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Importance: Unlike other surgical specialties, obstetrics and gynecology (OB-GYN) has been predominantly female for the last decade. The association of this with gender bias and sexual harassment is not known., Objective: To systematically review the prevalence of sexual harassment, bullying, abuse, and discrimination among OB-GYN clinicians and trainees and interventions aimed at reducing harassment in OB-GYN and other surgical specialties., Evidence Review: A systematic search of PubMed, Embase, and ClinicalTrials.gov was conducted to identify studies published from inception through June 13, 2023.: For the prevalence of harassment, OB-GYN clinicians and trainees on OB-GYN rotations in all subspecialties in the US or Canada were included. Personal experiences of harassment (sexual harassment, bullying, abuse, and discrimination) by other health care personnel, event reporting, burnout and exit from medicine, fear of retaliation, and related outcomes were included. Interventions across all surgical specialties in any country to decrease incidence of harassment were also evaluated. Abstracts and potentially relevant full-text articles were double screened.: Eligible studies were extracted into standard forms. Risk of bias and certainty of evidence of included research were assessed. A meta-analysis was not performed owing to heterogeneity of outcomes., Findings: A total of 10 eligible studies among 5852 participants addressed prevalence and 12 eligible studies among 2906 participants addressed interventions. The prevalence of sexual harassment (range, 250 of 907 physicians [27.6%] to 181 of 255 female gynecologic oncologists [70.9%]), workplace discrimination (range, 142 of 249 gynecologic oncologists [57.0%] to 354 of 527 gynecologic oncologists [67.2%] among women; 138 of 358 gynecologic oncologists among males [38.5%]), and bullying (131 of 248 female gynecologic oncologists [52.8%]) was frequent among OB-GYN respondents. OB-GYN trainees commonly experienced sexual harassment (253 of 366 respondents [69.1%]), which included gender harassment, unwanted sexual attention, and sexual coercion. The proportion of OB-GYN clinicians who reported their sexual harassment to anyone ranged from 21 of 250 AAGL (formerly, the American Association of Gynecologic Laparoscopists) members (8.4%) to 32 of 256 gynecologic oncologists (12.5%) compared with 32.6% of OB-GYN trainees. Mistreatment during their OB-GYN rotation was indicated by 168 of 668 medical students surveyed (25.1%). Perpetrators of harassment included physicians (30.1%), other trainees (13.1%), and operating room staff (7.7%). Various interventions were used and studied, which were associated with improved recognition of bias and reporting (eg, implementation of a video- and discussion-based mistreatment program during a surgery clerkship was associated with a decrease in medical student mistreatment reports from 14 reports in previous year to 9 reports in the first year and 4 in the second year after implementation). However, no significant decrease in the frequency of sexual harassment was found with any intervention., Conclusions and Relevance: This study found high rates of harassment behaviors within OB-GYN. Interventions to limit these behaviors were not adequately studied, were limited mostly to medical students, and typically did not specifically address sexual or other forms of harassment.

Objective: National data have shown worse endometrial cancer (EC) outcomes among racial and ethnic minorities. We aimed to analyze EC patient outcomes within a large urban academic health system, with a focus on patterns of care and recurrence rates., Methods: This was a retrospective chart review of EC patients at three system hospitals from 1/1/07-12/31/17. Demographic and clinical factors, including time from EMB to surgery, rate of chemotherapy completion, persistent or recurrent disease, and palliative care referrals were extracted. Descriptive statistics and survival curves were generated. Analysis was done using SAS version 9.4., Results: Black patients had lower overall survival compared to all others on univariate analysis only (p < 0.0001). Hospital site was associated with OS, with the academic anchor and satellite 1 having higher rates of all-cause mortality compared to satellite 2 (HR 4.68 academic anchor, 95 % CI 1.72-12.76, HR 5.36 satellite 1, 95 % CI 1.85-15.52). Time from EMB to surgery and rates of persistent disease following primary treatment were higher in Black patients. After adjusting for stage and grade, chemotherapy completion rate was significantly associated with race. Palliative care was utilized more for Black than White patients after adjusting for stage and grade (p = 0.005)., Conclusions: Racial disparities in EC are caused by a complex web of interconnected factors that ultimately lead to worse outcomes in Black women. While precision medicine has helped to close the gap, social determinants of health should be addressed, and models focusing on the complex interactions between biologic, genetic, and social factors should be utilized., (© 2024 The Authors.)

