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Objective: This study investigated the risk of an aggressive endometrial cancer (EC) diagnosis by race, ethnicity, and country of origin to further elucidate histologic disparities in non-Hispanic Black (NHB), Hispanic, Asian/Pacific Islander (API), American Indian/Alaskan Native (AIAN) vs. non-Hispanic White (NHW) patients, particularly in Hispanic or API subgroups., Methods: Patient diagnosed between 2004 and 2020 with low grade (LG)-endometrioid endometrial cancer (ECC) or an aggressive EC including grade 3 EEC, serous carcinoma, clear cell carcinoma, mixed epithelial carcinoma, or carcinosarcoma in the National Cancer Database were studied. The odds ratio (OR) and 95% confidence interval (CI) for diagnosis of an aggressive EC histology was estimated using logistic modeling., Results: There were 343,868 NHW, 48,897 NHB, 30,013 Hispanic, 15,015 API and 1646 AIAN patients. The OR (95% CI) for an aggressive EC diagnosis was 3.07 (3.01-3.13) for NHB, 1.08 (1.06-1.11) for Hispanic, 1.17 (1.13-1.21) for API and 1.07 (0.96-1.19) for AIAN, relative to NHW patients. Subset analyses by country of origin illustrated the diversity in the OR for an aggressive EC diagnosis among Hispanic (1.18 for Mexican to 1.87 for Dominican), Asian (1.14 Asian Indian-Pakistani to 1.48 Korean) and Pacific Islander (1.00 for Hawaiian to 1.33 for Samoan) descendants. Hispanic, API and AIAN patients were diagnosed 5-years younger that NHW patients, and the risk for an aggressive EC histology were all significantly higher than NHW patients after correcting for age. Insurance status was another independent risk factor for aggressive histology., Conclusions: Risk of an aggressive EC diagnosis varied by race, ethnicity, and country of origin. NHB patients had the highest risk, followed by Dominican, South/Central American, Cuban, Korean, Thai, Vietnamese, and Filipino descendants., Competing Interests: Declaration of competing interest Stuart S. Winkler, Chunqiao Tian, Nicholas W. Bateman, Suzanne Jokajtys, Calen W. Kucera, Christopher M. Tarney, Michael T. Richardson, Daniel Kapp, Cheng-I Liao, Megan Reddy, Michele L Cote, Timothy D. O'Connor, Nathaniel L. Jones, Matthew A. Powell, John Farley, Craig D. Shriver, Neil T. Phippen, G. Larry Maxwell and Kathleen M Darcy do not have any potential conflicts to disclose. Chad A. Hamilton reported personal fees from GlaxoSmithKline outside the submitted work. Yovanni Casablanca cited personal fees from AstraZeneca outside the submitted work. John K. Chan reported personal fees from Agenus, AstraZeneca, Eisai, Genmab, GlaxoSmithKline, Immunogen, Mersana, Molecular Targeting Technologies, Myriad, Roche, and Seagen outside the submitted work. Thomas P. Conrads is a ThermoFisher Scientific, Inc. SAB member and receives research funding from AbbVie outside the submitted work. Charles A. Leath, III received funding from the NIH UG1 CA23330 and P50 CA098252, contracted research with Agenus and Seattle Genetics, and served on a scientific advisory board for Seattle Genetics, all outside of the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: We investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities., Methods: Non-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC)., Results: This study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p < 0.0001). After balancing the selected demographic, socioeconomic and clinical factors, survival in Black vs. White patients was no longer different in those with SCC (AHR = 1.01, 95% CI 0.97-1.06) or AC (AHR = 1.09, 95% CI = 0.96-1.24). In SCC, the largest contributors to survival disparities were neighborhood income and insurance. In AC, age was the most significant contributor followed by neighborhood income, insurance, and stage. Diagnosis of AC (but not SCC) at ≥65 years old was more common in Black vs. White patients (26% vs. 13%, respectively)., Conclusions: Histology matters in survival disparities and diagnosis at ≥65 years old between Black and White cervical cancer patients. These disparities were largely explained by modifiable factors., Competing Interests: Declaration of competing interest Chad A. Hamilton reported personal fees from GlaxoSmithKline outside the submitted work. Yovanni Casablanca cited personal fees from AstraZeneca outside the submitted work. John K. Chan reported personal fees from Agenus, AstraZeneca, Eisai, Genmab, GlaxoSmithKline, Immunogen, Mersana, Molecular Targeting Technologies, Myriad, Roche, and Seagen outside the submitted work. Thomas P. Conrads is a ThermoFisher Scientific, Inc. SAB member and receives research funding from AbbVie outside the submitted work. Charles A. Leath, III received funding from the NIH UG1 CA23330 and P50 CA098252, contracted research with Agenus and Seattle Genetics, and served on a scientific advisory board for Seattle Genetics, all outside of the submitted work. The other authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials., Methods: Patients diagnosed with stage IVB cervical cancer during 2013-2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates., Results: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT ( p < 0.001). The AHR was 0.72 (95% CI = 0.64-0.80) for adding IMT overall, 0.72 for IMT + CT, 0.66 for IMT + CT + EBRT, and 0.69 for IMT + CT + EBRT + ICBT. IMT-associated survival improvements were suggested in all subgroups by age, race/ethnicity, comorbidity score, facility type, tumor grade, tumor size, and site of metastasis., Conclusions: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer.

