Germline Breast Cancer Susceptibility Gene Research Articles

Clinical significance of germline breast cancer susceptibility gene (gBRCA) testing and olaparib as maintenance therapy for patients with pancreatic cancer

BackgroundGermline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy.MethodsWe retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records.ResultsThe median patient age was 64 y (29–85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8–87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1–30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months.ConclusionsThe gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer.

Development and validation of ultrasound-based radiomics model to predict germline BRCA mutations in patients with breast cancer

BackgroundIdentifying breast cancer (BC) patients with germline breast cancer susceptibility gene (gBRCA) mutation is important. The current criteria for germline testing for BC remain controversial. This study aimed to develop a nomogram incorporating ultrasound radiomic features and clinicopathological factors to predict gBRCA mutations in patients with BC.Materials and methodsIn this retrospective study, 497 women with BC who underwent gBRCA genetic testing from March 2013 to May 2022 were included, including 348 for training (84 with and 264 without a gBRCA mutation) and 149 for validation(36 patients with and 113 without a gBRCA mutation). Factors associated with gBRCA mutations were identified to establish a clinicopathological model. Radiomics features were extracted from the intratumoral and peritumoral regions (3 mm and 5 mm) of each image. The least absolute shrinkage and selection operator regression algorithm was used to select the features and logistic regression analysis was used to construct three imaging models. Finally, a nomogram that combined clinicopathological and radiomics features was developed. The models were evaluated based on the area under the receiver operating characteristic curve (AUC), calibration, and clinical usefulness.ResultsAge at diagnosis, family history of BC, personal history of other BRCA-related cancers, and human epidermal growth factor receptor 2 status were independent predictors of the clinicopathological model. The AUC of the imaging radiomics model combining intratumoral and peritumoral 3 mm areas in the validation set was 0.783 (95% confidence interval [CI]: 0.702—0.862), which showed the best performance among three imaging models. The nomogram yielded better performance than the clinicopathological model in validation sets (AUC: 0.824 [0.755—0.894] versus 0.659 [0.563—0.755], p = 0.007).ConclusionThe nomogram based on ultrasound images and clinicopathological factors performs well in predicting gBRCA mutations in BC patients and may help to improve clinical decisions about genetic testing.

Genetic Testing in Metastatic Breast Cancer in the USA: A Podcast.

This podcast highlights the importance of genetic testing in patients with metastatic breast cancer, with a specific focus on germline or inherited breast cancer susceptibility gene (BRCA) mutations. In the USA, national guidelines recommend that all patients with recurrent or metastatic breast cancer should be offered genetic testing for germline breast cancer susceptibility gene 1 or 2 (BRCA1 or 2) mutations to identify patients potentially suitable for treatment with a poly(ADP-ribose) polymerase inhibitor. However, a retrospective study indicated that only 43% of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who may be eligible for genetic testing have undergone germline BRCA1 or 2 testing. Therefore, a large national effort is required to offer genetic testing to more patients with recurrent or metastatic breast cancer. The aim of this podcast is to provide physicians with information to support the early engagement of patients in discussions about genetic testing, and guidance on how to manage patient concerns about the potential implications of testing. Here, a healthcare professional discusses germline genetic testing with a patient advocate and answers questions regarding the importance of testing in patients with metastatic breast cancer. Furthermore, the authors discuss what it means to receive a positive or negative result for a germline BRCA mutation and the impact this may have on the patient and their family members. Overall, the authors emphasize the importance of healthcare professionals providing every patient with metastatic breast cancer with the relevant information about genetic testing so that patients can make informed decisions. Podcast Audio and Infographic available for this article.Podcast Audio and Infographic available for this article.

Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells

Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), “Ru-PIP”, with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP.

BRCA1/2 Mutation Testing in Patients with HER2-Negative Advanced Breast Cancer: Real-World Data from the United States, Europe, and Israel.

