Prevalence Of BRCA1 Mutations Research Articles

Prevalence of BRCA mutation in breast and ovarian cancer among women in India: A systematic review and meta-analysis protocol.

We present a methodically devised protocol for conducting a systematic review and meta-analysis aimed at ascertaining the prevalence of BReast CAncer gene (BRCA) mutations in breast and ovarian cancer (BOC) among women in India. The review will include cross-sectional, cohort, case-series, and registry-based studies focusing on females clinically diagnosed with any stage of BOC, tested for BRCA germline mutation and undergone any form of treatment. A Cochrane literature search will be carried out to identify all the published and unpublished articles available in English from 2010 till date across various electronic databases including PubMed, Psych Info, SCI, Cochrane Central, Embase, Scopus, IND Med and Google Scholar. A step-by-step process will be followed to select all the relevant studies for final inclusion using Rayyan software. The selection process of the review will be reported based on Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA) checklist. The protocol has been registered in PROSPERO (ID: CRD42023463452). Joanna Briggs Institute Critical Appraisal Checklist will be used to evaluate the methodological quality of the included studies. The outcome measure will be the prevalence of BRCA1/2 gene mutation in this population. Meta-analysis will be performed to report the pooled prevalence along with 95% confidence interval. The results of this review study will provide valuable insights for clinicians, and policy makers, enabling them to formulate guidelines that underscore the importance of screening for BRCA mutations in cases of BOC.

Abstract PO5-17-06: Prevalence of BRCA Mutations: A Predictive Model in a High-Risk Population of BC Patients at a Tertiary Care Center

Abstract Background: Breast cancer (BC) is a prevalent cancer in Saudi Arabia, with the majority of cases being sporadic. However, 25-30% of cases are associated with hereditary factors. Germline BRCA mutations are the most common mutations linked to hereditary BC predisposition syndromes, with a reported frequency of up to 11% in Saudi Arabia. Methods: This retrospective cohort study was conducted at a single institution in Saudi Arabia. Medical records of BC cases were reviewed where BRCA testing was performed, typically in patients with triple negative BC, hormone-positive (HR+) BC in younger premenopausal patients under the age of 45, or those with a personal or family history of BC. Patients meeting these criteria were diagnosed and treated at a tertiary care center in Saudi Arabia,between 2018 and 2021. The association between BRCA positivity and proposed risk factors was evaluated using chi-square analysis. Multivariate analysis was performed using logistic regression to assess the association between independent significant risk factors and BRACA+. Results: 482 cases of breast cancer were reviewed, with 412 testing negative for mutations and an overall BRCA positivity rate of 13.7%. Among BRCA positive patients, 62% had a positive family history (p-value < 0.001), and they tended to be younger, with a median age of 38 compared to BRCA negative patients with a median age of 42 (p-value = 0.01). Of the 469 female patients, 62 (13%) were BRCA positive, and of the 12 male patients, 3 (25%) were BRCA positive. Among the BRCA positive patients, 73% had BRCA1 mutations, and 26% had BRCA2 mutations. No patients with lobular BC tested positive for BRCA mutations. The odds ratio for BRCA positivity in triple negative BC was 3.6 (95% CI 2.1-6.2, p-value < 0.001). The odds ratio for BRCA positivity in HR+ cases was 2.5 (95% CI 1.4-4.2, p-value = 0.001). In HR+ cases, 4.6% had BRCA1 mutations, and 5% had BRCA2 mutations. In ER- cases, 20% had BRCA1 mutations, and 1.2% had BRCA2 mutations. Multivariate analysis revealed that increasing the age of diagnosis by one year reduced the chance of having BRCA positivity by 5% (p-value = 0.009). Having a positive family history increased the risk of BRCA positivity with an OR of 8 (95% CI 4-15.8, p-value < 0.001), and triple negative BC increased the risk of BRCA positivity with an OR of 4.1 (CI 2.2-7.5, p-value < 0.001). The model performance was evaluated using an AUC of 0.80. Conclusion: This study highlights the high prevalence of BRCA mutations in a high-risk population of BC patients. The proposed predictive model identified younger age, triple negativity, and a positive family history as independent predictors, with an AUC of 0.8. The study's predictive model suggest that these factors may be useful in identifying patients who are at increased risk of carrying BRCA mutations and could benefit from genetic counseling and testing. Citation Format: Kausar Suleman, Khalid Al-Khatib, Emaan Haque, Tusneem El Hassan, Abdullah Al Suwaidan, Sabah Alaklabi, Taher Twegieri, Adhar AlSayed, Dahish Ajarim, Meshari Al Zahrani, Syed Saad Akhtar, Osama Al Malik, Amal Al Hefdhi, Wafa Khayal, Sitah Al Zughaibi, Asma Tulbah. Prevalence of BRCA Mutations: A Predictive Model in a High-Risk Population of BC Patients at a Tertiary Care Center [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-17-06.

The BRCA mutation spectrum among breast and ovarian cancers in India: highlighting the need to screen BRCA1 185delAG among South Indians.

