BRCA1 Or BRCA2 Research Articles

Genomic instability in non-breast/ovarian malignancies of individuals with germline pathogenic variants in BRCA1/2.

Individuals with germline pathogenic variants (gPVs) in BRCA1 or BRCA2 (BRCA1/2) are at a high risk of breast- and ovarian carcinomas (BOCs) with BRCA1/2-deficiency and homologous recombination deficiency (HRD) that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances and genomic loss-of-heterozygosity. Malignancies with HRD are more sensitive to platinum-based therapies and PARP inhibitors. Here, we aim to investigate the fraction of non-BOC malignancies that have BRCA1/2-deficiency and genomic instability features. The full tumor history of a large historical clinic-based consecutive cohort of 2,965 individuals with gPVs in BRCA1/2 was retrieved via the Dutch nationwide pathology databank (Palga). In total, 169 non-BOC malignancies were collected and analyzed with targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second hit alterations and genomic instabilities indicative of HRD, respectively. BRCA1/2-deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-BOC malignancies of individuals with gPVs in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively). BRCA1/2-deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-BOC malignancies in individuals with gPVs in BRCA1 and BRCA2, respectively. Evaluation of the effectivity of PARP-inhibitors in these individuals should be focused on tumors with confirmed absence of a wild type allele.

(112) SEXUAL HEALTH AFTER RISK REDUCING SALPINGO-OOPHERECTOMY FOR BRCA PATIENTS

Abstract Introduction There is no study assessing the changes in sexual health after risk reducing oopherectomy in premenopausal women. Objective Objective: To evaluate the effect of risk-reducing salpingo-oophorectomy (RRSO) on change in sexual function in women aged 34-50 years with pathogenic variants in BRCA1 or BRCA2 (BRCA1/2). Methods Methods: The PROSper (Prospective Research of Outcomes after Salpingo-oophorectomy) study is a prospective cohort of women aged 34-50 years with BRCA1 or two germline pathogenic variants that compares health outcomes after RRSO to a non-RRSO control group with ovarian conservation. Women aged 34-50 years, who were planning either RRSO or ovarian conservation, were enrolled for 3 years of follow-up. Sexual Function was measured using the Sexual Health Outcomes in Women (SHOW-Q) a validated survey tool that measures sexual desire, frequency, satisfaction, orgasm, and discomfort specifically in patients with a history of a pelvic condition, including oophorectomy. Differences in sexual function between the RRSO and non-RRSO groups, were determined by using mixed effects multivariable linear regression models. Results Results: Of 100 PROSper participants, all completed SHOW Q. At baseline patients who had undergone RRSO before enrollment had lower SHOW-Q scores (71 vs 64). Across all 60 months of the study the SHOW-Q scores remained persistently lower in those undergoing RRSO raging from 6-13 points across the time studied (p &amp;lt;0.05) controlling for age, depression, partner, menopausal symptoms and hormone therapy Conclusions Conclusion: Women with pathogenic variants in BRCA1/2 who undergo RRSO before the age of 50 years have greater effects on sexual function than those that do not. The detrimental effect of rRRSO is not otherwise explained by hormone therapy, depression or menopausal symptoms. This information should be incorporated into counseling and post op management to consider options to improve sexual health post surgery Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: sprout pharma.

Impact of hormone receptor status and tumor subtypes on clinical behavior and outcomes of breast cancer in young BRCA carriers.

504 Background: Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer (BC). Among young patients harboring germline BRCA1or BRCA2 (BRCA) pathogenic variants (PVs), most of the tumors arising in BRCA2carriers express hormone receptors, while most BC cases in BRCA1 carriers do not; however, limited evidence exists on the impact of hormone receptor status on clinical behavior and outcomes in young patients harboring BRCA PVs. Methods: This is an international, multicenter, hospital-based, retrospective cohort study including young patients (≤40 years) diagnosed with invasive BC between January 2000 and December 2020, harboring germline PVs in BRCA genes. Our analysis investigates the impact of hormone receptor status on clinical behavior and outcomes of BC. The type and pattern of recurrence and survival outcomes (disease-free survival [DFS], BC specific survival [BCSS] and overall survival [OS]) were first investigated according to hormone receptors expression (positive vs. negative), and then according to BC subtype (luminal A-like vs. luminal B-like vs. triple-negative vs. HER2-positive BC). Results: From 78 centers worldwide, 4,709 BRCA carriers were included in this analysis, of whom 2,143 (45.5%) had hormone receptor-positive and 2,566 (54.5%) hormone receptor-negative BC. Patients with hormone receptor-positive BC were more likely to harbor BRCA2 PVs while less frequently had grade 3 tumors and nodal involvement. Median follow-up was 7.88 (IQR 4.47-12.61) years. The rate of distant recurrences was higher in patients with hormone receptor-positive BC (13.1% vs. 9.6%, p&lt;.001), while the rate of second primary BC was lower (9.1% vs. 14.7%, p&lt;.001) when compared to patients with hormone receptor-negative disease. The 8-years DFS was 65.8% in patients with hormone receptor-positive and 63.4% in those with hormone receptor-negative BC. No differences in terms of OS nor BCSS were observed. The hazard ratio of hormone receptor-positive vs. negative disease changed over time for DFS, BCSS, and OS (p&lt;.05 for interactions of hormone receptor status and survival time). Among the 4,363 patients eligible for subtypes analysis, 612 had luminal A-like, 1,038 luminal B-like, 2,373 triple-negative and 340 HER2-positive BC. Patients with Luminal A-like BC had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-years DFS: 60.8% in luminal A-like vs. 63.5% in triple-negative vs. 65.5% in HER2-positive and 69.7% in luminal B-like subtype). Conclusions: In young BRCAPVs carriers with early BC, hormone receptor status did not appear to be a positive prognostic factor. The differences in pattern of recurrence and second primary BC among hormone receptor-positive vs. negative disease warrants consideration in counseling patients on treatment, follow-up strategies and indication for risk-reducing surgery.