Objective: The primary goal of this study is to examine disparities in high-risk endometrial cancer (EC) patients in relation to rates of genetic referrals (GR), testing (GT), and counseling (GC)., Methods: This is a retrospective analysis of patients with newly diagnosed EC between January 1, 2014 and September 1, 2020 at a single institution. Patients were defined as high-risk EC patients when they were 1) diagnosed at 50 years or younger, 2) had a positive family history for cancer or 3) had evidence of loss of mismatch repair protein expression on tumor immunohistochemistry. Rates of GR, GT and GC were analyzed based on race, ethnicity, primary language and insurance status., Results: During the study period, 674 patients were diagnosed with EC and 249 (36.9%) were considered high-risk EC patients. Among high-risk patients, 128 (51.2%) were referred to GT and GC. Of those referred, 103 (80.5%) underwent GT and 85 (66.4%) completed GC. Out of all high-risk patients, 20 (18.4%) were positive for LS on GT and 29 (28.2%) had VUS results. In multivariate analysis, the odds of GT and GC referral were lower among patients who identified as Hispanic (OR=0.40; 95% CI=0.19-0.87; p=0.020). Patients who identified as black were less likely to receive GC when compared to patients of other races (p=0.030)., Conclusion: It is our hope that through this data we will increase awareness around existing disparities in genetic evaluation for patients with EC and ultimately create strategies to improve equitable access to care for all patients., Competing Interests: No potential conflict of interest relevant to this article was reported., (© 2023. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Social media outlets have increased in popularity within the last decade and are influencing the ways in which patients interact with the healthcare system. The objective of this study is to examine the presence of gynecologic oncology divisions on Instagram and to analyze the content of their posts. Secondary objectives included examining and analyzing the use of Instagram as a tool for patient education among people at increased genetic risk of gynecologic cancers. Seventy-one NCI-Designated Cancer Centers, their gynecologic oncology divisions and hereditary gynecologic cancer related posts were searched on Instagram. Content was reviewed and authorship was analyzed. Of the 71 NCI-designated Cancer Centers, 29 (40.8 %) had Instagram accounts, whereas, four (6 %) gynecologic oncology divisions had Instagram accounts. The search of the seven most common gynecologic oncology genetic terms yielded 126,750 posts with the majority under BRCA1(n = 56,900) and BRCA2 (n = 45,000) followed by Lynch syndrome (n = 14,700) and hereditary breast and ovarian cancer (n = 8,900). In terms of authorship, 93 (66 %) of all top 140 posts were written by patients, 20 (14.2 %) were written by health care providers and 27 (19.3 %) were written by "other." This study highlights the lack of presence of divisions of gynecologic oncology at NCI-designated Cancer Centers on Instagram but does demonstrate the existence of active discussion on hereditary gynecologic cancers on Instagram by patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Strong participant recruitment practices are critical to public health research but are difficult to achieve. Traditional recruitment practices are often time consuming, costly, and fail to adequately target difficult-to-reach populations. Social media platforms such as Facebook are well-positioned to address this area of need, enabling researchers to leverage existing social networks and deliver targeted information. The MAGENTA (Making Genetic Testing Accessible) study aimed to improve the availability of genetic testing for hereditary cancer susceptibility in at-risk individuals through the use of a web-based communication system along with social media advertisements to improve reach., Objective: This paper is aimed to evaluate the effectiveness of Facebook as an outreach tool for targeting women aged ≥30 years for recruitment in the MAGENTA study., Methods: We designed and implemented paid and unpaid social media posts with ongoing assessment as a primary means of research participant recruitment in collaboration with patient advocates. Facebook analytics were used to assess the effectiveness of paid and unpaid outreach efforts., Results: Over the course of the reported recruitment period, Facebook materials had a reach of 407,769 people and 57,248 (14.04%) instances of engagement, indicating that approximately 14.04% of people who saw information about the study on Facebook engaged with the content. Paid advertisements had a total reach of 373,682. Among those reached, just <15% (54,117/373,682, 14.48%) engaged with the page content. Unpaid posts published on the MAGENTA Facebook page resulted in a total of 34,087 reach and 3131 instances of engagement, indicating that around 9.19% (3131/34,087) of people who saw unpaid posts engaged. Women aged ≥65 years reported the best response rate, with approximately 43.95% (15,124/34,410) of reaches translating to engagement. Among the participants who completed the eligibility questionnaire, 27.44% (3837/13,983) had heard about the study through social media or another webpage., Conclusions: Facebook is a useful way of enhancing clinical trial recruitment of women aged ≥30 years who have a potentially increased risk for ovarian cancer by promoting news stories over social media, collaborating with patient advocacy groups, and running paid and unpaid campaigns., Trial Registration: ClinicalTrials.gov NCT02993068; https://clinicaltrials.gov/ct2/show/NCT02993068., (©Tara Coffin, Deborah Bowen, Karen Lu, Elizabeth M Swisher, Nadine Rayes, Barbara Norquist, Stephanie V Blank, Douglas A Levine, Jamie Nadine Bakkum-Gamez, Gini F Fleming, Olufunmilayo I Olopade, Iris Romero, Alan D'Andrea, Denise R Nebgen, Christine Peterson, Mark F Munsell, Kathleen Gavin, Jamie Crase, Deborah Polinsky, Rebecca Lechner. Originally published in JMIR Formative Research (https://formative.jmir.org), 26.09.2022.)

