Pathogenic BRCA1 Mutations Research Articles

Abstract PS5-19: Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study

Abstract Background: Young-PEARL study showed median progression-free survival (PFS) of 20·1 months in the palbociclib plus endocrine therapy group versus 14·4 months in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], log-rank p=0·0235). We conducted exploratory biomarker analysis to predict the efficacy of the trial. Methods: This was a phase II trial that randomized 184 patients with HR+ MBC in premenopausal women to palbociclib plus exemestane with GNRH agonist (Arm A, n=79) versus capecitabine (Arm B, n=62). We performed targeted sequencing (CancerSCANTM) containing 375 cancer-related genes (141 patients) and whole transcriptome sequencing (165 patients) using baseline tumor samples to examine genomic alteration in relation to drug response in terms of PFS. Result: By research-based PAM50 subtyping, 73% of patients classified as Luminal (Luminal A and Luminal B), and showed better prognosis in all patients and Arm A (p<0.05) in compared to no survival difference in Arm B (p=0.284). PFS difference between LumA and LumB was not statistically significant in Arm A (p=0.196). PIK3CA mutation (41%), TP53 mutation (33%), GATA3 mutation (25%), CCDN1 CNV (29%), BRCA2 mutation (14%) were the most frequently detected in this population. High TMB, TP53 mutation, ClinVar pathogenic somatic BRCA2 mutation (3.5%) showed worse prognosis in Arm A (p<0.05). Non-luminal patients with TP53 or BRCA2 mutations were poor prognosis in Arm A. Patients with BRCA2 pathogenic mutations showed worse prognosis regardless PAM50 subtypes, and luminal patients showed longer PFS compared to non-luminal patients among patients without BRCA2 pathogenic mutations in Arm A. RB1 loss, known as a resistant biomarker of CDK4/6 inhibitor was found in 4% of Arm A, and was associated with shorter PFS (log2 HR=2.26, 95% CI 0.51 to 4.01, p=0.011). AURKA mutation/amplification and RAD51C amplification were significantly associated to the patients with PFS less than 6 month. ESR1 mutations were found in 3.5% of patients, which was less than PEARL (29.4%) and PALOMA-3 (25.1%) trials. ESR1 mutations and ESR1/2 expression were not associated with shorter PFS. Notch 2/3/4 pathway expression was lower in patients with longer PFS (PFS more than 20month). ETIMATE ImmuneScore was higher in non-luminal compared to luminal patients, and didn’t show survival difference in Arm A, but luminal patients with low ImmuneScore showed better prognosis. The relative proportion of 22 immune cell types was deconvoluted by CIBERSORT, and T cell CD4 memory resting, Macrophage M0 and M2 were abundant. NK cell activated was higher proportion in patients with longer PFS. Low TIL patients with low interferon and high T cell regulation expression showed worse prognosis. Germline BRCA mutation and integrated analyses of genomic and transcriptomic profiles will be reported. Conclusions: The alteration of a few genes including Rb1 loss may be associated with resistance of palbociclib in HR-positive premenopausal population with MBC. Luminal type showed better prognosis, and BRCA2 pathogenic mutation showed worse prognosis regardless luminal/non-luminal type. ESR1 mutation was found in low population frequency because all patients didn’t received AI therapy. Further exploration of molecular variables is warranted to determine and validate biomarkers of efficacy. Clinical trial information: NCT02592746. Citation Format: Kyunghee Park, Gun Min Kim, Kyung Hae Jung, Seok Yun Kang, In Hae Park, Jee Hyun Kim, Hee Kyung Ahn, Woong-Yang Park, Seock-Ah Im, Yeon Hee Park. Exploratory biomarker analysis of Young-PEARL [palbociclib plus exemestane with GnRH agonist versus capecitabine in premenopausal women with HR (hormone receptor)-positive, HER2-negative metastatic breast cancer (MBC)] study [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 PS5-19.

Abstract PS16-25: Comparison of the genetic mutations in sporadic and BRCA1 carrier breast cancer through targeted next generation sequencing

