that antihormonal therapy (AHT) is a treatment option. However, only a subgroup of patients respond to AHT, and this response cannot be adequately predicted by currently used immunohistochemistry (IHC). A possible explanation is that IHC only takes the ligand, but not the activity, of the whole signal transduction pathway (STP) into account. Therefore, in this study, the authors assessed whether functional STP activity can be an alternative tool to predict response to AHT in LGOC.MethodsTumor tissue samples were obtained from patients with primary or recurrent LGOC who subsequently received AHT. Histoscores of ER and progesterone receptor (PR) were determined. In addition, STP activity of the ER STP and of six other STPs known to play a role in ovarian cancer was assessed and compared with the STP activity of healthy postmenopausal fallopian tube epithelium.ResultsPatients who had normal ER STP activity had a progression‐free survival (PFS) of 16.1 months. This was significantly shorter in patients who had low and very high ER STP activity, with a median PFS of 6.0 and 2.1 months, respectively (p < .001). Unlike ER histoscores, PR histoscores were strongly correlated to the ER STP activity and thus to PFS.ConclusionsAberrant low and very high functional ER STP activity and low PR histoscores in patients with LGOC indicate decreased response to AHT. ER IHC is not representative of functional ER STP activity and is not related to PFS.

The impact of the patient macroenvironment on molecular subgroups in endometrial cancer

Abstract More than half of endometrial cancer diagnoses can be attributed to obesity. A purely molecular classification in endometrial cancer hampers further understanding of the impact of patient macroenvironment as a major risk factor. The relationship between patient factors, such as age, body mass index (BMI), comorbidity, and ethnicity, and molecular subgroups was studied in a publicly available data set ( N  = 225) and two multicenter European cohorts ( N  = 223; N  = 946). Age at diagnosis was highest in the TP53 ‐mutated subgroup, and differed significantly between molecular subgroups. Patients with obesity were younger at diagnosis compared to their lean counterparts across all molecular subgroups (61.9 vs. 66.2 years; p  < .01). Survival was worst in the TP53 ‐mutated subgroup but improved with increasing BMI, which resulted in nonsignificant differences from other subgroups when BMI was >35. These data underscore that patient factors remain important, and their integration with molecular factors needs to be better understood to ultimately improve treatment and prevention strategies in endometrial cancer.

The time has come to implement primary human papillomavirus screening for cervical cancer in the United States

For the American Cancer Society (ACS), the time for primary human papillomavirus (HPV) screening implementation has unequivocally arrived for the United States, but it will require broad knowledge mobilization and addressing logistical barriers to engage the public and health providers. The ACS is using its convener role and marshalling its considerable educational and knowledge dissemination resources to advance primary HPV screening in the United States and to share best practices from countries that have done the same through the ACS Primary HPV Screening Initiative.

How social media can help to understand treatment experiences of survivors of rare cancers: Findings from the Granulosa Cell Tumor Survivor Sisters Facebook group member survey

AbstractBackgroundEngaging with online social media consumer groups for rare cancers may help to develop collaborations between consumers and researchers. This study, a collaboration with the Granulosa Cell Tumor‐Survivor Sisters (GCT‐SS) Facebook group, explores the results of their survey of member's treatment and follow‐up experiences.MethodsMembers of the closed multinational GCT‐SS Facebook group completed a 43‐item survey covering symptoms, diagnosis, treatment, recurrence, follow‐up, and possible risk factors for GCT. Group members could have adult (aGCT) or juvenile (jGCT) disease. Data was collected via an online survey between 2014 and 2019.ResultsA total of 743 members (average 4.4 years [SD = 5.9] post‐diagnosis) participated including 52 with jGCT. A total of 67% had stage I disease and 8% had stage III–IV at diagnosis, although 30% of aGCT and 25% of jGCT reported recurrent disease at survey completion. A total of 48% of aGCT had laparoscopic surgery, tumor encapsulation was reported by 49%, and tumor bagging reported by 29% overall (37% laparoscopic; 8% open). Recurrence rates were higher when the tumor was cut or ruptured (ruptured: p < .001; cut: p = .01). A total of 19% of aGCT had chemotherapy with this most common for stage II‐III disease. Bleomycin, etoposide, and cisplatin protocols became less common over time (diagnosed before 2015: 47% vs. diagnosed post‐2015: 21%).ConclusionsThis is one of the largest surveys of GCT treatment. Members of the GCT‐SS group report treatment patterns generally in line with those found from clinical audits. Using naturally forming consumer groups may assist with developing the evidence base for care and supporting those living with GCT ovarian cancer.Plain language summary This study is a collaboration between members of Granulosa Cell Tumor‐Survivor Sisters (GCT‐SS) Facebook group and researchers to assess members' experiences of treatment and follow‐up. A total of 743 members (52 with juvenile GCT) completed an online survey. A total of 67% had stage I disease at diagnosis. Treatment patterns were generally in line with those found from clinical audits: 95% had surgery and 19% of those with adult GCT had chemotherapy. A total of 30% reported recurrent disease, with recurrence occurring within 5 years of diagnosis for 33%. Using naturally forming consumer groups may assist with developing the evidence base for care and supporting those living with GCT ovarian cancer.