Importance: Disparities in survival exist between non-Hispanic Black (hereafter, Black) and non-Hispanic White (hereafter, White) patients with uterine cancer., Objective: To investigate factors associated with racial disparities in survival between Black and White patients with uterine cancer., Design, Setting, and Patients: This cohort study used data from the National Cancer Database on 274 838 Black and White patients who received a diagnosis of uterine cancer from January 1, 2004, to December 31, 2017, with follow-up through December 2020. Statistical analysis was performed in July 2022., Main Outcomes and Measures: Overall survival by self-reported race and evaluation of explanatory study factors associated with hazard ratio (HR) reduction for Black vs White patients. A propensity scoring approach was applied sequentially to balance racial differences in demographic characteristics, comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, and treatment., Results: The study included 32 230 Black female patients (mean [SD] age at diagnosis, 63.8 [10.0] years) and 242 608 White female patients (mean [SD] age at diagnosis, 63.5 [10.5] years) and had a median follow-up of 74.0 months (range, 43.5-113.8 months). Black patients were more likely than White patients to have low income (44.1% vs 14.0%), be uninsured (5.7% vs 2.6%), present with nonendometrioid histologic characteristics (46.1% vs 21.6%), have an advanced disease stage (34.1% vs 19.8%), receive first-line chemotherapy (33.8% vs 18.2%), and have worse 5-year survival (58.6% vs 78.5%). Among patients who received a diagnosis at younger than 65 years of age, the HR for death for Black vs White patients was 2.43 (95% CI, 2.34-2.52) in a baseline demographic-adjusted model and 1.29 (95% CI, 1.23-1.35) after balancing other factors. Comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, treatment, and unexplained factors accounted for 0.8%, 7.2%, 11.5%, 53.1%, 5.8%, 1.2%, and 20.4%, respectively, of the excess relative risk (ERR) among the younger Black vs White patients. Among patients 65 years or older, the HR for death for Black vs White patients was 1.87 (95% CI, 1.81-1.93) in the baseline model and 1.14 (95% CI, 1.09-1.19) after balancing other factors. Comorbidity score, neighborhood income, insurance status, histologic subtype, disease stage, treatment, and unexplained factors accounted for 3.0%, 7.5%, 0.0%, 56.2%, 10.6%, 6.9%, and 15.8%, respectively, of the ERR among Black vs White patients aged 65 years or older., Conclusions and Relevance: This study suggests that histologic subtype was the dominant factor associated with racial survival disparity among patients with uterine cancer, while insurance status represented the main modifiable factor for women younger than 65 years. Additional studies of interactions between biology and social determinants of health are merited.