Objective: Previvors are becoming more aware of the option of risk-reducing salpingectomy with delayed oophorectomy (RRS-DO) to mitigate their risk of ovarian cancer. In this qualitative study, we explored the clinical and non-clinical factors that impacted previvors' decision-making to pursue RRS-DO as a risk reduction strategy., Methods: Semi-structured telephone interviews were conducted with previvors and transcribed verbatim. Using ATLAS.ti® software, two primary investigators interpreted data through thematic analysis. After coding four interviews, the investigators discussed discrepancies between codes with a moderator and resolved and refined code. The investigators applied the universal codebook to all interviews and revised the codebook using an iterative approach. Examining codes within and across interviews allowed for major themes and patterns to emerge., Results: Interviews were conducted with seventeen previvors (ages 31-46). 6 (25%) previvors had a BRCA1 mutation, 7 (41%), a BRCA2 mutation, 3 (13%), a Lynch-related mutation, and 1 (6%), other (MUTYH mutation). At the time of interview, 12 previvors (71%) were planning (6) or had undergone (6) RRS-DO, 4 (23%) were planning (1) or had undergone (3) risk reducing salpingo-oophorectomy (RRSO), and 1 (6%) was undecided. Three major themes emerged: motivating factors for selecting surgical risk reduction option, barriers complicating surgical decision-making, and facilitating factors for surgical decision-making. RRS-DO-focused previvors prioritized avoiding menopause, and they also emphasized that self-advocacy and building rapport with providers facilitated their decision-making., Conclusion: By understanding previvors' priorities and experiences, physicians can better partner with previvors as they navigate their ovarian cancer risk reduction journey. This will ultimately optimize shared decision-making., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

The literature demonstrates that the quality of cancer family history (CFH) as currently collected in the outpatient setting is inadequate to assess disease risk. Prior to implementation of a web-based application for cancer family history collection, we aimed to review the quality of collected CFH in a gynecologic oncology outpatient clinic and determine contributing patient factors. Medical records were reviewed for 200 new patients presenting between 4/2019-7/2019. CFH was collected during the patient interview and evaluated for inclusion of eight elements based on standards set by the genetics community. Univariate and multivariable linear regression analyses were utilized to evaluate the effect of patient characteristics on the number of relatives included in the CFH. Among our cohort of 200 patients, CFH was documented for 185 patients (92.5%). On univariate analysis, patients with a family history of cancer and prior genetic testing had significantly greater median number of relatives included in the CFH. On multivariable analysis, patients with family members with cancer had significantly more relatives included. Our data are consistent with the literature, suggesting that the current collection methods may not adequately capture all measures of a high quality CFH. Patients reporting no family history of cancer and those without prior genetic testing were least likely to have CFH that included key quality elements and these patients might benefit from health information technology CFH collection tools., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier Inc.)