CCNE1 and survival of patients with tubo‐ovarian high‐grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Update on safety and feasibility of the combination of pembrolizumab and pelvic chemoradiation in locally advanced cervical cancer

AbstractBackgroundThe addition of immune checkpoint inhibitors to standard‐of‐care chemoradiation (CRT) is established as the new standard of care in high‐risk, locally advanced cervical cancer. However, the optimal sequencing of therapies is unknown. Defining safety and feasibility of the combination was a primary objective of this study examining concurrent versus sequential schedules.MethodsPembrolizumab was given after or during CRT in a randomized phase 2 design. Patients aged 18 years and older with locally advanced cervical cancer, stages IB–IVA (according to 2009 International Federation of Gynecology and Obstetrics staging) were randomized 1:1 to treatment regimens. CRT was identical for both arms. Pembrolizumab was administered every 3 weeks for three doses; no maintenance was allowed. Safety assessments included the incidence and severity of adverse events (AEs), and feasibility was measured by the completion of treatment in a predefined timeframe. Translational specimens (blood and tissue) were collected.ResultsIn total, 94 evaluable patients completed treatment. Treatment‐related grade ≥2 toxicity was experienced by 85 of 94 patients (90%); 40 patients (43%) had at least one grade 3 AE, and 22 (23%) had at least one grade 4 AE. There were no grade 5 AEs. Eighty percent of patients completed radiotherapy within 56 days, and 85% completed five or six doses of cisplatin and three doses of pembrolizumab (74 of 94 patients; 79%).ConclusionsThe final results of this study support the safety and feasibility of adding pembrolizumab to pelvic CRT, concurrently and sequentially. Progression‐free and overall survival were not affected or different between treatment arms. An analysis of the translational end points is ongoing and will inform future study designs.

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer

BackgroundFor women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.MethodsWomen with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.ResultsOf 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR‐deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1‐deficient tumors) followed by MSI for nonmethylated and/or MMR‐intact patients was the most sensitive (92.3%; 95% confidence interval, 64%‐99.8%) and specific (97.7%; 95% confidence interval, 94.2%‐99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.ConclusionsSequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost‐effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.

Empowerment and quality of life in gynecological cancer survivors: Outcomes from a multicenter quasi‐experimental cohort study from Norway (the LETSGO trial)

AbstractBackgroundIncreasing outpatient demands and unmet patient needs necessitate personalized follow‐up care for cancer survivors. This study investigated whether a self‐management–focused follow‐up model improves empowerment and quality of life (QoL) in gynecological cancer survivors compared to standard follow‐up.MethodsTwelve Norwegian hospitals participated in this cohort study. Patients initiating routine follow‐up after primary treatment were eligible and allocated to either intervention or standard care follow‐up groups based on their treatment hospital. The intervention included nurse‐led consultations using coaching techniques for education on symptom monitoring and healthy lifestyle, alternated with physician‐led consultations and access to a mobile app. Standard follow‐up consisted of physician‐led consultations only. The primary outcome was change in patient empowerment over 12 months, measured with the self‐monitoring and insight domain of the Health Education Impact Questionnaire (heiQ). Secondary outcomes included changes in remaining heiQ domains and QoL. Data were analyzed according to intention‐to‐treat principles using linear mixed effects models.ResultsAmong 741 participants (intervention: 378, standard: 363), baseline characteristics were comparable. At 12 months, no significant differences were observed in self‐monitoring and insight (Δ = 0.02 [95% confidence interval (CI), –0.04 to 0.08]; effect sizes [ES] = 0.29). However, health‐directed activity (Δ = 0.15 [95% CI, 0.04–0.25]; ES = 0.15), emotional well‐being (Δ = 0.12 [95% CI, 0.02–0.20]; ES = 0.15), social functioning (Δ = 5.2 [95% CI, 1.1–9.3]; ES = 0.41), and physical functioning (Δ = 2.5 [95% CI, 0.0–5.0]; ES = 0.20) were significantly more improved in the intervention group.ConclusionLifestyle and Empowerment Techniques in Survivorship of Gynaecologic Oncology follow‐up did not significantly impact self‐monitoring and insight, but positively influenced other survivorship domains, indicating its potential for enhancing self‐management and QoL in gynecological cancer survivors.

Attitudes toward the American Cancer Society’s 2020 cervical cancer screening guidelines: A qualitative study of a national sample of US clinicians

AbstractBackgroundThe 2020 American Cancer Society (ACS) guidelines are the most recent national guidelines for cervical cancer screening. These guidelines propose two major changes from current practice: initiating screening at age 25 years and using primary human papillomavirus (HPV) testing. Adoption of guidelines often occurs slowly, and therefore understanding clinician attitudes is important to facilitate practice change.MethodsInterviews with a national sample of clinicians who perform cervical cancer screening in a variety of settings explored attitudes toward the two major changes from the 2020 ACS cervical cancer screening guidelines. Clinicians participated in 30‐ to 60‐min interviews exploring their attitudes toward various aspects of cervical cancer screening. Qualitative analysis was performed.ResultsSeventy clinicians participated from across the United States. Few respondents were initiating screening at age 25 years, and none were using primary HPV testing. However, over half would be willing to adopt these practices if supported by scientific evidence and recommended by professional medical organizations. Barriers to adoption included the lack of endorsement by professional societies, lack of laboratory availability and insurance coverage, limited autonomy within large health care systems, and concerns related to missed disease.ConclusionsFew clinicians have adopted screening initiation or primary HPV testing, as recommended by the 2020 ACS guidelines, but over half were open to adopting these changes. Implementation may be facilitated via professional organization endorsement, clinician education, and laboratory, health care system, and insurance support.Plain Language Summary In 2020, the American Cancer Society (ACS) released updated guidelines for cervical cancer screening. The main changes to current practices were to initiate screening at age 25 years instead of age 21 years and to screen using primary human papillomavirus (HPV) testing rather than cytology alone or in combination with HPV testing. We performed in‐depth interviews with 70 obstetrics and gynecology, family medicine, and internal medicine physicians and advanced practice providers about their attitudes toward these guidelines. Few clinicians are following the 2020 ACS guidelines, but over half were open to changing practice if the changes were supported by evidence and recommended by professional medical organizations. Barriers to adoption included the lack of endorsement by professional medical organizations, logistical issues, and concerns about missed disease.