Background: Cyclin 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., Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated., Results: High-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., Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Ovarian cancer is the most lethal gynecologic cancer and intrinsically resistant to checkpoint immunotherapies. We sought to augment innate immunity, building on previous work with IFNs and monocytes., Patients and Methods: Preclinical experiments were designed to define the mechanisms of cancer cell death mediated by the combination of IFNs α and γ with monocytes. We translated these preclinical findings into a phase I trial of autologous IFN-activated monocytes administered intraperitoneally to platinum-resistant or -refractory ovarian cancer patients., Results: IFN-treated monocytes induced caspase 8-dependent apoptosis by the proapoptotic TRAIL and mediated by the death receptors 4 and 5 (DR4 and DR5, respectively) on cancer cells. Therapy was well tolerated with evidence of clinical activity, as 2 of 9 evaluable patients had a partial response by RECIST criteria, and 1 additional patient had a CA-125 response. Upregulation of monocyte-produced TRAIL and cytokines was confirmed in peripheral blood. Long-term responders had alterations in innate and adaptive immune compartments., Conclusions: Given the mechanism of cancer cell death, and the acceptable tolerability of the clinical regimen, this platform presents a possibility for future combination therapies to augment anticancer immunity. See related commentary by Chow and Dorigo, p. 299., (©2022 American Association for Cancer Research.)

Objectives: To determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients., Methods: All patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS)., Results: Of 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31-129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0-10 vs. 11-35 U/mL) were not predictive of outcome (p = 0.4)., Conclusions: Normal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients., Competing Interests: Declaration of Competing Interest The following authors reports no conflicts of interests: Drs. Chunqiao Tian, Michael Richardson, Ken Y Lin, Daniel S Kapp, Leah McNally, and Samuel Lentz. The following authors discloses various conflicts of interests: Dr. Robert M Wenham discloses receiving personal and institutional grants, consulting and clinical trial fees from Merck. The consulting fees are also received from Legend Biotech and Novacure as well as Merck. He also received personal and institutional grants and stock options from Ovation Diagnostics. His participation on a Data Safety Monitoring Board or Advisory Board and personal fees is supported by Seagen and GSK/Tesaro. More personal fees from Clovis, Seagen, Sonnet Biotherapeutics, Shattuck Labs, Novocurem Eisai and Immunogen. Institutional Clinical Trial fees are received from AstraZeneca, Abbvie, Regeneron, and Eisai. Sonnet Biotherapeutics also supported for Scientific Advisory Board. Dr. Nick M Spirtos discloses receiving support from NRG/GOG for manuscript funding and study materials and attending meetings or for institutional travel support as Co-chair of Surgical Oncology Committee. Dr. Thomas J. Herzog discloses receiving personal consulting fees from Aravive, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genentech Roche, GSK, and Merck. His participation on a Data Safety and Monitoring Board or Advisory Board is supported by Corcept and Incyte. GOG Foundation also supported for his leadership or fiduciary role in other board. Dr. Bradley J. Monk discloses receiving honorarium as a consultant and investigator from Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Eisai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, Immunogen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pieris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastern and Zentalis. Dr. Krishnansu S. Tewari discloses receiving sconsulting fees from Abbvie, Genentech, Merch, AstraZeneca, Tesaro/GSK, and Seagen. Dr. Tewari also received honoraria for lectures, presentations, and for manuscript writing from Merck, Astra Zeneca, and Clovis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Optimal cytoreduction to no residual disease (R0) correlates with improved disease outcome for high-grade serous ovarian cancer (HGSOC) patients. Treatment of HGSOC patients with neoadjuvant chemotherapy, however, may select for tumor cells harboring alterations in hallmark cancer pathways including metastatic potential. This study assessed this hypothesis by performing proteomic analysis of matched, chemotherapy naïve and neoadjuvant chemotherapy (NACT)-treated HGSOC tumors obtained from patients who had suboptimal (R1, n = 6) versus optimal (R0, n = 14) debulking at interval debulking surgery (IDS)., Methods: Tumor epithelium was harvested by laser microdissection from formalin-fixed, paraffin-embedded tissues from matched, pre- and post-NACT treated tumors for twenty HGSOC patients and analyzed by quantitative mass spectrometry-based proteomics., Results: Differential analysis of patient matched pre- and post-NACT treated tumors revealed proteins associated with cell survival and metabolic signaling to be significantly altered in post-NACT treated tumor cells. Comparison of pre-NACT treated tumors from suboptimal (R1) versus optimally (R0) debulked patients identified proteins associated with tumor cell viability and invasion signaling enriched in R1 patients. We identified five proteins altered between R1 and R0 patients in pre- NACT treated tumors that significantly correlated with PFS in an independent cohort of HGSOC patients, including Fermitin family homolog 2 (FERMT2), a protein elevated in R1 that correlated with disease progression in HGSOC patients (multivariate Cox HR = 1.65, Wald p = 0.022) and increased metastatic potential in solid-tumor malignancies., Conclusions: This study identified distinct proteome profiles in patient matched pre- and post-NACT HGSOC tumors that correlate with NACT resistance and that may predict residual disease status at IDS that collectively warrant further pre-clinical investigation., (© 2022. The Author(s).)

Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80-0.98) for MS7 compared with 0.69 (0.59-0.80) and 0.71 (0.58-0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival ( p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool., Competing Interests: The authors did not have any conflicts to disclose related to this research investigation. The authors provide the following disclaimer. The views expressed herein are those of the authors and do not reflect the official policy of the Uniformed Services University of the Health Sciences; the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.; Inova Health System; the Department of Army/Navy/Air Force; the Department of Defense; or the U.S. Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

Objectives: Develop conditional survival and risk-assessment estimates for uterine serous carcinoma (USC) overall and stratified by stage as tools for annual survivorship counseling and care planning., Methods: Patients in the National Cancer Data Base diagnosed between 2004 and 2014 with stage I-IV USC were eligible. Individuals missing stage or survival data or with multiple malignancies were excluded. Five-year conditional survival was estimated using the stage-stratified Kaplan-Meier method annually during follow-up. A standardized mortality ratio (SMR) estimated the proportion of observed to expected deaths in the U.S. adjusted for year, age, and race. The relationships between prognostic factors and survival were studied using multivariate Cox modeling at diagnosis and conditioned on surviving 5-years., Results: There were 14,575 participants, including 43% with stage I, 8% with stage II, 29% with stage III, and 20% with stage IV USC. Five-year survival at diagnosis vs. after surviving 5-years was 52% vs. 75% overall, 77% vs. 81% for stage I, 57% vs. 72% for stage II, 40% vs. 66% for stage III, and 17% vs. 60% for stage IV USC, respectively (P < 0.0001). Incremental improvements in 5-year conditional survival and reductions in SMR tracked with annual follow-up and higher stage. The adjusted risk of death at diagnosis vs. after surviving 5-years was 1.15 vs. 1.40 per 5-year increase of age, 1.26 vs. 1.68 for Medicaid insurance, 3.92 vs. 2.48 for stage III disease, and 6.65 vs. 2.79 for stage IV disease, respectively (P < 0.0001)., Conclusion: In USC, the evolution of conditional survival permits annual reassessments of prognosis to tailor survivorship counseling and care planning., Competing Interests: Declaration of Competing Interest Angela C. Nolin, Chunqiao Tian, Nicholas W. Bateman, Michele L. Cote, Craig D. Shriver, Matthew A. Powell, Thomas P Conrads, G. Larry Maxwell, and Kathleen M. Darcy do not have any conflicts to disclose. Chad A. Hamilton declared his role on the Board of Directors for the Foundation for Women's Cancer. Yovanni Casablanca cited stock or stock options for Pfizer and Regeneron specifying that no payments were made to her or her institution. John K. Chan reported consulting fees from AstraZeneca and GlaxoSmithKline; payments or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events for AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Merck, and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Immunogen, Myriad, Roche and Seagen. Please also see the attached conflict of interest disclosure forms., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Financial Disclosure Brittany Davidson reports receiving funding from GSK. Robert Wenham reports money was paid to his institution (Gynecologic Oncology Group Block Grant). Yovanni Casablanca reports receiving funding from AstraZeneca and owns stock in Regeneron and Pfizer. Nick M. Spirtos reports money was paid to his institution from the NRG/GOG Foundation. They receive per-capita reimbursement that does not cover their costs and have received such monies for the last 30 years. The other authors did not report any potential conflicts of interest.