Introduction: The density and distribution of the tumor immune microenvironment associated with brain metastases (BM) from gynecologic malignancies are unknown and have not been previously reported. We sought to describe the clinical features of a cohort of patients with BM from gynecologic malignancies and to characterize the tumor immune microenvironment from available archival surgical specimens., Methods: We performed a retrospective review of electronic medical records from 2002 to 2018 for patients with BM from gynecologic malignancies. Data on patient characteristics, treatment regimens, and clinical outcomes were procured. CD4, CD8, CD45RO, CD68, CD163, and FOXP3 immunohistochemistry were evaluated from available archival surgical specimens from primary disease site and neurosurgical resection., Results: A cohort of 44 patients with BM from gynecologic malignancies was identified, 21 (47.7%) endometrial primaries and 23 (52.3%) ovarian primaries. Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) were evaluated in 13 primary cases and 15 BM cases. For the 13 primary cases, CD4 + TILs were evident in 76.9% of cases, CD8 + in 92.3%, CD45RO + in 92.3%, and FOXP3 + in 46.2%, as well as CD68 + TAMs in 100% and CD163 + in 100%. For the 15 BM cases, CD4 + TILs were evident in 60.0% of cases, CD8 + in 93.3%, CD45RO + in 73.3%, and FOXP3 + in 35.7%, as well as CD68 + TAMs in 86.7% and CD163 + in 100%., Conclusion: An active tumor immune microenvironment is present with similar distribution in the primary disease site and BM from patients with gynecologic malignancies., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patient cohorts. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. We further confirmed the immunogenicity of frameshift peptides in T cell stimulation experiments using blood mononuclear cells isolated from both healthy donors and MSI-H cancer patients. Our study uncovers the widespread occurrence and strong immunogenicity of tumor-specific antigens derived from shared frameshift mutations in MSI-H cancer and Lynch syndrome patients, suitable for the design of common "off-the-shelf" cancer vaccines., Competing Interests: Declaration of Interests N.B. is an extramural member of the Parker Institute for Cancer Immunotherapy (PICI), receives research funds from Genentech, Oncovir, Regeneron and Dragonfly Therapeutics, and is on the advisory boards of Novartis, Roche, Avidea, Boehringer Ingelheim, Rome Therapeutics, BreakBio, Carisma Therapeutics, Roswell Park, and the Cancer Research Institute. C.B. is a PICI Bridge scholar. B.G. has received honoraria for speaking engagements from Merck, Bristol-Meyers Squibb, and Chugai Pharmaceuticals, has received research funding from Bristol-Meyers Squibb, and has been a compensated consultant for PMV Pharma and Rome Therapeutics of which he is a cofounder. V.R., C.C.B., N.B., B.G., S.B., and T.O. have a pending provisional patent application (no. 62/813,829 filed on March 5, 2019). The other authors have not declared any competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Postdischarge nausea and vomiting after ambulatory surgery is a common problem that is not adequately addressed in current practice. This prospective, randomized, double-blind, parallel-group, placebo-controlled study was designed to test the hypothesis that oral olanzapine is superior to placebo at preventing postdischarge nausea and vomiting., Methods: In a single-center, double-blind, randomized, placebo-controlled trial, the authors compared a single preoperative dose of olanzapine 10 mg to placebo, in adult female patients 50 years old or less, undergoing ambulatory gynecologic or plastic surgery with general anesthesia. All patients received standard antiemetic prophylaxis with dexamethasone and ondansetron. The primary composite outcome was nausea and/or vomiting in the 24 h after discharge. Secondary outcomes included severe nausea, vomiting, and side effects., Results: A total of 140 patients were randomized and evaluable. The primary outcome occurred in 26 of 69 patients (38%) in the placebo group and in 10 of 71 patients (14%) in the olanzapine group (relative risk, 0.37; 95% CI, 0.20 to 0.72; P = 0.003). Severe nausea occurred in 14 patients (20%) in the placebo group and 4 patients (6%) in the olanzapine group (relative risk, 0.28; 95% CI, 0.10 to 0.80). Vomiting occurred in eight patients (12%) in the placebo group and two patients (3%) in the olanzapine group (relative risk, 0.24; 95% CI, 0.05 to 1.10). The median score for sedation (scale 0 to 10, with 10 being highest) in the 24 h after discharge was 4 (interquartile range, 2 to 7) in the placebo group and 6 (interquartile range, 3 to 8) in the olanzapine group (P = 0.023)., Conclusions: When combined with ondansetron and dexamethasone, the addition of olanzapine relative to placebo decreased the risk of nausea and/or vomiting in the 24 hafter discharge from ambulatory surgery by about 60% with a slight increase in reported sedation.