Clinical behavior of breast cancer in young BRCA carriers and prognostic impact of the timing of genetic testing: Results from an international cohort study.

10503 Background: Germline BRCA testing is recommended in all patients (pts) diagnosed with breast cancer (BC) at a young age (40 years or younger). Limited evidence exists regarding clinical behavior of BC in young BRCA1and BRCA2 carriers or the impact of the timing of genetic testing (before or at diagnosis) on tumor characteristics and pts outcomes. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including pts harboring germline pathogenic variants (PVs) in BRCA1or BRCA2 and diagnosed with stage I-III invasive BC at 40 years or younger between January 2000 and December 2020 (NCT03673306). Baseline pt, tumor, and treatment characteristics, as well as survival outcomes (disease-free survival [DFS] and overall survival [OS]) were compared between BRCA1and BRCA2carriers. A further comparison was performed between pts who underwent genetic testing before (i.e. any time up to 2 months prior to BC diagnosis) or at (i.e. between 2 months prior and up to 6 months after diagnosis) BC diagnosis. Results: From 78 centers worldwide, 4,752 pts were included, of whom 3069 harbored BRCA1and 1683 BRCA2 PVs. Compared to BRCA2carriers, BRCA1 carriers were significantly younger, had more grade 3 tumors, less nodal involvement, lobular histology, hormone receptor and HER2 positivity, and received chemotherapy more frequently and endocrine therapy less frequently. Median follow-up was 7.8 years (range 4.4-12.6 years). Second primary BCs (13.7% vs. 9.3%) and non-breast new primary malignancies (4.5% vs. 3.0%) were significantly more frequent among BRCA1 carriers, while distant recurrences were less frequent (9.7% vs. 13.6%). No differences in DFS or OS were observed between BRCA1 and BRCA2 carriers. However, BRCA1 carriers had worse DFS and OS in the first 5 years due to a peak in DFS events in the first 2 years while BRCA2 carriers had a constant risk of recurrence over time and worse OS after year 9. Compared to pts tested for BRCA at BC diagnosis (n = 1671), those tested before BC diagnosis (n = 411) had significantly smaller tumors (T1: 61.3% vs 32.4%) and less nodal involvement (N0: 65.9% vs 50.8%). 8-year DFS and OS in patients tested before and at BC diagnosis were 73% vs 70% (HR 1.25; 95% CI 0.99-1.58) and 91% vs 87% (HR 1.65; 95% CI 1.08-2.52), respectively. Conclusions: In this global study of young BRCA carriers, different pts, tumor, and treatment characteristics, as well as pattern and risk of DFS/OS events over time were observed between BRCA1and BRCA2. Identification of carrying a BRCA PV in healthy individuals led to earlier BC diagnosis and improved OS. These findings highlight the importance of conducting efforts to identify women at risk for carrying a BRCA1or BRCA2PV to offer them genetic counseling and testing to inform not only prevention, but tailored earlier detection, treatment and follow-up strategies once diagnosed.

Familial disclosure of mutational status and cascade testing: Relationships with cancer-predisposing genes and race/ethnicity.

10605 Background: Patients (pts) with cancer-predisposing genes may differ in the patterns of genetic testing disclosure to family members and cascade testing. We examined the relationships between varying levels of cancer-predisposing gene penetrance and racial/ethnic differences in familial disclosure and cascade testing. Methods: Between July-September 2023, we conducted a follow-up survey of pts enrolled in the University of Chicago Cancer Prone Study, a longitudinal cohort of high-risk families initiated in 1992. Pts were asked questions about familial disclosure and cascade testing, including whether they 1) carry a gene mutation(s); 2) told any family member about their mutation status; 3) received a family letter from their genetic counselors after testing; and 4) had any family member having undergone testing for the familial mutation(s). Chi-squared or Fisher’s exact tests were performed. Results: Of 912 respondents, 35.3% (n=312) reported carrying a genetic mutation. The mean age was 54.8 years (SD=13.7); 86.9% were White, followed by 4.8% Black, 5.1% Hispanic, and 3.2% other/multiracial; 45.8% had a graduate/professional degree; 31.5% had an annual household income of ≥$200,000; 70.9% and 23.9% were privately insured and on Medicare/Medicaid, respectively. Among pts with a genetic mutation, 37.8% had a BRCA1 (n=63) or BRCA2 (n=55) mutation. The vast majority (96.5%) disclosed their mutation status to a family member. The disclosure status differed significantly by race/ethnicity (Hispanic 100.0%, White 98.5%, Black 92.3%, vs. other/multiracial 80.0%; p=0.013). First-degree relatives were the most communicated to, and the most cited reasons for disclosure were “awareness of potential risk” (n=264) and “support preventive measures” (n=224). Among pts carrying a gene mutation, 50.6% (n=158) reported having received a letter from their genetic counselors to share with any family member and of these, 82.2% (n=129) did share their family letters. Among pts who did not receive or did not know if they received a letter (n=149), 41.6% stated that the letter would have helped them disclose the information to their family members. Further, 79.1% of the pts reported that their family members underwent genetic testing, with no significant differences in cascade testing by race/ethnicity and other demographic characteristics. However, pts with a positive mutation in BRCA1or BRCA2 (92.6%) were more likely to have a cascade testing, when compared to pts with other mutations (76.8%; p&lt;0.001). Conclusions: Although familial disclosure of mutational status was high, cascade testing was not high enough and it depends on the penetrance of cancer-predisposing genes. Understanding genetic testing disclosure and cascade testing from a gene-to-gene basis could help improve genetic counseling and risk communication particularly for racial/ethnic minority pts.

