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Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8–76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two–fold increased risk (HR = 2.24; 95% CI 1.10–4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort. • We prospectively evaluated whether endometrial cancer is part of the BRCA - spectrum. • Cumulative incidence was 3.4% for BRCA1 and 1.6% for BRCA2 mutation carriers. • Tamoxifen use was a significant risk factor BRCA -endometrial cancer. • With few incident cases, we are not able to conclusively confirm an increased risk. • Hysterectomy at the time of preventive ophorectomy should be individualized. [ABSTRACT FROM AUTHOR]

To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population. • In women with BRCA undergoing risk-reducing minimally invasive surgery, one third had ovarian stroma beyond the visible ovary • Distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm • Current guidelines which recommend resection of 20 mm of tissue beyond the visible ovary are adequate in this population [ABSTRACT FROM AUTHOR]

Due to limited data on homologous recombination deficiency (HRD) in older patients (≥ 70 years) with advanced stage high grade serous ovarian cancer (HGSC), we aimed to determine the rates of HRD at diagnosis in this age group. From the Phase 3 trial VELIA the frequency of HRD and BRCA1/2 pathogenic variants (PVs) was compared between younger (< 70 years) and older participants. HRD and somatic(s) BRCA1/2 pathogenic variants (PVs) were determined at diagnosis using Myriad myChoice® CDx and germline(g) BRCA1/2 PVs using Myriad BRACAnalysis CDx®. HRD was defined if a BRCA PV was present, or the genomic instability score (GIS) met threshold (GIS ≥ 33 & ≥ 42 analyzed). Of 1140 participants, 21% were ≥ 70 years. In total, 26% (n = 298) had a BRCA1/2 PV and HRD, 29% (n = 329) were HRD/ BRCA wild-type, 33% (n = 372) non-HRD, and 12% HR-status unknown (n = 141). HRD rates were higher in younger participants, 59% (n = 476/802), compared to 40% (n = 78/197) of older participants (GIS ≥ 42) [ p < 0.001]; similar rates demonstrated with GIS ≥ 33, 66% vs 48% [ p < 0.001]. g BRCA PVs observed in 24% younger vs 8% of older participants (p < 0.001); s BRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to g BRCA was 35% vs 31% (p = 0.36). HRD frequency was similar in participants aged < 70 and ≥ 70 years (35% vs 31%) when the contribution of g BRCA was excluded; rates of s BRCA PVs were also similar (8% v 10%), thus underscoring the importance of HRD and BRCA testing at diagnosis in older patients with advanced HGSC given the therapeutic implications. [Display omitted] • 48% of high grade serous ovarian cancers (HGSC) in older patients are homologous recombination deficient (HRD). • Somatic or germline BRCA1/2 pathogenic variants (PVs) contribute to almost half of HGSC tumors with HRD. • Excluding the contribution of germline BRCA PVs, the frequency of HRD is similar in younger vs older patients with HGSC. • The frequency of somatic BRCA1/2 PVs is independent of age (8% younger v 10% older participants). • HRD testing should not be restricted by patient age. [ABSTRACT FROM AUTHOR]

To investigate the role of BRCA1/2 mutations in early ovarian cancer (eOC) (International Federation of Gynecology and Obstetrics FIGO 2014 stage I-II), and its impact on prognosis after relapse. In this multicenter retrospective study, clinical and survival data from high-grade serous (HGS)-eOC patients at presentation and recurrence were compared according to BRCA status: BRCA-mutated (BRCAmut) vs. BRCA wild-type (BRCAwt). Among 191 HGS-eOC patients, 89 were BRCAmut and 102 BRCAwt. There was no significant difference according to the BRCA status in terms of Progression-Free Survival (PFS). A longer Overall Survival (OS) was found in BRCAmut patients. Stage I patients had significantly improved PFS vs stage II, regardless of BRCA status. At multivariate analysis, stage at diagnosis was the only variable with a significant effect on PFS. No factors were significantly relevant on OS, albeit younger age and BRCA mutation showed a slight impact. Post-Recurrence Survival (PRS) in the BRCAmut population was significantly improved compared with BRCAwt. At multivariate analysis, Secondary Cytoreductive Surgery was the strongest predictor for longer PRS, followed by PARPi maintenance at recurrence. BRCA-status is not a prognostic factor in early ovarian cancer regarding PFS. However, our data suggest a better prognosis after relapse in BRCAm population. • Recurrence rate was similar in BRCAwt and BRCAmut groups (35.3% vs 29.2%). • The recurrence patterns were similar between BRCAmut and BRCAwt • BRCA status has no impact on Progression Free Survival. • Post-recurrence Survival was significantly longer in the BRCAmut group. • A longer Overall Survival was found in BRCAmut compared with BRCAwt patients. [ABSTRACT FROM AUTHOR]

Authors evaluated the performance of a commercially available next-generation sequencing assay kit; this was based on genomic content from Illumina's TruSight™ Oncology 500 research assay that identifies BRCA variants and proprietary algorithms licensed from Myriad and, with additional genomic content, measures the homologous recombination deficiency (HRD) genomic instability score (GIS) in tumor tissue (TSO 500 HRD assay). Data from the TSO 500 HRD assay were compared with data from the Myriad MyChoice®CDx PLUS assay (Myriad assay). Prevalence rates for overall HRD status and BRCA mutations (a deleterious or suspected deleterious BRCA1 or BRCA2 mutation or both) and assay agreement rates for HRD GIS and BRCA analysis were assessed in ovarian tumor samples. Pearson correlations of the continuous HRD GIS and analytic sensitivity and specificity were evaluated. The prevalence of overall HRD positivity was 51.2% (TSO 500 HRD assay) versus 49.2% (Myriad assay) and the prevalence of BRCA mutations was 27.6% (TSO 500 HRD assay) versus 25.5% (Myriad assay). After post-processing optimization, concordance of the HRD GIS was 0.980 in all samples and 0.976 in the non-BRCA mutation cohort; the area under the receiver operating characteristic curve was 0.995 and 0.992, respectively. Comparison between the Illumina and Myriad assays showed that overall HRD status, the individual components of BRCA analysis, and HRD GIS detection results were highly concordant (>93%), suggesting the TSO 500 HRD assay will approach the analytical accuracy of the FDA-approved Myriad assay. • HRD status was evaluated using two tests (Illumina TSO 500 HRD assay and Myriad MyChoice®CDx PLUS assay). • Overall HRD, BRCA mutation, and HRD GIS status detection showed >93% agreement between the tests. • Prevalence of HRD-positive and BRCA mutation status were similar between the tests. • HRD GIS was strongly correlated between the two tests. [ABSTRACT FROM AUTHOR]

In the era of target therapy and personalized medicine, BRCA mutational status has a major influence on survival in ovarian cancer patients. Our aim is to verify if the poorer prognosis of elderly ovarian cancer patients can be related to the biology of the tumor beyond their own morbidities and/or suboptimal treatments. This is a retrospective single-institution study evaluating prognosis of patients with a diagnosis of ovarian cancer and known BRCA status. We collected clinical and surgical characteristics and the distribution of BRCA mutational status according to age groups. 1840 patients were included in the analysis. The rate of BRCA mutated decreased over age-range from 49.7% in patients aged <50 years to 18.8% in ≥80 years old women. The prognostic role of BRCA status on survival is maintained when focusing on the elderly population, with improved Disease Free Survival (27.2 months vs 16.5 months for BRCA mutated and wild type respectively, p = 0.001) and Cancer Specific Survival (117.6 months vs 43.1 months for BRCA mutated and wild type respectively, p = 0.001) for BRCAmut compared to BRCAwt patients. In the multivariable analysis, among elderly women, upfront surgery and BRCA mutation are independent factors affecting survival. Elderly patients experiment a poorer prognosis due to multiple factors that include both their medical condition and comorbidities, under-treatment and most importantly disease characteristics. We found that beyond disparities, BRCA mutation is still the strongest independent prognostic factor affecting both the risk of recurrence and death due to disease. • The rate of BRCA mutated tumors decreases with age. • Tumor biology in elderly patients could be a crucial determinant of treatment. • BRCA mutation remains the strongest independent factor for survival. • Tumor biology is responsible of the worst prognosis of elderly population [ABSTRACT FROM AUTHOR]

