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Background BRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs). Methods We characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database. Results Among BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis ( P  = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage ( P for trend = 2 × 10 −5 ) and higher grade ( P for trend = 0.005) and were more likely to be oestrogen receptor–positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15–21.80] and progesterone receptor–positive (OR 5.04; 95 % CI 3.17–8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database ( P for trend = 4 × 10 −12 ). Conclusions On the basis of the largest series analysed to date, our results show that BRCA1 / 2 MBCs display distinct pathologic characteristics compared with BRCA1 / 2 FBCs, and we identified a specific BRCA2- associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a high mortality rate. While up to 20% of PDAC patients harbor mutations in genes involved in homologous recombination (HR) repair, only 5% of germline BRCA1/2 mutation carriers have an approved treatment option with the PARP inhibitor (PARPi) olaparib. Characterizing HR‐deficient (HRD) genotypes beyond gBRCA1/2 that are susceptible to PARPi has potential to substantially broaden the eligible patient population, and defining the optimal inhibitor may further optimize treatment strategies to advance personalized medicine in PDAC. Objective Our previous preclinical work showed synthetic lethality of a multi‐pronged DNA damage repair interference strategy using the PARPi olaparib, ATR inhibitor VE‐822, and DNA‐PK inhibitor CC‐115 (termed PAD) in ATM deficiency. In the present study, we challenged the role of olaparib in our PAD combination and assessed the regimen's efficacy across various HRD genotypes. Methods We assessed a spectrum of DNA damage repair‐interfering drugs to identify the most potent inhibitor in HRD. Using ATM, BRCA1, BRCA2 and PALB2‐defective versus HR‐proficient murine PDAC cells, we systematically investigated the feasibility of expanding an optimized PAD regimen within defined HRD genotypes in vitro and in vivo. The regimen's efficacy was validated in PDAC patient‐derived organoids with and without deleterious class IV/V alterations in HRD genes. Results and Conclusion Here, we demonstrate a remarkable potency of the PARPi talazoparib in HRD PDAC. Substituting olaparib, currently the only approved inhibitor in PDAC, with talazoparib in our PAD regimen enhanced its efficacy while maintaining comparable tolerability in vivo. Importantly, we show that PAD is an effective therapeutic regimen that can be extended to the most prevalent HR‐defective genotypes in PDAC including ATM, BRCA1, BRCA2 and PALB2 in a preclinical setting. Collectively, these data provide a strong rationale to implement the refined regimen, talazoparib‐based PAD, as a therapeutic concept tailored for HRD PDAC patients.

Breast Cancer Associated Susceptibility Proteins Type 1/2 (BRCA1/2) promote cellular functioning by modulating NRF2-mediated antioxidant signaling. Redox failure in women with BRCA1/2 insufficiency increases the risk for breast/ovarian/uterine cancers. Risk-reducing salpingo-oophorectomy (RRSO) is a prophylactic surgery of the reproductive organs, which is frequently conducted by the age of 40 to lower the occurrence of cancer in women with BRCA1/2 mutations. However, abrupt estrogen decline following RRSO causes ovarian failure, which implicates various cellular physiological processes, resulting in the increased release of free radicals and subsequent severe onset of menopausal symptoms. Comfort measures (e.g., hormonal replacement therapy (HRT) and mindfulness-based stress reduction (MBSR)) may improve chronological menopause-related quality of life, but their specific effects are not clear in women with gene mutations. Aiming to fill the gap, this study used path analysis to examine the effects of HRT and MBSR on menopausal symptoms among RRSO patients (N = 199, mean age = 50.5 ± 6.7 years). HRT directly alleviated the levels of urogenital symptoms (β = −0.195, p = 0.005), which mediated its indirect significant effects on the somatic–vegetative and psychological symptoms of menopause (β = −0.046, −0.067; both p values = 0.004, respectively), especially in BRCA2 carriers and in women who were currently physically active, premenopausal at the time of RRSO, had a high BMI, and had no history of breast cancer. It increased the severity of urogenital symptoms in women with a history of cancer. MBSR, on the other hand, was associated with indirect increases in the intensity of the somatic–vegetative and psychological symptoms of menopause (β = 0.108, 0.029; p = 0.003, 0.033, respectively). It exerted positive direct effects on different menopausal symptoms in multigroup analysis. The results suggest that young women undergoing recent RRSO may benefit from HRT at an individual level, while their need for extensive measures to optimize their psychological wellbeing is ongoing. The adverse effects of MBSR, which are captured in the present study, imply that MBSR may interfere with redox sensitivity associated with estradiol fluctuations in BRCA1/2 carriers. Investigations are needed to test this hypothesis and elaborate on the underlying mechanisms in these women.