Addressing disparities in the uptake of genetic counseling and testing in African American women; rationale, design and methods

BackgroundGenetic counseling and testing (GCT) informs risk reduction and management strategies in women at risk for carrying a pathogenic variation in the BRCA1 or BRCA2 (BRCA1/2) genes. African American (hereinafter referred to as Black) women are less likely to receive GCT services for hereditary breast and ovarian cancer (HBOC). The objective of this work was to examine existing literature regarding successful culturally tailored GCT interventions for Black women and to describe the rationale and protocol for a randomized feasibility trial to test the efficacy of a culturally tailored GCT intervention. Methods/designThe For Our Health (FOH) study is a two-arm randomized control trial designed to test the efficacy of a video intervention to promote the uptake of GCT among Black women with a high risk of HBOC. The culturally tailored video intervention targets key beliefs, knowledge gaps, misconceptions, and key anticipated emotions relevant for GCT. After completing the baseline survey, 50 women at risk of HBOC will be randomized (1:1) to one of two trial arms: a YouTube video intervention or a publicly available fact sheet. Final assessments will immediately follow receipt of either video or fact sheet. ConclusionFew studies have tested interventions to improve GCT uptake among Black women. The FOH trial will fill an important scientific gap in knowledge regarding strategies to reduce disparities in GCT among Black women at risk of HBOC.

Exceptional responses to PARP inhibitors in patients with metastatic breast cancer in oncologic crisis.

Cancers deficient in homologous recombination DNA repair, such as those with BRCA1 or BRCA2 (BRCA1/2) mutations rely on a pathway mediated by the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). PARP inhibitors (PARPi's) have demonstrated efficacy in treating patients with germline (g)BRCA1/2, somatic (s)BRCA1/2, and gPALB2 mutations in clinical trials. However, patients with a poor performance status (PS) and those with severe organ impairment are often excluded from clinical trials and cancer-directed treatment. We report the cases of two patientswith metastatic breast cancer who had poor PS, significant visceral disease, and gPALB2 and sBRCA mutations, who derived significant clinical benefit from treatment with PARP inhibition. Patient A had germline testing demonstrating a heterozygous PALB2 pathogenic mutation (c.3323delA) and a BRCA2 variant of unknown significance (c.9353T>C), and tumor sequencing revealed PALB2 (c.228_229del and c.3323del) and ESR1 (c.1610A>C) mutations. Patient B was negative for pathologic BRCA mutations upon germline testing, but tumor sequencing demonstrated somatic BRCA2 copy number loss and a PIK3CA mutation (c.1633G>A). Treatment with PARPi's in these two patients with an initial PS of 3-4 and significant visceral disease resulted in prolonged clinical benefit. Patients with a poor PS, such as those described here, may still have meaningful clinical responses to cancer treatments targeting oncogenic drivers. More studies evaluating PARPi's beyond gBRCA1/2 mutations and in sub-optimal PS would help identify patients who may benefit from these therapies.

Abstract P5-03-15: Application of 21-gene Breast Recurrence Score® assay to evaluate prognosis and benefit of adjuvant chemotherapy in BRCA1 and BRCA2 pathogenic variant carriers with early stage, estrogen receptor positive breast cancer