Chemotherapy response in low‐grade serous ovarian carcinoma at a comprehensive cancer center: Readdressing the roles of platinum and cytotoxic therapies

AbstractBackgroundData on platinum sensitivity of low‐grade serous ovarian carcinoma (LGSOC) in the upfront setting is lacking, and there is limited and contradictory information on chemotherapy responses in recurrent disease.MethodsPatients with LGSOC seen at a comprehensive cancer center from January 1, 1998 to September 30, 2021 were identified from institutional databases. Response to neoadjuvant chemotherapy (NACT) or adjuvant platinum‐based chemotherapy and to second‐ to fifth‐line regimens was retrospectively characterized by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Wilcoxon rank‐sum and two‐tailed Fisher exact tests were employed.ResultsOf 50 patients, 12 received platinum doublets for suboptimal residual disease and 11 as NACT. Of 12 patients with suboptimal residual disease, seven (58%) achieved objective responses (five partial responses [PRs] and two complete responses); of the 11 patients who underwent NACT, one (9%) achieved a PR (p = .027). The 15 remaining patients had stable disease on first‐line platinum chemotherapy. Of 44 patients who recurred, 20 had RECIST‐evaluable responses to second‐line and 27 to third‐line chemotherapy. Objective response rates to platinum‐based chemotherapy were 22% (two of nine) in the second line and 10% (one of 10) in the third. In second and third lines, highest response rates were observed with nonplatinum chemotherapy with bevacizumab, at 100% (two of two) and 30% (three of 10), respectively.ConclusionsPrimary platinum‐based chemotherapy has moderate activity in LGSOC and minimal activity in the recurrent setting, suggesting standard definitions of platinum sensitivity may not apply in LGSOC. In the second and third lines, nonplatinum chemotherapy/bevacizumab elicited the highest response rates.

Clinical implications of tumor‐based next‐generation sequencing in high‐grade epithelial ovarian cancer

AbstractBackgroundTumor‐based next‐generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor‐based next‐generation sequencing (tbNGS) in patients with ovarian cancer.MethodsThis retrospective study included patients with high‐grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression‐free survival (PFS) and overall survival were calculated and compared using log‐rank tests. Multivariate Cox regression and clustering analyses were used to identify patterns of genetic alterations associated with survival.ResultsOf 1092 patients in the described population, 409 (37.5%) had tbNGS results. Nearly all (96.1% [393/409]) had one or more genetic alterations. In 25.9% (106/409) of patients, an alteration that aligned with a targeted treatment was identified, and in an additional 48.7% (199/409), tbNGS results suggested eligibility for an investigational agent or clinical trial. The most frequent alterations were TP53, PIK3CA, and NF1 mutations, and CCNE1 amplification. Together, BRCA1 and BRCA2 mutations were associated with longer PFS (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.42–0.92; p = .02), whereas AKT2 amplification was associated with shorter PFS (HR, 3.86; 95% CI, 1.002–14.88; p < .05). Multivariate Cox regression and clustering analyses identified several combinations of genetic alterations that corresponded to outcomes in patients with high‐grade serous carcinoma.ConclusionstbNGS often yields clinically relevant information. Detailed analysis of population‐level tumor genomics may help to identify therapeutic targets and guide development of clinical decision support tools.Plain Language Summary Although more and more patients with ovarian cancer are undergoing tumor‐based next‐generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established. In a group of over 400 patients with ovarian cancer who underwent tumor‐based next‐generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option.

Beyond the estrogen receptor: In search of predictive biomarkers for low‐grade serous ovarian cancer

Estrogen receptor immunohistochemistry should not be used in the clinic as an indicator of response to antihormonal therapy; progesterone receptor immunohistochemistry may be prognostic, but further study is needed. Multigene assays to assess for estrogen receptor pathway activation hold potential as a viable diagnostic tool to help determine those patients least likely to respond to single‐agent endocrine therapy and potentially identify patients most appropriate for combination strategies.

Patient‐centered outcomes in the POLO study of active maintenance olaparib for germline BRCA‐mutated metastatic pancreatic cancer

AbstractBackgroundThe phase 3 POLO study demonstrated a significant progression‐free survival (PFS) benefit and preserved health‐related quality of life (HRQOL) for active maintenance treatment with olaparib vs placebo in patients with metastatic pancreatic cancer and a germline BRCA mutation. Here, we present a post hoc analysis of the patient‐centered outcomes: time without significant symptoms of disease progression or toxicity (TWiST) and quality‐adjusted TWiST (Q‐TWiST).MethodsPatients were randomized 3:2 to maintenance olaparib (300 mg tablets twice daily) or placebo. Overall survival time was divided into TWiST, toxicity (TOX; time before disease progression with significant symptoms of toxicity), and relapse (REL; time after disease progression until death or censoring). Q‐TWiST was the sum of TWiST, TOX, and REL, each weighted by HRQOL utility scores during the relevant health‐state period. A base‐case and three sensitivity analyses were performed using differing definitions of TOX.ResultsIn total, 154 patients were randomized (olaparib, n = 92; placebo, n = 62). TWiST was significantly longer for olaparib than placebo in the base‐case analysis (14.6 vs 7.1 months; 95% CI, 2.9–12.0; p = .001) and all sensitivity analyses. No statistically significant benefit for Q‐TWiST was observed in the base‐case analysis (18.4 vs 15.9 months; 95% CI, −1.1 to 6.1; p = .171) or the sensitivity analyses.ConclusionThese results support the previous findings that maintenance olaparib significantly improves PFS relative to placebo without compromising HRQOL and demonstrate that the clinically meaningful benefits of olaparib persist even when symptoms of toxicity are considered.