This qualitative interview study focuses on the experiences of a sample of British female BRCA 1/2 carriers who had predictive testing before the age of 30, which is the minimum age for breast screening in the UK. Following appropriate informed consent procedures participants were recruited through the Cancer Genetics Service for Wales. Semi-structured interviews were conducted face-to-face with seven participants, transcribed in full and analyzed using thematic analysis. The motives for testing and perceived advantages described by participants were similar to those identified in previous studies with older participants, such as increased awareness and knowledge and feeling more in control. However some of the perceived disadvantages were specific to younger women, including feeling pressured to make important life decisions earlier than they would have liked, such as about family planning and risk reducing surgery. Participants also reported feeling abandoned or forgotten because of lack of ongoing clinical contact, or feeling “stuck waiting” for screening to begin. However, none felt that these disadvantages were a reason to regret having testing. Findings in this small study suggest that having BRCA 1/2 predictive testing can have positive outcomes for young women even though they may be unable to access interventions such as breast screening. However it may be helpful to encourage young women during pre-test counseling to explore the decisions and choices they may face. These young women could benefit from ongoing support and follow up and increased interaction with healthcare professionals.

Triple-negative breast cancers (TNBCs) are defined by the absence of estrogen and progesterone receptors and the absence of HER2 overexpression. These cancers represent a heterogeneous breast cancer subtype with a poor prognosis. Few systemic treatment options exist besides the use of chemotherapy (CT). The heterogeneity of the disease has limited the successful development of targeted therapy in unselected patient populations. Currently, there are no approved targeted therapies for TNBC. However, intense research is ongoing to identify specific targets and develop additional and better systemic treatment options. Standard adjuvant and neoadjuvant regimens include anthracyclines, cyclophosphamide, and taxanes. Platinum-based CT has been proposed as another CT option of interest in TNBC. We review the role of this therapy in general, and particularly in patients carrying BRCA germ-line mutations. Available data concerning the role of platinum-based CT in TNBC were acquired primarily in the neoadjuvant setting. The routine use of platinum-based CT is not yet recommended by available guidelines. Many studies have reported the molecular characterization of TNBCs. Several actionable targets have been identified. Novel therapeutic strategies are currently being tested in clinical trials based on promising results observed in preclinical studies. These targets include androgen receptor, EGFR, PARP, FGFR, and the angiogenic pathway. We review the recent data on experimental drugs in this field. We also discuss the recent data concerning immunologic checkpoint inhibitors.

Background High-grade serous ovarian cancer is a detrimental disease. Treatment options in patients with a recurrent disease are dependent on BRCA1/2 mutation status since only patients with known BRCA mutation are eligible for treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). The aim of this study was to compare concordance of BRCA mutation analyses from cytological samples (CS) with BRCA mutation analyses from histological formalin fixed paraffin embedded (FFPE) samples. Methods Mutation analysis of BRCA1 and BRCA2 genes was performed in 44 women diagnosed with primary or recurrent high-grade ovarian cancer from three different samples: blood, cytological sample (ascites, pleural effusion and enlarged lymph nodes) and tumor tissue. Results from all three samples were compared. Results Among 44 patients, there were 15 germline mutations and two somatic mutations. A 100% concordance was found between cytological and histologic samples. Conclusion There is a 100% concordance in BRCA mutation testing between cytological and histologic samples. BRCA mutation testing from CS could replace testing from FFPE tissue in clinical decision making in ovarian cancer patients. Trial registration The study was retrospectively registered at ISRCTN registry on 24/11/2015 - ISRCTN42408038 .

PurposeThe molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants.MethodsFour BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay.ResultsWe identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities.ConclusionIn this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants.