Abstract IntroductionWomen who carry a germline mutation in BRCA1 (breast cancer type 1 susceptibility protein) have an increased risk of developing breast cancer in their lifetimes. Carriers tend to develop breast cancer at a younger age and their tumors are generally aggressive. Although BRCA1 breast cancers have been researched, many questions remain. The purpose of this study was to analyze the mutational landscape of tumors from BRCA1 carriers and compare them to tumors of sporadic breast cancer. MethodsPathology reports were reviewed to identify cases of breast cancer (BC) and the ER/PR/HER2 status was noted as well as the Ki67 proliferation index and patient age. Next generation sequencing (NGS) was performed on 72 BC tumors; 26 from BRCA1 carriers and 46 sporadic BC tumors. Two targeted panels were used for sequencing, the Oncomine Comprehensive Assay by Thermo Fisher Scientific on an Ion Torrent S5 XL sequencer and the AmpliSeq for Illumina Cancer HotSpot Panel. Mutations in a total of 44 cancer associated genes common to both panels were analyzed including TP53, RB1, PTEN, NRAS, ERBB2, PIK3CA, and BRAF. Missense and nonsense single nucleotide variants with a variant allele frequency >3% and coverage >150 reads were considered as well as insertions/deletions. Pathogenicity was determined using ClinVar and Varsome. Mutations were classified as benign, likely benign, variants of uncertain significance, likely pathogenic, and pathogenic.ResultsPathogenic/likely pathogenic variants were identified in 15 genes. TP53 was the most commonly mutated gene with pathogenic/likely pathogenic variants in 13 (50%) BRCA1 carriers’ tumors and 18 (39%) sporadic tumors. Having a TP53 mutation did not increase the likelihood of having other pathogenic mutations in either BRCA1 carriers or sporadic tumors; 74% of all tumors with p53 mutations had no additional pathogenic mutations overall. PIK3CA pathogenic/likely pathogenic mutations were significantly more common in sporadic tumors (26%) than BRCA1 carrier tumors (8%). PIK3CA mutation did not increase the likelihood of other gene mutations and did not correlate with TP53 mutations. BRCA1 pathogenic mutations were identified in four cases with no germline testing and likely represent somatic mutations. No pathogenic mutations were found in 12 (46%) of the BRCA1 carriers’ tumors and 10 (22%) sporadic tumors. There were four BRCA1 carriers with bilateral BCs; two pairs had the same mutations, one pair had different TP53 pathogenic mutations and another pair had different PIK3CA pathogenic mutations. A total of twenty-four cases were triple negative, 13 sporadic and 11 BRCA1 carriers (see table below). As expected, BRCA1 carriers were diagnosed with BC at a younger age with 21 (81%) cases diagnosed at age < 60 years while 22 (48%) of sporadic cases were in this age group. Conclusion TP53 is the most commonly mutated gene in BCs, even though more common in BRCA1 carriers’ tumors; however, they are not required for tumor development as seen in the 57% of cases in our study with normal TP53 (50% of BRCA1 carriers). No specific additional pathogenic mutation was commonly seen in BRCA1 tumors with TP53 mutations. PIK3CA was frequently mutated in sporadic cases and not in BRCA1 carriers. BRCA1 tumors were less likely to have other pathogenic mutations than sporadic tumors in this study of 44 genes. Additional studies will help further elucidate the molecular basis of BRCA1 tumor carcinogenesis. Citation Format: Cynthia Reyes Barron, David Hicks, Xi Wang. Comparison of the genetic mutations in sporadic and BRCA1 carrier breast cancer through targeted next generation sequencing [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 PS16-25.

Abstract PS16-29: Clinicopathological features of PALB2 and BRCA2 mutation carriers with breast cancer

Abstract Background: The PALB2 gene is recognized as one of the most clinically relevant moderate to high penetrance breast cancer (BC) predisposition genes. Its product, PALB2, plays a crucial role in the homologous recombination pathway as a partner and localizer of BRCA2. Previous studies have reported significant frequencies of germline PALB2 and BRCA2 pathogenic variants (PVs) in Hispanic populations. However, no study has yet compared the baseline clinicopathological features of Mexican BC patients who carry PVs in these closely related genes. Methods: Medical records of BC patients from two centers located in Monterrey, Mexico who underwent a next-generation sequencing panel for BC predisposition genes (APC, ATM, BRCA1, BRCA2, BRIP1, CHEK2, CDH1, CDKN2A, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, TP53) based on NCCN recommendations were reviewed. Patients with germline PVs in PALB2 or BRCA2 were considered eligible. Fisher’s exact and Mann Whitney U tests were employed to evaluate differences between groups based on mutation status. Results: Between 2014 and 2019, a total of 8 PALB2 (1.8%) and 24 BRCA2 (5.5%) pathogenic mutation carriers were identified from 437 BC cases. Baseline clinicopathological features are shown in Table 1. Overall, no statistically significant differences were observed between groups. The most common germline PVs were c.2167_2168delAT, p.Met723fs, frameshift mutation for PALB2 (57% of cases) and c.274C>T, p.Gln92Ter, nonsense mutation for BRCA2 (30% of cases). Of note, one male BC case occurred in a PALB2 mutation carrier, representing 13% (1/8) of BC cases in this carrier group and the only male BC case (out of three) associated with a germline PV. Conclusion: This is the first report detailing the clinicopathological features of Mexican BC patients with germline PALB2 PVs. According to our findings, BC tumors in PALB2 mutation carriers share similar baseline characteristics with those diagnosed in BRCA2 mutation carriers. Long-term follow-up is required in order to determine if prognosis is similar between groups and to further solidify the clinical relevance of germline PALB2 PVs in the Mexican population. Baseline clinicopathological features of PALB2 and BRCA2 mutation carriers with BCPALB2 mutation carriersBRCA2 mutation carriersMedian age at diagnosis (years)3938Median body mass index (kg/m2)2326Family history of BCYes5 (63%)19 (79%)No3 (38%)5 (21%)Clinical stageI2 (25%)2 (8%)II5 (63%)11 (46%)III08 (33%)IV1 (13%)3 (13%)Histological typeIDC6 (75%)22 (92%)Non-IDC2 (25%)2 (8%)Histological gradeG11 (13%)5 (21%)G24 (50%)10 (42%)G33 (38%)6 (25%)Missing03 (13%)Molecular subtypeHR+/HER2-6 (75%)11 (46%)HR+/HER2+04 (17%)HR-/HER2+00HR-/HER2-2 (25%)9 (38%)LateralityUnilateral8 (100%)21 (88%)Bilateral03 (13%) Citation Format: Alejandro Aranda-Gutierrez, Ana S Ferrigno, Juan Carlos A. García Marrufo, Mariana Moncada-Madrazo, Analy Gomez-Picos, Cynthia Villarreal-Garza, Dione Aguilar. Clinicopathological features of PALB2 and BRCA2 mutation carriers with breast cancer [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 PS16-29.