Providers who care for women at risk for hereditary gynecologic cancers must consider the impact of these conditions on reproductive and hormonal health. This document reviews potential options for cancer prevention, family building, genetic testing and management of surgical menopause in this patient population., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Studies have consistently indicated that the majority of individuals meeting the US Prevention Services Task Force guidelines for genetic testing have not had genetic counseling or testing. Despite increased availability and lower costs of multiplex cancer gene panels, there remains a gap in genetics services that has not been addressed by the current care delivery models. Lower cost of DNA sequencing with online patient-initiated ordering could increase test availability, but the ideal quantity and delivery method of patient education is not known. We hypothesized that online genetic education and testing with access to board certified genetic counselors could improve access to genetic testing while maintaining test quality and clinical utility. The MAGENTA (MAking GENetic Testing Accessible) trial is a nationwide randomized study designed to compare the effectiveness of online genetic education with pre- and post-test telephone genetic counseling to three potentially more accessible alternative approaches: online genetic education with optional telephone counseling, online genetic education with required pre-test telephone genetic counseling, and online genetic education with required post-test telephone genetic counseling., Methods: 3000 women nationwide will undergo genetic testing for 19 hereditary cancer genes. This is a randomized four-arm non-inferiority study with equal randomization. The four study arms were selected to independently assess the delivery of genetic information both before and after genetic testing (pre-test and post-test) by either requiring telephone genetic counseling or providing only online education with optional telephone counseling. Patients have post-test telephone counseling when testing positive for a pathogenic inherited mutation in all four arms. Surveys measuring psychological, behavioral and cognitive state are completed online at baseline, 3 months, 12 months and 24 months post-results disclosure. The primary study outcome is cancer-risk distress at 3 months post-result disclosure., Discussion: This trial will assess the use of a genetic service model using online access and electronic education, while evaluating the need for personal pre- and post-test genetic counseling. Data from this study may lead to increased options for delivery of genetic testing and possibly increase access to genetic testing. Identifying more individuals with inherited cancer susceptibility will allow targeted cancer prevention., Trial Registration: Clinicaltrials.gov: NCT02993068 (registered December 14, 2016).

Objective: To compare gynecological cancer risk management between women with BRCA variants of unknown significance (VUS) to women with negative genetic testing., Methods: Ninety-nine patients whose BRCA genetic testing yielded VUS were matched with 99 control patients with definitive negative BRCA results at a single institution. Demographics and risk management decisions were obtained through chart review. Primary outcome was the rate of risk-reducing bilateral salpingo-oophorectomy (RRBSO). Chi square tests, t-tests, and logistic regression were performed, with significance of p<0.05., Results: VUS patients were more likely to be non-Caucasian (p=0.000) and of Ashkenazi-Jewish descent (p=0.000). There was no difference in gynecologic oncology referrals or recommendations to screen or undergo risk-reducing surgery for VUS vs. negative patients. Ultimately, 44 patients (22%) underwent RRBSO, with no significant difference in surgical rate based on the presence of VUS. Ashkenazi-Jewish descent was associated with a 4.5 times increased risk of RRBSO (OR=4.489; 95% CI=1.484-13.579) and family history of ovarian cancer was associated with a 2.6 times risk of RRBSO (OR=2.641; 95% CI=1.107-6.299)., Conclusion: In our institution, patients with VUS were surgically managed similarly to those with negative BRCA testing. The numbers of patients with VUS are likely to increase with the implementation of multi-gene panel testing. Our findings underscore the importance of genetic counseling and individualized screening and prevention strategies in the management of genetic testing results., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