Mutations in BRCA1 and BRCA2 significantly elevate the risk of developing breast and ovarian cancer. Limited data exists regarding the prevalence ofBRCA mutations, and optimal, cost-effective testing strategies in developing countries like India. This study aimed to evaluate the utility of a Next Generation Sequencing (NGS) panel for BRCA1/2 mutation testing among women diagnosed with, or at risk of developing hereditary breast and ovarian cancers. We also aimed to identify population specific BRCA1/2 mutation hotspots, to enable the development of more affordable testing strategies. We identified 921 patients with breast and ovarian cancer who underwent mutation testing. The target enrichment wasfollowed by targeted NGS in 772 patients and an allele-specific PCR (ASPCR) based genotyping for BRCA1:c.68_69delAG (or 185delAG), was carried out in 149 patients. We identified 188 (20.4%) patients with BRCA1/2 variants: 118 (62.8%) withpathogenic/likely pathogenic and 70 (37.2%)with VUS. The 185delAG was identified as a recurrent mutation in the Southern Indian population, accounting for 24.6% of the pathogenic variants. In addition, a family history of breast, ovary, pancreas, or prostate (BOPP) cancer was found to be associated with an increased risk of identifying a deleterious BRCA1/2 variant [OR = 2.11 (95% CI 1.45-3.07) p ≤ 0.001]. These results suggest that TargetedNGS is a sensitive and specific strategy for BRCA testing. For Southern Indian patients, a two-tiered approach can be considered: Initial screening with ASPCR for BRCA1185delAG followed by NGS for those testing negative. Expanding the gene panel and identifying other population-specific mutation hot spots is a promising area with potential for improvements in testing and treatment strategies.

BRCA1/2 MUTATIONS IMPACT ON THE DEVELOPMENT OF BREAST IMPLANT‐ASSOCIATED LYMPHOMA (BIA‐ALCL) IN WOMEN WITH BREAST CANCER RECONSTRUCTED WITH TEXTURED BREAST IMPLANTS

Introduction: Breast Implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a subtype of T-cell lymphoma arising as a seroma and/or mass in relation to the capsule of textured breast implants. Previous research in a Dutch population suggests a higher-than-expected prevalence of BRCA1/2 carriers in women with BIA-ALCL. Here we analyze the risk of BIA-ALCL occurrence related to BRCA in a large population of women with implants followed long term after breast cancer (BC) mastectomy. Methods: We compared the prevalence of BRCA1/2 pathogenic variants (pv) between women from a large cohort of BC patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) who did and did not develop BIA-ALCL after reconstruction with textured implants. Hazard ratios (HRs) of developing BIA-ALCL were estimated using Cox regression. To best control for age at BC diagnosis and length of follow up, we conducted a nested case-control within the cohort, matching 1:3, analyzed with conditional logistic regression. Results: Among 3312 women with BC assessed for pv in the context of MSK-IMPACT tumor and normal study at MSKCC the prevalence of BRCA mutations was 5.3%. Among 526 patients with textured implants post BC mastectomy, followed long term at MSKCC (median FU 82 mo, range 12, 316) and clinically assessed for BRCA1/2, the prevalence of pv of BRCA1/2 was 7.8%. Of 31 BIA-ALCL post-BC cases seen at MSKCC, 16 received capsulectomy at MSKCC and 5/13 (38.4%) were BRCA1–2 positive. Within the cohort of 526 patients with BC tested for BRCA, reconstructed with textured implants and followed long-term, the age-adjusted rate of developing BIA-ALCL for women with BRCA mutations was 11.0 times the rate of BIA-ALCL among women without BRCA (HR 95% CI 3.6, 33.9, p < .0001). Carrying bilateral versus unilateral implants (HR 6.9, 95% CI 0.9, 53.2), prior chemotherapy exposure (HR 0.7, 95% CI 0.2, 2.05), prior radiation therapy exposure (HR 0.5, 95% CI 0.1, 2.5) were not significantly associated with the rate of BIA-ALCL. Within this cohort, 13 BIA-ALCL cases were matched 1:3 with 39 controls. Median ages at BC mastectomy were 47.2 (37, 66) and 46.8 (35, 65) in cases and controls, respectively. The median time between reconstruction for BC and BIA-ALCL was 130 (80, 190) months. The odds ratio of BIA-ALCL associated with carriership of a BRCA1/2 pathogenic variant was 12.4 (Wald 95% CI 1.4, 109.5 p = 0.0074). Conclusions: In this study, we define the role of BRCA1/2 mutations as a significant risk factor in the development of BIA-ALCL in patients with BC reconstructed with textured implants. These results will help decision making for women with BRCA1/2 mutations undergoing breast reconstruction, or with textured implants in place. Analysis of pathogenic variants in other DNA repair genes in this cohort potentially affecting lymphomagenesis is ongoing. The research was funded by: NIH R03 grant number R03CA267435 Keywords: aggressive T-cell non-Hodgkin lymphoma, prevention and cancer interception No conflicts of interests pertinent to the abstract.

Survival outcomes of BRCA1/BRCA2 mutated breast cancers: Study from a tertiary care cancer centre in India.