This study assessed the efficacy, safety, and health-related quality of life (HRQoL) of the treatment regimen of dostarlimab, a programmed death-1 inhibitor, combined with niraparib, a poly (ADP-ribose) polymerase inhibitor, in patients with BRCA wild type (BRCA wt) recurrent platinum-resistant ovarian cancer (PROC) who had previously received bevacizumab treatment. This Phase II, open-label, single-arm, multicenter study, conducted in the USA, enrolled patients with recurrent PROC to receive niraparib and dostarlimab until disease progression or unacceptable toxicity (up to 3 years). A preplanned interim futility analysis was performed after the first 41 patients had undergone ≥1 radiographic evaluation (approximately 9 weeks from the first treatment). The prespecified interim futility criterion was met and the study was therefore terminated. For the 41 patients assessed, the objective response rate (ORR) was 7.3% (95% confidence interval: 1.5–19.9); no patients achieved a complete response, 3 patients (7.3%) achieved a partial response (duration of response; 3.0, 3.8, and 9.2 months, respectively) , and 9 patients (22.0%) had stable disease. In total, 39 patients (95.1%) experienced a treatment-related adverse event, but no new safety issues were observed. HRQoL, assessed using FOSI, or Functional Assessment of Cancer Therapy – Ovarian Symptom Index scores, worsened over time compared with baseline scores. The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCA wt PROC. [Display omitted] • Overall response rate did not improve with niraparib and dostarlimab in recurrent BRCA wt platinum-resistant ovarian cancer (124/125). • Low objective response rate versus standard of care triggered prespecified futility criteria and early study termination (122/125). • No new safety signals were reported for niraparib and dostarlimab combination therapy (87/125). • Health-related quality of life measures worsened over time from baseline, with no control group for comparison (112/125). [ABSTRACT FROM AUTHOR]

We aimed to validate whether pathologic response (pR) to neoadjuvant chemotherapy (NACT) using a three-tier chemotherapy response score (CRS) is associated with clinical outcome in ovarian cancer (OC) and could be used as surrogate marker for survival. We conducted a retrospective study of OC patients with FIGO stage III/IV disease who received NACT and graded response as no or minimal (CRS 1), partial (CRS 2), or complete/near-complete (CRS 3) pR using tissue specimens obtained from omentum. Uni- and multivariate survival analyses were performed accounting for age, FIGO stage, debulking and BRCA status as well as neoadjuvant use of bevacizumab. CRSs 1, 2 and 3 were found in 41(31%), 62 (47%) and 30 (22%) of the 133 examined cases. Response to NACT was associated with significantly improved progression-free (PFS, p < 0.001) and overall survival (OS, p = 0.011). Complete/ near-complete pathologic response (CRS3) was associated with improved PFS (median 24.8 vs. 12.5 months, unadjusted HR 0.28 [95%CI 0.15–0.54], p < 0.001; adjusted hazard ration (aHR) 0.31 [95% CI 0.14–0.72], p = 0.007) and OS (median 63.3 vs. 32.1 months, unadjusted HR 0.27 [95%CI 0.10–0.68], p = 0.006; aHR 0.32 [95% CI 0.09–1.11], p = 0.072) when compared to no or minimal response (CRS1). We validate a three-tier CRS for assessment of pathologic response to NACT in OC and demonstrate its prognostic independence of BRCA status or neoadjuvant bevacizumab use. Improving pR rates may be a useful goal of NACT in OC with the expectation of improved survival. The CRS may be a useful endpoint in clinical trials in OC. • The chemotherapy response score (CRS) assesses the pathologic response to neoadjuvant chemotherapy in ovarian cancer. • Complete/near complete (CRS3) response to chemotherapy is associated with improved progression free and overall survival. • The prognostic relevance of CRS is independent of BRCA mutation status or neoadjuvant bevacizumab use. • A three-tier scoring system has the potential to become a surrogate marker for accelerated drug development in OC. [ABSTRACT FROM AUTHOR]

Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While pathogenic variants in several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), the role of partner and localizer of BRCA2 (PALB2) remains uncertain. We sought to utilize meta-analysis to evaluate the association between PALB2 germline pathogenic variants and ovarian cancer. We conducted a systematic review and meta-analysis. We searched key electronic databases to identify studies evaluating multigene panel testing in people with ovarian cancer. Eligible trials were subjected to meta-analysis. Fifty-five studies met inclusion criteria, including 48,194 people with ovarian cancer and information available on germline PALB2 pathogenic variant status. Among people with ovarian cancer and available PALB2 sequencing data, 0.4% [95% CI 0.3–0.4] harbored a germline pathogenic variant in the PALB2 gene. The pooled odds ratio (OR) for carrying a PALB2 pathogenic variant among the ovarian cancer population of 20,474 individuals who underwent germline testing was 2.48 [95% CI 1.57–3.90] relative to 123,883 controls. Our meta-analysis demonstrates that the pooled OR for harboring a PALB2 germline pathogenic variant among people with ovarian cancer compared to the general population is 2.48 [95% CI 1.57–3.90]. Prospective studies evaluating the role of germline PALB2 pathogenic variants in the development of ovarian cancer are warranted. • There is emerging evidence that germline PALB2 pathogenic variants are associated with ovarian cancer. • Meta-analysis finds 0.4% [95% CI 0.30.4] of people with ovarian cancer harbor a germline PALB2 pathogenic variant. • People with ovarian cancer are more than twice as likely to carry germline PALB2 pathogenic variants compared to controls. [ABSTRACT FROM AUTHOR]

Aldehyde dehydrogenase (ALDH) enzymatic activity is a marker of cancer-initiating cells (CIC) in many tumor types. Our group and others have found that ALDH1A family inhibitors (ALDHi) can preferentially induce death of ovarian CIC in established ovarian cancer. We sought to determine if ALDHi, by targeting CIC at the time of tumor initiation, could function as a chemopreventive for ovarian cancer. As BRCA1/2 mutation carriers represent a population who could benefit from an ovarian cancer chemopreventive, we focused on BRCA mutation-associated tumor cell lines and murine tumor models. We found that, compared to BRCA wild-type cells, BRCA mutant ovarian cancer cells are more sensitive to the ALDHi673A. Similarly, while 673A treatment of wild-type fallopian tube epithelial (FTE) cells is non-toxic, 673A induces death in FTE cells with BRCA1 knockdown. Using a murine fallopian tube organoid model of ovarian carcinogenesis, we show that 673A reduced organoid complexity and significantly reduce colony formation of BRCA -mutant cells. Organoids that persisted after 673A treatment were predominantly BRCA1wt, but NF1 mutant, suggesting a resistance mechanism. Finally, using the BPRN (Brca1, Trp53, Rb1, Nf1 inactivated) mouse model of tubo-ovarian cancer, we evaluated the impact of intermittent 673A therapy on carcinogenesis. 673A treatment resulted in a significant reduction in serous tubal intraepithelial carcinoma (STIC) lesions and carcinomas. Collectively, the findings suggest that ALDHi, such as 673A, could serve as chemopreventive agents for BRCA1/2 mutation carriers. • We developed a novel FTE based ex-vivo organoid model that can be used to evaluate compounds for chemo-prevention studies. • Using the FTE organoids, we find that the ALDH inhibitor 673A reduces BRCA-driven tumorigenesis. • 673A reduced cancer initiation in the p53/BRCA driven model of high grade serous cancer. • These studies indicate ALDH inhibitors may serve as chemoprevention agents for BRCA driven cancers. [ABSTRACT FROM AUTHOR]

To describe the prevalence of germline pathogenic variants (gPVs) in endometrial and ovarian carcinosarcomas and determine if gPVs are drivers of carcinosarcoma. Patients with endometrial or ovarian carcinosarcomas who underwent clinical tumor-normal sequencing from 1/1/2015 to 6/1/2021 and consented to germline assessment of ≥76 cancer predisposition genes were included. In patients with gPVs, biallelic inactivation was identified through analysis of loss of heterozygosity and somatic pathogenic alterations. Of 216 patients identified, 167 (77%) were diagnosed with endometrial carcinosarcoma and 49 (23%) with ovarian carcinosarcoma. Overall, 33 gPVs were observed in 29 patients (13%); 20 gPVs (61%) had biallelic loss in tumors. The rate of high-penetrance gPVs overall was 7% (16 of 216); 88% of high-penetrance gPVs had biallelic loss. In the endometrial carcinosarcoma cohort, 22 gPVs were found in 19 (11%) of 167 patients; 12 gPVs (55%) had biallelic loss in tumors, including 8 (89%) of 9 in high-penetrance gPVs. Among the ovarian carcinosarcoma cohort, 11 gPVs were found in 10 (20%) of 49 patients; 8 gPVs (73%) had biallelic loss in tumors, and all evaluable high-penetrance gPVs (n = 6) had biallelic loss. All gPVs in homologous recombination (BRCA1 , BRCA2 , RAD51C) and Lynch syndrome (MSH2 , MSH6) genes had biallelic loss in tumors (n = 15). gPVs in genes affecting homologous recombination- or Lynch-associated mismatch repair exhibited biallelic inactivation within tumors, suggesting likely drivers of gynecologic carcinosarcoma. Our data support germline testing for patients with gynecologic carcinosarcomas, given implications for treatment and risk-reduction in patients and at-risk family members. • In this cohort of patients with gynecologic carcinosarcomas, 13% had a germline pathogenic variant (gPV). • In endometrial carcinosarcoma, 8 (89%) of 9 gPVs in high-penetrance genes exhibited biallelic inactivation. • In ovarian carcinosarcoma, all 6 gPVs in high-penetrance genes exhibited biallelic inactivation. • All gPVs in homologous recombination and Lynch syndrome-related genes had biallelic loss in tumors. • Germline testing of patients with gynecologic carcinosarcomas is important, as some gPVs drive carcinosarcoma development. [ABSTRACT FROM AUTHOR]

