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Purpose of Review: To describe current and future strategies to reduce the burden of ovarian cancer through prevention., Recent Findings: Current strategies in genetic testing are missing a substantial number of individuals at risk, representing a missed opportunity for ovarian cancer prevention. Past efforts at screening and early detection have thus far failed to improve ovarian cancer mortality, and novel techniques are needed. Surgical prevention is highly effective, but surgical menopause from oophorectomy has significant side effects. Novel surgical strategies aimed at reducing risk while minimizing these harms are currently being studied. To maximize ovarian cancer prevention, a multi-pronged approach is needed. We propose that more inclusive and accurate genetic testing to identify more individuals at risk, novel molecular screening and early detection, surgical prevention that maximizes quality of life while reducing risk, and broader adoption of targeted and opportunistic salpingectomy will together reduce the burden of ovarian cancer., Competing Interests: Declarations. Human and Animal Rights: All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines). Conflict of Interest: Isabel Rodriguez, Talayeh Ghezelayagh, Kathryn Pennington and Barbara Norquist declare no conflict of interest. This work was supported by T32 Training Grant T32CA9515-37 (IR), Department of Defense Ovarian Cancer Research Program OC180282 (BN), and the Nancy Kelley Jensen Fund for Gynecologic Cancer Research (BN)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Individuals with germline BRCA1 and BRCA2 pathogenic variants (BRCA carriers) are at high risk of developing high grade serous ovarian carcinoma (HGSC). HGSC is predominantly driven by TP53 mutations, but mutations in this gene are also commonly found in non-cancerous tissue as a feature of normal human aging. We hypothesized that HGSC predisposition in BRCA carriers may be related to increased TP53 somatic evolution, which could be detectable by ultra-deep sequencing of TP53 mutations in gynecological liquid biopsies., Methods: Duplex sequencing was used to identify TP53 mutations with high sensitivity in peritoneal washes and cervical liquid-based cytology (LBC) collected at surgery from 60 individuals including BRCA1 and BRCA2 carriers, and non-carriers. TP53 mutation pathogenicity was compared across groups and with TP53 cancer mutations., Results: TP53 mutations were more abundant in cervical LBC than in peritoneal washes but increased with age in both sample types. In peritoneal washes, but not in cervical LBC, pathogenic TP53 mutation burden was increased in BRCA1 carriers compared to non-carriers, independently of age. Five individuals shared identical pathogenic TP53 mutations in peritoneal washes and cervical LBC, but not in blood., Conclusions: Ultra-deep sequencing of TP53 mutations in peritoneal washes collected at surgery reveals increased burden of pathogenic TP53 mutations in BRCA1 carriers. This excess of pathogenic TP53 mutations might be linked to the elevated risk of HGSC in these individuals. In some patients, concordant TP53 mutations were found in peritoneal washes and cervical LBCs, but the cell of origin remains unknown and deserves further investigation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RAR is a consultant and equity holder at TwinStrand Biosciences Inc. and an equity holder at NanoString Technologies Inc. RAR is named inventor on patents owned by the University of Washington and licensed to TwinStrand Biosciences Inc. RAR received research funding from a joint research grant with TwinStrand Biosciences Inc. and Ovartec GmbH., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Somatic TP53 mutations are prevalent in normal tissue but little is known about their association with cancer risk. Cervical liquid-based cytology (LBC), commonly known as Pap test, provides an accessible gynecological sample to test the value of TP53 somatic mutations as a biomarker for high-grade serous ovarian cancer (HGSC), a cancer type mostly driven by TP53 mutations. We used ultra-deep duplex sequencing to analyze TP53 mutations in LBC and blood samples from 70 individuals (30 with and 40 without HGSC) undergoing gynecologic surgery, 30 carrying BRCA1 or BRCA2 germline pathogenic variants (BRCApv). Only 30% of the tumor mutations were found in LBC samples. However, TP53 pathogenic mutations were identified in nearly all LBC and blood samples, with only 5.4% of mutations in LBC (20/368) also found in the corresponding blood sample. TP53 mutations were more abundant in LBC than in blood and increased with age in both sample types. BRCApv carriers with HGSC had more TP53 clonal expansions in LBC than BRCApv carriers without cancer. Our results show that, while not useful for direct cancer detection, LBC samples capture TP53 mutation burden in the gynecological tract, presenting potential value for cancer risk assessment in individuals at higher hereditary risk for ovarian cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone., Methods: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated., Results: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths., Conclusions: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