Background: Risk-reducing bilateral salpingo-oophorectomy (RRBSO) increases survival in patients at high risk of developing ovarian cancer. While many general gynecologists perform this procedure, some argue it should be performed exclusively by specialists. In this retrospective observational study, we identified how often optimal techniques were used and whether surgeons' training impacted implementation., Methods: We used the ACOG guidelines highlighting various aspects of the procedure to determine which elements were consistent with best practices to maximize surgical prophylaxis. All cases of RRBSO from 2006 to 2010 were identified. We abstracted data from the operative and pathology reports to review the techniques employed. Fisher's exact test and chi-square were utilized to compare differences between groups (InStat, La Jolla, CA)., Results: Among 263 RRBSOs, 22 were performed by general gynecologists and 241 by gynecologic oncologists. Gynecologic oncologists were more likely to perform pelvic washings-217/241 vs. 10/22 (p < .0001). They were more likely to include a description of the upper abdomen-220/241 vs. 12/22 (p < .0001). Oncologists were more likely to utilize a retroperitoneal approach to skeletonize the infundibulopelvic ligaments-157/241 vs. 3/22 (p < .0001). When operations were performed by oncologists, the specimens were more often completely sectioned-217/241 vs. 16/22 (p = .003). The use of a retroperitoneal approach among gynecologic oncologists increased over the study period (chi-square for trend, p < .0001). There was no visible trend in performance improvement in any other area when looking at either group., Conclusion: Gynecologic oncologists are more likely to adhere to best practice techniques when performing RRBSO, though there was room for improvement for both groups.

We discovered that pigment epithelium-derived factor (PEDF)-null mice have endometrial hyperplasia, the precursor to human type I endometrial cancer (ECA), which is etiologically linked to unopposed estrogen (E2), suggesting that this potent antiangiogenic factor might contribute to dysregulated growth and the development of type I ECA. Treatment of both ECA cell lines and primary ECA cells with recombinant PEDF dose dependently decreased cellular proliferation via an autocrine mechanism by blocking cells in G1 and G2 phases of the cell cycle. Consistent with the known opposing effects of E2 and progesterone (Pg) on endometrial proliferation, Pg increases PEDF protein synthesis and release, whereas E2 has the converse effect. Using PEDF luciferase promoter constructs containing two Pg and one E2 response elements, E2 reduced and Pg increased promoter activity due to distal response elements. Furthermore, E2 decreases and Pg increases PEDF secretion into conditioned media (CM) by both normal endometrial stromal fibroblasts (ESFs) and cancer-associated fibroblasts (CAFs), but only CM from ESFs mediated growth-inhibitory activity of primary endometrial epithelial cells (EECs). In addition, in cocultures with primary EECs, Pg-induced growth inhibition is mediated by ESFs, but not CAFs. This is consistent with reduced levels of Pg receptors on CAFs surrounding human malignant glands in vivo. Taken together, the data suggest that PEDF is a hormone-regulated negative autocrine mediator of endometrial proliferation, and that paracrine growth inhibition by soluble factors, possibly PEDF, released by ESFs in response to Pg, but not CAFs, exemplifies a tumor microenvironment that contributes to the pathogenesis of ECA., (Copyright © 2017 Endocrine Society.)

There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K-AKT-mTOR pathway signaling, DNA damage and repair response (DDR) gene expression, and translational control were all investigated. We show that platinum-resistant OVCAR-3 ovarian cancer cells are resensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum-resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared with animals treated with carboplatin plus everolimus, which inhibits only mTORC1. Reduced tumor growth, metastasis, and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT-activating phosphorylation and increased 4E-BP1 hypophosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses, and translation, promoting improved survival in the background of platinum resistance. Mol Cancer Ther; 15(7); 1557-67. ©2016 AACR., (©2016 American Association for Cancer Research.)

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

•This is the first report of occult cancer diagnosed at risk-reducing salpingectomy.•We propose a two-step risk-reducing strategy for premenopausal high-risk women, to begin and expedite surgical prevention.