e22546 Background: There exists a discrepancy amongst various studies over the years on survival outcomes of BRCA (Breast cancer susceptibility gene) mutated breast cancers. Prevalence of BRCA mutation varies from 10 to 18% among Indian population and there is a paucity of data on the survival outcomes of this population. Methods: This ambispective observational study assessed the survival outcomes of 71 BRCA mutated breast cancer patients, treated with uniform protocol at AIIMS New Delhi between January 2014 to December 2022, using survival analysis and cox regression methods. Results: Amongst the 71 patients, BRCA1 and BRCA2 mutated cases were 52 (73.2%) and 19 (26.8%) respectively. The median age was 39 years (24-63 years) in both the groups. Positive family history for malignancy (BRCA1- 69.2% vs BRCA2- 36.8%) and incidence of Triple negative histology (BRCA1-82.7% VS 36.8%) were more commonly associated with BRCA1 positivity. Eight patients (11.3%) had synchronous cancer, most common being a contralateral breast primary. 4 patients (5.6%) developed metachronous cancer. Eighty percent of patients were premenopausal at presentation. There was no difference in stage at presentation, incidence of synchronous and metachronous cancers across both the groups. Of 71 patients, 18 (25%) and 17 (24%) patients underwent risk reducing mastectomy and risk reducing oophorectomy respectively. Thirty five (49.3%) presented with stage I &amp; II disease, while 28 (34.4%) and 7 (9.9%) presented with stage III and metastatic disease respectively. Forty seven patients (67.1%) received neoadjuvant chemotherapy with pathologic complete response rate of 42.5% which was uniform among both the groups. Over the study period, 10 (14.1%) patients had disease relapse with 7 (70%) being metastatic and 3 patients died of the disease. With a median follow up of 36.9 months, 3-year disease free survival (DFS) was 84.2% (BRCA1: 81.1% vs BRCA2: 93.1%) and overall survival (OS) was 94.7% for both groups. Median DFS and OS were not achieved. BRCA type, receptor status, age and menopausal status were not predictors of survival in our study. Conclusions: In our study population of BRCA1/BRCA2 mutated breast cancer, survival outcomes were comparable to historical cohorts of Indian breast cancer patients. Thus, BRCA mutation positivity doesn’t seem to have any prognostic significance in breast cancer outcome.

Abstract P6-02-17: A Real-World Study of BRCA1 and BRCA2 Germline Mutations among High Hereditary Risk Subjects and Patients with Breast and Ovarian Cancer in Lebanon

Abstract Background: The prevalence of pathogenic BRCA mutations in high hereditary risk breast cancer patients (pts) in ethnic Lebanese Arab women was 5.6% in a study published in 2015 (El Saghir, et al. The Oncologist). In this study, we look at real world practice prevalence of BRCA mutations among pts with breast and/or ovarian cancer referred for testing because of positive family history (FH) and/or young age at the American University of Beirut Medical Center (AUBMC). Methods: The study was approved by the Institutional Review Board at AUBMC. We retrospectively collected clinical, radiological, pathological and genetic information on breast and ovarian cancer pts at a high hereditary risk for whom Sanger sequencing of all coding exons and immediately flanking intronic regions of BRCA1 and BRCA2 was performed between January 1, 2010 and Jan 1, 2019 at AUBMC. Between Jan 2019 and Aug 2020, Next Generation Sequencing (NGS) of 70 cancer-associated genes was referred to and done in Centogene labs (Germany). 346 subjects were included in the study; 235 pts with breast and/or ovarian cancer, and 101 subjects of young age or with a positive family history. Results: 210 pts had breast cancer (209 females, 1 male); 81 were diagnosed at age ≤40, 81 aged 41-50, and 48 aged &amp;gt;50. 185 pts had BRCA sequencing and 25 had NGS panel testing. 31 pts had ovarian cancer; 28 had BRCA testing and 3 had NGS. 3 pts had ovarian and breast cancer; all had Sanger sequencing, 1 male pt with both breast and prostate cancers had BRCA testing. The 101 subjects who were tested in the setting of positive FH of cancers or a known deleterious mutation in first degree family members were either target tested for the known familial mutation or had BRCA screening. The incidence of BRCA1 and BRCA2 mutations in women with breast cancer was 8.5% (18/210 patients) and 19.3% (6/31 patients) in women with ovarian cancer. Of the 3 pts who had both breast and ovarian cancer, 1 had a BRCA1 mutation. Almost all patients with hereditary breast cancer had a positive FH and the majority were &amp;lt; 40 years of age. 8 out of 13 BRCA1 pts had Triple Negative disease (61%). Of the 101 subjects with no history of cancer, 9 out of 30 with relatives who had BRCA1 mutation carried the same mutation, and 3 out of 15 with BRCA2 carried the mutation. The remaining 56 pts were tested because of positive FH; 3 out of 56 had a pathogenic mutation (1 BRCA1, 1 BRCA2 and 1 RAD51D). Of the 28 pts who had NGS panel sequencing, 1 patient had RAD51D, 1 had a PALB2 mutation, 1 had BARD1 and 1 had APC risk variant. Conclusions: In this real-world practice study of patients and subjects referred for germline mutation testing. BRCA mutation rate in pts with breast cancer was 8.5% (18/210) and 19% in ovarian cancer (6/31). Young age (&amp;lt; 40 years) and a positive FH are the most useful criteria to select pts with breast cancer for mutation testing, especially in the setting of limited resources. This is the first study to report a 20% rate of BRCA pathogenic variants in patients with ovarian cancer in Lebanon and Arab countries; we highlight the need to refer all ovarian cancer pts for counseling and genetic testing. NGS is important to detect mutations other than BRCA1 and BRCA2 in our population where 50% of cases are below age 50. Table 1. Incidence of BRCA1/2 mutations, age, and family history in pts with breast and ovarian cancer. Citation Format: Nagi El Saghir, Nadine Safi, Ahmad Masri, Firas Kreidieh, Deborah Mukherji, Nada Assaf, Rami Mahfouz, Hiba Moukadem. A Real-World Study of BRCA1 and BRCA2 Germline Mutations among High Hereditary Risk Subjects and Patients with Breast and Ovarian Cancer in Lebanon [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 P6-02-17.

BRCA1, BRCA2, TP53, PIK3CA, PTEN and AKT1 genes mutations in Burkina Faso breast cancer patients: prevalence, spectrum and novel variant.