Abstract Background: Minimal data exists for the utilization of the Oncotype Dx® assay specifically in breast cancers associated with BRCA1/2 pathogenic variants (PVs). It is unknown whether estrogen receptor positive (ER+) breast cancer associated with an inherited BRCA1 or BRCA2 (BRCA1/2) PV is more aggressive than disease seen in patients who do not carry an inherited PV, and whether there are differences between BRCA1 and BRCA2. In prostate cancer patients with inherited cancer predisposition due to a BRCA2 PV, more aggressive cancers are observed, which influences first-line treatment. Limited data exists for the optimal management of early stage ER+ breast cancer in BRCA1/2 PV carriers. Comparing Recurrence Score® (RS) results in ER+ breast cancer patients with an inherited BRCA1/2 PV (cases) versus matched patients who test negative for a PV in BRCA1/2 (controls) may inform whether biologically more aggressive breast cancer is seen in BRCA1/2 carriers and optimal treatment approaches. Methods: A retrospective case control study was performed to compare RS results in women with breast cancer with an inherited BRCA1/2 PV versus patients who tested negative for an inherited BRCA1/2 PV. Female breast cancer patients seen between 2005-2020 at NorthShore University Health System with ER+Her2- early stage invasive breast cancer with 0-3 lymph nodes who completed genetic testing for BRCA1/2 were eligible for enrollment. BRCA1/2 cases were defined as individuals with an inherited PV in BRCA1/2 and controls were negative for BRCA1/2 or other known breast cancer risk gene PVs tested. Subjects were excluded if they had neoadjuvant therapy (hormonal or cytotoxic chemotherapy). Eligible cases were matched to control patients by age, grade, and stage. The Recurrence Score result was obtained by chart review; if not previously evaluated, Oncotype Dx assay was performed by Exact Sciences. Statistical analysis of the primary outcome used the paired t-test to determine mean difference in RS results between BRCA1/2 PV carriers and patients negative for a PV in BRCA1/2 using a 1:1 matched pairs design. Results: A total of 46 matched cases and controls were analyzed. Median age was 50 with a range of 28-74. Of the cases, 18 had a BRCA1 PV and 28 had a BRCA2 PV. Cases and controls were well matched for age (&amp;gt; 50 and ≤ 50); race, grade, stage, and progesterone receptor status. As expected, a higher number of BRCA1/2 carriers were treated with mastectomy while more of the controls received breast-conserving surgery. Chemotherapy was utilized more frequently in the cases (67.4%) versus the controls (54.4%). The average RS result was higher in the cases (27) than the controls (21.3) by a mean difference of 5.7 (p = 0.0195). Using Oncotype Dx cutoffs of low &amp;lt; 18, intermediate 18-30 and high ≥ 31, a statistically significant difference in RS result was noted in the cases versus controls. For cases in the highest risk group (Oncotype Dx ≥ 31), only 20% of their matches also had a score in the highest risk group while 35% had a score in the lowest risk group. Subgroup analysis showed that the cases had the largest difference in RS result from their controls in premenopausal women (age ≤ 50), BRCA1 carriers, and the node negative population. Conclusion We present one of the largest data sets available to date of a well-matched cohort of cases and controls which shows that BRCA1/2 PV carriers are more likely to have a higher Recurrence Score result than their matched controls when matched for age, grade, and stage. These findings suggest ER+ breast cancer in BRCA1/2 PV carriers is biologically more aggressive. Further investigation is warranted to evaluate how this important finding impacts adjuvant therapy recommendations for BRCA1/2 PV carriers. Citation Format: Poornima Saha, Ashley Aller, Amanda Deliere, Peter Hulick, Katharine Yao, Kristine Kuchta, Megan Sullivan, Allison DePersia. Application of 21-gene Breast Recurrence Score® assay to evaluate prognosis and benefit of adjuvant chemotherapy in BRCA1 and BRCA2 pathogenic variant carriers with early stage, estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-03-15.

Abstract P4-01-22: Clinical outcomes of metastatic breast cancer patients treated with poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi): the Mayo Clinic experience