Abstract PS8-19: High rates of BRCA1 and BRCA2 variants of uncertain significance (VUS) among Jordanian breast cancer patients

Abstract Background: Contrary to pathogenic BRCA mutations, recommendations for management of Variants of Uncertain Significance (VUS) is not clear and focus more on clinical factors, personal and family history of cancer; breast and ovarian in particular. Genetic variants that may or may not have clinical consequence can be confusing and anxiety-provoking to patients and physicians, alike. No data exist on Arab patients with VUS mutations. In this study we search for the frequency of VUS among high risk breast cancer patients tested for BRCA mutations and study risk-reduction interventions related to such findings. Methods: We utilized an institutional database started January 2015 for all patients with breast cancer tested for BRCA mutations as per the National Comprehensive Cancer Network (NCCN) guidelines, including those with early onset cancers, triple-negative disease and positive family history. We also reviewed surgical interventions patients had in relation to their breast cancer and VUS mutation identification. RESULTS: Between January 2015 and May 2020, a total of 1181 patients were tested for BRCA1 and BRCA2 mutations as per the NCCN guidelines. Pathogenic mutations were detected in 134 (11.3%) patients, while 109 (9.2%) others had VUS; 79 (72.5%) were in BRCA2. At time of testing, all VUS patients had breast cancer; 7 (6.4%) with metastatic disease. Median age (range) was 39 (25-66) years with 63 (57.8%) were 40 years or younger at diagnosis. Twelve (11.0%) had triple negative disease while 14 (13.1%) others had bilateral or two or more unilateral primary breast cancers. Family history of breast, ovarian or pancreatic cancers, in at least one close relative, was identified in 52 (47.7 %) patients. Among 101 patients with nonmetastatic disease, 48 (48.0%) had breast conserving surgery (BCS) while only 5 (5.0%) had bilateral mastectomies, all were due to bilateral disease and not prophylactic. VUS diagnosis was known prior to initial surgery in 33 (32.7%) patients; 11 (33.3%) of them had lumpectomy only. Since we started genetic testing 5 years ago, there is a slight decline in VUS rate but none of the VUS reported mutations so far were reclassified. Conclusions: Despite significant decline in VUS rates reported in the western societies, our rate continues to be high and alarming. Our knowledge of VUS had not significantly impacted on therapeutic or prophylactic surgical decisions. Given the relatively high rate of second breast cancers among such patients, management should be dictated by their personal or family history. A regional (Arab) VUS registry and comprehensive genetic counseling to ensure appropriate follow up and understanding by affected patients, are highly needed. Citation Format: Hikmat Abdel-Razeq, Faris Tamimi, Lama Abujamous, Razan Abu Khashabeh. High rates of BRCA1 and BRCA2 variants of uncertain significance (VUS) among Jordanian breast cancer patients [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 PS8-19.

Contralateral Prophylactic Mastectomy in Patients with Breast Cancer.

Introduction: The rate of contralateral prophylactic mastectomy (CPM) increased within the recent years. The main reasons are: genetic testing, availability of breast reconstruction, more often use of preoperative breast MRI, improvement of postoperative aesthetic results and reimbursement of breast reconstruction. The purpose of this study was to analyze the indication of CPM, it's evolution and the surgical techniques used for this type of surgery. Materials and methods: This prospective study enrolled patients with unilateral breast cancer for which conservative treatment was not an option and underwent CPM concomitant with therapeutic mastectomy, using different techniques, followed by immediate breast reconstruction using alloplastic materials. Results: A total of 45 patients with unilateral breast cancer underwent therapeutic mastectomy and CPM followed by immediate breast reconstruction, between January 2015-December 2020. The mean age was 43.5 years, 64,44% patients had stage I and II breast cancer and 22,22% were triplenegative. The indications for CPM were: pathogenic mutation of BRCA or of other genes associated with high risk of breast cancer, strong family history, suspicious findings on breast MRI, extended micro-calcifications, dense breasts, and extreme anxiety. Conclusions: A growing rate of bilateral mastectomy for unilateral breast cancer was observed. Availability of immediate breast reconstruction and reimbursement plays an important role for patients in choosing CPM. Factors associated with CPM include: young age, pathogenic BRCA mutation, significant family history and triple-negative disease. The rate of immediate postoperative complications was low. CPM is a valid option to reduce the risk of contralateral breast cancer and to achieve a good aesthetic outcome for patients with unilateral breast cancer with high risk of contralateral breast cancer.

Характеристика BRCA-ассоциированного рака молочной железы в российской популяции

"Standard" diagnostic panels allow identification of only a few of BRCA1 and BRCA2 gene mutations most common in a population. Therefore, tests relying on such panels may return false negative results, since the coding regions of these genes may have other defects. For breast cancer (BC) patients, false negative test results may translate into selection of inadequate therapy by their doctors. This study aimed to identify the features of BRCA-associated breast cancer in the population of the Russian Federation. The study included breast cancer patients (n = 4440). At the first stage, all patients were screened for the eight most common BRCA1 and BRCA2 genes mutations with the help of real-time PCR. Next, patients that exhibited clinical signs of a hereditary disease (CSHD) in the absence of common mutations (n = 290) had the entire coding regions of BRCA1 and BRCA2 genes studied with next generation sequencing (NGS). "Standard" mutations in the BRCA1 and BRCA2 genes were identified in 169 (3.8%) cases. In the CSHD group, such mutations were revealed in 15.4% of cases. NGS uncovered 33 rare pathogenic BRCA1 and BRCA2 gene mutations in 40 out of 290 breast cancer patients (13.8%). It was concluded that among the residents of the Russian Federation, the range of pathogenic variants of BRCA-associated breast cancer is wide, and it stretches beyond the mutations considered by the "standard" diagnostic panels. Analysis of the entire coding regions of BRCA1 and BRCA2 genes allows increasing efficiency of detection of germline mutations in breast cancer patients at least twofold.