The open-label, single-arm, multicenter ORZORA trial (NCT02476968) evaluated the efficacy and safety of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) who had tumor BRCA mutations (BRCAm) of germline (g) or somatic (s) origin or non-BRCA homologous recombination repair mutations (HRRm) and were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Patients received maintenance olaparib capsules (400 mg twice daily) until disease progression. Prospective central testing at screening determined tumor BRCAm status and subsequent testing determined gBRCAm or sBRCAm status. Patients with predefined non-BRCA HRRm were assigned to an exploratory cohort. The co-primary endpoints were investigator-assessed progression-free survival (PFS; modified Response Evaluation Criteria in Solid Tumors v1.1) in BRCAm and sBRCAm cohorts. Secondary endpoints included health-related quality of life (HRQoL) and tolerability. 177 patients received olaparib. At the primary data cut-off (17 April 2020), the median follow-up for PFS in the BRCAm cohort was 22.3 months. The median PFS (95% CI) in BRCAm, sBRCAm, gBRCAm and non-BRCA HRRm cohorts was 18.0 (14.3–22.1), 16.6 (12.4–22.2), 19.3 (14.3–27.6) and 16.4 (10.9–19.3) months, respectively. Most patients with BRCAm reported improvements (21.8%) or no change (68.7%) in HRQoL and the safety profile was as expected. Maintenance olaparib had similar clinical activity in PSR OC patients with sBRCAm and those with any BRCAm. Activity was also observed in patients with a non-BRCA HRRm. ORZORA further supports use of maintenance olaparib in all patients with BRCA-mutated, including sBRCA-mutated, PSR OC. • Clinical activity of maintenance olaparib in platinum-sensitive relapsed ovarian cancer was seen with any BRCA mutation. • This included activity in patients with somatic BRCA mutations. • Activity was also seen in patients with non-BRCA homologous recombination repair mutations. • Safety and tolerability were consistent with previous studies in this setting. [ABSTRACT FROM AUTHOR]

Financial toxicity (FT), the cumulative financial burden experienced due to medical care, is a well-established adverse effect of healthcare. Patients with BRCA mutations have significantly increased cancer risks compared to non-affected individuals, requiring more frequent screenings and, at times, prophylactic surgery, increasing their risk for FT. Our primary aim in this study was to describe rates of FT among BRCA carriers. We performed a novel, cross-sectional study of FT in BRCA1/2 carriers. Participants were recruited via phone and/or email to complete consents and surveys on REDCap. The FACIT-COST tool, a validated tool for measuring FT, was used to assess FT; scores were divided into tertiles, with high FT defined as COST score < 24. 265 BRCA positive female participants met enrollment criteria; 76 (28.7%) consented to participate and completed the survey. Participants were primarily non-Hispanic White (97.4%), privately insured (82.9%), and employed full time (67.1%). A significant proportion (22.7%) of participants reported delaying or avoiding care secondary to finances. No statistically significant association was seen between financial toxicity groups and analyzed demographics. Participants with high FT were more likely to engage in all surveyed cost-saving measures, with 41.7% of participants reporting delays/avoidance of care due to cost (p = 0.02). This study of FT in BRCA carriers shows that financial toxicity exists as an issue in this high-risk patient population. This work serves as the first description of FT in BRCA mutation carriers and highlights the importance of incorporating routine counseling on cost when discussing recommendations for screening and clinical care with this patient population. • BRCA mutation carriers are at high risk of financial toxicity (FT) due to regular screenings and prophylactic surgery • No studies have evaluated FT in genetic mutation carriers despite known FT risk in patients with breast & ovarian cancers • Financial toxicity exists among BRCA carriers • BRCA carriers with high FT are statistically significantly more likely to engage in all cost-saving measures • 41.7% of patients in our study with high FT report delay or avoidance of care due to cost [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the proportion of patients meeting the National Comprehensive Cancer Network (NCCN)'s BRCA genetic testing criteria prior to a diagnosis of a BRCA-related cancer. This was a cross-sectional study of patients with BRCA pathogenic variants and a diagnosis of a BRCA - related cancer. Patients were included if they had known dates of genetic testing and cancer diagnosis. NCCN criteria (version 2.2021) were applied to determine if patients met criteria for testing before a BRCA-related cancer diagnosis. The outcome of interest was the proportion of patients undergoing genetic testing following a diagnosis of a BRCA-related cancer who qualified for genetic testing based on NCCN criteria. Chi-square, Mann-Whitney U test, and logistic regression were performed with significance at p < 0.05. Of 270 patients with a BRCA-related cancer, 229 (85%) underwent genetic testing after a cancer diagnosis. Most patients (97%) met at least one NCCN criteria for BRCA testing; 166 (73%) of patients who were tested following a BRCA-related cancer diagnosis also met the criteria for testing by family history. Publicly insured or uninsured patients were three times more likely to undergo BRCA testing after a diagnosis of cancer (odds ratio [OR] 3.03, 95% confidence interval [CI] 1.09–8.40). Patients with a family history of pathogenic variants were more likely to undergo testing before a cancer diagnosis (OR 0.10, 95% CI 0.05–0.23). Most patients with BRCA-associated cancers undergo genetic testing after their cancer diagnosis. Increased education on genetic testing criteria and novel methods to improve testing are desperately needed. • Most patients with a BRCA pathogenic variant and associated cancer underwent genetic testing following a cancer diagnosis. • 73% of these patients also met criteria by family history and may have qualified for earlier genetic testing. • Early identification of patients at high risk for pathogenic variants is critical in improving cancer risk-reduction. [ABSTRACT FROM AUTHOR]

The real-world management of patients with non-BRCA, homologous recombination repair pathway variants with increased or uncertain risks of ovarian cancer is unknown. The objective was to determine the adoption of risk-reducing salpingo-oophorectomy (RRSO) for carriers of variants with increased or uncertain risks of ovarian cancer beyond BRCA. This was a retrospective cohort study of patients at three hospitals with non-BRCA, homologous recombination repair pathway variants with increased risk (BRIP1, RAD51C, RAD51D) and uncertain risk (ATM, BARD1, NBN, PALB2) of ovarian cancer. Outcomes of interest were adoption of RRSO and factors associated with adoption of RRSO. Wilcoxon rank-sum, chi-square, and logistic regression were performed with p < 0.05. Of 318 patients, 76 (24%) had pathogenic variants with increased risks of ovarian cancer (BRIP1, 45; RAD51C, 20; RAD51D, 11), and 242 (76%) had variants with uncertain risks of ovarian cancer (ATM, 145; PALB2, 69; NBN , 23; BARD1, 5). Of 64 patients eligible for RRSO by National Comprehensive Cancer Network (NCCN) criteria or family history, 31 (48%) underwent RRSO. Among eligible patients who did not undergo RRSO, 24 (73%) were not referred for gynecologic oncology consultation. Older age at testing (adjusted odds ratio [aOR] 1.08, 95% confidence interval [CI] 1.03–1.13) and referral to gynecologic oncology (aOR 33.48, CI 8.10–138.39) were associated with increased adoption of RRSO when adjusting for personal and family history of breast and ovarian cancer. Half of RRSO-eligible patients by NCCN criteria beyond BRCA did not undergo RRSO. Opportunities exist for improving education to increase referrals to facilitate RRSO for these patients. • Of patients with BRIP1, RAD51C, and RAD51D or ovarian cancer family history, less than half underwent risk-reducing surgery. • Of eligible patients who did not undergo risk-reducing surgery, 73% were not referred to gynecologic oncology. • A quarter of all patients with BRIP1, RAD51C, and RAD51D were not referred to gynecologic oncology. • Referral to gynecologic oncology was associated with a 30-fold increase in uptake of risk-reducing surgery. [ABSTRACT FROM AUTHOR]