BRCA1 and BRCA2 are the two most commonly mutated tumor suppressor genes associated with hereditary breast cancer (BC). Also, mutations in TP53, PIK3CA, PTEN and AKT1 were observed at a high frequency in BC with their mutation spectrum exhibiting a subgroup particularity with enormous clinical significance in the prevention, classification and treatment of cancers. Unfortunately, the mutation spectrum of these genes is still unknown in most Sub-Saharan African population. Therefore, using samples from 133 unselected BC patients, we aimed to assess the contribution of these mutations by direct Sanger sequencing. The analysis revealed pathogenic germline variants on BRCA1 exon 11 (c.3331C > T, 0.75%) and BRCA2 exon 11 (c.5635G > T, c.6211delA; 1.5%). Five other pathogenic variants were identified in 61 of the 133 subjects (45.86%), with 39.09% for PIK3CA, 12.78% for TP53. Interestingly, a variant in PIK3CA found in high frequency in our population was different from the one usually found in other populations (c.1634A > C, 38.34%), and four patients carried mutations linked to Cowen Syndrome 5 c.[1634A > C;1658_1659delGTinsC]. A novel variant (c.312G > T) was found in TP53 gene at 12.78%. Overall, mutation carriers were found more in Her2 negative and in patients that underwent surgery and chemotherapy. No pathogenic variant was found in PTEN and AKT1. Our population displayed a high frequency of PIK3CA mutations with an unusual distribution and spectrum as well as a relatively low prevalence of BRCA mutations. Our results provided novel data on an unstudied population and may help in prevention, and the establishment of suitable therapeutic approaches for our population.

Abstract LB561: Germline mutational profiling of TNBCs in an Indian cohort

Abstract Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer associated with poor prognosis. The high TNBC prevalence (&amp;gt;25%) in India as compared to the western population (10-15%) remains to be a challenge in clinical management. The association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. However, these studies are predominantly from germline profiling of TNBCs representative of western population. Therefore, we aimed to investigate the germline profiles of breast cancer patients in India using a multi-institutional TNBC cohort based on ACMG consensus multi-gene NGS panel. Of 193 TNBC patients, we identified 57 pathogenic mutations (diagnostic yield = 29.53%) from various genes of which BRCA1 (41/57, 71.93%) and BRCA2 (8/57, 14.03%) were most commonly mutated. We observed a high prevalence of BRCA1 mutations (41/193, 21.24%) and BRCA2 mutations (8/193, 4.14%) in our cohort as compared to published literature. Additionally, 8 pathogenic mutations were also reported in non-BRCA cancer pre-disposing genes associated with the HR pathway like ATM, CHEK2, PALB2. 10 novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. The most common type of mutations was found to be frame-shift which may cause protein truncation and loss of function. Furthermore, we identified 48 variants of unknown significance (24.9%) of which about 7% were in the BRCA1/2 genes. Data mining from global databases like TCGA, Genome Asia indicated that the novel mutations were unique to the Indian population compared to the germline profiles of different ethnicities. Our study confirms the major contribution of BRCA1/2 genes in TNBCs as reported in the literature. A high percentage of the women were found to be associated with young age onset which may be attributed to BRCA mutations. We have also assessed the association of clinicopathological parameters such as tumor grade, stage, recurrence to the germline mutational status. Our analysis shows significant association of germline mutational status with family history thus underlin the importance of multi-gene panel testing as recommended by NCCN guidelines. Moreover, our results also emphasize the need for designing/implementing guidelines specific to Indian population. In summary our results indicate that Indian TNBCs have a high prevalence of BRCA1/2 mutations. Large scale studies in future are warranted to validate these preliminary findings. Citation Format: Chaitanyanand Koppiker, Ashwini Bapat, Siddharth Gahlaut, Naveen Luke, Jisha John, Rupa Mishra, Aishwarya Konnur, Namrata Namewar, Ruhi Reddy, Shaheen Shaikh, Rituja Banale, Smeeta Nare, Laleh Busheri, Asha Reddy, Ashraf Mannan, Sabarinathan Radhakrishnan, Selvi Radhakrishna, Santosh Dixit. Germline mutational profiling of TNBCs in an Indian cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB561.

Endometrial Cancer and BRCA Mutations: A Systematic Review.

This systematic review identifies, evaluates, and summarises the findings of all relevant individual studies on the prevalence of BRCA mutation (BRCAm) in endometrial cancer patients and the incidence of endometrial cancer in BRCAm women patients. Consequently, the benefits and limits of a prophylactic hysterectomy at the time of the risk-reducing salpingo-oophorectomy are analysed and discussed. A systematic literature search was performed in the databases of PubMed, Cochrane, and Web of Science until May 2022; 13 studies met the eligibility criteria. Overall, 1613 endometrial cancer patients from 11 cohorts were tested for BRCA1/2 mutation. BRCA1/2m were identified in 4.3% of women with endometrial cancer (70/1613). BRCA1m was the most represented (71.4%) pathogenic variant. Alongside, a total of 209 BRCAm carriers from 14 studies were diagnosed with endometrial cancer. Only 5 out of 14 studies found a correlation between BRCAm and an increased risk of endometrial cancer. Nevertheless, two studies found a statistical difference only for BRCA1m women. The present systematic review does not provide strong evidence in favour of performing routine hysterectomy at the time of risk-reducing salpingo-oophorectomy; however, it provides epidemiological data that can be useful for counselling patients in order to offer a tailored approach.