Genomic biomarker discovery of first-line gemcitabine/nabpaclitaxel treatment in Chinese advanced pancreatic carcinoma patients.

436 Background: Pancreatic carcinoma is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Gemcitabine plus Nab-paclitaxel (GNp) has been recommended by international guidelines for first-line treatment of locally advanced or metastatic pancreatic carcinoma. However, exploration into molecular biomarkers of GNp treatment is still limited. This study aims to observe and evaluate the efficacy and safety of first-line GNp treatment of pancreatic carcinoma, and to explore potential predictive and prognostic biomarkers to screen advantageous population. Methods: From December 20, 2018 to July 6, 2020, patients with metastatic pancreatic carcinoma, who received first-line GNp treatment, were enrolled. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events (AE). Patients were collected formalin fixed paraffin embedded (FFPE) samples and sequenced by a next-generation sequencing (NGS)-based 450 gene panel carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: In this study, tissue samples from 101 patients were assessed by NGS, including 58 (57.4%) primary tissues and 43 (42.6%) metastasis tissues. So far, 72 patients were available for efficacy analysis, the ORR and DCR were 38.2% and 77.9%, respectively, and were similar between patients sampled from primary lesions and metastasis lesions. The PFS and OS were 176 days and 308 days, respectively. The most frequently mutated genes were KRAS (91.9%), TP53 (76.8%), CDKN2A (32.3%) and SMAD4 (26.3%). Germline pathogenic BRCA2 mutations were detected in 3 (3.0%) patients, while somatic mutations of BRCA2 were found in 2 (2.0%) patients. For KRAS, missense mutations resulted in single amino acid substitutions primarily at G12 (88.1%), and lower frequencies at Q61 (4.0%) and V14 (1.0%). At G12, five different amino acid substitutions have been identified, with G12D (37.6%) the predominant mutation, G12V (32.7%), G12R (11.9%), G12C (3.0%) and G12A (1.0%). The ORR to AG treatment was significantly higher in TP53-alteration (-alt, 47.1%) than in TP53-wild-type (-WT, 11.1%) subgroups (p=0.01). Median OS times in CDKN2B-alt and CDKN2B-WT patients were 180 days and 323 days (p=0.029), respectively. Conclusions: Current evidence indicates that GNp is a valuable option for the first-line treatment of metastatic pancreatic cancer. TP53 may serve as a novel response-predictive gene for GNp treatment in pancreatic carcinoma. Overall survival was significantly prolonged in CDKN2B-WT patients compared with CDKN2B-alt patients. This study provided insights in identifying patients who might potentially benefit from GNp therapy. Clinical trial information: NCT03768687.

Diagnostic and therapeutic ERβ, HER2, BRCA biomakers in the histological subtypes of lung adenocarcinoma according to the IASLC/ATS/ERS classification

Several studies revealed that non–small cell lung cancers (NSCLCs) frequently express ER, PR, HER2 and carry BRCA mutation. However, these markers in histological subtypes of lung adenocarcinoma have not been thoroughly investigated. We retrospectively evaluated a total of 640 lung adenocarcinoma samples for ERα, ERβ, PR and HER2 expression by immunohistochemistry and western-blotting, for EGFR and BRCA mutation by real-time PCR and sequencing. Furthermore, HER2 amplification and mutation were explored in samples harboring immunopositivity HER2 using fluorescence in situ hybridization and real-time PCR, respectively. The micropapillary and invasive mucinous predominant adenocarcinoma were frequently detected the higher level of cytoplasmic ERβ (64.9% and 56.6%), HER2 (68.1% and 60.1%) protein expression. But, amplification of HER2 was detected in only three cases (3/110, 2.7%) and 26 HER2 mutations in 110 cases were identified (23.6%) in the HER2 immunopositivity patients. Logistic regression analysis showed that cytoplasmic ERβ (P = 0.032) and HER2 (P = 0.015) expression were independently associated with EGFR mutation. 8 patients (8/640, 1.25%) harbored pathogenic BRCA mutations, 6 with germline BRCA mutations and 2 with somatic BRCA1 mutations were detected with lacking ERβ, PR and HER2 expression. Acinar predominant adenocarcinoma had the higher percentage of BRCA mutations than other subtypes. A systematic examination of ERβ, HER2 and BRCA biomarkers could potentially be useful to diagnosis and identify patients with the histological subtypes of lung adenocarcinoma, who might benefit from the further individualized treatment of anti-hormone, anti-HER2 and/or PARP inhibitors therapeutics.