The objective of this study is to externally validate the KELIM (rate of elimination of CA-125 elimation) score in patients with high grade serous ovarian cancer(HGSC)undergoing NACT and determine its relation to outcome of cytoreduction, platinum sensitivity, progression free(PFS) and overall survival(OS). This is a retrospective cohort study of patients with Stage III-IV HGSC diagnosed between January 1, 2010 and December 31, 2019 and treated with NACT. KELIM score was calculated using at least 3 CA-125 values within the first 100 days of chemotherapy. Demographic parameters were collected and Kaplan Meier survival analyses were performed for PFS and OS. This study was approved by local ethics board. 217 patients met inclusion criteria. Median follow-up was 28.93 months(range 2.86–135.06). There was no significant difference in stage, functional status, cytoreductive outcome or BRCA status(germline or somatic) between patients with a KELIM ≥ 1 and <1. Patients with a KELIM<1 had a lower median PFS (13.58 vs 19.69, p < 0.001), median platinum free interval(PFI) (7.66 vs 13.64, p < 0.001) and 5-year OS (57% vs 72%, p = 0.0140) compared to patients with KELIM≥1. After adjusting for stage, treatment delays, bevacizumab or poly adenosine diphosphate-ribose polymerase(parp)-inhibitor use, and BRCA status, patients with KELIM<1 had a high risk of disease progression(HR = 1.57 (95% CI 1.08–2.28) and death(HR = 1.99 (95% CI 1.01–3.95) compared to KELIM≥1. BRCA status was independently associated to an increase on KELIM score (OR = 1.917, 95% CI 1.046–3.512, p = 0.035). Patients with advanced HGSC undergoing NACT with a KELIM <1 were more likely to have platinum-resistant disease, worse PFS and worse OS when compared to patients with KELIM≥1. The KELIM score can be a helpful tool to predict chemo-response and aid in treatment decision making. • KELIM score may be a marker of chemosensitivity in patients with ovarian cancer treated with neoadjuvant chemotherapy. • Patients with a KELIM<1 had a lower progression free- and overall survival compared to patients with KELIM ≥1. • Patients with KELIM<1 had higher risk of disease progression and death compared to patients with KELIM ≥1. • BRCA positive mutation status was independently associated with a higher KELIM score. • Patients with KELIM<1 were more likely to have platinum-resistant disease and worse progression free- and overall survival. [ABSTRACT FROM AUTHOR]

To establish a quantitative method to evaluate the DNA methylation level of an immediate upstream region of major BRCA1 transcriptional start sites (TSSs), and to investigate whether methylation of the region is a prognostic factor in high-grade serous ovarian cancer patients after neoadjuvant chemotherapy. Ninety-two FFPE samples of advanced high-grade serous ovarian cancers after neoadjuvant chemotherapy between 2011 and 2018 were used for mutation and methylation analysis. DNA methylation levels were assessed by pyrosequencing and DNA methylation microarray. An association between methylation level (or a mutation) and progression-free survival was assessed by Kaplan-Meier analysis. Major BRCA1 transcripts and CpG sites immediately upstream of their TSSs were identified, and a pyrosequencing method was developed. BRCA1 methylation, BRCA1/2 mutations, and a RAD51C mutation were detected in 17/79 (21.5%), 17/92 (18.5%), and 1/92 (1.1%) high-grade serious ovarian cancer samples. In univariate analysis, BRCA1 methylation and no residual tumor were associated with progression-free survival (BRCA1 methylation: P = 0.025, no residual tumor: P = 0.0026). Multivariate analysis showed that both BRCA1 methylation (P = 0.038, HR = 0.47, 95% CI: 0.21–0.96) and no residual tumor (P = 0.012, HR = 0.49, 95% CI: 0.28–0.85) were significant favorable prognostic factors. A quantitative method to estimate the methylation level of the immediate upstream region of major BRCA1 TSSs was established. Methylation of the region of was an independent favorable prognostic factor in high-grade serous ovarian cancer patients. • A pyrosequencing primer set was developed to measure the methylation level of an immediate upstream region of BRCA1. • BRCA1 methylation was observed in 21.5% of high-grade serous ovarian cancers. • BRCA1 methylation was a prognostic factor for progression-free survival in patients with high-grade serous ovarian cancer. [ABSTRACT FROM AUTHOR]

To describe breast and ovarian cancer risk reduction strategies in the clinical management of women who test positive for non- BRCA hereditary breast and ovarian cancer (HBOC) pathogenic variants compared to those who test positive for pathogenic BRCA variants or have negative germline panel testing. Examination of imaging and preventive surgeries in women undergoing HBOC genetic testing from 1/1/2015 to 12/31/2018, with follow up to 03/31/2020 in Kaiser Permanente Northern California. A total of 13,271 tests which included HBOC genes were identified. Rate of bilateral salpingo-oophorectomy after genetic testing were similar for BRCA and the non- BRCA moderate risk ovarian pathogenic variants (PVs) (47.4% vs 54%, p = 0.25). Rates were lower for low risk or unknownrisk non- BRCA PVs (12.8%, p < 0.001, 5.3% (p < 0.001). Rates of surveillance for ovarian cancer with ultrasound and CA 125 in the first year was 63.3% and 64.7% for BRCA PV, 37.5% and 27.1%, for non- BRCA moderate risk PVs and 13.7% and 4.6%, for low-risk PVs. Bilateral mastectomy rates were 19.7% for BRCA PV, 10.1% (p = 0.028) for non- BRCA breast high risk PVs, for moderate risk PVs 7.7% (p < 0.001) and for unknown risk 0.4% (p < 0.001). MRI surveillance rates in the first year similarly were 47.4% for non- BRCA BRCA PV, 43% for breast high risk PV, 39.4% for moderate risk and 4.9% for unknown risk PV. Surgical and surveillance strategies are underutilized for HBOC PV, however there is concordance of uptake of preventive strategies with specific risk associated with non- BRCA PVs. • Preventive surgical and surveillance strategies are underutilized for all HBOC PV including BRCA and non-BRCA PV. • There is stratification of preventive and surveillance management uptake commensurate with specific risks of each HBOC PVs. • The gap in uptake of prevention strategies is especially low in those with Lynch PVs. [ABSTRACT FROM AUTHOR]

ARIEL3 (NCT01968213) is a placebo-controlled randomized trial of the poly(ADP-ribose) polymerase inhibitor rucaparib as maintenance treatment in patients with recurrent high-grade ovarian carcinoma who responded to their latest line of platinum therapy. Rucaparib improved progression-free survival across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Patients were randomized 2:1 to receive rucaparib 600 mg twice daily or placebo. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were evaluated for association with exceptional benefit (progression-free survival ≥2 years) versus progression on first scan (short-term subgroup) and other efficacy outcomes. Rucaparib treatment was significantly associated with exceptional benefit compared with placebo: 79/375 (21.1%) vs 4/189 (2.1%), respectively (p < 0.0001). Exceptional benefit was more frequent among patients with favorable baseline clinical characteristics and with carcinomas harboring molecular evidence of homologous recombination deficiency (HRD). A comparison between patients who derived exceptional benefit from rucaparib and those in the short-term subgroup revealed both clinical markers (no measurable disease at baseline, complete response to latest platinum, longer penultimate platinum-free interval) and molecular markers (BRCA1, BRCA2, RAD51C , and RAD51D alterations and genome-wide loss of heterozygosity) significantly associated with exceptional benefit. Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable clinical characteristics or molecular features associated with HRD. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of patients with recurrent high-grade ovarian carcinoma. • Clinical/molecular characteristics associated with exceptional benefit from rucaparib maintenance in ARIEL3 were explored. • 21% of patients in the rucaparib arm derived exceptional benefit (PFS ≥2 years) compared with only 2% in the placebo arm. • Clinical characteristics associated with exceptional outcomes on rucaparib were related to platinum sensitivity. • BRCA1 , BRCA2 , RAD51C, and RAD51D mutations were associated with exceptional benefit from rucaparib. • A diverse set of patients with high-grade ovarian carcinoma can derive exceptional benefit from rucaparib maintenance. [ABSTRACT FROM AUTHOR]

