Germline Mutations In BRCA1 Research Articles

Aggressive approach to metastatic pancreatic cystadenocarcinoma in a patient harboring BRCA-1 germline mutation: a case report.

Aggressive approach to metastatic pancreatic cystadenocarcinoma in a patient harboring BRCA-1 germline mutation: a case report.

Genomic Profiling Comparison of Germline BRCA and Non-BRCA Carriers Reveals CCNE1 Amplification as a Risk Factor for Non-BRCA Carriers in Patients With Triple-Negative Breast Cancer.

Background: Differences in genomic profiling and immunity-associated parameters between germline BRCA and non-BRCA carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets.Methods: The study cohort included 21 consecutive TNBC cases with germline BRCA1/2 mutations and 54 non-BRCA carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan–Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between CCNE1 amplification and cyclin E1 protein overexpression.Results: The cohort included 16 and five patients with germline BRCA1 and BRCA2 mutations, respectively. Patients with germline BRCA1/2 mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non-BRCA carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in MSH3 (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-BRCA and BRCA carriers, respectively. PIK3CA missense mutation (p = 0.046) and CCNE1 amplification (p = 0.2) were found only in the non-BRCA carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). BRCA status did not affect disease-free survival (DFS, p = 0.15) or overall survival (OS, p = 0.52). CCNE1 amplification was an independent risk factor for DFS in non-BRCA carriers with TNBC (HR 13.07, 95% CI 2.47–69.24, p = 0.003). Consistency between CCNE1 amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity.Conclusions: We found differences in genetic alterations between germline BRCA and non-BRCA carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.

Innovations in targeted therapies for triple negative breast cancer.

Triple negative breast cancer (TNBC) is defined by a lack of targets, namely hormone receptor (HR) expression and human epidermal growth factor receptor 2 amplification. Cytotoxic chemotherapy remains the mainstay of treatment. Though TNBC constitutes approximately 10-15% of breast cancer, it is disproportionally lethal, but it is hoped that outcomes will improve as targetable oncogenic drivers are identified. Translational work in TNBC has focused on subsets defined by defects in homologous recombination repair, immune cell infiltration, or programmed death ligand receptor 1 expression, an over-active phosphoinositide-3 kinase pathway, or expression of androgen receptors. Though not specific to TNBC, the novel cell surface antigen trophoblast antigen 2 has also been identified and successfully targeted. This work has led to Food and Drug Administration approvals for small molecule poly-ADP-ribosyl polymerase inhibitors in patients with deleterious germline mutations in BRCA1 or BRCA2, the combination of nab-paclitaxel with immune checkpoint inhibitor antibodies in the first-line metastatic setting for programmed death ligand receptor 1+ TNBC, and use of the antibody-drug conjugate sacituzumab govitecan in the later-line metastatic setting. Identification of targetable oncogenic drivers in TNBC is an area of intense cancer biology research, hopefully translating to new therapies and improved outcomes.

Prevalence of germline BRCA mutations in HER2-negative metastatic breast cancer: global results from the real-world, observational BREAKOUT study