Abstract Background: Two poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) are currently FDA-approved for the treatment of HER2-negative metastatic breast cancer (MBC) in carriers of germline pathogenic variants (PVs) in BRCA1 or BRCA2 (BRCA1/2). This study explores the clinical outcomes of MBC patients treated with a PARPi. Methods: In this retrospective study, we included MBC patients treated with a PARPi between January 2017 and February 2022 at Mayo Clinic (Minnesota, Arizona, Florida, and Mayo Clinic Health Systems). We used the Kaplan Meier method to estimate the time-to-treatment-failure (TTF) and the log-rank test to compare different subsets. In addition, predictors of TTF were identified in a multivariate cox-proportional hazard regression model, including age at PARPi initiation, race, ethnicity, histology, estrogen receptor (ER), progesterone receptor (PR), and HER2 expression of the tumor, the number of prior therapies, type of PARPi, and PV carrier status (germline BRCA1/2 or PALB2 vs. somatic BRCA1/2 vs. other). Results: Sixty-five patients treated with PARPi (olaparib: 51; talazoparib: 14) were included in the final analysis. Fifty-five patients were carriers of germline PVs in BRCA1 (n=24, 37%), BRCA2 (n=27, 42%) or PALB2 (n=4, 6%), whereas ten patients (15%) had no germline PVs but the tumor had a somatic mutation in the homologous recombination-related (HRR) genes (7 in BRCA1/2, 2 in ATM, and 1 in CDKN2A and CDH1). At the data cutoff, 48 (74%) patients had discontinued PARPi due to progression or death. Fifteen (23%) patients required a dose reduction due to side effects. Occurrence of grade ≥ 3 side effects: anemia in 8, fatigue in 4, neutropenia in 2, and thrombocytopenia in 2 patients. Eight (15.7%) patients in the olaparib group and seven (50%) patients in the talazoparib group required a dose reduction for side effects. No patient on olaparib required drug discontinuation due to side effects, whereas two patients on talazoparib were switched to olaparib due to cytopenias and could tolerate olaparib. Median TTF in the overall population was 8 months (95% confidence interval [CI]: 6.4 – 9.6), and there was no difference (p=0.64) in TTF between the olaparib and talazoparib groups. Median TTF in the germline BRCA1, BRCA2, and PALB2 PV carriers were 7, 8, and 11 months, respectively (p=0.57). Among patients with somatic BRCA1/2 mutations, the median TTF was 4 months. Numerically, patients with HER2-positive tumors (n=8) had a shorter TTF compared to HER2-negative tumors (Median TTF: 4 vs. 8 months, p=0.098). No significant difference in TTF was observed by ER or PR status of the tumor, age at initiation of PARPi, the number of prior therapies, and prior use of platinum-based chemotherapy or CDK4/6 inhibitors. In multivariate analysis, HER2 positivity (hazard ratio [HR]: 8.0, 95% CI: 2.2 – 29.4, p=0.002), somatic BRCA1/2 mutations (HR: 7.6, 95% CI: 1.2 – 50.0, p=0.03) and somatic mutations in other HRR genes (HR: 19.1, 95% CI: 3.1 – 118.6, p=0.002) were associated with worse TTF. Conclusions: In the real world, PARPi were well-tolerated with promising time-to-treatment-failure (TTF) benefits comparable to data from clinical trials. Notably, relatively shorter TTF was observed in patients with somatic BRCA1/2 and other HRR gene mutations and HER2-positive MBC. These findings improve our understanding of the role of PARPi in MBC and will help to guide treatment decisions with PARPi in the clinical setting. Citation Format: Nusrat Jahan, Jodi Taraba, Karthik V. Giridhar, Roberto A. Leon-Ferre, Amye J. Tevaarwerk, Elizabeth Cathcart-Rake, Ciara C. O’Sullivan, Prema Peethambaram, Timothy J. Hobday, Kathryn Ruddy, Lida A. Mina, Pooja Advani, Felipe Batalini, Matthew P. Goetz, Tufia C. Haddad, Fergus J. Couch, Siddhartha Yadav. Clinical outcomes of metastatic breast cancer patients treated with poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi): the Mayo Clinic experience [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-22.

BRCA1/2 Pathogenic Variants Are Not Common in Merkel Cell Carcinoma: Comprehensive Molecular Study of 30 Cases and Meta-Analysis of the Literature

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine cancer. Management of advanced MCC is mainly based on immune-checkpoint inhibitors. The high failure rate warrants an investigation of new therapeutic targets. The recent identification of BRCA1 or BRCA2 (BRCA1/2) mutations in some MCC raises the issue of the use of poly-(ADP-Ribose)-polymerase inhibitors in selected advanced cases. The main objective of our study is to determine the accurate frequency of BRCA1/2 pathogenic variants. We studied a series of 30 MCC and performed a meta-analysis of BRCA1/2 variants of published cases in the literature. In our series, we detected only one BRCA2 pathogenic variant. The low frequency of BRCA1/2 pathogenic variants in our series of MCC (3%) was confirmed by the meta-analysis of BRCA1/2 variants in the literature. Among the 915 MCC from 13 published series studied for molecular alterations of BRCA1/2, only 12 BRCA1/2 pathogenic mutations were identified (1-2% of MCC), whereas many other BRCA1/2 variants were variants of unknown significance or benign. BRCA1/2 pathogenic variants are uncommon in MCC. However, in BRCA-mutated MCC, poly-(ADP-Ribose)-polymerase inhibitors might be a valuable therapeutic option requiring validation by clinical trials.

The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models.

Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease. To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC. Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 (BRCA1/2), four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken. Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2-mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1. The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.

Association and performance of polygenic risk scores for breast cancer among French women presenting or not a familial predisposition to the disease

BackgroundThree partially overlapping breast cancer polygenic risk scores (PRS) comprising 77, 179 and 313 SNPs have been proposed for European-ancestry women by the Breast Cancer Association Consortium (BCAC) for improving risk prediction in the general population. However, the effect of these SNPs may vary from one country to another and within a country because of other factors. ObjectiveTo assess their associated risk and predictive performance in French women from (1) the CECILE population-based case-control study, (2) BRCA1 or BRCA2 (BRCA1/2) pathogenic variant (PV) carriers from the GEMO study, and (3) familial breast cancer cases with no BRCA1/2 PV and unrelated controls from the GENESIS study. ResultsAll three PRS were associated with breast cancer in all studies, with odds ratios per standard deviation varying from 1.7 to 2.0 in CECILE and GENESIS, and hazard ratios varying from 1.1 to 1.4 in GEMO. The predictive performance of PRS313 in CECILE was similar to that reported in BCAC but lower than that in GENESIS (area under the receiver operating characteristic curve (AUC) = 0.67 and 0.75, respectively). PRS were less performant in BRCA2 and BRCA1 PV carriers (AUC = 0.58 and 0.54 respectively). ConclusionOur results are in line with previous validation studies in the general population and in BRCA1/2 PV carriers. Additionally, we showed that PRS may be of clinical utility for women with a strong family history of breast cancer and no BRCA1/2 PV, and for those carrying a predicted PV in a moderate-risk gene like ATM, CHEK2 or PALB2.