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To assess the presentation, characteristics, and prognostic significance of symptoms in patients with high-risk early-stage epithelial ovarian cancer., Methods: A retrospective chart review was performed on all patients enrolled in a phase III clinical trial (GOG 157). All patients had surgically staged, high-risk early-stage epithelial ovarian cancer (stage IA-IB and grade 3, any clear cell, stage IC or II). Chi-square and Kaplan-Meier estimates and Cox proportional hazards models were used for statistical analyses., Results: Of 419 patients evaluated for symptoms, 301 (72%) presented with one or more symptoms, and 118 (28%) were asymptomatic but had a mass found on examination. Forty percent had only one symptom, and 32% had more than one symptom. Among those with at least one symptom, the most common were abdominal and pelvic pain (31%), and increased girth or fullness (26%). Overall, 23% of patients with tumors 10 cm or smaller, 27% of patients with tumors larger than 10 cm to 15 cm, and 46% of patients with tumors larger than 15 cm had multiple symptoms (P<.001). There was no significant difference in presentation of symptoms based on age, stage, or histologic subtype. Symptoms at diagnosis were not associated with recurrence or survival., Conclusion: More than 70% of patients with high-risk early-stage, epithelial ovarian cancer present with one or more symptoms, with the most common being abdominal or pelvic pain. The proportion of women with symptoms and the number of symptoms increase with enlarging tumor size., Competing Interests: Financial Disclosure Dr. John K. Chan received funds from NRG/GOG for consortium trial participation and funds for research, consultant, and speaker bureau from AbbVie, Acerta, Aravive, AstraZeneca, Clovis, Eisai, GlaxoSmithKline, Merck, Myriad, Roche, Seagen. Bradley J. Monk is on the board for the GOG Foundation and is a paid consultant. Brittany Davidson received money from GSK. Joan L. Walker disclosed that Stephenson Cancer Center is an NRG Oncology Laps site and she is NCORP PI, but unrelated to this study. Robert Wenham received GOG funds for consortium trial participation, money from Regeneron, Tesaro/GSK, and Genentech. In the past 3 years, he has received funds from Seagen, Ovation Diagnostics, AbbVie, Clovis, AstraZeneca, Prescient Therapeutics, and Merck. Yovanni Casablanca received funding from AstraZeneca. Nick M. Spirtos received funding from John Wiley and Sons, and NRG Oncology. The other authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with disease pathogenesis. Nonsynonymous single-nucleotide polymorphisms encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis identified that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R 2  = 0.99). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues combined resulted in the quantitation of 62 pAIMs that correlate with patient race and genotype-confirmed ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. pAIMs will support generalized proteoancestry assessment as well as efforts investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms., Competing Interests: G.L.M. is a consultant for Kiyatec, GSK, and Merck. T.P.C. is a ThermoFisher Scientific, Inc SAB member and receives research funding from AbbVie. G.J.P. has received a patent based on concepts presented in this study (US 8,877,455 B2, Australian Patent 2011229918, Canadian Patent CA 2794248, and European Patent EP11759843.3)., (© 2021 The Author(s).)

Human papillomavirus (HPV) is the most common sexually transmitted infection (STI) in the U.S. military and accounts for more healthcare visits than the next two most common STIs combined. Human papillomavirus is preventable with a safe, effective, prophylactic vaccine that has been available since 2006, yet vaccination rates remain low. The vaccine is approved for females and males aged 9-45 years for prevention of HPV-related dysplasia and cancers. Although it is recommended by the Centers for Disease Control and Prevention (CDC)'s Advisory Committee on Immunization Practices (ACIP), it is not part of the U.S. military's mandatory vaccine list. Human papillomavirus does not just affect female service members-male service members have a higher reported seropositive rate than their civilian counterparts and can develop oropharyngeal, anal, or penile cancers as sequelae of HPV. Oropharyngeal cancer, more common in males, is the fastest growing and most prevalent HPV-related cancer in the USA. Several countries, such as Australia and Sweden, have successfully implemented mandatory vaccine programs and have seen rates of HPV-related diseases, including cancer, decline significantly. Some models project that cervical cancer, which is the fifth-most common cancer in active duty women, will be eliminated in the next 20 years as a result of mandatory vaccination programs. Between higher seropositive rates and lack of widespread vaccination, HPV dysplasia and cancer result in lost work time, decreased force readiness, negative monetary implications, and even separation from service. With more than half of the 1.3 million service