BRCA mutations have been associated with improved outcomes in ovarian cancer patients. This study's objective was to compare the secondary cytoreduction surgery (SCS) rates among ovarian cancer patients by BRCA mutation status. The study was retrospective and included platinum sensitive recurrent high grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018. Demographic and genetic data, tumor characteristics, patterns of recurrence and surgical and medical treatments were obtained from electronic charts. Patients were grouped according to BRCA mutation status. Logistic regression analyses were used to explore potential prognostic factors of secondary cytoreduction. 147 patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a BRCA mutation, including 39 (26.5%) germline mutations and 8 (5.5%) somatic mutations. Thirty-one patients (21.1%) underwent SCS. The rate of SCS was 33.3% among the germline BRCA mutation carriers and 15.7% among patients without germline BRCA mutation (p = 0.026). Predictors of secondary cytoreduction included germline BRCA mutation (OR = 2.5, p = 0.03), time to recurrence (OR = 1.004 per month, p < 0.001), absence of lymphatic recurrence (OR = 3.08, p = 0.013), three or fewer lesions at recurrence (OR = 36.74, p < 0.001) and absence of ascites (OR = 9.1, p = 0.034). After adjusting for the number of lesions at recurrence, no other variable remained a significant predictor. Germline BRCA mutation carriers are more likely to undergo secondary cytoreduction. This may be mediated in part by lower volume disease at recurrence. This observation should be considered when planning surveillance for these patients after first-line treatment. • Germline BRCA mutation carriers are more likely to undergo secondary cytoreduction surgery. • Longer time to recurrence, non-lymphatic recurrence and no ascites at recurrence were significant predictors of secondary cytoreduction. • Oligometastatic disease was the only independent predictor of secondary cytoreduction. [ABSTRACT FROM AUTHOR]

Olaparib treatment resulted in significant improvement in objective response rates (ORRs) and progression-free survival (PFS) over non‑platinum chemotherapy in patients with BRCA1 / BRCA2 -mutated (BRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) and ≥2 prior lines of platinum-based chemotherapy in the phase III SOLO3 study. LIGHT (NCT02983799) prospectively evaluated olaparib treatment for patients with PSROC and known BRCAm and homologous recombination deficiency (HRD) status. In this phase II open-label multicenter study, patients with PSROC and ≥1 prior line of platinum-based chemotherapy were assigned to cohorts by presence of germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive tumors without BRCAm, or HRD-negative tumors. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR) and PFS. Tumors were analyzed using Myriad BRACAnalysis CDx and myChoice HRD assays; HRD-positive tumors were defined using a genomic instability score of ≥42. Of 272 enrolled patients, 271 received olaparib and 270 were included in efficacy analyses. At data cut-off, ORRs in the gBRCAm, sBRCAm, HRD-positive, and HRD-negative cohorts were 69.3%, 64.0%, 29.4%, and 10.1%, respectively. DCRs were 96.0%, 100.0%, 79.4%, and 75.3% in each cohort, respectively. Median PFS was 11.0, 10.8, 7.2, and 5.4 months, respectively. The most common (≥ 20%) treatment-emergent adverse events included nausea, fatigue/asthenia, vomiting, anemia, constipation, diarrhea, and decreased appetite. Olaparib treatment demonstrated activity across all cohorts. The greatest efficacy was observed in the BRCAm cohorts, regardless of gBRCAm/sBRCAm. For patients without a BRCAm, greater efficacy was observed in the HRD-positive than the HRD-negative cohorts. The safety profile was consistent with that established in previous olaparib studies. [ABSTRACT FROM AUTHOR]

Women with ovarian cancer who have a pathogenic germline variant in BRCA 1 or BRCA 2 (BRCA) have been shown to have better 5-year survival after diagnosis than women who are BRCA -wildtype (non-carriers). Modifiable lifestyle factors, including smoking, physical activity and body mass index (BMI) have previously been associated with ovarian cancer survival; however, it is unknown whether these associations differ by germline BRCA status. We investigated measures of lifestyle prior to diagnosis in two cohorts of Australian women with invasive epithelial ovarian cancer, using Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). In the combined studies (n = 1923), there was little association between physical activity, BMI or alcohol intake and survival, and no difference by BRCA status. However, the association between current smoking status before diagnosis and poorer survival was stronger for BRCA variant carriers (HR 1.98; 95% CI 1.20–3.27) than non-carriers (HR 1.18; 95% CI 0.96–1.46; p-interaction 0.02). We saw a similar differential association with smoking when we pooled results from two additional cohorts from the USA and UK (n = 2120). Combining the results from all four studies gave a pooled-HR of 1.94 (95% CI 1.28–2.94) for current smoking among BRCA variant carriers compared to 1.08 (0.90–1.29) for non-carriers. Our results suggest that the adverse effect of smoking on survival may be stronger for women with a BRCA variant than those without. Thus, while smoking cessation may improve outcomes for all women with ovarian cancer, it might provide a greater benefit for BRCA variant carriers. • It is unknown whether associations between lifestyle factors and ovarian cancer survival differ by BRCA variant status. • The adverse effects of smoking on ovarian cancer survival may be stronger for women with a BRCA variant than those without. • There was no differential association in survival by BRCA variant status for physical activity, BMI or alcohol intake. [ABSTRACT FROM AUTHOR]

Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation. • Whether other modes of contraception reduce the risk of ovarian cancer among BRCA mutation carriers has not been evaluated. • In this case-control study, use of contraceptive implants and oral contraceptives were inversely associated with risk. • There was a suggestive decreased risk with IUDs and injections; however, this was based on a small number of exposed cases. [ABSTRACT FROM AUTHOR]

The crosstalk between tumor microenvironment (TME) and cancer cells plays a critical role in the occurrence and development of ovarian cancer. Imprinted gene MEST is a tumor-promoting factor that modulates several carcinogenic signaling pathways. This study aimed to investigate the expression pattern of MEST and its association with immune cell infiltration. The transcriptome data of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database was utilized, and the expression and immune characteristics of MEST were verified by immunohistochemistry of ovarian cancer specimens. Kaplan-Meier Plotter was used to assess the prognostic value in patients with ovarian cancer. We found that high expression of MEST was associated with diminished immune cell infiltration and worse prognosis of ovarian cancer patients in independent cohorts. There was a positive correlation between MEST and BRCA1 expression. The MESThighBRCA1high ovarian cancer group was correlated with lower infiltration of CD4+ cells, CD57+ cells, CD68+ cells and MPO+ cells, had worse overall survival (OS) in TCGA (HR = 1.57, p = 0.0004) and GSE27651 (HR = 4.27, p = 0.0002) cohorts, and predicted poor progress free survival (PFS) in GSE9891 (HR = 1.76, p = 0.0098) and GSE15622 (HR = 4.80, p = 0.0121) cohorts. Moreover, the expression of PD-L1 predicted unfavorable OS (HR = 2.48, p = 0.0415) and PFS (HR = 2.36, p = 0.0215) in MESTlowBRCA1low ovarian cancer group in GSE9891 cohort. These findings suggest that the co-expression of MEST and BRCA1 may be an ideal combination for predicting the prognosis and response to immunotherapy in patients with ovarian cancer. • MEST was associated with prognosis and immune infiltration in ovarian cancer. • There was a positive correlation between MEST and BRCA1 expression. • Co-expression of MEST and BRCA1 affected the prognostic value of PD-L1 for ovarian cancer. [ABSTRACT FROM AUTHOR]