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

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy., Primary Objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk., Study Hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 ( BRCA1 ) or 45-50 ( BRCA2 ) years, compared with the current standard salpingo-oophorectomy at age 35-40 ( BRCA1 ) or 40-45 ( BRCA2 ) years, is non-inferior in regard to tubo-ovarian cancer risk., Trial Design: In this international prospective preference trial, participants will choose between the novel salpingectomy with delayed oophorectomy and the current standard salpingo-oophorectomy. Salpingectomy can be performed after the completion of childbearing and between the age of 25 and 40 ( BRCA1 ), 25 and 45 ( BRCA2 ), or 25 and 50 ( BRIP1, RAD51C, and RAD51D pathogenic variant carriers) years. Subsequent oophorectomy is recommended at a maximum delay of 5 years beyond the upper limit of the current guideline age for salpingo-oophorectomy. The current National Comprehensive Cancer Network (NCCN) guideline age, which is also the recommended age for salpingo-oophorectomy within the study, is 35-40 years for BRCA1 , 40-45 years for BRCA2, and 45-50 years for BRIP1 , RAD51C , and RAD51D pathogenic variant carriers., Major Inclusion/exclusion Criteria: Premenopausal individuals with a documented class IV or V germline pathogenic variant in the BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D gene who have completed childbearing are eligible for participation. Participants may have a personal history of a non-ovarian malignancy., Primary Endpoint: The primary outcome is the cumulative tubo-ovarian cancer incidence at the target age: 46 years for BRCA1 and 51 years for BRCA2 pathogenic variant carriers., Sample Size: The sample size to ensure sufficient power to test non-inferiority of salpingectomy with delayed oophorectomy compared with salpingo-oophorectomy requires 1500 BRCA1 and 1500 BRCA2 pathogenic variant carriers., Estimated Dates for Completing Accrual and Presenting Results: Participant recruitment is expected to be completed at the end of 2026 (total recruitment period of 5 years). The primary outcome is expected to be available in 2036 (minimal follow-up period of 10 years)., Trial Registration Number: NCT04294927., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment., Methods: A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area. Guideline-concordant testing (GCT) was assessed annually according to guideline updates. Frequency of testing according to patient/cancer characteristics was evaluated using chi-squared tests, and factors associated with receipt of genetic testing were identified using multivariable logistic regression., Results: Testing occurred in 17% of HBOPP patients, increasing from 9% in 2013 to 21% in 2019 (p < 0.001). Ovarian cancer had the highest testing (40%) and prostate cancer the lowest (4%). Age < 50, female sex, non-Hispanic White race, commercial insurance, urban location, family history of HBOPP, and triple negative breast cancer (TNBC) were associated with increased testing (all p < 0.05). GCT increased from 38% in 2013 to 44% in 2019, and was highest for early age at breast cancer diagnosis, TNBC, male breast cancer, and breast cancer with family history of HBOPP (all > 70% in 2019), and lowest for metastatic prostate cancer (6%)., Conclusions: The frequency of genetic testing for HBOPP cancer has increased over time. Though GCT is high for breast cancer, there are gaps in concordance among patients with other cancers. Increasing provider and patient education, genetic counseling, and insurance coverage for testing among HBOPP patients may improve guideline adherence., (© 2022. Society of Surgical Oncology.)

Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53 -specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.