Identification of Novel BRCA1 Germline Deleterious Variant Among a Tunisian Family

Inherited predisposition to breast and ovarian cancer are most frequently due to germline mutations in the main genes BRCA1 (OMIM# 113705) and BRCA2 (OMIM# 600185). These inactivating mutations, essentially frameshift and nonsense variation, occurs mainly across conserved regions. The aim of the present study is to report a novel germline BRCA1 mutation identified in a Tunisian family case with early onset of breast and ovarian cancer and to evaluate the genotype phenotype correlation. The proband had high-grade tumors, invasive unilateral ductal carcinoma developed at the age of 38 and a serous ovarian adenocarcinoma after a gap of twelve years. The molecular analysis revealed a novel heterozygous nonsense BRCA1 mutation NM_007294.4: c.915T>A p.(C305*) in the proband and her daughter. This mutation leads to a truncated protein which pathogenicity was validated by bioinformatics tools. This variant is subject to nonsense-mediated mRNA decay. We also underlined the immunohistochemistry usefulness by lack of expression of BRCA1 protein in paraffin embedded breast tumor contrasting with normal tissue. Clinical and pathological data tend to be homogeneous and led to the conclusion that there is a genotype phenotype correlation in BRCA1, an element that must be taken into account in genetic counselling. Conclusively, we are the first to report this novel BRCA1 germline likely deleterious variant extending the molecular and clinical spectrum of BRCA1 pathogenic point mutations. Further in vitro functional experiments needs to be established. High-risk individuals carrying this BRCA1 mutation benefit from preventive measures to reduce morbidity.

Do we know properly young age breast cancer patients: a double centre study

Background: According to American Cancer Society, an estimated 268,600 new cases of invasive breast cancer was diagnosed among women, and nearly 50,000 women were under age 50 years. Therefore, the identification of young age breast cancer patients can have a collosal impact on treatment, and medical follow-up. The present study aimed to understand the young age breast cancer pathophysiology and redound new BRCA variants to literature. Methodology: This was a double-centre study performed in the Medical Genetics Department of Kahramanmaras Necip Fazıl City Hospital. In this study, sixty female patients, who are under 45 years old, diagnosed with primer breast cancer in the oncology clinic of the same hospital and Kahramanmaraş Sutcu İmam University were included. The patients were selected for BRCA mutation testing based on NCCN Guideline Version 3.2019 BRCA1/2 Testing Criteria. Relatives who meet the same criteria from the same family were not included to prevent repetition. Patients with known other cancer syndromes were also excluded. Results: We found that Luminal-B type breast cancer was the most frequent subtype (p < 0.001), patients with Luminal-A subtype breast cancer had significantly smaller tumor size and smaller grade than those had other subtypes of breast cancer at diagnosis stage (p = 0.03 and p < 0.001, respectively). Regarding tumor localization, the breast carcinomas were mostly localized in the right breast (53.3%). Two patients (3.3%) had BRCA1 pathogenic mutation and five patients (8.3%) had BRCA2 pathogenic mutation. Additionally, we found two new variations in BRCA2 gene (c.478_488delGTATGTGGGAG and c.8830 A>T (rs4987047). All BRCA1/2 MLPA results were normal. Conclusion: The incidence of young age breast cancer varies among countries, and it is higher in developing countries. Understanding of young age breast cancer cases will be helpful to provide suitable treatment options and will help to reduce the death rate of these patients.

Abstract IA25: Black Lives Matter Worldwide: Retooling Precision Oncology for True Equity of Cancer Care

Abstract Analysis of cancer genomes has provided fundamental insights into the process of malignant transformation, and cancer genomes have rapidly become an integral part of the practice of clinical oncology, with implications for diagnosis, prognosis, treatment and prevention. Inherited and sporadic cancers often share common mutational events. When inherited mutations are identified, genetic counseling is an essential component of care. Risk-stratified breast cancer screening strategies are a paradigm shift from the one-size-fits-all screening approach. Previous age-based screening strategies proved to be disadvantageous to specific minority populations, particularly those at high risk for interval breast cancers developed at a younger age with a poorer prognosis. With the increasing use of personalized risk assessment tools in the clinic and the uptake of risk-reducing prevention and early detection interventions, risk-stratified screening approaches promise to reduce racial disparity in breast cancer outcomes. Using high throughput whole genome strategies, including genome-wide association studies, whole exome sequencing, and whole genome sequencing, we can now deeply explore the most foundational instigators of the most aggressive forms of breast cancer. Work from our group and others have demonstrated the significant burden of early onset ER negative breast cancer as well as high rates of pathogenic BRCA1 and BRCA2 mutations among African American and Hispanic women in the US. Globally, breast cancer is a disease of young women and pathogenic mutations in BRCA1 and BRCA2 are the strongest predictors of risk and have also been categorized as the strongest predictors of aggressive prostate cancer risk. Our work is informed by attentive, interdisciplinary study of the most aggressive phenotypes of breast cancer in diverse populations in the US and abroad. BRCA-associated basal-like breast cancers have defects in homologous recombination pathways and based on the fundamental biology of these tumors, there are novel pathways including DNA repair, metabolic and immune pathways that can potentially be targeted for more effective management strategies. While basal-like breast cancer remains the molecular subtype with the worst outcome in all populations, we have evidence from randomized clinical trials that it is most curable when diagnosed early and treated promptly with multimodality cancer therapies. Work from our group as well as other laboratories show that high temporal resolution Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) is likely to increase lesion conspicuity and diagnostic accuracy. Our group is also pioneering the potential of an automated, quantitative radiomics platform on DCE-MRI breast imaging for inferring underlying activity of clinically relevant gene expression pathways of invasive breast cancers at diagnosis. Waiting to treat advanced cancer with targeted therapies is a failure of primary prevention and population-based strategies for risk assessment and management in high-risk populations will be needed. I will discuss our recent findings and future directions for the early detection and prevention of the most aggressive subtypes of breast cancer in vulnerable high-risk populations. Citation Format: Olufunmilayo Olopade. Black Lives Matter Worldwide: Retooling Precision Oncology for True Equity of Cancer Care [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA25.