Brain metastases in patients with ovarian cancer

Background Brain metastasis (BM) are uncommon among women with epithelial ovarian cancer (EOC). The frequency, risk factors and clinical repercussions of BM in these patients are not well described. Methods We retrospectively evaluated EOC patients treated at our center from 2002 to 2020 and assessed their clinical parameters, risk for BM development and association with overall survival (OS). This cohort has a known high frequency of BRCA mutation carriers (BRCAm) due to women of Ashkenazi Jewish descent. Results Among 1035 EOC patients, 29 (2.8%) were diagnosed with BM. The prevalence of BRCA mutations was more common among women with BM (56.5% vs. 34.3%, p = 0.033). The BM rate in patients with BRCAm was higher than the BM rate in those with wildtype BRCA (BRCAw; 5.1% vs. 2.1%, OR = 2.6; 95% CI: 1.2–5.4, p = 0.013). Median time from diagnosis to BM and from disease recurrence to BM was longer among patients with BRCAm. Median OS was not significantly different among patients with BM versus those without BM (59.4 vs. 73.4 months, p = 0.243). After BM diagnosis, median OS was not statistically significantly different between patients with BRCAm and those with BRCAw (20.6 vs. 12.3 months, p = 0.441). Treatment with poly (ADP-ribose) polymerase inhibitors and bevacizumab had no impact on subsequent development of BM. Conclusions BM are rare among EOC patients. However, the risk is three-fold higher among patients with BRCAm. BM do not significantly alter OS among EOC patients. The higher rate of BM in patients with BRCAm may be related to longer OS in this subpopulation.

Abstract P3-07-08: Germline mutational profiling in Indian TNBCs

Abstract Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer associated with poor prognosis. The high TNBC prevalence (&amp;gt;25%) in India as compared to the western population (10-15%) remains to be a challenge in clinical management. The association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. However, these studies are predominantly from germline profiling of TNBCs representative of western population. Therefore, we aimed to investigate the germline profiles of Indian breast cancer patients using a multi-institutional TNBC cohort based on ACMG consensus multi-gene NGS panel. In our study cohort of 193 TNBC patients, we identified 57 pathogenic mutations (diagnostic yield = 29.53%) from various genes of which BRCA1 (41/57, 71.93%) and BRCA2 (8/57, 14.03%) were most commonly mutated. We observed a high prevalence of BRCA1 mutations (41/193, 21.24%) and BRCA2 mutations (8/193, 4.14%) in our cohort as compared to published literature. Additionally, 8 pathogenic mutations were also reported in non-BRCA cancer pre-disposing genes associated with the HR pathway like ATM, CHEK2, PALB2. 10 novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. The most common type of mutations was found to be frame-shift which may cause protein truncation and loss of function. Furthermore, we identified 48 variants of unknown significance (24.9%) of which about 7% were in the BRCA1/2 genes. Data mining from global databases like TCGA, Genome Asia indicated that the novel mutations were unique to the Indian population compared to the germline profiles of different ethnicities. Our study confirms the major contribution of BRCA1/2 genes in TNBCs as reported in the literature. A high percentage of the women were found to be associated with young age onset which may be attributed to BRCA mutations. Further analysis to investigate the association of tumor size, tumor grade, survival analysis with mutational profiles is in process. Similarly, we are also assessing. family history to underline the importance of multi-gene panel testing as recommended by NCCN guidelines. Moreover, our results also emphasize the need for designing/implementing guidelines specific to Indian population. In summary our results indicate that Indian TNBCs have a high prevalence of BRCA1/2 mutations. Large scale studies in future are warranted to validate these preliminary findings. Citation Format: C B Koppiker. Germline mutational profiling in Indian TNBCs [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 P3-07-08.

Prevalence and clinical characterization of BRCA1 and BRCA2 mutations in Korean patients with epithelial ovarian cancer.

This study was performed to investigate the prevalence, clinical characteristics, and treatment response according to BRCA1 and BRCA2 (BRCA) mutations in Korean patients with epithelial ovarian cancer (EOC). Two‐hundred and ninety‐eight Korean women diagnosed with high‐grade serous and/or endometrioid EOC from 2010 to 2015 were tested for germline and 86 specimens for somatic BRCA mutations, regardless of the family history. Clinical characteristics including survival outcomes were compared in patients with and without BRCA mutations (NCT02963688). A total of 43 different germline BRCA mutations were identified in 78 patients among 298 patients (26.2%). Somatic BRCA mutations were identified in 11 (12.8%) patients among patients without germline BRCA mutations. Haplotype analysis demonstrated no founder mutations in our Korean patient cohort. Insignificant differences in age at diagnosis, primary site, and residual disease after surgery were observed between patients with and without BRCA mutations. In multivariate analysis for overall survival (OS), the presence of BRCA mutation was significantly associated with OS (P = .049) in addition to platinum sensitivity (P < .001), indicating it is an independent prognostic factor for survival regardless of platinum sensitivity to first‐line chemotherapy. In addition, a higher response rate to subsequent chemotherapy after recurrence was observed in EOC patients with BRCA mutations resulting in better OS. In the current study, the prevalence of BRCA mutations in Korean patients with EOC was higher than previously reported in other ethnic groups. We demonstrated characteristics and treatment response in Korean EOC patients with BRCA mutations. These findings may provide valuable information to be considered in future clinical trials including Asian patients.

Changing Patterns in Clinicopathological Characteristics of Breast Cancer and Prevalence of BRCA Mutations: Analysis in a Rural Area of Southern China.