members in the catch-up vaccination age range of less than 26 years of age, we are poised to have a profound impact through mandatory active duty service member vaccination. Although multiple strategies for improving vaccination rates have been proposed, mandatory vaccination would be in line with current joint service policy that requires all ACIP-recommended vaccines. It is time to update the joint service guidelines and add HPV vaccine to the list of mandatory vaccines., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: The mortality rate for Black women with endometrial cancer (EC) is double that of White women, although the incidence rate is lower among Black women. Unequal access to care may contribute to this racial disparity. This study aimed to assess whether survival varied between non-Hispanic Black (NHB) and non-Hispanic White (NHW) women with EC in the Military Health System (MHS) which provides equal access care to its beneficiaries despite racial/ethnic background., Methods: The study was conducted using data from the U.S. Department of Defense's (DoD) Automated Central Tumor Registry (ACTUR). Study subjects included NHB and NHW women with histologically confirmed and surgically managed EC diagnosed between 1988 and 2013. The study outcome was all-cause death. Overall survival between NHB and NHW women was compared using multivariable Cox modeling., Results: The study included 144 NHB and 1439 NHW women with EC. Kaplan-Meier curves showed NHB women had worse survival than NHW women (log-rank P < 0.0001). The disparity in survival between NHB and NHW women persisted after adjusting for age, diagnosis period, tumor stage, tumor histology/grade, and adjuvant treatment (HR = 1.64, 95% CI = 1.19 to 2.27). Multivariable analyses stratified by tumor features or treatment showed that the racial disparity was confined to women with low-risk features (stage I/II disease or low-grade EC) or no adjuvant treatment., Conclusion: There were racial differences in overall survival between NHB and NHW women with EC in the MHS equal access healthcare system, suggesting that factors other than access to care may be related to this racial disparity., Competing Interests: Declaration of competing interest Dr. Casablanca reports other from Pfizer, other from Regeneron, outside the submitted work., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment., Methods: We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk., Results: We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI., Conclusions: Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer., Competing Interests: Declaration of Competing Interest Dr. Van Le reports royalties from Wolters Kluwer (as an editor of TeLinde's textbook). Dr. Huh reports money paid to him from consultancy with DYSIS. Dr. Miller reports money paid to him from consultancy with Tesaro, Eisai, Incyte, Karyopharm, and Genentech as well as money paid to his institution from Merck. He also reports money paid to his institution from grants or grants pending with nVision Medical, Advenchen, Forty Seven, Merck, Syros, and US BIOTEST. Dr. Ragab reports money paid to him from Consultancy with Regeneron. Dr. Viswanathan reports employment with money paid to her from Elsevier as the Ediotr in Chief for Seminars in Radiation Oncology. She also has an R01 NIH grant with money to her institution, and she received textbook royalties from Springer. Dr. Tewari has received money paid to him from consultancy with Clovis, Merck, Abbvie, Amgen, GSK, and Astra-Zenega, as well as payment for lectures from Clovis, Merck, Abbvie, Amgen, GSK, Astra-Zenega. Drs. Levinson, Fader, Beavis, Wolfson, Waggoner, Guntupalli, Lee, Kelly, McNally, Casablanca, Rositch, Spirtos, Wilkinson, Holman and Chris Purdy have no financial disclosures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten high-grade serous ovarian carcinomas (HGSOCs) and analyzed by mass spectrometry, reverse phase protein arrays, and RNA sequencing. Unsupervised analyses of protein abundance data revealed independent clustering of an enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering driven by overall tumor "purity." Comparing these data to previously defined prognostic HGSOC molecular subtypes revealed protein and transcript expression from tumor epithelium correlated with the differentiated subtype, whereas stromal proteins (and transcripts) correlated with the mesenchymal subtype. Protein and transcript abundance in the tumor epithelium and stroma exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial tumor microenvironment protein heterogeneity that directly bears on prognostic signatures, biomarker discovery, and cancer pathophysiology and underscore the need to enrich cellular subpopulations for expression profiling., Competing Interests: T.P.C. is a ThermoFisher Scientific, Inc SAB member and receives research funding from 10.13039/100006483AbbVie. E.F.P. receives research funding from 10.13039/100004328Genentech, 10.13039/100004319Pfizer, and 10.13039/100006483AbbVie and is a co-inventor of the RPPA technology described herein and receives royalties on the related license agreements., (© 2021 The Author(s).)