Tumor phenotype and concordance in synchronous bilateral breast cancer in young women.

Synchronous bilateral breast cancer is uncommon, and its pattern and incidence among younger women is unknown. Here we report the incidence, phenotypes, and long-term oncologic outcomes of bilateral breast cancer in women enrolled in the Young Women's Breast Cancer Study (YWS). The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40years. Those with synchronous bilateral breast cancer formed our study cohort. Tumor phenotypes were categorized as luminal A (hormone receptor (HR)+/HER2-/grade 1/2), luminal B (HR+ /HER2+ or HER2- and grade 3), HER2-enriched (HR-/HER2+), or basal-like (HR-/HER2-). Descriptive statistics were used to evaluate tumor phenotypes of bilateral cancers for concordance. Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38years (range 18-40years). Seventeen (81.0%) underwent genetic testing with 6 found to have pathogenic germline mutations in BRCA1, BRCA2, or TP53. The majority of patients (76.2%) underwent bilateral mastectomy. On pathology, 2 patients had bilateral in-situ disease, 6 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, 10 (76.9%) had bilateral luminal tumors and, when fully characterized, 6 were of the same luminal subtype. Only 1 patient had bilateral basal-like breast cancer. At median follow-up of 8.2years, 14 patients are alive with no recurrent disease. Bilateral breast cancer is uncommon among young women diagnosed with breast cancer at age ≤ 40. In our cohort, the majority of invasive tumors were of the luminal phenotype, though some differed by grade or HER2 status. These findings support the need for thorough pathologic workup of bilateral disease when it is found in young women with breast cancer to determine risk and tailor treatment.

Cancer Previvors in an Active Duty Service Women Population: An Opportunity for Prevention and Increased Force Readiness.

BackgroundThe majority of active duty service women (ADS) are young, have access to healthcare, and meet fitness standards set by the U.S. military, suggesting that ADS represent a healthy population at low risk of cancer. Breast cancer is, however, the most common cancer in ADS and may have a significant effect on troop readiness with lengthy absence during treatment and inability to return to duty after the treatment. The identification of unaffected ADS who carry germline mutations in cancer predisposition genes (“previvors”) would provide the opportunity to prevent or detect cancer at an early stage, thus minimizing effects on troop readiness. In this study, we determined (1) how many high-risk ADS without cancer pursued genetic testing, (2) how many previvors employed risk-reducing strategies, and (3) the number of undiagnosed previvors within an ADS population.MethodsThe Clinical Breast Care Project (protocol WRNMMC IRB #20704) database of the Murtha Cancer Center/Walter Reed National Military Medical Center was queried to identify all ADS with no current or previous history of cancer. Classification as high genetic risk was calculated using National Comprehensive Cancer Network 2019 guidelines for genetic testing for breast, ovary, colon, and gastric cancer. The history of clinical genetic testing and risk-reducing strategies was extracted from the database. Genomic DNA from ADS with blood specimens available for research purposes were subjected to next-generation sequencing technologies using a cancer predisposition gene panel.ResultsOf the 336 cancer-free ADS enrolled in the Clinical Breast Care Project, 77 had a family history that met National Comprehensive Cancer Network criteria for genetic testing for BRCA1/2 and 2 had a family history of colon cancer meeting the criteria for genetic testing for Lynch syndrome. Of the 28 (35%) high-risk women who underwent clinical genetic testing, 11 had pathogenic mutations in the breast cancer genes BRCA1 (n = 5), BRCA2 (n = 5), or CHEK2 (n = 1). Five of the six ADS who had a relative with a known pathogenic mutation were carriers of the tested mutation. All of the women who had pathogenic mutations detected through clinical genetic testing underwent prophylactic double mastectomy, and three also had risk-reducing salpingo-oophorectomy. Two (6%) of the 33 high-risk ADS tested only in the research setting had a family history of breast/ovarian cancer and carried pathogenic mutations: one carried a BRCA2 mutation, whereas the other carried a mutation in the colon cancer predisposition gene PMS2. No mutations were detected in the 177 low-risk women tested in the research setting.DiscussionWithin this unaffected cohort of ADS, 23% were classified as high risk. Although all of the previvors engaged in risk-reduction strategies, only one-third of the high-risk women sought genetic testing. These data suggest that detailed family histories of cancer should be collected in ADS and genetic testing should be encouraged in those at high risk. The identification of previvors and concomitant use of risk-reduction strategies may improve health in the ADS and optimize military readiness by decreasing cancer incidence.

Breast cancer survival in Nordic BRCA2 mutation carriers\u2014unconventional association with oestrogen receptor status

BackgroundThe natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers.MethodsWe studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression.ResultsAbout 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26–0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07–3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26–4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11–3.59, P = 0.02).ConclusionsThe adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.

Recurrent BRCA1 Mutation, but no BRCA2 Mutation, in Vietnamese Patients with Ovarian Carcinoma Detected with Next Generation Sequencing.