In the Phase 3 VELIA trial (NCT02470585), veliparib added to carboplatin plus paclitaxel concomitantly and as maintenance for women with newly-diagnosed advanced ovarian cancer significantly improved progression-free survival (PFS) versus chemotherapy alone. Here we present exploratory analyses by paclitaxel dosing schedule and germline BRCA (g BRCA) status. Women with untreated ovarian carcinoma were randomized (1:1:1) to: veliparib during chemotherapy and maintenance (veliparib-throughout), veliparib during chemotherapy followed by placebo maintenance (veliparib-combination only), or placebo during chemotherapy and maintenance (control). Chemotherapy included carboplatin plus dose-dense (DD; weekly) or every-3-week (Q3W) paclitaxel (a stratification factor at randomization), selected at the investigator's discretion pre-randomization. PFS was assessed by paclitaxel dosing schedule using a Cox proportional hazard model adjusted by treatment arm and stratification factors; safety was analyzed based on paclitaxel dosing schedule and g BRCA status. 1132 patients were analyzed by paclitaxel schedule. Pooled treatment arms demonstrated longer median PFS with DD (n = 586) versus Q3W (n = 546) paclitaxel (ITT: 20.5 vs 15.7 months, hazard ratio [HR] 0.77; homologous recombination proficient cancer: 15.1 vs 11.8 months, HR 0.64; BRCA wt: 18.0 vs 12.9 months, HR 0.70). Comparison between arms favored veliparib-throughout versus control in both DD (PFS, 24.2 vs 18.3 months, hazard ratio 0.67) and Q3W (19.3 vs 14.6, hazard ratio 0.69) subgroups. DD paclitaxel was associated with higher incidence of Grade 3/4 neutropenia, fatigue, and anemia versus Q3W. There were no differences in toxicity between g BRCA m (n = 211) and g BRCA wt (n = 902) subgroups. DD paclitaxel was tolerable and associated with longer PFS in the HR proficient and g BRCA wt groups, versus Q3W. g BRCA status did not impact safety. • Weekly (compared to every 3 weeks) paclitaxel was associated with longer PFS in HRP and BRCA wt cohorts • PFS was improved with veliparib compared with control regardless of paclitaxel dosing schedule • In general, grade 3/4 adverse events were more common in dose-dense paclitaxel groups compared with every-3-week paclitaxel • Germline BRCA status showed no impact on incidences of adverse events across arms [ABSTRACT FROM AUTHOR]

An "ovarian cancer cluster region" (OCCR) has been reported in both BRCA1 and BRCA2. However, the clinical significance of the OCCR of BRCA1/2 has not yet been investigated. The medical records of 991 patients with epithelial ovarian, primary peritoneal, and fallopian tube cancer who underwent genetic testing for BRCA1 and/or BRCA2 from January 1, 2006, to August 31, 2019, were retrospectively reviewed. Sanger and next-generation sequencing analyses were used to test the BRCA1 and BRCA2 mutation status. Progression-free survival (PFS) and overall survival (OS) were compared according to the mutation location (OCCR vs. non-OCCR region). Survival outcomes were determined using Kaplan–Meier survival analysis. A total of 162 patients had BRCA1 pathogenic variants (PVs), and 76 had BRCA2 PVs. Patients with BRCA1 PV that in the OCCR region showed shorter PFS than those with BRCA1 PV outside the OCCR (22.6 months vs. 27.6 months, P = 0.038). In the platinum-sensitive subgroup of BRCA1 , patients with BRCA1 PV in the OCCR region showed shorter PFS than those in the non-OCCR group (P = 0.0197). On the other hand, BRCA2 variants did not exhibit any particular trend (32.8 months vs. 27.9 months , P = 0.468). However, no significant differences were detected in OS between patients with BRCA1/2 PVs, regardless of the location of the variants. Patients with BRCA1 PV in the OCCR had shorter PFS than those outside the OCCR. This tendency was more pronounced in the platinum-sensitive subgroup. To our knowledge, this is the first study of BRCA1/2 mutations based on the OCCR. • The clinical impact of pathogenic variants in the ovarian cancer cluster region (OCCR) of BRCA1 and BRCA2 was assessed. • The patients with BRCA1 mutations in the OCCR had shorter progression-free survival than those outside the OCCR. • This tendency was increased in platinum-sensitive patients. [ABSTRACT FROM AUTHOR]

In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy. Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, CA-125 levels were measured at baseline and each cycle; radiographic responses were assessed every 9 weeks. Of 1140 patients randomized, 742 had BRCA wild type (BRCA wt) tumors (HRP, n = 373; HRD/ BRCA wt, n = 329). PFS hazard ratios between veliparib-throughout versus control were similar in both BRCA wt populations (HRD/ BRCA wt: 22.9 vs 19.8 months; hazard ratio 0.76; 95% confidence interval [CI] 0.53–1.09; HRP: 15.0 vs 11.5 months; hazard ratio 0.765; 95% CI 0.56–1.04). By Cycle 3, the proportion with ≥90% CA-125 reduction from baseline was higher in those receiving veliparib (pooled arms) versus control (34% vs 23%; P = 0.0004); particularly in BRCA wt and HRP subgroups. Complete response rates among patients with measurable disease after surgery were 24% with veliparib (pooled arms) and 18% with control. These results potentially broaden opportunities for PARPi utilization among patients who would not qualify for frontline PARPi maintenance based on other trials. [Display omitted] • The VELIA trial assessed the PARPi veliparib, combined with frontline chemotherapy and continued as maintenance monotherapy. • Within the BRCA wild type population, survival outcomes were improved regardless of homologous recombination status. • During chemotherapy, radiographic and CA-125 responses were numerically higher with veliparib vs control in all subgroups. • PARPi could benefit a broader patient population than those currently eligible based on prior Phase 3 trials. [ABSTRACT FROM AUTHOR]

To estimate the cost-effectiveness of olaparib after being funded by the Spanish National Health Service (SNHS) as first-line monotherapy maintenance treatment in patients with advanced high-grade serous ovarian carcinoma (HGSOC) and BRCA mutations in Spain. A semi-Markov model with one-month cycles was adapted to the Spanish healthcare setting, using the perspective of the SNHS, and a time horizon of 50 years. Two scenarios were compared: receiving olaparib vs. no maintenance treatment. The model comprised four health states and included the clinical results of the SOLO1 study, along with the direct healthcare costs associated with the use of first-line and subsequent treatment resources (2020 €). A discount rate of 3% was applied for future cost and quality-of-life outcomes. A probabilistic sensitivity analysis (PSA) was also carried out and a cost-effectiveness threshold of €25,000 per quality adjusted life year (QALY) was considered. The introduction of olaparib as a first-line maintenance treatment for advanced HGSOC patients with BRCA mutations implied a cost of €131,614.98 compared to €102,369.54 without olaparib (difference: €29,245.44), with an improvement of 2.00 QALYs (5.56 and 3.57, respectively). Therefore, olaparib is cost-effective for advanced HGSOC patients with BRCA mutations, with an incremental cost-effectiveness ratio of €14,653.2/QALY. The results from the PSA showed that 92.1% of the simulations fell below the €25,000/QALY threshold. The model showed that olaparib could improve the overall survival by 2 years, vs. no maintenance treatment. Olaparib as first-line maintenance treatment is cost-effective in advanced HGSOC patients with BRCA mutations in Spain. • Our results suggest that olaparib could delay disease progression and improve OS by 2 years vs. no maintenance treatment. • Treatment with olaparib resulted in a gain of 2.00 QALYs vs. no maintenance treatment, at an ICER of €14,653,2/QALY. • First-line maintenance with olaparib is cost-effective in advanced HGSOC patients with BRCA mutations in Spain. [ABSTRACT FROM AUTHOR]

BRCA 1 or 2 mutation carriers have increased risk of developing breast cancer (BC) and serous epithelial ovarian cancer (EOC). The incidence of BC over time after EOC is unknown. Optimal BC surveillance for BRCA mutation carriers following EOC has not been defined. A multi-institutional retrospective chart review was performed. Patients with BRCA -associated EOC diagnosed between 1996 and 2016 were followed for an average of 80 months. Women with previous bilateral mastectomy were excluded; women with prior BC and an intact breast were included. Descriptive statistics, Chi Square, and univariate survival analysis were performed. 184 patients with BRCA -associated EOC were identified. Eighteen (10%) were diagnosed with BC a median of 48 months following EOC. Two (1%) with prior BC developed contralateral BC and 16 (9%) developed primary BC. The majority of BC (55%) was diagnosed 3 years following EOC. The 3-, 5- and 10-year incidence of BC was 5.6%, 9.5% and 33.3%. Annual mammography was performed in 43% and MRI in 34%. Twenty-eight (15%) women underwent risk-reducing mastectomy (RRM). There was no statistically significant difference in BC screening between women with, and without, a prior BC. BC was most commonly detected on mammogram. Three (17%) women had occult BC at the time of RRM. Nine (50%) had DCIS, and 8 (44%) had stage I/II BC. Median 5- and 10-year survival was 68% and 43% and was comparable between groups. Ten percent of women developed BC after EOC. The incidence of BC following EOC in BRCA carriers increases over time, and surveillance is recommended given their enhanced survival of EOC. Timely genetic testing for women with EOC is imperative to better triage BC screening resources and treatment. • Ten percent of women with BRCA associated EOC developed breast cancer. • Average 3.3 years of subsequent breast cancer diagnosis after EOC in BRCA carriers. • The incidence of breast cancer rises 3 years following diagnosis of serous EOC. • Breast cancer screening among women with BRCA -associated EOC was underutilized. • Prioritize non-invasive breast cancer screening 3 years after BRCA -associated EOC [ABSTRACT FROM AUTHOR]