New test for detecting cervical adenocarcinoma

Ovarian juvenile granulosa cell tumor: A report from the International Ovarian and Testicular Stromal Tumor and International Pleuropulmonary Blastoma/DICER1 Registries

AbstractBackgroundOvarian juvenile granulosa cell tumors (juvGCT) are rare sex cord‐stromal tumors that occur primarily in children and adolescents. This study summarizes the clinical presentation and outcomes of patients with juvGCT.MethodsPatients were enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries. Available medical records were abstracted, and pathology was centrally reviewed. Surgical staging was classified using the 2014 International Federation of Gynecology and Obstetrics (FIGO) criteria.ResultsIn total, 70 patients with juvGCT enrolled and were diagnosed between 2001 and 2024; most patients (81%, 57 of 70) presented with FIGO stage I disease. Adjuvant chemotherapy was given in 30% (21 of 70); all regimens were platinum‐based. Three‐year event‐free survival among patients with stage IA tumors was 80.2% (95% confidence interval [CI], 62.4%–100.0%), IC1 was 87.4 (95% CI, 72.4%–100.0%), IC2‐IC3 was 63.6% (95% CI, 40.7%–99.5%), and II‐IV was 48% (95% CI, 24.6%–93.8%). Of the patients with recurrent juvGCT with known mitotic index (MI), all had MI greater than 19 mitoses per 10 high power fields (HPF) at diagnosis.ConclusionOutcomes were worse for patients with FIGO stage ≥IC2 disease and for tumors with >19 mitoses per 10 HPF. Given the prognostic significance of MI, the authors strongly recommend the assessment of MI for all juvGCTs. More information about tumor biology is critical to identify which patients may benefit from adjuvant chemotherapy and to facilitate the development of novel therapies.

Attack of the clones: Unveiling subclonal/heterogenous mismatch repair/microsatellite instability status in endometrial cancer

Any time there are two or more tests for a given analyte, there will be some degree of disagreement between them. This editorial contextualizes the recent findings by Riedinger and colleagues regarding discordant mismatch repair and microsatellite instability testing in endometrial cancer.

Top advances of the year: Cervical cancer

AbstractThe year 2023 was an extraordinary year for the further development and expansion of novel treatments for all patients with cervical cancer, ranging from early stage to later stage and metastatic or recurrent disease. Individuals with early‐stage disease will benefit from less invasive surgery with subsequent improvement in quality of life. The effectiveness of immunotherapy has been demonstrated in upfront, locally advanced cervical cancer and confirmed in advanced metastatic disease. Induction chemotherapy will play a role in some patients with locally advanced disease, particularly those in low resource areas of the world. Novel therapeutics including antibody–drug conjugates have shown efficacy even in pretreated patients. As we continue to explore innovative therapeutics in this space, however, we must also continue to improve the diversity of clinical trial accrual to allow for generalizable results. At the same time, we must focus on eradicating this disease with appropriate screening and vaccination.

HPV testing in older women may improve cervical cancer prevention

Cancer incidence in the US military: An updated analysis

AbstractBackgroundMilitary and general populations differ in factors related to cancer occurrence and diagnosis. This study compared incidence of colorectal, lung, prostate, testicular, breast, and cervical cancers between the US military and general US populations.MethodsData from the US Department of Defense’s Automated Central Tumor Registry (ACTUR) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program were analyzed. Persons in ACTUR were active‐duty members 20–59 years old during 1990–013. The same criteria applied to persons in SEER. Age‐adjusted incidence rates, incidence rate ratios, and 95% confidence intervals were calculated by sex, race, age, and cancer stage. Temporal trends were analyzed.ResultsACTUR had higher rates of prostate and breast cancers, particularly in 40‐ to 59‐year‐olds. Further analyses by tumor stage showed this was primarily confined to localized stage. Incidence rates of colorectal, lung, testicular, and cervical cancers were significantly lower in ACTUR than in SEER, primarily for regional and distant tumors in men. Temporal incidence trends were generally similar overall and by stage between the populations, although distant colorectal cancer incidence tended to decrease starting in 2006 in ACTUR whereas it increased during the same period in SEER.ConclusionHigher rates of breast and prostate cancers in servicemembers 40–59 years of age than in the general population may result from greater cancer screening utilization or cumulative military exposures. Lower incidence of other cancers in servicemembers may be associated with better health status.

Psychosocial factors associated with genetic testing status among African American women with ovarian cancer: Results from the African American Cancer Epidemiology Study

BackgroundRacial disparities in the uptake of cancer genetic services are well documented among African American (AA) women. Understanding the multiple social and psychological factors that can influence the uptake of genetic testing among AA women is needed.MethodsData came from 270 AA women diagnosed with ovarian cancer and participating in a population‐based, case‐control study of ovarian cancer who were asked about genetic testing. Logistic regression analyses tested the associations of predisposing, enabling, and need factors with reported genetic testing uptake.ResultsOne‐third of the sample (35%) reported having had genetic testing. In the multivariable model, AA women with higher incomes had more than double the odds of being tested than those with the lowest income (odds ratio [OR] for $25,000‐$74,999, 2.04; 95% confidence interval [CI], 1.06‐3.99; OR for ≥$75,000, 2.32; 95% CI, 0.92‐5.94). AA women who reported employment discrimination were significantly less likely to report genetic testing than those who did not report job discrimination (OR, 0.39; 95% CI, 0.14‐0.95). Marital status, Medicaid versus other insurance, prayer frequency, and perceived social support were significantly associated with genetic testing uptake in bivariate analyses but were not significant contributors in multivariable analyses.ConclusionsConsistent with other studies of AA women, a minority of African American Cancer Epidemiology Study participants had undergone genetic testing. Having a lower income and experiencing job discrimination decreased the likelihood of testing. These results provide foundational evidence supporting the need for interventions to improve the uptake of genetic testing among AA women by reducing cost barriers and providing credible assurances that genetic results will be kept private and not affect social factors such as employability.