Purpose: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1 / 2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO., Methods: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA -PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA -PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study., Results: From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO., Conclusion: BRCA -PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events., Competing Interests: Marielle NobbenhuisConsulting or Advisory Role: Intuitive Surgical Mateja KrajcConsulting or Advisory Role: AstraZeneca, Pfizer Vilius RudaitisHonoraria: MedtronicConsulting or Advisory Role: AstraZeneca/MedImmuneResearch Funding: Inovio PharmaceuticalsTravel, Accommodations, Expenses: MSD Oncology, Roche, Karl Storz Elizabeth M. SwisherLeadership: IDEAYA BiosciencesNo other potential conflicts of interest were reported.

Objective: Routine genetic testing for ovarian cancer and identification of germline mutations can help improve early detection of cancer as well as guide treatment. Knowledge of genetic counseling and referral rates for genetic testing has been lower for Black patients, compared to White patients. We aimed to describe the demographics and presence of germline mutations in Black individuals with ovarian, fallopian tube or peritoneal carcinoma at two large academic institutions., Methods: Fifty-one Black patients with invasive epithelial ovarian, fallopian tube, or primary peritoneal carcinoma were identified via institutional tissue banks over a 20-year time-period. Germline DNA was sequenced using BROCA, a targeted capture and parallel sequencing assay that identified pathogenic germline mutations in ovarian carcinoma susceptibility genes., Results: Germline mutations in ovarian cancer susceptibility genes were found in 25.5% of women, most commonly BRCA1 and BRCA2. This mutation frequency mirrors those previously described among predominantly White populations. Our data suggests there may be an advantage in survival among those with germline mutations, although this was not statistically significant., Conclusions: Given similar frequencies of germline mutations between Black and White patients with ovarian cancer, we conclude that there are not major differences in the genetic predisposition to ovarian carcinoma. Equitable access to genomic advancements including germline and tumor sequencing would facilitate equal access to PARP inhibitors, the standard of care for patients with BRCA mutated advanced ovarian cancer., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier Inc.)

Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic and prognostic research on ovarian carcinoma., (Published by Oxford University Press 2021.)