PurposeAlthough the burden of breast cancer remains especially high in rural China, data on the clinicopathological characteristics and prevalence of the breast cancer susceptibility gene 1/2 (BRCA1/2) mutations in patients with breast cancer remain limited. We investigated the clinicopathological characteristics, changing patterns, and prevalence of BRCA1/2 mutations in patients with breast cancer.Patients and MethodsThe clinicopathological characteristics of 3712 women with pathologically confirmed primary breast cancer treated at Meizhou People’s Hospital between January 2005 and December 2018 were evaluated. The prevalence of BRCA1/2 mutations in 340 patients with breast cancer diagnosed between January 2017 and September 2018 was also evaluated.ResultsThe median age at diagnosis was 49±10.5 (range, 20–94) years. Positivity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was observed in 59.0%, 52.5%, and 24.9% of patients, respectively. Time trend analysis revealed that an increasing trend was observed for age at diagnosis (p = 0.001), proportion of patients without a reproductive history (p < 0.001), postmenopausal patients (p = 0.001), invasive pathological cancer type (p = 0.008), ER-positive rate (p < 0.001), PR-positive rate (p = 0.008), and HER2-positive rate (p < 0.001). Compared with patients without BRCA1/2 mutations, those with BRCA1/2 mutations were more likely to have a family history of breast or ovarian cancer (p < 0.001) and have triple-negative breast cancer (TNBC) (p < 0.001). Family history of breast or ovarian cancer (odds ratio [OR], 103.58; 95% confidence interval [CI], 20.58–521.45; p < 0.001) and TNBC subtype (OR, 5.97; 95% CI, 1.16–30.90; p = 0.033) were independent predictors for BRCA1/2 mutation.ConclusionThe clinicopathological characteristics of patients with breast cancer in this rural area have changed during the past decade. BRCA1/2 testing should be performed in patients with breast cancer with a family history of breast or ovarian cancer and TNBC.

765P Prognosis of BRCA1 and BRCA2 ovarian cancer: Prospective follow-up data from a multidisciplinary program

BRCA1 and BRCA2 are tumour suppressor genes associated with the hereditary breast and ovarian cancer syndrome (HBOC). Previous data regarding BRCA1/2 penetrance estimated a median cumulative risk of ovarian cancer (OC) by 70 years of 25-40% and 11-18% for BRCA1 and BRCA2 carriers, respectively. In contrast to other populations, HBOC Portuguese patients (pts) have a higher prevalence of BRCA2 mutations, partially due to the effect of the founder BRCA2: c.156_157insAlu. In this study, we analyse the effect on prognosis of BRCA1 and BRCA2 variants in a Portuguese OC cohort.

Prevalence and predictors of germline BRCA1 and BRCA2 mutations among young patients with breast cancer in Jordan

BRCA1 and BRCA2 mutations are not uncommon in breast cancer patients. Western studies show that such mutations are more prevalent among younger patients. This study evaluates the prevalence of germline mutations in BRCA1 and BRCA2 among breast cancer patients diagnosed at age 40 or younger in Jordan. Blood samples of patients with breast cancer diagnosed at age 40 years or younger were obtained for DNA extraction and BRCA sequencing. Mutations were classified as benign/likely benign (non-carrier), pathogenic/likely pathogenic variant (carrier) and variant of uncertain significance (VUS). Genetic testing and counseling were completed on 616 eligible patients. Among the whole group, 75 (12.2%) had pathogenic or likely pathogenic variants; two of the BRCA2 mutations were novel. In multivariate analysis, triple-negative disease (Odd Ratio [OR]: 5.37; 95% CI 2.88–10.02, P < 0.0001), breast cancer in ≥ 2 family members (OR: 4.44; 95% CI 2.52–7.84, P < 0.0001), and a personal history ≥ 2 primary breast cancers (OR: 3.43; 95% CI 1.62–7.24, P = 0.001) were associated with higher mutation rates. In conclusion, among young Jordanian patients with breast cancer, mutation rates are significantly higher in patients with triple-negative disease, personal history of breast cancer and those with two or more close relatives with breast cancer.

Abstract PS8-31: Patterns, predictors and prevalence of germline BRCA1 and BRCA2 mutations among young patients with breast cancer in Jordan

Abstract Introduction: Hereditary causes, mostly related to BRCA1 and BRCA2 mutations, are not uncommon causes for breast cancer. Western studies had shown that such mutations are more prevalent among younger patients. In this study, we evaluate the prevalence of germline mutations in BRCA1 and BRCA2 among breast cancer patients diagnosed at age 40 or younger. Methods: Data on Jordanian breast cancer patients diagnosed at age 40 years or younger was reviewed. Blood samples were obtained for DNA extraction and BRCA sequencing was performed at reference labs. BRCA1 and BRCA2 mutations were classified as pathogenic/likely pathogenic and variant of uncertain significance (VUS). Results: A total of 616 patients aged 40 years or younger were enrolled. Genetic testing and genetic counseling have been completed for all. Majority (n=499, 81.0%) had a family history of breast cancer and 12.6% had triple-negative disease. Among the whole group, 75 (12.2%) were tested positive for pathogenic or likely pathogenic mutations, mostly (66.7%) in BRCA2 and an additional 57 (9.3%) had VUS. In multivariate analysis, triple-negative disease (Odd Ratio [OR]: 5.37; 95% CI: 2.88-10.02, p&amp;lt;0.0001), breast cancer in two or more family members (OR: 4.44; 95% CI: 2.52-7.84, p&amp;lt;0.0001), and a personal history of two or more primary breast cancers (OR: 3.43; 95% CI: 1.62-7.24, p=0.001) were associated with higher BRCA mutation rates (Table). In multivariate analysis, triple-negative disease (Odds Ratio [OR]: 5.37; 95% CI: 2.88-10.02, p&amp;lt;0.0001), breast cancer in two or more family members (OR: 4.44; 95% CI: 2.52-7.84, p&amp;lt;0.0001), and a personal history of two or more primary breast cancer (OR: 3.43; 95% CI: 1.62-7.24, p=0.001), were associated with higher BRCA mutation rates. A spectrum of 39 different mutations, 22 in BRCA2 and 17 in BRCA1 were detected. To our knowledge, three mutations in BRCA2 (c.4222_4223del and c.6193C&amp;gt;T in exon 11 and c.1013del in exon 10) have not been reported previously in any database. Conclusions: Among young Jordanian patients with breast cancer, mutation rates are significantly higher in patients with triple-negative disease, personal history of breast cancer and those with two or more close relatives with breast cancer. Variables TotalPositive MutationsBRCA1BRCA2BRCA1&amp; BRCA2P-ValueAge at diagnosis (years)≤ 35341163450 (14.7%)0.017&amp;gt; 3527591625 (9.1%)One or more close relative with breast cancer at any ageYes30593746 (15.1%)0.029No311151429 (9.3%)One or more close relatives with breast cancer diagnosed at age 50 years or youngerYes15332427 (17.6%)0.017No463222648 (10.4%)Diagnosed at ≤ 60 years with triple negative diseaseYes6916723 (33.3%)&amp;lt;0.001No54794352 (9.5%)Any age with at least 2 breast cancer primariesYes486814 (29.2%)&amp;lt;0.001No568194261 (10.7%)Two or more close relatives with breast cancerYes9752429 (30.0%)&amp;lt;0.001No519202646 (8.9%)All Patients616255075 (12.2%) Citation Format: Hikmat Abdel-Razeq, Lama Abujamous, Mahmoud Abunasser, Sarah Edaily, Rayan Bater. Patterns, predictors and prevalence of germline BRCA1 and BRCA2 mutations among young patients with breast cancer in Jordan [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-31.