A cross‐sectional survey examining clinician characteristics, practices, and attitudes associated with adoption of the 2019 American Society for Colposcopy and Cervical Pathology risk‐based management consensus guidelines

AbstractBackgroundThe 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) risk‐based management consensus guidelines are the most recent national guidelines for the management of abnormal cervical cancer screening tests. These guidelines benefit patients by concentrating testing and treatment in those at highest cervical cancer risk. Adoption of guidelines often occurs slowly, with few studies examining the factors associated with guideline‐adherent management of abnormal results.MethodsTo elucidate the factors associated with the use of the 2019 ASCCP guidelines among clinicians who perform cervical cancer screening, physicians and advanced practice professionals who perform cervical cancer screening were cross‐sectionally surveyed. Clinicians responded to screening vignettes with differing recommendations for management between the 2019 and prior management guidelines. Screening vignette 1 involved reduction of invasive testing on a low‐risk patient; screening vignette 2 involved increased surveillance testing on a high‐risk patient. Binomial logistic regression models determined the factors associated with the use of the 2019 guidelines.ResultsA total of 1251 clinicians participated from across the United States. For screening vignettes 1 and 2, guideline‐adherent responses were given by 28% and 36% of participants, respectively. Management recommendations differed by specialty and were incorrect in different situations: there was inappropriate invasive testing by obstetrics and gynecology physicians (vignette 1) and inappropriate discontinuation of screening by family and internal medicine physicians (vignette 2). Regardless of their chosen response, over half erroneously believed they were guideline adherent.ConclusionsMany clinicians who believe they are following appropriate guidelines may not realize their management strategy is inconsistent with the 2019 guidelines. Education initiatives tailored to clinician specialty could address the understanding of current guidelines, encourage the use of updated guidelines, maximize patient benefits, and minimize harms.Plain Language Summary The 2019 American Society for Colposcopy and Cervical Pathology risk‐based management consensus guidelines are the most recent national guidelines for abnormal cervical cancer screening test management. We surveyed over 1200 obstetrics and gynecology (OB/GYN), family medicine, and internal medicine physicians and advanced practice providers about their screening and abnormal results follow‐up practices in relation to guidelines. Few clinicians are following the 2019 guidelines. Management recommendations differed by clinician specialty and were incorrect in different situations: there was inappropriate invasive testing by OB/GYN physicians and inappropriate screening discontinuation by family and internal medicine physicians. Education tailored by clinician specialty could address the understanding of current guidelines, encourage the use of updated guidelines, maximize patient benefits, and minimize harms.

The risks of cancer in older women with BRCA pathogenic variants: How far have we come?

AbstractBackgroundThe purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant.MethodsParticipants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow‐up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow‐up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan–Meier method.ResultsThere were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk‐reducing mastectomy and bilateral salpingo‐oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%.ConclusionWomen with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.

Risk‐adapted starting age of breast cancer screening in women with a family history of ovarian or other cancers: A nationwide cohort study

BACKGROUNDThere is a lack of evidence‐based recommendations for the age at which women with a family history of cancers other than breast cancer should start breast cancer screening.METHODSUsing Swedish family cancer data sets, the authors conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931 (follow‐up, 1958‐2015). Accounting for calendar time, they calculated the relative risk of breast cancer for women with a family history of a discordant cancer in 1 first‐degree relative. Furthermore, the authors used 10‐year cumulative risk to determine the ages at which women with a family history of discordant cancer reached risk thresholds at which women in the general population were recommended to start breast cancer screening.RESULTSA family history of cancer at 15 sites was associated with an increased risk of breast cancer. Among women younger than 50 years, the highest risk of breast cancer was observed for those with a family history of ovarian cancer (standardized incidence ratio, 1.44; 95% confidence interval, 1.26‐1.64). In these women, the risk of breast cancer associated with a family history at other cancer sites ranged from 1.08‐fold for prostate cancer to 1.18‐fold for liver cancer. When breast cancer screening was recommended to be started at the age of 50 years for the general population, women with 1 first‐degree relative with ovarian cancer attained the threshold risk for screening at the age of 46 years. Women with a family history of other discordant cancers did not reach the risk thresholds for screening at younger ages.CONCLUSIONSMany cancers showed familial associations with breast cancer, but women with a family history of these cancers (except for ovarian cancer) did not reach risk thresholds for screening at younger ages.

Intraperitoneal chemotherapy: Hot, timely, and relevant?

The use of hyperthermic intraperitoneal chemotherapy has been growing in popularity in recent years. Even with a positive randomized trial, issues concerning the study design and the statistical analysis raise questions about whether this technique should be recommended as a standard‐of‐care approach. There are many questions that remain unanswered.

Pembrolizumab with chemoradiotherapy followed by pembrolizumab for stage III–IVa cervical cancer: is the ENGOT‐cx11/GOG‐3047/KEYNOTE‐A18 trial practice changing?