Objectives: Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes., Methods: We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance., Results: TP53 mutations were identified in 76.8% of the total cohort (n = 302/393) and 87.9% of HGSC (n = 247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n = 84/91, 92.3% vs. n = 218/302, 72.2%, p < 0.001). TP53 mutations were not associated with overall survival, even when stratified by BRCA mutation. TP53 mutations were associated with platinum sensitivity, even after adjusting for BRCA mutation status (OR 0.41, p = 0.048). The choice of TP53 mutation classification scheme was not found to alter any significant outcome., Conclusions: BRCA mutations significantly co-occur with TP53 mutations. After adjusting for BRCA mutations, TP53 mutations are associated with platinum sensitivity, and this effect is not dependent on TP53 mutation type., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Women with fallopian tube carcinoma (FTC) are reported to have a higher frequency of inherited BRCA mutations than those with ovarian carcinoma (OC) or primary peritoneal carcinoma (PPC). We hypothesized that routine serial sectioning of fallopian tubes would increase the proportion of cases designated as FTC and change the frequency of inherited mutations between carcinoma types., Methods: Eight hundred and sixty-seven women diagnosed from 1998 to 2018 were enrolled at diagnosis into an institutional tissue bank. Germline DNA, available from 700 women with FTC (N = 124), OC (N = 511) and PPC (N = 65), was assessed using targeted capture and massively parallel sequencing for mutations in ovarian carcinoma susceptibility genes. Cases were divided between those prior to routine serial sectioning (1998-2008) and after (2009-2019), and the frequency of FTC and inherited mutations was assessed., Results: The proportion of carcinomas attributed as FTC after 2009 was 28% (128/465), significantly higher than before 2009 [5% (21/402), p < .0001, OR 6.9, 95% CI 4.3-11.2], with subsequent decreases in OC and PPC. In the sequenced group, overall inherited mutation frequency in FTC (24/124, 19%), OC (106/511, 21%, p = .42), and PPC (16/65, 25%, p = .25) were similar. Germline mutation rates in FTC were lower after 2009,16/107 cases (15%), compared to 8/17 cases (47.1%) before 2009 (p = .005, OR 0.20, 95% CI 0.06-0.64)., Conclusions: The prevalence of inherited mutations is similar in FTC compared to OC or PPC when using modern pathological assignment. Complete serial sectioning of fallopian tubes has significantly increased the diagnosis of FTC, and subsequently decreased the frequency of inherited mutations within this group., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Risk-reducing salpingo-oophorectomy (RRSO) is recommended for women at increased risk of ovarian, fallopian tube (FT), and peritoneal carcinoma (collectively OC). We describe rates of occult neoplasia in the largest single-institution prospective cohort of women undergoing RRSO, including those with mutations in non-BRCA homologous repair (HRR) genes., Methods: Participants undergoing RRSO enrolled in a prospective tissue bank between 1999 and 2017. Ovaries and FTs were serially sectioned in all cases. Participants had OC susceptibility gene mutations or a family history suggesting OC risk. Analyses were completed in Stata IC 15.1., Results: Of 644 women, 194 (30.1%) had mutations in BRCA1, 177 (27.5%) BRCA2, 27 (4.2%) other HRR genes, and 15 (2.3%) Lynch Syndrome-associated genes. Seventeen (2.6%) had occult neoplasms at RRSO, 15/17 (88.2%) in the FT. Of BRCA1 carriers, 14/194 (7.2%) had occult neoplasia, 8/194 (4.1%) invasive. One PALB2 and two BRCA2 carriers had intraepithelial FT neoplasms. Occult neoplasm occurred more frequently in BRCA1/2 carriers ≥45 years of age (6.5% vs 2.2%, chi square, p = .04), and 211/371 (56.9%) BRCA1/2 carriers had surgery after guideline-recommended ages. Four in 8 (50%) invasive and 2/9 (22%) intraepithelial neoplasms had positive pelvic washings. None with intraepithelial neoplasms developed recurrence or peritoneal carcinoma., Conclusions: BRCA1 carriers have the highest risk of occult neoplasia at RRSO, and the frequency increased with age. Women with BRCA1/2 mutations often have RRSO beyond recommended ages. One PALB2 carrier had FT intraepithelial neoplasia, a novel finding. Serial sectioning is critical to identifying occult neoplasia and should be performed for all risk-reducing surgeries., Competing Interests: Declaration of competing interest Dr. Elizabeth Swisher has received grant support via the National Institutes of Health, 1R01CA131965. Otherwise, there are no conflicts of interest or disclosures from any of the other authors., (Copyright © 2020. Published by Elsevier Inc.)

Salpingectomy with interval oophorectomy has gained traction as an ovarian cancer prevention strategy, but is not currently recommended for high risk women. Nevertheless, some choose this approach. We aimed to understand risk perception and plans for oophorectomy in BRCA1 and BRCA2 (BRCA) mutation carriers choosing salpingectomy for ovarian cancer prevention. This was a longitudinal survey study of BRCA mutation carriers who underwent bilateral salpingectomy to reduce ovarian cancer risk. An initial written questionnaire and telephone interview was followed by annual phone interviews. 22 women with BRCA mutations were enrolled. Median follow-up was three years. The median age at salpingectomy was 39.5 years (range 27-49). Perceived lifetime ovarian cancer risk decreased by half after salpingectomy (median risk reduction 25%, range 0-40%). At final follow-up, five (22.7%) had undergone oophorectomy and five women (22.7%) were not planning to undergo completion oophorectomy. BRCA mutation carriers who had salpingectomy after the recommended age of prophylactic surgery (vs. before the recommended age) were less likely to plan for future oophorectomy (28.6% vs. 66.7%, p = 0.037). All women were satisfied with their decision to undergo salpingectomy with eighteen (81.8%) expressing decreased cancer-related worry. There were no diagnoses of ovarian cancer during our study period. In conclusion, most BRCA mutation carriers undergoing risk-reducing salpingectomy are satisfied with their decision and have lower risk perception after salpingectomy, though some older mutation carriers did not plan on future oophorectomy. Salpingectomy with delayed oophorectomy in BRCA mutation carriers remains investigational and should preferably be performed within a clinical trial to prevent introduction of an innovation before safety has been proven.