Abstract OT-30-01: KEYLYNK-009: A phase 2/3, open-label, randomized study of pembrolizumab plus olaparib vs pembrolizumab plus chemotherapy after induction with first-line pembrolizumab plus chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC)

Abstract Background: Combination therapy with immunotherapy + chemotherapy is a promising approach for first-line treatment of locally recurrent, inoperable TNBC or metastatic TNBC (mTNBC). However, an unmet need exists for effective and tolerable maintenance regimens in mTNBC to sustain clinical benefit after induction therapy and avoid potential toxicity or resistance to prolonged chemotherapy. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has shown efficacy in the maintenance setting for platinum-sensitive ovarian cancer, and the high prevalence of BRCA mutations (or “BRCAness”) in TNBC may make these tumors particularly sensitive to DNA-damaging agents. Moreover, evidence suggests that combination therapy with olaparib and the PD-1 inhibitor pembrolizumab may provide clinical benefit greater than treatment with either single-agent. KEYLYNK-009 (NCT04191135) is a phase 2/3, open-label, randomized study of pembrolizumab + olaparib or pembrolizumab + chemotherapy after induction with first-line pembrolizumab + chemotherapy in patients with locally recurrent, inoperable TNBC or mTNBC.Methods: This 2-in-1 study design will enroll ~317 patients in phase 2; if a planned efficacy boundary is met, ~615 additional patients will be enrolled in phase 3. Patients eligible for induction therapy must have measurable, locally recurrent, inoperable TNBC that cannot be treated with curative intent or mTNBC previously untreated with chemotherapy in the metastatic setting. All patients will receive up to 6 cycles of induction therapy with pembrolizumab 200 mg Q3W + chemotherapy (carboplatin AUC 2 + gemcitabine 1000 mg/m2 on days 1 and 8 Q3W). Patients eligible for postinduction treatment must achieve complete or partial response or maintain stable disease during induction after 4-6 treatment cycles, with ECOG PS 0/1 and no persistent grade &amp;gt;1 toxicities related to induction therapy (excluding alopecia, hemoglobin ≥9.0 g/dL, grade 2 hyper-/hypothyroidism, or grade 2 hyperglycemia). These patients will be randomized 1:1 to receive pembrolizumab 200 mg Q3W + olaparib 300 mg twice daily or continue pembrolizumab + chemotherapy (same as induction regimen). Olaparib and chemotherapy may continue until progression or unacceptable toxicity; pembrolizumab may continue for ≤35 cycles (including induction), unacceptable toxicity, or progression. Phase 3 dual primary endpoints are PFS per RECIST version 1.1 by blinded independent central review and OS. Secondary endpoints are OS and PFS in patients with BRCA mutation, health-related quality of life, and safety. PFS and OS will be estimated using the Kaplan-Meier method, treatment differences will be assessed using a stratified log-rank test, and HRs and 95% CIs will be assessed using a stratified Cox proportional hazard model with Efron's method of tie handling. AEs are monitored until 30 days (90 days for serious AEs) after treatment discontinuation per NCI CTCAE version 5.0. Patient enrollment is ongoing with a total planned enrollment of 932 patients. Contact Hope S. Rugo at hope.rugo@ucsf.edu for additional information. Citation Format: Hope Rugo, Antonio Llombart-Cussac, Fabrice Andre, Mark E. Robson, Shigehira Saji, Nadia Harbeck, Peter Schmid, David Cescon, Jin Seok Ahn, Rita Nanda, Li Fan, Jaime Alberto Mejia, Vassiliki Karantza, Aditya Bardia. KEYLYNK-009: A phase 2/3, open-label, randomized study of pembrolizumab plus olaparib vs pembrolizumab plus chemotherapy after induction with first-line pembrolizumab plus chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-30-01.