AbstractAt the second interim analysis, the ENGOT‐cx11/GOG‐3047/KEYNOTE‐A18 demonstrated an overall survival (OS) benefit after 36 months in stage III–IVa cervical cancer patients treated with chemoradiotherapy and concurrent pembrolizumab followed by 90 weeks of pembrolizumab as compared to placebo (82.6% vs. 74.8%, hazard ratio for death, 0.67 [confidence interval, 0.50–0.90]). Only 51 of 193 progressing patients in the control arm were exposed to immunotherapy after progressing. The reported OS benefit could be explained by suboptimal post‐progression treatment in the control group. Even if pembrolizumab as administered in the ENGOT‐cx11/GOG‐3047/KEYNOTE‐A18 was efficacious, the treatment duration is excessively long. The associated costs render it unattainable in the regions where burden of cervical cancer is highest. Based on these concerns, the findings at the interim analysis of the ENGOT‐cx11/GOG‐3047/KEYNOTE‐A18 RCT should not change practice.

Hyperthermic intraperitoneal chemotherapy in interval debulking surgery for advanced epithelial ovarian cancer: A single‐center, real‐life experience

BackgroundAn improvement in survival without increasing perioperative morbidity in patients with advanced epithelial ovarian cancer treated with hyperthermic intraperitoneal chemotherapy (HIPEC) after interval debulking surgery (IDS) has been recently demonstrated in a randomized controlled trial. This study was aimed at assessing the feasibility and perioperative outcomes of the use of HIPEC after IDS at a referral cancer center.MethodsOver the study period, 149 IDSs were performed. Patients who had at least International Federation of Gynecology and Obstetrics stage III disease, with <2.5 mm of residual disease (RD) at the end of surgery and were not participating in clinical trials received HIPEC. Moreover, specific exclusion criteria were considered. These patients were compared with 51 patients with similar clinical characteristics at the same institution and within the same timeframe who did not receive HIPEC.ResultsNo differences in patient or disease characteristics with the exception of the type of neoadjuvant chemotherapy (P = .002) were found between the 2 groups. As for surgical characteristics, significant differences were found in RD after IDS (P = .007) and in the duration of surgery (P < .001), whereas the bowel resection and diversion rates (P = .583 and P = .213, respectively) and the postoperative intensive care unit and hospital stays (P = .567 and P = .727, respectively) were comparable. The times to start adjuvant chemotherapy were also similar (P = .998). Equally, the rates of any grade of both intraoperative complications (P = .189) and early postoperative complications (P = .238) were superimposable.ConclusionsIn the authors' experience, the addition of HIPEC to IDS is feasible in 35% for the population. This value might increase with changes in the inclusion/exclusion criteria. HIPEC does not increase perioperative complications and does not affect a patient's recovery or time to start adjuvant chemotherapy. HIPEC should be offered to select patients listed for IDS.

Survival and clinical outcomes of patients with ovarian cancer who were treated on phase 1 clinical trials

BackgroundPatients with ovarian cancer who are enrolled on phase 1 trials typically have platinum‐resistant and heavily pretreated disease, with a poor prognosis. In the current study, the authors assessed prognostic factors and survival in women with recurrent ovarian cancer who were treated on phase 1 clinical trials.MethodsThe authors performed a retrospective analysis of patients treated from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics and treatment and toxicity‐related survival data were assessed. Descriptive statistics and Cox proportional hazards models were used to identify risk factors associated with survival time.ResultsA total of 132 patients were treated on phase 1 clinical trials. Patients had a median age of 59 years (range, 33‐88 years) with a median of 5.5 previous chemotherapy lines (range, 1‐13 lines). Of the 132 patients, 53 (40%) were treated on multiple phase 1 trials with a median of 1 (range, 0‐5) prior phase 1 trial. The overall response rate was 14.7%. The median overall survival was 11.3 months (95% CI, 9.1‐13.4 months). Two patients died on trial due to progression of disease whereas no patients died of treatment‐related toxicity. Independent risk factors found to be predictive of shorter survival were an elevated cancer antigen 125 (CA 125) level (hazard ratio [HR], 2.8; 95% CI, 1.6‐5.2) and albumin <3.5 g/dL (HR, 2.5; 95% CI, 1.65‐3.79). A body mass index >25 kg/m2 was predictive of longer survival (HR, 0.65; 95% CI, 0.44‐0.96).ConclusionsIn the current single‐institution series, patients with heavily pretreated ovarian cancer who were treated on phase 1 clinical trials experienced a median overall survival of 11.3 months. When available, phase 1 clinical trials represent a reasonable treatment option for patients with heavily pretreated ovarian cancer with a preserved performance status.

Epithelial‐mesenchymal transition polarization in ovarian carcinomas from patients with high social isolation