Objective: Germline and somatic BRCA1 and BRCA2 (BRCA) mutations predict treatment response in patients with epithelial ovarian, peritoneal or fallopian tube cancer (OC), yet only germline testing is routinely pursued or reimbursed at diagnosis. We report our experience with clinical testing of paired tumor and germline DNA for OC mutations., Methods: Simultaneous sequencing using the BROCA assay of DNA from paired blood and neoplastic tissue became clinically available at our institution in 2017. We retrospectively reviewed the medical records of OC cases tested from 7/2017 to 7/2018. We calculated the rates of known pathogenic germline mutations and actionable somatic mutations, defined as those for which targeted therapies exist., Results: We identified 43 women (36 new diagnoses, seven recurrences) who underwent testing. Average age at diagnosis was 60. OC samples came from surgical specimens in 31 cases (72.1%), from biopsy in 11 cases (25.6%), and from cytology in one case (2.3%). We identified pathogenic germline mutations in six cases (14%), actionable somatic mutations in 15 cases (35%), and both a somatic and germline mutation in one case (2%). BRCA mutations accounted for 59% of all mutations. Of 40 cases with sufficient follow-up, providers documented reviewing results of genetic testing in 34 (85%), which influenced clinical decisions in 12 (30%)., Conclusions: Simultaneous germline and tumor sequencing is an efficient way to provide enhanced information to guide the care of OC patients. This approach can identify somatic BRCA mutations at diagnosis, allowing physicians to provide PARP inhibitor maintenance and improve outcomes for those patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Pap tests hold promise as a molecular diagnostic for serous ovarian cancer, but previous studies reported limited sensitivity. Furthermore, the presence of somatic mutations in normal tissue is increasingly recognized as a challenge to the specificity of mutation-based cancer diagnostics. We applied an ultra-deep sequencing method with the goal of improving sensitivity and characterizing the landscape of low-frequency somatic TP53 mutations in Pap tests., Methods: We used CRISPR-DS to deeply sequence (mean Duplex depth ~3000×) the TP53 gene in 30 Pap tests from 21 women without cancer and 9 women with serous ovarian carcinoma with known TP53 driver mutations. Mutations were annotated and compared to those in the TP53 cancer database., Results: The tumor-derived mutation was identified in 3 of 8 Pap tests from women with ovarian cancer and intact tubes. In addition, 221 low-frequency (≲0.001) exonic TP53 mutations were identified in Pap tests from women with ovarian cancer (94 mutations) and without ovarian cancer (127 mutations). Many of these mutations resembled TP53 mutations found in cancer: they impaired protein activity, were predicted to be pathogenic, and clustered in exons 5 to 8 and hotspot codons. Cancer-like mutations were identified in all women but at higher frequency in women with ovarian cancer., Conclusions: Pap tests have low sensitivity for ovarian cancer detection and carry abundant low-frequency TP53 mutations. These mutations are more frequently pathogenic in women with ovarian cancer. Determining whether low-frequency TP53 mutations in normal gynecologic tissues are associated with an increased cancer risk warrants further study., Competing Interests: Declaration of competing interest RAR shares equity in NanoString Technologies Inc. and is the principal investigator on a NIH SBIR R44CA221426 subcontract research agreement with TwinStrand Biosciences Inc., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma., Methods: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m 2 ) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry., Results: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2 , HRR, and CD31 were not predictive of bevacizumab activity., Conclusion: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