Poly(adenosine diphosphate-ribose) polymerase inhibitors are approved to treat patients harboring a germline breast cancer susceptibility gene 1 or 2 mutation (BRCA1/2mut) with human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This study evaluated differences in patient demographics, clinical characteristics, and BRCA1/2mut testing within the United States (US), European Union 4 (EU4; France, Germany, Italy, and Spain), and Israel in a real-world population of patients with HER2- ABC. Oncologists provided chart data from eligible patients from October 2019 through March 2020. In the US, EU4, and Israel, 73%, 42%, and 99% of patients were tested for BRCA1/2mut, respectively. In the US and the EU4, patients who were not tested versus tested for BRCA1/2mut were more likely to have hormone receptor-positive (HR+)/HER2- ABC (US, 94% vs. 74%, p < 0.001; EU4, 96% vs. 78%, p < 0.001), less likely to have a known family history of BRCA1/2-related cancer (US, 6% vs. 19%, p = 0.002; EU4, 10% vs. 28%, p < 0.001), and were older (US, 68.9 vs. 62.5 years, p < 0.001; EU4, 66.7 vs. 58.0 years, p < 0.001). Among tested patients, genetic counseling was received by 45%, 53%, and 98% with triple-negative breast cancer, and 36%, 36%, and 98% with HR+/HER2- ABC in the US, EU4, and Israel, respectively. Efforts should be made to improve BRCA1/2 testing rates in the US and Europe.

Real-world study of patients with germline BRCA1/2-mutated human epidermal growth factor receptor 2‒Negative advanced breast cancer: Patient demographics, treatment patterns, adverse events, and physician-reported satisfaction in the United States, Europe, and Israel

BackgroundCurrent guidelines for the treatment of human epidermal growth factor receptor 2‒negative (HER2−) advanced breast cancer (ABC) are informed by tumor characteristics and include platinum- and non–platinum-based chemotherapy, chemotherapy plus immunotherapy, endocrine monotherapy, or endocrine therapy plus a targeted therapy. In addition, poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have recently demonstrated improved clinical and patient-reported outcomes and manageable toxicity profiles compared with chemotherapy in patients with germline breast cancer susceptibility gene 1 or 2 (gBRCA1/2)‒mutated HER2− ABC in clinical trials and are now approved to treat this patient population. This study provides complementary real-world data regarding treatment patterns, adverse events, and physician-reported treatment satisfaction in this population. MethodsThis retrospective analysis using the Adelphi Real World ABC Disease Specific Programme in the United States, European Union, and Israel included patients aged ≥18 years receiving therapy for stage IIIb or IV gBRCA1/2-mutated HER2− ABC. Oncologists completed a patient record form detailing patient demographics, clinical assessments, and treatment history and a survey regarding their use of and satisfaction with treatments. ResultsAmong the 543 patients, mean age was 55 years, 25% were premenopausal, 70% had hormone receptor‒positive (HR+) ABC, and 30% had triple-negative breast cancer (TNBC). PARPi were used in 5%, 11%, and 12% of first-line, second-line, and third-line therapies, respectively, for patients with HR+ ABC; for TNBC, percentages were 18%, 44%, and 36%. Across treatment lines, neutropenia, anemia, and nausea occurred in 16%, 24%, and 32% of patients receiving PARPi, respectively; 22%, 38%, and 33% of patients receiving platinum chemotherapy; and 20%, 20%, and 33% of patients receiving non–platinum-based chemotherapy. Physician satisfaction was highest with PARPi and with chemotherapy plus immunotherapy. ConclusionsFindings in this real-world population complement clinical trial observations and provide further support for treatment of patients with PARPi in gBRCA1/2-mutated HER2− ABC.

Relevance of Platinum-free Interval and BRCA Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for gBRCA Advanced Breast Cancer (BROCADE3 Crossover).

Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (gBRCA)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel. Eligible patients (N = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300-400 mg twice daily continuous). Antitumor activity and adverse events were assessed during crossover veliparib treatment. BRCA reversion mutations at crossover were analyzed retrospectively using next-generation sequencing on plasma circulating tumor DNA (ctDNA). Seventy-five patients in the placebo plus carboplatin/paclitaxel arm received ≥1 dose of crossover veliparib postprogression (mean treatment duration: 154 days). Eight of 50 (16%) patients with measurable disease had a RECIST v1.1 response. Activity was greater in patients with PFI ≥180 days compared with <180 days [responses in 23.1% (3/13) vs. 13.5% (5/37) of patients]. BRCA reversion mutations that restored protein function were detected in ctDNA from 4 of 28 patients tested, and the mean duration of crossover veliparib monotherapy was <1 month in these 4 patients versus 7.49 months in patients lacking reversion mutations. The most frequent adverse events were nausea (61%), vomiting (29%), and fatigue (24%). Crossover veliparib monotherapy demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel. PFI appeared to affect veliparib activity. BRCA reversion mutations may promote cross-resistance and limit veliparib activity following progression on platinum.

Niraparib for the Treatment of Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer.