BackgroundSocial isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. In patients with ovarian cancer, social isolation has been found to be related to decreased survival and multiple biomarkers supporting tumor progression. However, to the authors' knowledge, little is known regarding the relationship between social isolation and the molecular characteristics of ovarian tumors. Herein, the authors have used genome‐wide transcriptional profiling to quantify associations between social isolation and epithelial‐mesenchymal transition (EMT) polarization in ovarian tumors and transcriptome‐driven, promoter‐based bioinformatics analyses to identify gene regulatory pathways that may potentially underlie these changes.MethodsTumor was sampled during primary surgical resection and immediately frozen in liquid nitrogen. After RNA extraction, microarray analysis of the transcriptome was performed and samples were analyzed to assess associations between EMT‐related gene transcripts and social isolation (as indicated by a Social Provisions Scale Attachment subscale score <15). Convergent validation was provided by a promoter‐based bioinformatic analysis of transcription factor activity.ResultsPrimary analyses of 99 women demonstrated a lower average expression of gene transcripts previously associated with epithelial differentiation in women with high social isolation (−0.143 ± 0.048 log2 mRNA abundance; P = .004), but no difference in mesenchymal differentiation as a function of social isolation (+0.007 ± 0.0064 log2 mRNA abundance; P = .900). Upregulated activity was shown for 3 of the 4 targeted EMT‐related transcription factors, including GATA4 (P = .014); SMAD2, SMAD3, and/or SMAD4 (P < .001); and TWIST1 (P < .001). Analyses of SNAIL2/SLUG activity indicated a directional trend toward increased activity that did not reach statistical significance (P = .123).ConclusionsThe findings of the current study demonstrated differential EMT polarization and EMT‐related transcription factor activity according to social isolation, a known socioenvironmental risk factor.Lay Summary Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. Herein, the authors examined the relationship between social isolation and the molecular characteristics of ovarian tumors. The authors investigated the epithelial‐mesenchymal transition (EMT), a process whereby tumor cells lose epithelial characteristics and become more embryonic (mesenchymal), thereby enhancing invasiveness. Primary analyses demonstrated lower expression of genes previously associated with epithelial differentiation and increased activity of specific EMT‐related transcription factors in individuals with high social isolation, indicating increased EMT polarization in these patients. These findings extend the understanding of how socioenvironmental factors may modulate tumor growth.

Residential segregation and overall survival of women with epithelial ovarian cancer

BackgroundTo the authors' knowledge, the etiology of survival disparities in patients with epithelial ovarian cancer (EOC) is not fully understood. Residential segregation, both economic and racial, remains a problem within the United States. The objective of the current study was to analyze the effect of residential segregation as measured by the Index of Concentration at the Extremes (ICE) on EOC survival in Florida by race and/or ethnicity.MethodsAll malignant EOC cases were identified from 2001 through 2015 using the Florida Cancer Data System (FCDS). Census‐defined places were used as proxies for neighborhoods. Using 5‐year estimates from the American Community Survey, 5 ICE variables were computed: economic (high vs low), race and/or ethnicity (non‐Hispanic white [NHW] vs non‐Hispanic black [NHB] and NHW vs Hispanic), and racialized economic segregation (low‐income NHB vs high‐income NHW and low‐income Hispanic vs high‐income NHW). Random effects frailty models were conducted.ResultsA total of 16,431 malignant EOC cases were diagnosed in Florida among women living in an assigned census‐defined place within the time period. The authors found that economic and racialized economic residential segregations influenced EOC survival more than race and/or ethnic segregation alone in both NHB and Hispanic women. NHB women continued to have an increased hazard of death compared with NHW women after controlling for multiple covariates, whereas Hispanic women were found to have either a similar or decreased hazard of death compared with NHW women in multivariable Cox models.ConclusionsThe results of the current study indicated that racial and economic residential segregation influences survival among patients with EOC. Research is needed to develop more robust segregation measures that capture the complexities of neighborhoods to fully understand the survival disparities in EOC.

Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition

BackgroundPoor outcomes for patients with ovarian cancer relate to dormant, drug‐resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease.MethodsBy using unbiased small‐interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small‐molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP‐binding protein Di‐Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib‐induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short‐hairpin RNA knockdown of autophagic proteins, and small‐molecule inhibitors of STAT3 and BCL‐2.ResultsInduction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3‐expressing tumors treated with crizotinib had significantly decreased tumor burden and long‐term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy‐mediated apoptosis by decreasing phosphorylated STAT3 and BCL‐2 signaling.ConclusionsCrizotinib may eliminate dormant, autophagic, drug‐resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second‐look operations should be seriously considered.

Combination therapy may create a practice change for advanced or recurrent endometrial cancer

This news section offers Cancer readers timely information on events, public policy analysis, topical issues, and personalities. In this issue, two new studies show the value of adding immunotherapy to standard‐of‐care chemotherapy to improve progression‐free survival in endometrial cancer. In addition, mirvetuximab soravtansine is confirmed as a new standard of care for platinum‐resistant ovarian cancer, and leaving ovaries during benign hysterectomies may have benefits that outweigh the potential risks of removing them.

First person profile: Robert C. Bast Jr MD

Associations of serum trimethylamine N‐oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort

AbstractBackgroundDietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N‐oxide (TMAO) and its precursors, choline, L‐carnitine, and betaine.MethodsProspective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L‐carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori–selected dietary exposures with the four metabolites were also investigated.ResultsTMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10 [95% CI] = 1.90 [CI, 1.24–2.92; p = .003] and 1.26 [1.17–1.36; p < .0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI] = 0.77 [0.76–0.79; p < .001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho = 0.10; p = .0003).ConclusionsSerum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Experts say that cervical cancer could be eliminated worldwide with screening, human papillomavirus vaccine

Gender equity gap persists, addressing the root cause through the lens of gynecologic oncology: An evidenced‐based review

AbstractMany studies have addressed the inequities of gender within medicine. And although more attention has been brought to this topic in the past couple of decades, studies demonstrate that there is an equity gap in the workplace, in the research sphere, and in pay compensation. Internet searches prove that leadership in academic spaces as well as private practice both remain predominantly male. As an example, the field of gynecologic oncology is a field that specifically addresses and serves the health needs of patients who identify as women. However, although the specialty should be at the forefront of the effort to address gender inequities, it still has considerable progress to make in this area. This article seeks to describe the literature regarding gender disparities in medicine, and what gender equity can look like while laying out strategies to address the inequities that persist – using gynecologic oncology as an example.