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: The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival., Methods: Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HR-mediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C., Results: Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (P = 0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (P = 0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25-0.59))., Conclusions: Patients that have both CD3+ TILs and HRD OC are afforded the greatest improvement in overall survival. This finding may have therapeutic implications for OC patients treated with emerging immunotherapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab. Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS). Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non- BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57-0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50-0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66-0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59-0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40-0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25-0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations. Conclusions: HRR mutations, including non- BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777-83. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Objective: In ovarian carcinoma, mutations in homologous recombination DNA repair (HRR) genes, including BRCA1 and RAD51C, are associated with increased survival and specific clinical features. Promoter hypermethylation is another mechanism of reducing gene expression. We assessed whether BRCA1 and RAD51C promoter hypermethylation is associated with similar survival and clinical characteristics., Methods: Promoter methylation of BRCA1 and RAD51C was evaluated using methylation-sensitive PCR in 332 primary ovarian carcinomas. Damaging germline and somatic mutations in 16 HRR genes were identified using BROCA sequencing., Results: BRCA1 methylation was detected in 22 carcinomas (6.6%) and RAD51C methylation in 9 carcinomas (2.7%). These small numbers limited the power to detect differences in survival and platinum sensitivity. Mutations in one or more HRR genes were found in 95 carcinomas (29%). Methylation of BRCA1 or RAD51C was mutually exclusive with mutations in these genes (P=0.001). Patients whose carcinomas had BRCA1 methylation (57.7years±2.5) or BRCA1 mutations (54.1years±1.4) were younger than those without (63.3years±0.8; P=0.029, P<0.0001). BRCA1 methylation and germline BRCA1 mutation were associated with high grade serous (HGS) histology (P=0.045, P=0.001). BRCA1 mutations were associated with increased sensitivity to platinum chemotherapy while BRCA1 methylation was not (P=0.034, P=0.803). Unlike HRR mutations, methylation was not associated with improved overall survival compared to cases without methylation or mutation., Conclusions: Patients with BRCA1-methylated carcinomas share clinical characteristics with patients with BRCA1-mutated carcinomas including younger age and predominantly HGS histology. However, unlike mutation, RAD51C and BRCA1 methylation were not associated with improved survival or greater sensitivity to platinum chemotherapy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Most molecular analyses of high-grade serous ovarian, peritoneal and fallopian tube carcinomas (HGSC) require ≥70% tumor (neoplastic) cell nuclei. We characterized the distribution of the percentage of neoplastic nuclei (PNN) in a large cohort of HGSC and correlated PNN with clinical outcomes to determine the fraction of cases outside this range and whether this cut-off introduces selection bias., Methods: Subjects were prospectively enrolled and normal and neoplastic tissues were snap-frozen. All subjects had grade 2 to 3 HGSC. Subjects that received neoadjuvant chemotherapy were excluded. PNN was determined by estimating the fraction of neoplastic nuclei relative to non-neoplastic nuclei on a representative hematoxylin and eosin stained frozen section from the primary neoplasm. Germline BRCA mutation status was determined with Sanger or BROCA sequencing., Results: PNN was <70% in 101 (33%) of 306 cases. PNN was significantly higher among subjects without optimal cytoreduction (P=0.018). 55 subjects had germline BRCA1/BRCA2 mutations. HGSC associated with BRCA2 but not BRCA1 mutations had significantly lower PNN compared to HGSC in non-carriers (54% vs. 70%, P=0.018). Overall survival was not significantly different between subjects with <70% or ≥70% PNN (median survival 51.8 vs. 46.6months, P=0.858)., Conclusions: One-third of HGSC has PNN <70%. Higher PNN is associated with suboptimal cytoreduction, while lower PNN is associated with inherited BRCA2 mutations. Our findings suggest a nonrandom distribution of PNN that may reflect cancer biology. Further studies exploring the stromal microenvironment are needed. Molecular analyses of HGSC selected for high PNN exclude a significant fraction of patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Importance: Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized., Objective: To determine the frequency and importance of germline mutations in cancer-associated genes in OC., Design, Setting, and Participants: A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay., Main Outcomes and Measures: Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status., Results: Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations., Conclusions and Relevance: Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.