Background:Identification of germline and somatic BRCA1/2 mutations in ovarian cancer is important for genetic counseling and treatment decision making with poly ADP ribose polymerase inhibitors. Unfortunately, data on the frequency of BRCA1/2 mutations in Vietnamese patients are scare. Methods:We aim to explore the occurrence of BRCA1/2 mutations in 101 Vietnamese patients with ovarian cancer including serous (n = 58), endometrioid (n = 14), mucinous (n = 24), and clear cell (n = 5) carcinomas. BRCA1/2 mutations were detected from formalin-fixed parafin-embedded tumor samples using the OncomineTM BRCA Research Assay on Personal Genome Machine Platform with Ion Reporter Software for sequencing data analysis. The presence of pathogenic mutations was confirmed by Sanger sequencing. Results:We found no BRCA2 mutation in the entire cohort. Four types of pathogenic mutations in BRCA1 (Ser454Ter, Gln541Ter, Arg1751Ter, and Gln1779AsnfsTer14) were detected in 8 unrelated patients (7.9%) belonging to serous and endometrioid carcinoma groups. Except for the c.1360_1361delAG (Ser454Ter) mutation in BRCA1 exon 11 that was somatic, the other mutations in exons 11, 20, and 22 were germline. Interestingly, the recurrent Arg1751Ter mutation in BRCA1 exon 20 appeared in 4 patients, suggesting that this is a founder mutation in Vietnamese patients. Conclusion:Mutational analysis of tumor tissue using next generation sequencing allowed the detection of both germline and somatic BRCA1/2 mutations.

Patterns and Prevalence of Germline BRCA1 and BRCA2 Mutations among High-Risk Breast Cancer Patients in Jordan: A Study of 500 Patients.

Purpose Knowledge of BRCA1 and BRCA2 mutations has a significant clinical impact on the management and prevention of breast cancer. In this study, we evaluate the pattern and prevalence of germline mutations in BRCA1 and BRCA2 among high-risk Jordanian breast cancer patients selected as per international guidelines. Methods BRCA1 and BRCA2 testing were performed at a reference genetic lab. Mutations were classified as pathogenic/likely pathogenic and variant of uncertain significance (VUS). Results A total of 517 patients, median age: 39 (range: 19–78) years, were enrolled. Among the whole group, 72 (13.9%) patients had pathogenic or likely pathogenic BRCA1 (n = 24, 4.6%) or BRCA2 (n = 48, 9.3%) mutations, while 53 (10.3%) others had VUS. Among 333 younger (≤40 years) patients, mutations were observed in 44 (13.2%). Positive mutations were found in 40 (16.5%) patients with one or more close relatives with breast cancer and in 20 (35.1%) of the 57 patients with triple-negative disease. Multivariate analysis showed that a triple-negative status, history of two or more close relatives with breast cancer, and history of one or more close relatives with invasive ovarian cancer were associated with significant high odds ratios (OR) of carrying a pathogenic variant, with an OR (95% CI) of 5.08 (2.66–9.67), 3.24 (1.78–5.89), and 2.97 (1.04–8.52), respectively. Conclusions BRCA1 and BRCA2 mutations are not uncommon among Jordanian patients. Young age has the weakest association with positive mutations, while patients with triple-negative disease, especially those with an additional positive family history, have the highest mutation rate.

Management of breast cancer risk inBRCA1/2mutation carriers who are unaffected with cancer

Pathogenic mutations in BRCA1 and BRCA2 genes markedly increase the risk of breast cancer and other cancers such as ovarian/fallopian tube, pancreatic, prostate, and melanoma. Patients with BRCA1 mutations have a slightly higher lifetime risk of breast cancer than BRCA2 mutation carriers, and both BRCA1 and BRCA2 carriers tend to develop breast cancer at an earlier age than the general population. In this review, we will discuss management recommendations to reduce breast cancer risk for BRCA1/2 mutation carriers including special populations of carriers such as pregnant or lactating patients and men. Breast cancer screening, including clinical breast examination, mammogram, and breast MRI, is important for detecting breast cancer at an early and likely curable stage. In addition to screening, counseling on risk-reducing surgeries is strongly recommended for BRCA1/2 carriers. Risk-reducing mastectomy decreases the risk of breast cancer development, and risk-reducing salpingo-oophorectomy decreases ovarian cancer-specific as well as overall mortality, but controversy exists regarding its impact on breast cancer-specific mortality. Given the effectiveness of screening for breast cancer, further management should be carried out on an individual basis taking into account quality of life and psychosocial factors, and recommendations should be readdressed periodically as science progresses and patients' goals may change.

Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial

IntroductionMolecular profiling is considered a standard of care in advanced NSCLC. A comprehensive next-generation sequencing panel can discover somatic or germline BRCA1/2 mutations that are new druggable molecular alterations. However, the phenotypic and potential therapeutic relevance of BRCA1/2 mutation in NSCLC remains poorly defined. MethodsFrom April 2014 to March 2017, 600 newly diagnosed, EGFR/ALK negative patients with advanced NSCLC were enrolled in the SAFIR02-Lung trial. Molecular profiling was done at study entry on archival tissue or frozen tissue collected from a new biopsy specimen before the third cycle of platinum-based chemotherapy. The prevalence of BRCA1/2 variants and its biological relevance were assessed. A homologous recombinant deficiency (HRD) score was based on the copy number variation data, and the germline status was determined by blood analysis. The BRCA Share database and the French CGG consortium were the references for the variant classification. ResultsOf 379 patients with a molecular profile discussed in a tumor molecular board, BRCA1/2 variants were identified in 20 patients (5.3%), including eight patients (2.1%) with a confirmed pathogenic BRCA mutation. Two patients (0.5%) harbored a germline BRCA2 mutation, and for six others, a somatic BRCA mutation was identified (1.6%). All were men and mainly smokers (88%). The overall response rate to chemotherapy was 13%. BRCA variants of unknown significance were detected in 12 patients (3.2%), achieving an 8.3% overall response rate with chemotherapy. One-third of tumors carrying pathogenic BRCA mutations or variants of unknown significance had biallelic inactivation and high HRD score. Overall survival of this cohort was 12.8 months. ConclusionsPathogenic BRCA1/2 mutations occur in 2.1% of patients with advanced NSCLC. The predictive role of BRCA mutation for making treatment decisions in NSCLC seems limited based on clinical response (low platinum sensitivity) and molecular features (discrepancy between biallelic inactivation and high HRD score).