Low‐income, Asian American women benefit from human papillomavirus self‐sampling tests

Psychological stress is associated with a higher risk of cervical cancer mortality

Lower Cervical Cancer Risk Associated With HPV Vaccine

Prevalence of human papillomavirus genotypes in high‐grade cervical precancer and invasive cervical cancer from cancer registries before and after vaccine introduction in the United States

BackgroundUS population‐based cancer registries can be used for surveillance of human papillomavirus (HPV) types found in HPV‐associated cancers. Using this framework, HPV prevalence among high‐grade cervical precancers and invasive cervical cancers were compared before and after HPV vaccine availability.MethodsArchived tissue from 2 studies of cervical precancers and invasive cervical cancers diagnosed from 1993‐2005 (prevaccine) were identified from 7 central cancer registries in Florida; Hawaii; Iowa; Kentucky; Louisiana; Los Angeles County, California; and Michigan; from 2014 through 2015 (postvaccine) cases were identified from 3 registries in Iowa, Kentucky, and Louisiana. HPV testing was performed using L1 consensus polymerase chain reaction analysis. HPV‐type–specific prevalence was examined grouped by hierarchical attribution to vaccine types: HPV 16, 18, HPV 31, 33, 45, 52, 58, other oncogenic HPV types, and other types/HPV negative. Generalized logit models were used to compare HPV prevalence in the prevaccine study to the postvaccine study by patient age, adjusting for sampling factors.ResultsA total of 676 precancers (328 prevaccine and 348 postvaccine) and 1140 invasive cervical cancers (777 prevaccine and 363 postvaccine) were typed. No differences were observed in HPV‐type prevalence by patient age between the 2 studies among precancers or invasive cancers.ConclusionsThe lack of reduction in vaccine‐type prevalence between the 2 studies is likely explained by the low number of cases and low HPV vaccination coverage among women in the postvaccine study. Monitoring HPV‐type prevalence through population‐based strategies will continue to be important in evaluating the impact of the HPV vaccine.

Pembrolizumab is effective for endometrial cancer

Significant overall survival benefit with dostarlimab plus chemotherapy in advanced endometrial cancer

Favorable overall survival trend with pembrolizumab plus chemotherapy for endometrial cancer

Improved survival in cervical cancer patients receiving care at National Cancer Institute–designated cancer centers

BackgroundLocally advanced cervical cancer (CC) remains lethal in the United States. We investigate the effect of receiving care at an National Cancer Institute–designated cancer center (NCICC) on survival.MethodsData for women diagnosed with CC from 2004 to 2016 who received radiation treatment were extracted from the California Cancer Registry (n = 4250). Cox proportional hazards regression models assessed whether (1) receiving care at NCICCs was associated with risk of CC‐specific death, (2) this association remained after multivariable adjustment for age, race/ethnicity, and insurance status, and (3) this association was explained by receipt of guideline‐concordant treatment.ResultsMedian age was 50 years (interquartile range [IQR] 41–61 years), with median follow‐up of 2.7 years (IQR 1.3–6.0 years). One‐third of patients were seen at an NCICC, and 29% died of CC. The hazard of CC‐specific death was reduced by 20% for those receiving care at NCICCs compared with patients receiving care elsewhere (HR = .80; 95% CI, 0.70–0.90). Adjustment for guideline‐concordant treatment and other covariates minimally attenuated the association to 0.83 (95% CI, 0.74–0.95), suggesting that the survival advantage associated with care at NCICCs may not be due to receipt of guideline‐concordant treatment.ConclusionsThis study demonstrates survival benefit for patients receiving care at NCICCs compared with those receiving care elsewhere that is not explained by differences in guideline‐concordant care. Structural, organizational, or provider characteristics and differences in patients receiving care at centers with and without NCI designation could explain observed associations. Further understanding of these factors will promote equality across oncology care facilities and survival equity for patients with CC.

Excellent outcomes with radiation alone for localized recurrences of endometrial cancer

T‐cell receptor–like chimeric antigen receptor T cells targeting mesothelin: A first‐in‐human dose‐escalation trial for platinum‐resistant advanced ovarian cancer

Abstract Background Ovarian cancer remains a formidable therapeutic challenge due to late diagnosis, high recurrence rates, and limited treatment options. Mesothelin (MSLN) is highly expressed in ovarian cancer, making it a promising target for immunotherapy. Given this target profile, the authors developed a novel T‐cell receptor (TCR)‐like chimeric antigen receptor (CAR) T‐cell therapy targeting MSLN, designated KT127. Methods A first‐in‐human, dose‐escalation trial of KT127 was conducted following preclinical evaluation in vitro and in vivo. A combination of rapid titration and a standard “3 + 3” dose‐escalation design was implemented. Eleven patients received KT127 at doses ranging from 1 × 10 6 to 2 × 10 7 cells/kg following lymphodepletion. The primary objectives were to assess the safety and tolerability of KT127. Secondary objectives included overall survival, disease control rate (DCR), and progression‐free survival as efficacy measures. Quality of life (QOL) was assessed using the European Organisation for Research and Treatment of Cancer QLQ‐OV28 questionnaire. Results No dose‐limiting toxicities, cytokine release syndrome, or immune effector cell‐associated neurotoxicity syndrome were observed. The DCR was 80% (95% confidence interval, 44.4%–97.5%). QOL assessments indicated improvement in abdominal/gastrointestinal symptoms post‐treatment ( p  = .037), with no significant deterioration in other domains. Proteomic analysis identified differential expression of kallikrein‐related peptidases (KLK13, KLK14) and chemokine CXCL17 at baseline, potentially linked to treatment outcomes. Conclusions This study highlights that KT127 has a manageable safety profile and shows preliminary biological activity in patients with advanced ovarian cancer, particularly those who have failed multiple lines of therapies.