Pathogenic mutations in fumarate hydratase (FH) drive hereditary leiomyomatosis and renal cell cancer (HLRCC) and increase the risk of developing uterine leiomyomas (ULMs). An integrated proteogenomic analysis of ULMs from HLRCC (n = 16; FH-mutation confirmed) and non-syndromic (NS) patients (n = 12) identified a significantly higher protein:transcript correlation in HLRCC (R = 0.35) vs. NS ULMs (R = 0.242, MWU p = 0.0015). Co-altered proteins and transcripts (228) included antioxidant response element (ARE) target genes, such as thioredoxin reductase 1 (TXNRD1), and correlated with activation of NRF2-mediated oxidative stress response signaling in HLRCC ULMs. We confirm 185 transcripts previously described as altered between HLRCC and NS ULMs, 51 co-altered at the protein level and several elevated in HLRCC ULMs are involved in regulating cellular metabolism and glycolysis signaling. Furthermore, 367 S-(2-succino)cysteine peptides were identified in HLRCC ULMs, of which sixty were significantly elevated in HLRCC vs. NS ULMs (LogFC = 1.86, MWU p < 0.0001). These results confirm and define novel proteogenomic alterations in uterine leiomyoma tissues collected from HLRCC patients and underscore conserved molecular alterations correlating with inactivation of the FH tumor suppressor gene.

Background: Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P., Methods: TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P., Results: Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53., Conclusions: This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574., Competing Interests: Declaration of competing interest Kimberly K. Leslie: Dr. Leslie attests that she has no conflicts of interest. Virginia L. Filiaci: Dr. Filiaci is supported by institutional grants from NIH during the conduct of the study; Institutional contracts from GOG Foundation, Inc. outside the submitted work. Adrianne R. Mallen: Dr. Mallen reports no conflicts of interest. Kristina W. Thiel: Dr. Thiel is a co-founder of and holds equity in Immortagen, Inc. Eric J. Devor: Dr. Devor reports no conflict of interest. Katherine Moxley: Dr. Moxley attests that she has nothing to declare. Debra Richardson: Dr. Richardson reports that she serves on Advisory Boards for Genentech, Tesaro/GSK, AstraZeneca, Bayer, Deciphera, Mersana and Foundation Medicine. David Mutch: Dr. Mutch attests that he has no conflicts of interest. Angeles Alvarez Secord(:) Dr. Alvarez Secord discloses clinical trial grant funding received from AbbVie, Amgen, Astellas Pharma Inc., Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Eisai, Exelixis, Immutep Ltd., Incyte, Merck, PharmaMar, Roche/Genentech, Seattle Genetics, Inc., Tesaro/GSK, VBL Therapeutics and National Cancer Trial Network. Dr. Alvarez Secord has also received honoraria for Advisory Boards from Aravive, AstraZeneca, Clovis, Cordgenics, Eisai, Merck, Myriad, Oncoquest, Roche/Genentech and Tesaro/GSK within the past 24 months. Krishnansu S Tewari: Dr. Tewari served as a consultant and attended advisory boards for the manufacturers of bevacizumab (i.e., Genentech/Roche). Megan E McDonald: Dr. McDonald has no conflicts of interest to disclose. Cara Mathews: Dr. Mathews reports grants from National Institute of Health during the conduct of the study; grants from Syros, grants from Deciphera, grants from Astra Zeneca, grants from Astellas Pharma, grants from Tesaro/GSK, grants from Seattle Genetics and grants from Regeneron outside the submitted work. Casey Cosgrove: Dr. Cosgrove attests that she has no conflicts of interest. Summer Dewdney: Dr. Dewdney attests that she has nothing to declare. Yovanni Casablanca: Dr. Casablanca reports that spouse owns shares in Celsion (biotech company), but not related to this manuscript. Amanda Jackson: Peter G Rose: Dr. Rose attests that he has no conflicts of interest. Xun Clare Zhou: - Dr. Zhou attests that she has no conflicts of interest. Michael McHale: - Dr. McHale has no conflicts of interest to report. Heather Lankes: Dr. Lankes attests that she has no conflicts of interest. Douglas Levine: - Dr. Levine reports serving in a consulting/advisory role for Tesaro/GSK, Merck. Research funding to institution from Merck, Tesaro, Clovis Oncology, Regeneron, Agenus, Takeda, Immunogen, VBL Therapeutics, Genentech, Celsion, Ambry, Splash Pharmaceuticals. Founder Nirova BioSense, Inc. Carol Aghajanian: Dr. Aghajanian reports personal fees from Tesaro, personal fees from Immunogen, grants and personal fees from Clovis, grants from Genentech, grants from AbbVie, grants from Astra Zeneca, grants from Astra Zeneca, personal fees from Eisai/Merck, personal fees from Mersana Therapeutics, personal fees from Roche, personal fees from Abbvie, outside the submitted work., (Copyright © 2021. Published by Elsevier Inc.)