Abstract PS9-37: Hereditary breast and ovarian cancer syndrome (HBOC) diagnosis impacts more the life quality of women than men: A case-control report

Abstract INTRODUCTION: HBOC syndrome is directly associated with a variant in BRCA1/2 genes and the diagnosis may increase anxiety and depression levels because of the need for preventive measures. Psychic impacts on women with mutations have been further explored in the literature, although the emotional aspects linked to the diagnosis in male breast cancer is poorly known. AIM: This work aimed to compare the anxiety, depression, and quality of life levels in male and female cancer patients HBOC-suspected, immediately after the result of the genetic test. METHODOLOGY: A retrospective case-control study was carried out with five men matched for age with 39 women, both with National Comprehensive Cancer Network (NCCN) criteria for HBOC. The Hospital Anxiety and Depression (HAD) scale and the WHOQOL-bref quality of life inventory were used. Sociodemographic, clinical, molecular, and psychological data were analyzed using χ2/Fisher's exact and Mann-Whitney, Friedman/Dunn, and Wilcoxon tests (SPSS, 20.0; p &amp;lt;0.05). RESULTS: All patients were &amp;gt;45 years old, all recruited women had breast cancer as the primary tumor and eight of them (20.5%) had ovary cancer. We had two male breast cancer and three prostate cancer Gleason&amp;gt;7. Sociodemographic characteristics did not differ between the genders (p&amp;gt; 0.05). Men had a higher prevalence of pathogenic mutation (p=0,031). Women had a higher prevalence of BRCA1 mutations (p=0,014) while men had of BRCA2 mutation (p=0,001). There was no difference in the anxiety and depression levels immediately after receiving the result, but it was observed that only women had lower quality of life in the physical domain (p=0,048). This domain showed the lowest scores in female patients (p&amp;lt;0,001). Although men have a higher prevalence of the pathogenic mutation in BRCA1/2, the emotional impact is greater in women whose impact on the physical domain may be directly associated with cancer treatment, which may have physical and psychological consequences, negatively affecting the quality of life of these women. CONCLUSION: These results reinforce the need to address the psycho-emotional aspects of women with HBOC, to promote better treatment coping, providing a better quality of life. Research Sponsor: Ministerio da Saude, Brasil (PRONON) Citation Format: Francisca Fernanda Barbosa Oliveira, Paulo Goberlanio de Barros Silva, Isabelle JoyceLima Silva-Fernandes, Clarissa Gondim Picanço-Albuquerque, Maria Claudia dos Santos Luciano, Maria Júlia Barbosa Bezerra, Rosane Oliveira Sant´anna, Flavio Silveira Bitencourt, Marcos Venicio Alves Lima. Hereditary breast and ovarian cancer syndrome (HBOC) diagnosis impacts more the life quality of women than men: A case-control report [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-37.

FLABRA, frontline approach for BRCA testing in an ovarian cancer population: aLatin America epidemiologic study.

Aim:FLABRAevaluated the prevalence of BRCA mutations, genetic counseling and management approaches in patients with ovarian cancer in Latin America. Patients & methods: Patients with ovarian cancer from six Latin-American countries were enrolled. Tumor samples were tested for BRCA mutations(BRCAmut). In cases with BRCAmut, blood samples were analyzed to determine germline versus somatic mutations. Medical records were reviewed for counseling approach and treatment plan. Results: From 472 patients enrolled, 406 samples yielded conclusive results: 282 were BRCA wild-type (BRCAwt), 115 wereBRCAmutand ninewere variants of uncertainsignificance. In total, 110/115were tested for germline mutations (77 germline and 33 somatic). Conclusion: Tumor testing to identify mutations in BRCA1/2inovarian cancer can help optimize treatment choices, meaning fewer patients require germline testing and genetic counseling, a scant resource in Latin America. Clinicaltrial registration: NCT02984423(ClinicalTrials.gov).

315P High-penetrance breast and/or ovarian cancer susceptibility genes in Filipinos

Breast cancer is the most common cancer seen in women worldwide. In the Philippines, 24,798 cases of breast cancer were diagnosed in 2018, making up 17.6% of 141,021 newly diagnosed cases of cancer in the country. Genetic counseling and testing for hereditary cancers is a relatively new undertaking for medical oncologists in the Philippines. Previous studies show that prevalence of BRCA mutations in Filipinos is 5.1% to 6.8%, which is consistent with data found in the Asian population. However, no studies have yet been done looking at multigene panel testing for Filipino patients who meet the testing criteria for high-penetrance breast and/or ovarian cancer susceptibility genes. From September 2019 to May 2020, we did multigene panel testing (Invitae Multi-Cancer Panel) for patients who met the testing criteria for high-penetrance breast and/or ovarian cancer susceptibility genes (NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 1.2020 – December 4, 2019). We tested 24 patients (23 females, 1 male; 29-81 years old), including 14 with breast cancer, 4 with ovarian cancer, 1 with both breast and ovarian cancer, 2 with pancreatic cancer, and 3 with no cancer but strong family history. Among the 24 patients tested, none had pathogenic BRCA1/2 mutations. However, one (4%) had a pathogenic PALB2 mutation (c.757_758del (p.Leu253Ilefs*3)), fourteen (58%) had one or more variants of uncertain significance (ALK, ATM, BARD1, BRCA2, CDKN1B, EGFR, KIT, MSH2, MSH6, MUTYH, NF1, NTHL1, POLE, RAD51D, RECQL4, SDHA, SDHB, SMARCA4, SMARCB1, TSC1), and nine (38%) had negative results. As cancer genetics becomes more mainstream, use of multigene panels has been increasing, and cost of testing has been decreasing, making this more accessible to the average Filipino cancer patient. This is the first study to document the presence of other high-penetrance breast and/or ovarian cancer susceptibility genes in Filipinos. However, more research has to be done as we still do not know all the genes that may cause hereditary breast cancer and use of multigene panels increases the rates of detecting variants of uncertain significance and other incidental findings.