In many human cancers, the tumor suppressor, p27(kip1) (p27), a cyclin-dependent kinase inhibitor critical to cell cycle arrest, undergoes perpetual ubiquitin-mediated proteasomal degradation by the E3 ligase complex SCF-Skp2/Cks1 and/or cytoplasmic mislocalization. Lack of nuclear p27 causes aberrant cell cycle progression, and cytoplasmic p27 mediates cell migration/metastasis. We previously showed that mitogenic 17-β-estradiol (E2) induces degradation of p27 by the E3 ligase Skp1-Cullin1-F-Box- S phase kinase-associated protein2/cyclin dependent kinase regulatory subunit 1 in primary endometrial epithelial cells and endometrial carcinoma (ECA) cell lines, suggesting a pathogenic mechanism for type I ECA, an E2-induced cancer. The current studies show that treatment of endometrial carcinoma cells-1 (ECC-1) with small molecule inhibitors of Skp2/Cks1 E3 ligase activity (Skp2E3LIs) stabilizes p27 in the nucleus, decreases p27 in the cytoplasm, and prevents E2-induced proliferation and degradation of p27 in endometrial carcinoma cells-1 and primary ECA cells. Furthermore, Skp2E3LIs increase p27 half-life by 6 hours, inhibit cell proliferation (IC50, 14.3μM), block retinoblastoma protein (pRB) phosphorylation, induce G1 phase block, and are not cytotoxic. Similarly, using super resolution fluorescence localization microscopy and quantification, Skp2E3LIs increase p27 protein in the nucleus by 1.8-fold. In vivo, injection of Skp2E3LIs significantly increases nuclear p27 and reduces proliferation of endometrial epithelial cells by 42%-62% in ovariectomized E2-primed mice. Skp2E3LIs are specific inhibitors of proteolytic degradation that pharmacologically target the binding interaction between the E3 ligase, SCF-Skp2/Cks1, and p27 to stabilize nuclear p27 and prevent cell cycle progression. These targeted inhibitors have the potential to be an important therapeutic advance over general proteasome inhibitors for cancers characterized by SCF-Skp2/Cks1-mediated destruction of nuclear p27.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers., Competing Interests: The authors have declared that no competing interests exist.

The levels of proteins that control the cell cycle are regulated by ubiquitin-mediated degradation via the ubiquitin-proteasome system (UPS) by substrate-specific E3 ubiquitin ligases. The cyclin-dependent kinase inhibitor, p27kip1 (p27), that blocks the cell cycle in G1, is ubiquitylated by the E3 ligase SCF-Skp2/Cks1 for degradation by the UPS. In turn, Skp2 and Cks1 are ubiquitylated by the E3 ligase complex APC/Cdh1 for destruction thereby maintaining abundant levels of nuclear p27. We previously showed that perpetual proteasomal degradation of p27 is an early event in Type I endometrial carcinogenesis (ECA), an estrogen (E2)-induced cancer. The present studies demonstrate that E2 stimulates growth of ECA cell lines and normal primary endometrial epithelial cells (EECs) and induces MAPK-ERK1/2-dependent phosphorylation of p27 on Thr187, a prerequisite for p27 ubiquitylation by nuclear SCF-Skp2/Cks1 and subsequent degradation. In addition, E2 decreases the E3 ligase [APC]Cdh1 leaving Skp2 and Cks1 intact to cause p27 degradation. Furthermore, knocking-down Skp2 prevents E2-induced p27 degradation and growth stimulation suggesting that the pathogenesis of E2-induced ECA is dependent on Skp2-mediated degradation of p27. Conversely, progesterone (Pg) as an inhibitor of endometrial proliferation increases nuclear p27 and Cdh1 in primary EECs and ECA cells. Pg, also increases Cdh1 binding to APC to form the active E3ligase. Knocking-down Cdh1 obviates Pg-induced stabilization of p27 and growth inhibition. Notably, neither E2 nor Pg affected transcription of Cdh1, Skp2, Cks1 nor p27. These studies provide new insights into hormone regulation of cell proliferation through the UPS. The data implicates that preventing nuclear p27 degradation by blocking Skp2/Cks1-mediated degradation of p27 or increasing Cdh1 to mediate degradation of Skp2-Cks1 are potential strategies for the prevention and treatment of ECA.

Endometrial cancer is the most common gynecologic malignancy. Although it is highly treatable in the early stages of disease, therapies for advanced and recurrent disease are rarely curative. A molecular and genetic understanding of endometrial cancer involves the mTOR signaling pathway, an emerging target for treatment of type I disease (the most common presentation). Endometrial cancers show a significant reliance on the mTOR pathway for survival, and studies to date have revealed a clinical advantage in targeting this pathway. Less well developed in the study of endometrial cancer is an understanding of mTOR signaling to its major downstream effector, translational control. Given the poor rate of success for treatment of late-stage endometrial cancer, increasing attention is being directed to the development of new therapeutic approaches, including targeting the mTOR pathway. Here, we discuss the potential benefit of targeting mTOR combined with existing chemotherapies by monitoring its impact on translational regulatory pathways and key translation targets in endometrial cancer. We also highlight laboratory and clinical research findings that will provide new avenues for future research and clinical development., (©2011 AACR.)