Clinical outcome and toxicity from taxanes in breast cancer patients with BRCA1 and BRCA2 pathogenic germline mutations.

Germline variations in genes coding for proteins involved in the oxidative stress and DNA repair greatly influence drug response and toxicity. Because BRCA1 and BRCA2 proteins play a role in DNA damage repair, we postulated that taxane-related toxicity is potentially higher and clinical outcome in different in patients with BRCA pathogenic variants (PV). Seven hundred nineteen women who underwent BRCA genetic testing and were treated with taxane-containing chemotherapy for early-stage breast cancer between 1997 and 2018 were included in the study. Patients with BRCA variants of uncertain significance were excluded. The Kaplan-Meier product-limit method was used to estimate recurrence-free survival (RFS) and overall survival (OS) rates. Logistic regression models were used to assess the association between chemotherapy toxicity and factors of interest. Cox regression models were used to assess the association between RFS and OS and factors of interest. Ninety-four (13%) and 54 (7%) patients had BRCA1 and BRCA2-PVs, respectively. While anemia (P=.0025) and leukopenia (P=.001) were more frequently seen in BRCA noncarriers, there was no difference in regards to peripheral neuropathy or other toxicities between the groups. Increasing doses of taxane were associated with increased risk of neutropenia, stomatitis, nausea, vomiting, acne/rash, and peripheral neuropathy across all groups. In a multivariate logistic regression model, BRCA2 status remained as an independent significant predictor for decreased hematologic toxicity (HR: 0.36; 95% CI: 0.20-0.67; P=.001) and increased gastrointestinal toxicity (HR: 1.93; 95% CI: 1.02-3.67; P=.04). Being overweight, obese and African-American race were significant predictors for peripheral neuropathy (P=.04; P=.03; P=.06, respectively). Total taxane dose received did not have any impact on survival outcomes. Our study demonstrates that taxane-containing chemotherapy regimens do not increase risk of peripheral neuropathy or hematologic toxicity in patients with BRCA PVs. The mechanisms for this finding need to be further investigated as it may provide an opportunity to combine taxanes with other agents, such as platinum salts or PARP inhibitors, with less anticipated toxicity.

Abstract C041: Complexities of hereditary breast cancer: Investigating a large African American family

Abstract Breast cancer (BC) is a very serious health concern being the second most commonly diagnosed cancer among American women. Although the overall incidence rate of BC in African American (AA) and European American women converged in 2012, AA women are reported to have a higher mortality rate at every age, and a higher incidence rate under the age of 45, which is a hallmark of hereditary BC. Characteristics of hereditary BC include a family history of the disease, early ages of onset, bilateral BC, male BC, as well as the occurrence of other associated cancers such as ovarian and prostate. Cancer incidences in these families are influenced by inherited risk factors; currently, mutations in known susceptibility genes, including BRCA1/2, explain ~20-30% of hereditary cases, leaving up to ~70% genetically unsolved. Despite the universal need to decipher the currently unexplained cases, it is important to note that these statistics are mainly the result of studying individuals of European descent. The mutational landscape that explains AA hereditary BC is more obscure since, comparatively, it has been vastly understudied. Recognizing this knowledge gap, our group is committed to adding to the current limited resources necessary to better understand AA BC genetics. We are doing this through a strategic community-based recruitment protocol to enroll underrepresented individuals in Alabama, adding to the Alabama Hereditary Cancer Cohort. With over 150 AAs enrolled to date, we have ascertained some impressive AA BC families. Of those families, Family 1CAD is one of the largest with over 15 family members enrolled. Their participation was fostered through an invitation to their family reunion. There, it was disclosed that a deceased family member had a pathogenic BRCA1 mutation (p.M1796R). Therefore, all participating family members were first screened for the BRCA1 mutation through polymerase chain reactions and Sanger sequencing; interestingly, not all cancer-affected individuals screened positive for this mutation. Therefore, five cancer-affected individuals (three mutation-positive and two mutation-negative) were selected and screened using an exploratory research-based gene panel that targets genes that have been suggested, predicted, or clinically proven to be associated with BC and associated cancers. Firstly, this screening confirmed each individual’s mutation status. It also provided additional insight; for example, all three cancer-affected individuals who have BRCA1 M1796R also share a truncation variant in a candidate gene on the panel, which plays an important role in cell cycle regulation (GeneX). A preliminary analysis using AA BC cases from The Cancer Genome Atlas and ethnic-specific controls from the Exome Variant Server, suggests that truncation variants in GeneX are associated with AA BC risk. We are in the process of validating these findings and determining how this truncation variant modifies risk in BRCA1 mutation carriers. Citation Format: Sophonie Omeler-Fenaud, Madison Bishop, Elizabeth Stallworth, Isaac McNeely, Nancy Merner. Complexities of hereditary breast cancer: Investigating a large African American family [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C041.