Uptake of BRCA1/BRCA2 predictive genetic testing in an Irish population is low: a missed opportunity.

Predictive testing for BRCA1 or BRCA2 allows at-risk individuals to engage with appropriate screening and treatment services if a pathogenic mutation is identified. Previous studies have shown uptake of predictive testing to most commonly range between 20% and 40% (Table 2). This represents a missed cancer prevention opportunity. Possible explanations for this low uptake include lack of disclosure of at-risk status to relatives, lack of awareness of cancer genetics services, or patient preference. The goal of the current study was to investigate the uptake of BRCA1 or BRCA2 predictive testing in an Irish population. We performed a multicentre, retrospective analysis of 63 pedigrees from two Irish tertiary referral hospitals over a five-year period (2012-2017). Family pedigrees were reviewed to identify at-risk family members eligible for predictive BRCA1 or BRCA2 mutation testing as per international guidelines, and testing rates were determined. A total of 1048 eligible individuals were identified, 318 (30.4%) proceeded to BRCA1 or BRCA2 germline testing including [215 (37.5%) females and 99 males (21.5%)]. Women were significantly more likely to test than men (T= 3.7, p< .0002). Uptake of testing was significant higher amongst first-degree relatives 45% (150/323) compared to 20% (50/258) amongst second degree relatives, and 10 % (33/317) amongst more distant relatives (F= 25.32, p < 0.00001). Uptake of BRCA1 OR BRCA2 mutation testing in Ireland is suboptimal, particularly amongst Irish males and distant relatives. Further research is needed to identify strategies which may improve uptake within current legal and ethical frameworks.

Methylated DNA markers discriminate ovarian cancer from benign tissue in BRCA carriers.

e17610 Background: Methylated DNA markers (MDMs) associated with sporadic ovarian cancer (OC) are detected in plasma from patients with treatment naïve tumors, but not cancer-free controls. To assess potential benefits to patients at risk for hereditary OC, the aim of this study was to measure the performance of validated sporadic OC MDMs in OC and benign ovarian tissue (BOT), surgically obtained from germline BRCA1 or BRCA2 ( BRCA1/2) mutation carriers. Methods: BRCA1/2 carriers with OC and BRCA1/2 carriers who had undergone risk-reducing salpingo-oophorectomy (SO) were identified at a comprehensive cancer center. BRCA1/2 carriers in both OC and BOT groups were balanced on age and year of surgery with non- BRCA carriers with sporadic OC or benign indications for SO. OC and BOT formalin fixed paraffin embedded (FFPE) tissues were macrodissected following pathologist selection of representative sites; DNA was extracted, and bisulfite converted. 15 OC MDMs ( GDF6, IFFO1, MAX.chr1.147790358, MAX.chr6.10382190, MAX.chr11.14926602, C2CD4D, PDRM14, NCOR2, SKI, DSCR6, SIM2, PALLD, CDO1, GPRIN1, BCAT1) previously identified in sporadic OC were assayed by quantitative methylation specific PCR, normalized by β-actin, by blinded personnel. Areas under the receiver operating characteristic curve (AUC) were generated for each MDM to assess discrimination of OC from benign tissue and compared between BRCA1/2 and sporadic (non- BRCA) patients, using a z-test. Results: Among BRCA1/2 carriers, there were 48 OC ( BRCA-OC) and 48 BOT ( BRCA-BOT); among non- BRCA, we matched 48 OC (Sporadic-OC) and 48 BOT (non- BRCA-BOT). The median AUC for OC MDM discriminated between OC and BOT with AUCs in BRCA1/2 carriers was 0.87, (IQR, 0.83-0.93). Sporadic-OC vs non- BRCA-BOT median AUC was 0.88 (IQR, 0.83-0.92). AUCs were not significantly different for each MDM when stratified by BRCA or sporadic status. MDMs with an AUC of ≥0.9 in either group are shown (Table). Conclusions: OC MDMs identified and validated in sporadic OC are highly discriminant for OC from BOT in DNA extracted from tissues of people who carry a BRCA1/2 mutation. Testing the performance of these OC MDMs in plasma from BRCA1/2 carriers with and without OC may be of clinical value for high-risk patients and inform multi-cancer early detection testing strategies.[Table: see text]

Upregulation of CXCL1 and LY9 contributes to BRCAness in ovarian cancer and mediates response to PARPi and immune checkpoint blockade.

Mutations in BRCA1 or BRCA2 (BRCA1/2) cause homologous recombination deficiency (HRD). Ovarian cancer (OvCa) patients harbouring HRD beyond BRCA1/2 mutation result in a state referred to as "BRCAness". OvCa with BRCAness could benefit from PARP inhibitors. This study aims to identify a signature to detect the BRCAness population at the transcriptome level. We used a rank-based algorithm to develop a qualitative BRCAness signature for OvCa. Upregulation of CXCL1 with downregulation of SV2A and upregulation of LY9 with downregulation of CHRNB3 were constructed as the BRCAness signature (2 gene pairs, 2-GPS) for OvCa. OvCa samples that were classified as BRCAness by 2-GPS showed improved overall survival, progression-free survival and exhibited increased multi-omics alterations in homologous recombination genes and enhanced sensitivity to immune checkpoint blockade. BRCAness cells were sensitive to PARP inhibitors. By biological experiments, we validated SKOV3 cells and patients with HRD exhibited higher expression of CXCL1 than SV2A and higher expression of LY9 than CHRNB3 at mRNA level. Both SKOV3 and A2780 with HRD were sensitive to mitomycin C, cisplatin and olaparib. In conclusion, 2-GPS could robustly predict BRCAness OvCa at the individual level and extend the population who may benefit from PARP inhibitors.