Previously, Vigil demonstrated clinical benefit to prolong relapse free and overall survival in the BRCA wild-type (BRCA-wt), homologous recombination proficient (HRP) patient population. Here we provide long term follow up of 3 years in the HRP patient population enrolled in the Phase 2b VITAL study. HRP patients treated with Vigil (n = 25) or placebo (n = 20) who were enrolled in the Phase 2b, double-blind, placebo-controlled (VITAL study, NCT02346747) were followed for safety, OS and RFS. OS and RFS from time of randomization (immediately prior to maintenance therapy) and from debulking tissue procurement time points were analyzed by Kaplan-Meier (KM) and restricted mean survival time (RMST) analysis. OS for Vigil treated patients at 3 years has not yet reached median OS time point (95% CI 41.6 months to not achieved) compared to 26.9 (95% CI 17.4 months to not achieved) in placebo treated patients (HR 0.417 p = 0.020). Three year RFS also showed benefit to Vigil (stratified HR 0.405, p = 0.011) and no long term toxicity to Vigil was observed. Three year OS for Vigil of 70% vs. 40% for placebo from time of randomization was observed (p = 0.019). RMST analysis was also significant for OS (45.7 vs. 32.8 months, p = 0.008) and RFS (p = 0.025). In conclusion, results suggest durable activity of Vigil on RFS and OS and support further evaluation of Vigil in HRP ovarian cancer. • Treatment options for HRP ovarian cancer are limited and associated with significant toxicity and limited clinical benefit. • Previously, Vigil has shown both safety and efficacy in the BRCA wild type, homologous recombination proficient patients. • Continued 3 year follow up has shown Vigil demonstrates durable clinical benefit to prolong OS and RFS in HRP patients. [ABSTRACT FROM AUTHOR]

Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor. Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined. 289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1 m and BRCA2 m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1- mutated tumors (n = 144) and 98% of germline BRCA2- mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2 m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off. Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis. • There are limited data on the concordance between tumor BRCA (tBRCA) and germline BRCA (gBRCA) testing in ovarian cancer. • In SOLO2, concordance between tBRCA and gBRCA testing was very high (98%) in gBRCA-mutated patients. • Large insertions or deletions accounted for only a small subset (5%) of gBRCA mutations. • The near 100% rate of bi-allelic loss of BRCA suggests that routine testing for BRCA zygosity is not required. • Results are in keeping with BRCA loss being a driver of tumorigenesis in ovarian cancer. [ABSTRACT FROM AUTHOR]

To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. This post hoc analysis pooled patients from Study 10 (NCT01482715 ; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344 ; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10–0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C , RAD51D , or CDK12 mutations. Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants. • Patients with recurrent ovarian cancer (OC) who responded to rucaparib treatment in Study 10 and ARIEL2 were characterized. • Duration of response (DOR) was used to group long- (≥1 y), intermediate- (6 mo to <1 y), and short-term responders (<6 mo). • The majority of long- and intermediate-term responders with BRCA wild-type OC had high genome-wide loss of heterozygosity. • BRCA structural variants were common in long-term responders and associated with longer DOR than other alteration types. • Our analyses show that reversion-resistant BRCA structural variants contribute to extended DOR to PARP inhibitor therapy. [ABSTRACT FROM AUTHOR]

The clinical utility of maintenance therapy (MT) for patients with platinum-sensitive recurrent ovarian cancer has been validated in several clinical trials. We assessed "real-world" treatment patterns using an electronic health record (EHR) database. A retrospective study of patients diagnosed with ovarian cancer between January 1, 2011 and July 31, 2019 was conducted using the US nationwide Flatiron Health (EHR)-derived de-identified database. Patients were included if they received second- or third-line (2 L or 3 L) platinum-based chemotherapy (PBCT). Information regarding biomarker status was obtained. 2292 patients with ovarian cancer received at least two lines of therapy. 222 patients completed PBCT on or after March 1, 2017 and had ≥2 months of active surveillance or received MT with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) or bevacizumab. 46 (20%) had BRCA mutations (BRCAm), 132 (59%) had a wildtype BRCA (BRCAwt) gene, and 47 (21%) were unknown. Of patients with BRCAm , 63% received a PARPi, 17% received bevacizumab, and 20% underwent active surveillance. Of patients with BRCAwt , 40% received a PARPi, 23% received bevacizumab, and 36% underwent active surveillance. MT was more common in those with younger age and a BRCA mutation. PARPi use increased on average by 1.3% every 3 months (p =.02) with no statistically significant change in use of bevacizumab. In this real-world population, MT is becoming progressively more common following 2 L or 3 L PBCT regardless of biomarker status. The results provide insight into the shifting treatment patterns for patients with recurrent ovarian cancer. • Maintenance therapy is more common depending on age and performance status. • One-third of patients with a BRCA mutation did not receive PARP inhibitor therapy. • PARP inhibitor initiation has increased study with no change in use of bevacizumab. [ABSTRACT FROM AUTHOR]

To assess CA 125 and transvaginal ultrasound surveillance in women with BRCA1 or BRCA2 pathogenic variants in a pragmatic clinical setting with>1 year follow up. Retrospective cohort study in a large integrated health care system of women identified from 1/1/2003 to 12/31/2017 with a BRCA1 or BRCA2 pathogenic variant with at least one intact ovary. Demographic and clinical data were collected from date of genetic testing until oophorectomy, an ovarian cancer diagnosis, or 7/1/2019. Primary outcome was frequency and findings of CA 125 tests and ultrasounds performed; secondary outcome was epithelial ovarian cancers diagnosed. There were 1418 women, age ≥ 30 years with a BRCA1 or BRCA2 pathogenic variant with at least one intact ovary. Of the total of 1683 ultrasounds and 2437 CA 125 tests done, 1022 ultrasounds and 1709 CA 125 tests were performed for surveillance in 771 women followed >1 year. Of these women 241 (31%) women had no surveillance, and 530 (69%) women underwent any surveillance. Only 108 (20%) underwent regular surveillance. The number who underwent regular surveillance declined each year. Twenty-one women underwent surveillance indicated surgery with only 2 ovarian cancers found by surveillance. Many women with BRCA1 or BRCA2 pathogenic variants undergo ultrasound and CA 125 surveillance testing but abnormal surveillance testing led to diagnosis of ovarian cancer in only two cases. These findings question the use of CA 125 and ultrasound surveillance in the clinical setting for ovarian cancer detection in women with BRCA1 or BRCA2 pathogenic variants. • Only 20% of BRCA carriers with ovaries beyond one year have annual ovarian cancer surveillance with ultrasound and CA 125. • Adherence to annual surveillance with CA 125 and ultrasound declines yearly from time of gene test. • Only two ovarian cancers were detected with 2731 surveillance CA 125 and ultrasound tests. [ABSTRACT FROM AUTHOR]

A recent study showed that even a few months of breastfeeding is associated with a significant decrease in the risk of ovarian cancer in the general population. This study aimed to perform a systematic review and meta-analysis to determine the significance of the length of the breastfeeding period on ovarian cancer risk in BRCA1/2 mutation carriers. PubMed, EMBASE, and Cochrane databases were searched up to June 1, 2021. We included case-control and cohort studies that contained information on breastfeeding and the risk of ovarian cancer in BRCA1/2 mutation carriers. Odds ratios (OR) were meta-analytically pooled using a fixed-effects model.dd Five studies, including one cohort study and four case-control studies, were included in this meta-analysis. Of the 14,601 BRCA1/2 mutation carriers, the overall pooled OR of ever having performed breastfeeding in patients who had ovarian cancer was 0.767 (95% confidence interval [CI], 0.688–0.856) and 0.817 (95% CI, 0.650–1.028) for patients with BRCA1 and BRCA2 mutation, respectively. Breastfeeding for >1 year acted as a protective factor in both BRCA1 [OR: 0.787 (95% CI, 0.682–0.907)] and BRCA2 [OR: 0.567 (95% CI, 0.400–0.802)] mutation carriers. No significant heterogeneity was present (I2 = 0%), and the funnel plot was also properly distributed, showing no publication bias. Breastfeeding is a preventive, modifiable factor for ovarian cancer in BRCA1/2 mutation carriers. Ever having performed breastfeeding was significantly preventive for ovarian cancer in the BRCA1 mutation carriers, however a period of 1 year or more of breastfeeding is required for a reduced ovarian cancer risk in BRCA2 mutation carriers. • Ovarian cancer (OC) risk in BRCA1/2 mutation carriers who breastfed was investigated. • Ever having breastfed was preventive against OC in BRCA1 mutation carriers. • Breastfeeding >1 year was required for reduced OC risk in BRCA2 mutation carriers. [ABSTRACT FROM AUTHOR]