To review the efficacy and safety of niraparib for the treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (OC, FTC, and PPC). A literature search via MEDLINE through PubMed from August 2013 to January 2020 was performed using the key terms niraparib, PARP inhibitors, ovarian cancer, fallopian tube cancer, and primary peritoneal cancer. Completed and ongoing trials were identified through a review of the website trial registry https://www.clinicaltrials.gov. In a phase III, double-blind clinical trial, progression-free survival improved in patients treated with niraparib compared with placebo as maintenance treatment for patients with platinum-sensitive, recurrent OC: 21 versus 5.5 months in the germline breast cancer susceptibility gene (gBRCA) cohort (hazard ratio [HR] = 0.27; 95% CI = 0.17 to 0.41; P < 0.001) and 9.3 versus 3.9 months in the overall nongermline breast cancer susceptibility gene (non-gBRCA) cohort (HR = 0.45; 95% CI = 0.34 to 0.61; P < 0.001). Adverse events included thrombocytopenia and anemia. Poly (ADP-ribose) polymerase (PARP) inhibitors have gained a place in the therapeutic management of OC, FTC, and PPC because of their ability to suppress growth of homologous recombination deficiency-positive tumors, including those with BRCA1/2 mutations. Niraparib inhibits the DNA repair mechanism vital to the survival of cancer cells, poly-ADP ribose polymerase. PARP inhibitors can be used as a single agent for maintenance therapy for platinum-sensitive recurrent disease in patients with partial or complete response following 2 or more rounds of platinum-based therapy.

Abstract P1-09-13: A real world evidence study of BRCA mutations and survival in HER2-negative breast cancer

Abstract Background: Limited data exist on the natural history (treated with standard of care) of metastatic breast cancer (mBC) characterized by germline breast cancer susceptibility gene mutations (gBRCAm). Real-world data examining survival for patients with gBRCAm mBC, overall and separated into gBRCA1m and gBRCA2m, compared to gBRCA wild type (wt) mBC, can help to clarify the prognostic outlook associated with the gBRCA mutation. Methods: Adults with human epidermal growth factor receptor 2 negative (HER2-) mBC diagnosed from January 2013 – August 2017 were retrospectively selected from the Flatiron Health Oncology electronic medical record database. Patients were classified as having gBRCA1m, gBRCA2m, or gBRCAwt disease. Those who did not receive the genetic testing or who had equivocal results were classified as gBRCA unknown. Overall survival (OS) was calculated from first diagnosis of mBC, as well as from the start of first- and second-line therapy for metastatic disease. Lines of therapy included both hormonal and systemic therapies. Kaplan-Meier analyses provided median OS with 95% confidence interval (CI). Unadjusted log-rank tests compared OS between gBRCA1m and gBRCA2m, and between overall gBRCAm and gBRCAwt. Results: Of 8,080 patients selected, mean age at first mBC diagnosis was 64 years, 98.7% were female, and 82.0% had evidence of hormone receptor positive disease. gBRCA status was known for 1,852 (22.9%) of patients, of whom 89 (4.8%) had gBRCA1m, 152 (8.2%) had gBRCA2m, and 8 (0.4%) had both gBRCA mutations. Patients with known gBRCA status were younger, with mean ages of 52 years for gBRCAm, 55 years for gBRCAwt, and 67 years for gBRCA unknown. Hormone receptor positive disease was less common among those with known gBRCA status (71.9%, 77.2%, and 83.6% for gBRCAm, gBRCAwt, and gBRCA unknown, respectively). Median (95% CI) OS from mBC diagnosis was 22 (14 - 26) months for gBRCA1m and 30 (27 - 37) months for gBRCA2m (p = 0.01), though numbers were quite small by the median timepoint. Overall gBRCAm disease was associated with median survival of 28 (25 - 32) months, compared to 32 (30 - 35) months for gBRCAwt (p = 0.07); survival was similar between groups for the first 24 months but declined thereafter in the gBRCAm group. Similar patterns were observed for OS after the start of first- and second-line therapy, although no comparisons were significant. Further analyses will present adjusted results and comparisons with outcomes for the patients with gBRCA unknown. Conclusions: This real-world study of patients receiving care in largely community oncology clinics suggests that survival after diagnosis of mBC is reduced in patients with gBRCA1m compared to gBRCA2m disease and may be reduced in gBRCAm mBC overall. Effective treatments targeted for the gBRCAm subtypes of mBC appear to be needed. Citation Format: Dalvi T, McLaurin K, Briceno J, Nordstrom B, Bennett J, Hettle R, Murphy B, Collins J, McCutcheon S. A real world evidence study of BRCA mutations and survival in HER2-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-13.

Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial

ObjectiveTo analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial. MethodsThe trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors. ResultsPatients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%). ConclusionsFor patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population.

Peritoneal washing is an adequate source for somatic BRCA1/2 mutation testing in ovarian malignancies

Genetic screening for BRCA mutations should be offered to all women diagnosed with epithelial ovarian, fallopian tube, and/or peritoneal cancers given the implications for treatment options and cancer risk assessments. Yet, while germline breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) testing is commonly performed, BRCA1/2 somatic mutations testing is rather challenging since the poor quality of DNA extracted from formalin fixed paraffin embedded (FFPE) samples can significantly impair this process. Peritoneal lavage is routinely performed in surgeries of suspected ovarian malignancies. We have analyzed fresh tumor, peritoneal lavage and blood samples from ten patients and we have found an excellent agreement (88%) between fresh tumor and peritoneal lavage for BRCA mutation testing. Importantly, 112 of the 114 genomic alterations detected in fresh tumor samples were also found in peritoneal lavage fluids. Our data suggest that peritoneal washings can indeed streamline BRCA genes mutation testing procedures.

Germline breast cancer susceptibility gene mutations and breast cancer outcomes

BackgroundIt is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis.MethodsThe study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic.ResultsWe detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29–4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40–6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64–6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22–3.51; P = 0.007).ConclusionsWithout prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.

Abstract P5-08-28: Incidence of germline BRCA1- and BRCA2-mutated breast cancer in the US

Abstract Background: Breast cancer is the most common cancer and second leading cause of cancer death among women in the United States (US).1 Inherited mutations in germline breast cancer susceptibility gene 1 and 2 (gBRCAm) are associated with increased risk of developing cancers, including breast cancer.2 No published reports of gBRCAm incidence within an unselected US breast cancer population are available based on a comprehensive literature review (CLR). The main objective of this analysis is to estimate the incidence of gBRCAm breast cancer in the US. Methods: For this analysis the Surveillance, Epidemiology, and End Results (SEER) Program 18 registries captured incidence of breast cancer by stage, age and gender.3 The size of the US population was based on United Nation's population projections and standardized to the 2010 population.4 Age-specific gBRCAm distribution and gBRCAm-specific hormonal subtype for estrogen-receptor and progesterone-receptor (ER/PR), and human epidermal growth factor receptor-2 (HER2) estimates were determined from a CLR.5-8 Tumor cells negative for ER/PR and HER2 are referred to as triple-negative breast cancer (TNBC). Results: In 2016, it is projected that approximately 250,000 individuals will be diagnosed with invasive breast cancer (all genders). Median age range of the population with invasive breast cancer is 65-69 years and 99% are females. Majority (72%) of female invasive breast cancer cases are ER/PR+ whereas 11% of cases are TNBC. Corroborating with current publications, gBRCAm is estimated at 5% for individuals less than 50 years old and 1% among all ages. Median age range of the gBRCAm cohort is 40-44 years. After applying currently available gBRCAm specific literature parameters, the majority (55%) of gBRCAm diagnoses are TNBC. Conclusion: In the US, patients with gBRCAm represent a small proportion (1%) of all breast cancer tissues evaluated. Majority of gBRCAm patients are diagnosed with TNBC (55%) and are younger (median age range 40-44 years) than overall breast cancer population. Age differences noticed in gBRCAm may have been due to disparity in genetic screening practices among breast cancer population in the US rather than a reflection of gBRCAm expressions. These estimates of gBRCAm incidence are driven by limited reports on an unselected population of breast cancer gBRCAm cohort; therefore sensitivity analysis is required to assess the robustness of these estimates. 1. American Cancer Society. Facts and Figures 2016. 2. Miki Y et al. Science. 1994;266:66-71. 3. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) Research Data (1973-2013), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2016, based on the November 2015 submission. 4. United Nations Population Division. World Population Prospects, the 2015 Revision. http://esa.un.org/unpd/wpp/. 5. van den Broek et al. Eur J Hum Genet. 2015;23:588-95. 6.Turkovic L et al. BMC Cancer. 2010;10:466. 7. Atchley DP et al. J Clin Oncol. 2008;26:4282-4321. 8. Spurdle AB et al. Breast Cancer Res. 2014;16:3419. Citation Format: Kim R, Peterson A, Isherwood A, Uppal H, Barlev A. Incidence of germline BRCA1- and BRCA2-mutated breast cancer in the US [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-08-28.