Rucaparib for BRCA1/2-mutated pretreated ovarian cancer: reflections from the ARIEL4 trial.

The discovery that homologous recombination deficiency (HRD), a DNA repair defect present in tumours with BRCA1 or BRCA2 (BRCA1/2) mutations, can prevent affected cells from overcoming replicative or drug-induced DNA double-strand breaks both suggested a new therapeutic possibility and explained the observed heterogeneity of chemotherapy effectiveness in women with ovarian cancer. Oral PARP inhibitors were predictably active against BRCA1/2-mutated tumours, by disrupting other DNA repair mechanisms,1 an effect known as synthetic lethality.

Interrelation of functional homologous recombination deficiency and hrr pathway alterations in prostate cancer.

151 Background: The use of PARP inhibitors (PARPi) may trigger synthetic lethality of tumor cells in the context of deficient homologous recombination repair (HRR). Approximately 10-20% of patients with prostate cancer harbor mutations in the HRR pathway, but HRR-associated mutations do not consistently predict the response to PARPi. Considering alternative methods to define Homologous Recombination Deficiency (HRD)—the inability to repair double strand breaks—may aid in identifying additional tumors that are sensitive to PARPi. Here, we evaluate the relationship between HRD status and HRR mutations amongst a large cohort of patients with prostate cancer. Methods: Retrospective analysis of 1,022 de-identified patients with prostate cancer that underwent next generation sequencing (NGS) with the Tempus|xT assay (DNA-seq of 648 genes at 500x coverage, whole-exome capture RNA-seq) was performed. Comparison groups were defined based on HRR alterations—either mono- or bi-allelic alterations of BRCA1 or BRCA2 ( BRCA1/2), ATM, or other HRR pathway genes. HRD status was determined via the Tempus RNA-based HRD algorithm. Results: Among this cohort, mono (-/+) or biallelic (-/-) alterations of HRR genes were found in 432 patients: BRCA1/2 -/- (n = 31), BRCA1/2 -/+ (n = 87), ATM-/- (n = 24), ATM-/+ (n = 67), other HRR-/- (n = 54), other HRR-/+ (n = 169) or no HRR alterations (n = 590). The BRCA1/2-/- group had a higher frequency of Asians (17% vs. &lt; 7% in all other groups) and were diagnosed at younger ages (median 62 years vs. &gt; 65 for all other groups). We identified 130/1022 (13%) patients with prostate cancer to be HRD-positive (HRD+) and observed significant differences in HRD positivity according to the type of HRR alteration observed (Table). Notably, 54% (70/130) of HRD+ patients had no mutations in any genes associated with the HRR pathway. Conversely, 89% (278/314) of patients with non- BRCA1/2 HRR mutations were HRD negative. Amongst all individuals with biallelic loss of any HRR gene, HRD positivity was most enriched for BRCA2-/- (16/29, p &lt; 0.001) and PALB2-/- (3/4, p = 0.082). Conclusions: By using an RNA-based HRD algorithm, we found 13% of patients with prostate cancer are HRD+. This RNA-based HRD signature not only captures patients with HRR mutations but also identifies a substantial population of HRD+ patients who are currently undetectable by methods based solely on sequencing HRR genes. Further research is needed to assess the clinical response to PARPi in this HRD+ population, as well as the response to PARPi in the HRD negative population who harbor HRR gene alterations.[Table: see text]