Importance: Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established., Observations: To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < .001), and, in patients exposed to chemotherapy, with older age at blood draw (recurrent OC odds ratio [OR], 17.24; 95% CI, 6.80-43.69; and primary OC postchemotherapy OR, 4.82; 95% CI, 1.43-16.18). In contrast, somatic mosaic mutations in TP53 were not significantly associated with chemotherapy or age. In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%)., Conclusions and Relevance: Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. Care should be taken to control for chemotherapy exposure and age at blood draw when testing the association of somatic mosaic mutations in PBMCs with cancer risk.

Objective: Ovarian carcinoma (OC) is rare in young women and the fraction of early onset OC attributable to inherited mutations in known OC genes is uncertain. We sought to characterize the fraction of OC that is heritable in women diagnosed with ovarian, fallopian tube, or peritoneal carcinoma at forty years of age or younger., Methods: We sequenced germline DNA from forty-seven women diagnosed with OC at age 40 or younger ascertained through a gynecologic oncology tissue bank or referred from outside providers using BROCA, a targeted capture and massively parallel sequencing platform that can detect all mutation classes. We evaluated 11 genes associated with ovarian carcinoma (BARD1, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51D, and RAD51C) and additional candidate genes in DNA repair (ATM, BAP1, CHEK2, MRE11A, NBN, PTEN, TP53). We counted only clearly damaging mutations., Results: Damaging mutations in OC genes were identified in 13 of 47 (28%) subjects, of which 10 (77%) occurred in BRCA1 and one each occurred in BRCA2, MSH2, and RAD51D. Women with a strong family history were no more likely to have an OC gene mutation (8/17, 47%) than those without a strong family history (9/30, 30%, P=0.35). Additionally, damaging mutations in non-OC genes were identified, one in NBN and one in CHEK2., Conclusions: A high proportion of young women with invasive OC have mutations in BRCA1, and a smaller fraction have mutations in other known OC genes. Family history was not associated with mutation status in these early onset cases., (Copyright © 2015. Published by Elsevier Inc.)

Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain., Experimental Design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway., Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation., Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials., (©2013 AACR.)

Objectives: Few studies have comprehensively tested all ovarian cancer patients for BRCA1 and BRCA2 (BRCA1/2) mutations. We sought to determine if clinically identified mutation carriers differed in clinical characteristics and outcomes from mutation carriers not identified during routine clinical care., Methods: We included women with ovarian, tubal or peritoneal carcinoma. BROCA, an assay using targeted capture and massively parallel sequencing was used to identify mutations in BRCA1/2 and 19 other tumor suppressor genes. We identified subjects with BRCA1/2 mutations using BROCA that had not previously received standard genetic testing (BROCA, n=37) and compared them to subjects with BRCA1/2 mutations identified during routine clinical care (known, n=70), and to those wildtype for 21 genes using BROCA (wildtype, n=291)., Results: BROCA mutation carriers were older than known carriers, median age of 58 (range 41-77), vs. 51 (range 33-76, p=0.003, Mann-Whitney). 58/70 (82.9%) of known carriers had a strong family history, compared with 15/37 (40.5%) of BROCA carriers, p<0.0001, (Fisher's Exact). Median overall survival was significantly worse for BROCA mutation carriers compared to known mutation carriers, (45 vs. 93months, p<0.0001, HR 3.47 (1.79-6.72), Log-rank test). The improved survival for BRCA1/2 mutation carriers (known and BROCA) compared with wildtype cases (69 vs. 44months, p=0.0001, HR 0.58 (0.43-0.77), Log-rank test) was driven by known mutation carriers., Conclusions: Older age, absence of a strong family history, and poor survival are all associated with decreased clinical identification of inherited BRCA1/2 mutations in women with ovarian cancer. Using age and family history to direct genetic testing will miss a significant percentage of mutation carriers. Testing should be initiated at the time of diagnosis to maximize identification of mutations and minimize survival bias., (Published by Elsevier Inc.)