Previously we have shown inhibition of endometrial cancer cell growth with progesterone and calcitriol. However, the mechanisms by which the two agents attenuate proliferation have not been well characterized yet. Herein, we investigated how progesterone and calcitriol induce apoptosis in cancer cells. DNA fragmentation was upregulated by progesterone and calcitriol in ovarian and endometrial cancer cells. Time-dependent treatment of ovarian cancer cells, ES-2, and TOV-21G with progesterone enhanced caspase -8 activity after 12 h, whereas OV-90, TOV-112D, HEC-1A, and HEC-59 cells showed increased activity after 24 h. Caspase 9 activity was increased in all cell lines after 24 h treatment with calcitriol. Pretreatment of cancer cells with a caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (Z-LEHD-fmk) significantly attenuated progesterone and calcitriol induced caspase-8 and caspase-9 expression, respectively. The expression of FasL, Fas, FAD, and pro-caspase-8, which constitute the death-inducing signaling complex (DISC), was upregulated in progesterone treated cancer cells. Knockdown of FAS or FADD with specific siRNAs significantly blocked progesterone-induced caspase-8. Cleavage of the BID was not affected by caspase-8 activation suggesting the absence of cross-talk between caspase-8 and caspase-9 pathways. Calcitriol treatment decreased mitochondrial membrane potential and increased the release of cancer cytochrome C. These findings indicate that progesterone induces apoptosis through activation of caspase-8 and calcitriol through caspase-9 activation in cancer cells. A combination of progesterone-calcitriol activates both extrinsic and intrinsic apoptotic pathways in cancer cells.

Objective: To compare receipt of National Comprehensive Cancer Network Guideline-adherent treatment for gynecologic cancers, inclusive of uterine, cervical, and ovarian cancer, between non-Hispanic White women and racial-ethnic minority women in the equal-access Military Health System., Methods: We accessed MilCanEpi, which links data from the Department of Defense Central Cancer Registry and Military Health System Data Repository administrative claims data, to identify a cohort of women aged 18-79 years who were diagnosed with uterine, cervical, or ovarian cancer between January 1, 1998, and December 31, 2014. Information on tumor stage, grade, and histology was used to determine which treatment(s) (surgery, chemotherapy, radiotherapy) was indicated for each patient according to the National Comprehensive Cancer Network Guidelines during the period of the data (1998-2014). We compared non-Hispanic Black, Asian, and Hispanic women with non-Hispanic White women in their likelihood to receive guideline-adherent treatment using multivariable logistic regression models given as adjusted odds ratios (aORs) and 95% CIs., Results: The study included 3,354 women diagnosed with a gynecologic cancer of whom 68.7% were non-Hispanic White, 15.6% Asian, 9.0% non-Hispanic Black, and 6.7% Hispanic. Overall, 77.8% of patients received guideline-adherent treatment (79.1% non-Hispanic White, 75.9% Asian, 69.3% non-Hispanic Black, and 80.5% Hispanic). Guideline-adherent treatment was similar in Asian compared with non-Hispanic White patients (aOR 1.18, 95% CI 0.84-1.48) or Hispanic compared with non-Hispanic White women (aOR 1.30, 95% CI 0.86-1.96). Non-Hispanic Black patients were marginally less likely to receive guideline-adherent treatment compared with non-Hispanic White women (aOR 0.73, 95% CI 0.53-1.00, P=.011) and significantly less likely to receive guideline-adherent treatment than either Asian (aOR 0.65, 95% CI 0.44-0.97) or Hispanic patients (aOR 0.56, 95% CI 0.34-0.92)., Conclusion: Racial-ethnic differences in guideline-adherent care among patients in the equal-access Military Health System suggest factors other than access to care contributed to the observed disparities., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2021 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)