Background Despite the association of pathogenic variants (PVs) in cancer predisposition genes with significantly increased risk of breast cancer (BC), uptake of genetic testing (GT) remains low, especially among ethnic minorities. Our prior study identified that a patient decision aid, RealRisks, improved patient-reported outcomes (including worry and perceived risk) relative to standard educational materials. This study examined patients’ GT experience and its influence on subsequent actions. We also sought to identify areas for improvement in RealRisks that would expand its focus from improved GT decision-making to understanding results. Methods Women enrolled in the parent randomized controlled trial were recruited and interviewed. Demographic data was collected from surveys in the parent study. Interviews were conducted, transcribed, and coded to identify recurring themes. Descriptive statistics were generated to compare the interviewed subgroup to the original study cohort of 187 women. Results Of the 22 women interviewed, 11 (50%) had positive GT results, 2 (9.1%) with a BRCA1/2 PV, and 9 (40.9%) with variants of uncertain significance (VUS). Median age was 40.5 years and 15 (71.4%) identified as non-Hispanic. Twenty (90.9%) reported a family history of BC, and 2 (9.1%) reported a family history of BRCA1/2 PV. The emerging themes included a preference for structured communication of GT results and the need for more actionable knowledge to mitigate BC risk, especially among patients with VUS or negative results. Few patients reported lifestyle changes following the return of their results, although they did understand that their behaviors can impact their BC risk. Conclusions Patients preferred a structured explanation of their GT results to facilitate a more personal testing experience. While most did not change lifestyle behaviors in response to their GT results, there was a consistent call for further guidance following the initial discussion of GT results. Empowering patients, especially those with negative or VUS results, with the context to internalize the implications of their results and form accurate risk perception represents a powerful opportunity to optimize subsequent risk management strategies. Informed by this study, future work will expand RealRisks to include the return of results and decision support to navigate concrete next steps.

BackgroundGenetic testing for BRCA1 and BRCA2 pathogenic variants (PVs) has been available in North West England since 1995. We assessed uptake of pre-symptomatic testing in 1564 families with PVs over a 24.5year follow-up (FU) period.MethodsFirst-degree relatives (FDRs) in families with BRCA1 or BRCA2 PVs were eligible from date of index family report if unaffected by a relevant cancer and alive at report date. FDRs were censored as not having undergone a pre-symptomatic test at diagnosis of a relevant cancer, date of death, age 93 or 30/03/2019. Time to uptake of pre-symptomatic testing was assessed by Kaplan–Meier curves, by gender and children.Results2554 male and 3115 female FDRs were eligible. Overall uptake was 775 (30.3%) in men and 1935 (62.1%) in women. This increased at 15 years to 33.6% and 67.9%, and continued to rise until 24 years (p<0.001). For women, the 29-year to 39-year age group had the highest uptake at 10 years FU (72.5%; p<0.01), whereas the 50-year to 59-year age group was highest in men (37.2%; p<0.01). Women <18 years at the time of familial variant identification had lower initial uptake, but this rose to >80% by 15 years. Uptake was higher in parous women (p<0.001) and in men with daughters (p<0.0001).ConclusionUptake of BRCA1/2 pre-symptomatic testing is age, gender and time-dependent, and higher in women with children and men with daughters.

Despite some populations show a wide spectrum of different BRCA pathogenic variants (PVs), particular ethnic groups carry at high frequency a single or a few recurrent PVs, usually due to a founder effect. The identification of these founder PVs, with simple molecular methods, improves BRCA1/2 testing and cancer risk assessment. In this study, we developed a rapid and reliable PCR method, coupled with capillary electrophoresis (CE) for genotyping the Italian founder BRCA1 c.4964_4982del19 (rs80359876) variant. In addition, we compared the performance of two CE platforms: (Agilent 2100 Bioanalyzer and the Experion Automated Electrophoresis system) to identify this variant. Our findings suggest that CE represents a simple and standardized diagnostic strategy for the unambiguously identification of the BRCA1 c.4964_4982del19 variant, on both germline and somatic DNA samples. The results and performance obtained by two platforms are absolutely superimposable in terms of specificity and sensitivity, as well as for their feasibility, time of analysis and costs.