Objectives: 53BP1, a critical mediator of the DNA damage response, functions by regulating the balance between homologous recombination (HR) and the more error-prone non-homologous endjoining (NHEJ). Deletion of 53BP1 in brca1 (but not brca2) null cells partially restores HR and reverses sensitivity to poly-ADP-ribose polymerase inhibitors (PARPi). We characterized 53BP1 and BRCA1 expression and their association with clinical outcomes in sporadic and inherited ovarian carcinomas., Methods: We evaluated 53BP1 and BRCA1 protein expression using immunohistochemistry in 248 ovarian carcinomas and mRNA expression in 89 cases with quantitative reverse transcriptase PCR. All subjects were comprehensively characterized for germline mutations in BRCA1 and BRCA2., Results: BRCA1-mutated (but not BRCA2-mutated) ovarian carcinomas had significantly higher 53BP1 protein expression than wildtype carcinomas. 53BP1 message levels were significantly associated with BRCA1 message levels in wildtype and BRCA1-mutated but not BRCA2-mutated carcinomas. In wildtype carcinomas, lower 53BP1 message predicted improved survival (p=0.02, median survival 74 vs. 41months, HR 0.49, 95% CI 0.27-0.88). Survival was not impacted by BRCA1 message level. 53BP1 expression was not associated with primary platinum resistance. In 54 paired primary and recurrent cases, 53BP1 protein expression was equally likely to decrease or increase, and there was no association between decreased 53BP1 at recurrence and the development of platinum resistance., Conclusions: BRCA1-mutated ovarian carcinomas have higher 53BP1 protein expression than wildtype or BRCA2-mutated carcinomas, in opposition to previous findings in breast carcinomas. Higher 53BP1 protein, which promotes NHEJ, could explain the frequent chromosomal aberrations that are characteristic of BRCA1-mutated ovarian carcinomas. In wildtype ovarian carcinomas, decreased 53BP1 message predicts improved survival, but message and protein expression were not associated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: BRCA1 or BRCA2 (BRCA1/2)-mutated ovarian carcinomas may originate in the fallopian tube. The authors of this report investigated alterations in BRCA1/2 tubal epithelium to define the molecular pathogenesis of these carcinomas., Methods: Tubal epithelium was evaluated from 31 BRCA1/2 mutation carriers with gynecologic carcinomas (BRCA CA), 89 mutation carriers who underwent risk-reducing salpingo-oophorectomy (RRSO), and 87 controls. Ki-67 expression and p53 foci (≥10 of 12 consecutive staining cells) were scored by 2 investigators who were blinded to patient designations. Expression levels of p27 and p21 were evaluated within p53 foci. Loss of heterozygosity at the BRCA1/2 mutation site was evaluated in microdissected p53 foci and tubal neoplasms., Results: Background tubal proliferation as measured by Ki-67 staining was increased in the BRCA1 RRSO group (P = .005) compared with the control group. Women who had BRCA1/2 mutations had more p53 foci identified per tubal segment than women in the control group (P = .02). Levels of p27 were decreased in 12 of 28 p53 foci from women with BRCA1 mutations and in 0 of 16 p53 foci from controls (P = .002). There was no loss of the wild type BRCA1/2 allele in 5 tested p53 foci. Tubal neoplasia lost the wild type allele in 6 of 6 foci (P = .002)., Conclusions: The current results suggested a model of tubal carcinogenesis in women with BRCA1/2 mutations. Increased proliferation occurred globally in at-risk tubal epithelium. A mutation in the tumor protein p53 gene TP53 with clonal proliferation and loss of p27 occurred before neoplastic proliferation. Loss of the wild type BRCA1/2 allele occurred with neoplastic proliferation and before invasion., (Copyright © 2010 American Cancer Society.)