Abstract OT2-18-01: Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer

Abstract Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) that occurs in the context of a germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial studied the selective estrogen receptor downregulator fulvestrant and the CDK4 and CDK6 inhibitor (CDK4/6i) palbociclib in patients with HR+ MBC. Compared with fulvestrant and placebo, combination fulvestrant and palbociclib demonstrated significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival. The OlympiAD trial examined patients with HER2-negative MBC and a germline BRCA1/2 mutation who were treated with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib or non-platinum chemotherapy. Olaparib resulted in improved PFS, double the response rate, and a lower risk of disease progression or death compared to chemotherapy. Despite these remarkable therapeutic advances, resistance to treatment inevitably develops and contributes to mortality in patients with MBC. Targeting dual therapeutic drivers concurrently may delay or circumvent resistance; however, olaparib and palbociclib have overlapping hematologic toxicity and the safety of combined olaparib, palbociclib and fulvestrant has not been determined. Methods: HOPE (NCT03685331) is a phase I/II clinical trial to evaluate the safety and efficacy of olaparib, palbociclib and fulvestrant in patients with HR+ MBC and a pathogenic or likely pathogenic germline or somatic variant in BRCA1/2. Eligible patients are biological males, postmenopausal females, or premenopausal females on ovarian suppression who have an ECOG performance status 0-1, measureable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior platinum chemotherapy is allowed for curative intent treatment if completed at least 12 months prior to diagnosis of metastatic disease, or for MBC if there was no progression during therapy. Prior PARPi and prior CDK4/6i are permitted without restriction during phase I, and are permitted during phase II provided there was no progression on these therapies. Treatment (28-day cycles) consists of: olaparib 300mg by mouth twice daily continuously; fulvestrant 500mg intramuscularly on day 1 of each cycle and day 15 of the first cycle; and oral palbociclib once daily on days 1-21. For phase I, palbociclib dose is based on dosing cohort. Dose Levels (DL) are: DL 0 (starting level), 75mg; DL 1, 100mg; DL 2, 125mg. Phase I treatment begins with a 28-day safety run-in of fulvestrant and olaparib alone. For phase II, palbociclib will be dosed at MTD. Subjects will have archival tissue collection or fresh biopsy at baseline as well as research blood samples for cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). The phase I primary endpoint is determination of MTD. A 3+3 dose escalation design will be utilized with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. This schema yields a minimum of 2 and a maximum of 18 patients on the phase I. For the phase II trial, the primary endpoint is PFS estimated using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. The phase II trial will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with olaparib monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment has begun. Citation Format: Alexandra Torres, Carey Kokkonen, Mary Oladeji, Kurt D'Andrea, Rosemarie Mick, Vivek Narayan, Michael Mallamaci, Gayle Ewing, Hayley Knollman, Nadine M. Tung, Mark Robson, Katherine L. Nathanson, Susan Domchek, Payal D. Shah. Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-18-01.

Anti‐tumoural activity of the G‐quadruplex ligand pyridostatin against BRCA1/2‐deficient tumours

The cells with compromised BRCA1 or BRCA2 (BRCA1/2) function accumulate stalled replication forks, which leads to replication‐associated DNA damage and genomic instability, a signature of BRCA1/2‐mutated tumours. Targeted therapies against BRCA1/2‐mutated tumours exploit this vulnerability by introducing additional DNA lesions. Because homologous recombination (HR) repair is abrogated in the absence of BRCA1 or BRCA2, these lesions are specifically lethal to tumour cells, but not to the healthy tissue. Ligands that bind and stabilise G‐quadruplexes (G4s) have recently emerged as a class of compounds that selectively eliminate the cells and tumours lacking BRCA1 or BRCA2. Pyridostatin is a small molecule that binds G4s and is specifically toxic to BRCA1/2‐deficient cells in vitro. However, its in vivo potential has not yet been evaluated. Here, we demonstrate that pyridostatin exhibits a high specific activity against BRCA1/2‐deficient tumours, including patient‐derived xenograft tumours that have acquired PARP inhibitor (PARPi) resistance. Mechanistically, we demonstrate that pyridostatin disrupts replication leading to DNA double‐stranded breaks (DSBs) that can be repaired in the absence of BRCA1/2 by canonical non‐homologous end joining (C‐NHEJ). Consistent with this, chemical inhibitors of DNA‐PKcs, a core component of C‐NHEJ kinase activity, act synergistically with pyridostatin in eliminating BRCA1/2‐deficient cells and tumours. Furthermore, we demonstrate that pyridostatin triggers cGAS/STING‐dependent innate immune responses when BRCA1 or BRCA2 is abrogated. Paclitaxel, a drug routinely used in cancer chemotherapy, potentiates the in vivo toxicity of pyridostatin. Overall, our results demonstrate that pyridostatin is a compound suitable for further therapeutic development, alone or in combination with paclitaxel and DNA‐PKcs inhibitors, for the benefit of cancer patients carrying BRCA1/2 mutations.

Diagnostic chest X-rays and breast cancer risk among women with a hereditary predisposition to breast cancer unexplained by a BRCA1 or BRCA2 mutation

BackgroundDiagnostic ionizing radiation is a risk factor for breast cancer (BC). BC risk increases with increased dose to the chest and decreases with increased age at exposure, with possible effect modification related to familial or genetic predisposition. While chest X-rays increase the BC risk of BRCA1/2 mutation carriers compared to non-carriers, little is known for women with a hereditary predisposition to BC but who tested negative for a BRCA1 or BRCA2 (BRCA1/2) mutation.MethodsWe evaluated the effect of chest X-rays from diagnostic medical procedures in a dataset composed of 1552 BC cases identified through French family cancer clinics and 1363 unrelated controls. Participants reported their history of X-ray exposures in a detailed questionnaire and were tested for 113 DNA repair genes. Logistic regression and multinomial logistic regression models were used to assess the association with BC.ResultsChest X-ray exposure doubled BC risk. A 3% increased BC risk per additional exposure was observed. Being 20 years old or younger at first exposure or being exposed before first full-term pregnancy did not seem to modify this risk. Birth after 1960 or carrying a rare likely deleterious coding variant in a DNA repair gene other than BRCA1/2 modified the effect of chest X-ray exposure.ConclusionEver/never chest X-ray exposure increases BC risk 2-fold regardless of age at first exposure and, by up to 5-fold when carrying 3 or more rare variants in a DNA repair gene.Further studies are needed to evaluate other DNA repair genes or variants to identify those which could modify radiation sensitivity. Identification of subpopulations that are more or less susceptible to ionizing radiation is important and potentially clinically relevant.