In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1. Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130). Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparib-treated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily. Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients. • Detailed safety data from the SOLO1 trial of maintenance olaparib in newly diagnosed, advanced BRCA-mutated ovarian cancer. • Maintenance olaparib had a predictable tolerability profile with no new safety signals identified. • Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients. • Risk of MDS/AML with maintenance olaparib in the newly diagnosed setting remained <1.5% with long-term follow-up of 5 years. • The majority of patients were able to remain on the recommended starting dose of olaparib 300 mg twice daily. [ABSTRACT FROM AUTHOR]

BRCA -associated ovarian cancers are biologically unique; it is unclear if this translates to favorable outcomes at the time of primary cytoreduction (PCS). The aim of this study was to compare the amount of residual disease after PCS in BRCA mutated (BRCAm) and wild-type (BRCAwt) high-grade serous ovarian cancers (HGSC), and to assess whether BRCA status was an independent predictor of complete cytoreduction. We conducted a retrospective analysis of patients with stage III/IV HGSC with known germline and somatic BRCA status, treated with PCS from 2000 to 2017. We compared the complete, optimal and suboptimal cytoreduction rates between the BRCA m and BRCA wt cohorts and built a predictive model to assess whether BRCA status was predictive of complete cytoreduction. Of 303 treated with PCS, 120 were germline/somatic BRCA m (40%) and 183 were BRCA wt (60%). BRCA m women tended to be younger, but there were no differences between the two groups in preoperative CA-125, disease burden, surgical complexity, length of surgery, or perioperative complications. BRCA m group had a higher rate of complete cytoreduction to no residual disease (0 mm) [72% vs. 48%] (p < 0.001). In a multivariate model, after accounting for age, length of surgery, CA-125 level, stage, disease burden and surgical complexity, BRCA m status was predictive of 0 mm residual disease with odds ratio of 5.3 (95% CI 2.45–11.5; p < 0.001). BRCA m status is predictive of complete cytoreduction at the time of PCS. Despite similar disease burden and surgical efforts, one is more likely to achieve complete resection in BRCAm HGSC. • BRCA mutation status predicts complete cytoreduction at primary cytoreductive surgery for high-grade serous ovarian cancers. • BRCA mutation status must be known to aid treatment decision-making at time of initial diagnosis. • BRCA mutated tumors may be more 'resectable', which may explain the improved survival outcomes compared to wildtype cohort. [ABSTRACT FROM AUTHOR]

Examine the risk of cardiovascular disease (CVD) following risk reducing bilateral salpingo-oophorectomy (RRBSO) among women with BRCA mutations. In this retrospective population-based study in British Columbia, Canada, between 1996 and 2017, we compared the risk of CVD among women with known BRCA mutations who underwent RRBSO before the age of 50 (n = 360) with two groups of age-matched women without known BRCA mutations: 1) women who underwent bilateral oophorectomy (BO) for benign conditions (n = 3600); and, 2) women with intact ovaries who had hysterectomy or salpingectomy (n = 3600). Our primary outcome was CVD (a composite (any of) myocardial infarction, heart failure, and/or cerebrovascular disease). Secondary outcomes included a diagnostic code for predisposing conditions (hypertension, dyslipidemia, and/or diabetes mellitus), and use of cardioprotective medications (statins and/or beta-blockers). We report no significant increased risk for CVD between women with BRCA mutations and women who underwent BO (aHR = 1.08, 95%CI: 0.72–1.62), but women with BRCA mutations were less likely to be diagnosed with predisposing conditions (aHR = 0.69, 95%CI: 0.55–0.85). Compared to women without BRCA mutations with intact ovaries who underwent hysterectomy or salpingectomy, women with BRCA mutations had significantly increased risk for CVD (aHR = 1.82, 95%CI: 1.18–2.79) and were less likely to be diagnosed with predisposing conditions (aHR = 0.78, 95%CI: 0.62–0.97) and to fill cardioprotective medications (aHR = 0.88, 95%CI: 0.64–1.22). Our results suggest an opportunity for improved prevention of CVD in women with BRCA mutations after prophylactic oophorectomy. Despite the observed lower prevalence of predisposing conditions for CVD and lesser use of cardioprotective medications, this population did not have a lower rate of CVD. • Women with BRCA mutations undergoing RRBSO were less likely to be diagnosed with predisposing conditions for CVD. • There was also a non-significant trend of lower use of cardioprotective medications among these women. • However, there was no reduced hazard of CVD among these women compared to women without mutations undergoing oophorectomy. • The hazard of CVD was higher among these women compared to women without mutations and intact ovaries. • We expect CVD prevention can be improved by optimizing diagnosis of predisposing conditions and preventive strategies. [ABSTRACT FROM AUTHOR]

We evaluated the incidence of breast cancer and overall survival in a multi-center cohort of ovarian cancer patients carrying BRCA1/2 mutations in order to assess risks and formulate optimal preventive interventions and/or surveillance. Medical records of 502 BRCA1/2 mutation carriers diagnosed with ovarian cancer between 2000 and 2018 at 7 medical centers in Israel and one in New York were retrospectively analyzed for breast cancer diagnosis. Data included demographics, type of BRCA mutations, surveillance methods, timing of breast cancer diagnosis, and family history of cancer. The median age at diagnosis of ovarian cancer was 55.8 years (range, 23.9–90.1). A third (31.5%) had a family history of breast cancer and 17.1% of ovarian cancer. Most patients (67.3%) were Ashkenazi Jews, 72.9% were BRCA1 carriers. Breast cancer preceded ovarian cancer in 17.5% and was diagnosed after ovarian cancer in 6.2%; an additional 2.2% had a synchronous presentation. Median time to breast cancer diagnosis after ovarian cancer was 46.0 months (range, 11–168). Of those diagnosed with both breast cancer and ovarian cancer (n = 31), 83.9% and 16.1% harbored BRCA1 and BRCA2 mutations, respectively. No deaths from breast cancer were recorded. Overall survival did not differ statistically between patients with an ovarian cancer diagnosis only and those diagnosed with breast cancer after ovarian cancer. The low incidence of breast cancer after ovarian cancer in women carrying BRCA1/2 mutations suggests that routine breast surveillance, rather than risk-reducing surgical interventions, may be sufficient in ovarian cancer survivors. • Breast cancer incidence was assessed in ovarian cancer patients carrying BRCA mutations. • Breast cancer was diagnosed after ovarian cancer in 6.2% of patients. • Overall survival was not statistically different in the patient groups analyzed. • Routine breast surveillance may be sufficient in ovarian cancer survivors. [ABSTRACT FROM AUTHOR]

In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR). Patients received veliparib or placebo with carboplatin-paclitaxel (6 cycles) and as maintenance (30 additional cycles). The primary analysis compared PFS in the veliparib-throughout arm to the carboplatin-paclitaxel only arm in the BRCA mutation (BRCAm), homologous recombination deficiency (HRD), and intention-to-treat (ITT) populations. Exploratory analyses of PFS in BRCA wildtype (BRCAwt), homologous recombination proficient (HRP), and HRD + BRCAwt populations were also performed. PFS per BICR and overall concordance rates between INV and BICR assessments were analyzed. Hazard ratios for PFS by INV and BICR were consistent in each of the primary analysis and exploratory populations. In the ITT population, median PFS per INV was 23.5 months in the veliparib-throughout arm versus 17.3 months in the control arm (hazard ratio [HR] 0.683, 95% confidence interval [CI] 0.562–0.831; P < 0.001). Median PFS by BICR was 29.3 months versus 19.2 months (HR 0.687, 95% CI 0.504–0.806). In the ITT population, the overall concordance rates between INV and BICR were 78% and 75% for the veliparib-throughout and control arms, respectively. Hazard ratios for PFS per BICR and per INV were consistent, with no suggestion of investigator bias. These findings support the reliability of PFS by INV in ovarian cancer trials. • Addition of veliparib to chemotherapy and as maintenance improved (INV)-assessed progression-free survival (PFS). • Hazard ratios for PFS by blinded independent central review (BICR) were consistent with hazard ratios for PFS per INV. • Analyses of overall concordance between INV and BICR assessments indicated a lack of investigator bias. [ABSTRACT FROM AUTHOR]