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer., Competing Interests: The authors have declared that no competing interests exist.

Even after countered with and responding to maximal surgical and chemotherapy efforts, advanced ovarian cancer usually ultimately recurs. One strategy employed to forestall recurrence is maintenance chemotherapy, an extension of treatment following a complete response to conventional measures. Many agents have been studied and many more are currently under investigation in maintenance regimens. While phase III data suggest that taxane maintenance prolongs progression-free survival, no overall survival benefit has been established. This article reviews the current status of maintenance therapy for advanced ovarian cancer, including phase III evidence and new and upcoming trials.

Background: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers., Methods: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach., Results: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers., Conclusion: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

We studied the therapeutic value of Sindbis vectors for advanced metastatic ovarian cancer by using two highly reproducible and clinically accurate mouse models: a SCID xenograft model, established by i.p. inoculation of human ES-2 ovarian cancer cells, and a syngenic C57BL/6 model, established by i.p. inoculation of mouse MOSEC ovarian cancer cells. We demonstrate through imaging, histologic, and molecular data that Sindbis vectors systemically and specifically infect/detect and kill metastasized tumors in the peritoneal cavity, leading to significant suppression of the carcinomatosis in both animal models. Use of two different bioluminescent genetic markers for the IVIS Imaging System permitted demonstration, for the first time, of an excellent correlation between vector delivery and metastatic locations in vivo. Sindbis vector infection and growth suppression of murine MOSEC tumor cells indicate that Sindbis tumor specificity is not attributable to a species difference between human tumor and mouse normal cells. Sindbis virus is known to infect mammalian cells using the Mr 67,000 laminin receptor. Immunohistochemical staining of tumor cells indicates that laminin receptor is elevated in tumor versus normal cells. Down-regulated expression of laminin receptor with small interfering RNA significantly reduces the infectivity of Sindbis vectors. Tumor overexpression of the laminin receptor may explain the specificity and efficacy that Sindbis vectors demonstrate for tumor cells in vivo. We show that incorporation of antitumor cytokine genes such as interleukin-12 and interleukin-15 genes enhances the efficacy of the vector. These results suggest that Sindbis viral vectors may be promising agents for both specific detection and growth suppression of metastatic ovarian cancer.

Herpes simplex virus type 1 (HSV-1)-based oncolytic treatment is a promising therapeutic approach for malignancy. Recombinant strains of HSV-1 containing mutations in the ICP 34.5 protein have been shown to replicate preferentially in rapidly proliferating malignant cells, resulting in a direct cytolytic effect. We assessed the efficacy of multimutated HSV-1 strains on human cervical cancer, and then used these viruses in combination with radiation therapy, the standard treatment for cervical cancer. The HSV-1 mutants 4009, 7020, 3616, and G207 induced significant lysis of three established human cervical cancer cell lines in vitro in a dose-dependent manner. G207 intratumoral treatment of established subcutaneous C33a tumors in severe combined immunodeficient (SCID) mice significantly reduced tumor burden by 50%. Weekly and triweekly treatments improved efficacy and inhibited flank tumor growth in an administration frequency-dependent manner without toxicity. Combination therapy of a low dose of radiation (1.5 or 3 Gy) and replication-selective HSV mutants infection exhibited increased antitumor effects against cervical cancer cells in vitro. The in vivo effect of G207 combined with low-dose radiation was studied in Me180 xenografts in athymic mice. Treatment of established Me180 tumor nodules with 3 Gy followed by intratumoral G207 administration greatly improved efficacy, resulting in 42% complete eradication of tumor. In conclusion, single and multiple intratumoral injections of G207 significantly reduced tumor burden in xenogeneic models of cervical cancer, and the addition of low-dose radiation further potentiated the effect. These results suggest that replication-selective HSV-1 mutants may be potent oncolytic agents for the treatment of cervical cancer.