BackgroundThe global observational BREAKOUT study investigated germline BRCA mutation (gBRCAm) prevalence in a population of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC).MethodsEligible patients had initiated first-line cytotoxic chemotherapy for HER2-negative MBC within 90 days prior to enrollment. Hormone receptor (HR)-positive patients had experienced disease progression on or after prior endocrine therapy, or endocrine therapy was considered unsuitable. gBRCAm status was determined using baseline blood samples or prior germline test results. For patients with a negative gBRCAm test, archival tissue was tested for somatic BRCAm and homologous recombination repair mutations (HRRm). Details of first-line cytotoxic chemotherapy were also collected.ResultsBetween March 2017 and April 2018, 384 patients from 14 countries were screened and consented to study enrollment; 341 patients were included in the full analysis set (median [range] age at enrollment: 56 [25–89] years; 256 (75.3%) postmenopausal). Overall, 33 patients (9.7%) had a gBRCAm (16 [4.7%] in gBRCA1 only, 12 [3.5%] in gBRCA2 only, and 5 [1.5%] in both gBRCA1 and gBRCA2). gBRCAm prevalence was similar in HR-positive and HR-negative patients. gBRCAm prevalence was 9.0% in European patients and 10.6% in Asian patients and was higher in patients aged ≤ 50 years at initial breast cancer (BC) diagnosis (12.9%) than patients aged > 50 years (5.4%). In patients with any risk factor for having a gBRCAm (family history of BC and/or ovarian cancer, aged ≤ 50 years at initial BC diagnosis, or triple-negative BC), prevalence was 10.4%, versus 5.8% in patients without these risk factors. HRRm prevalence was 14.1% (n = 9/64) in patients with germline BRCA wildtype.ConclusionsPatient demographic and disease characteristics supported the association of a gBRCAm with younger age at initial BC diagnosis and family history of BC and/or ovarian cancer. gBRCAm prevalence in this cohort, not selected on the basis of risk factors for gBRCAm, was slightly higher than previous results suggested. gBRCAm prevalence among patients without a traditional risk factor for harboring a gBRCAm (5.8%) supports current guideline recommendations of routine gBRCAm testing in HER2-negative MBC, as these patients may benefit from poly(ADP-ribose) polymerase (PARP) inhibitor therapy.Trial registrationNCT03078036.

Surgicaland Systemic Treatment of Hereditary Breast Cancer: A Mini-Review With a Focus on BRCA1 and BRCA2 Mutations.

Hereditary breast cancer accounts for 5%–10% of breast cancer cases. The majority of familial cases have been linked to germline mutations in BRCA1 and BRCA2 genes, though other high penetrance susceptibility genes have also been identified through genomic testing advances. Optimal surgical treatment for these patients, who are of a younger age, has several challenges as it usually involves aggressive therapeutic and risk reducing interventions. At the same time, the therapeutic armamentarium for BRCA1/2 mutation carriers apart from platinum salts, has been enriched with the addition of poly-ADP ribose polymerase (PARP) inhibitors with promising outcomes. In this review we provide a succinct and comprehensive overview of the surgical and systemic treatment options for patients with BRCA1/2 mutation related breast cancer and an update on the most recent systemic treatment advances.

The molecular detection of germline mutations in BRCA1 and BRCA2 genes in a small group of patients from Romania

Objective: The purpose of this study was to identify and classify the spectrum of small polymorphisms found in BRCA1 and BRCA2 genes in breast cancer risk-assessed patients. Methods and results: The detection of germline mutations was performed by targeted amplification of 47 samples, followed by NGS and mutation data analysis. We identified 62 short polymorphisms that were classified according to their clinical significance reported in ClinVar database: three pathogenic, four with conflicting interpretations of pathogenicity, five likely benign, 46 benign, two without clinical evaluation and two not previously reported. Conclusions: Among the detected polymorphisms a few are shared by most patients and might be prevalent in the Romanian population, a hypothesis that requires further investigation. The detection of only three pathogenic mutations suggests the need to extend the panel of breast cancer predisposing genes. It is conceivable that a mutational screening based primarily on risk factor evaluation would detect a lower number of pathogenic mutations than in confirmed breast cancer cases. Our results contribute to the setup of a BRCA1 and BRCA2 mutations database for the Romanian population.

A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses. We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were gBRCA mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers. We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17). In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.

The DNA damaging revolution.

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that plays a critical role in the repair of single-strand DNA damage via the base excision repair pathway. PARP inhibitors have substantial single-agent antitumor activity by inducing synthetic lethality. They have also emerged as promising anticancer targeted therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA) mutations. PARP inhibition produces single-strand DNA breaks, which may be repaired by homologous recombination, a process partially dependent on BRCA1 and BRCA2. The PARP inhibitors olaparib, veliparib, talazoparib, niraparib, and rucaparib have predominantly been studied in patients with breast or ovarian cancers associated with deleterious germline mutations in BRCA1 and BRCA2. Ongoing clinical trials are evaluating the role of PARP inhibitors alone and in combination with other therapies, including selective inhibitors against key targets involved in the DNA damage response. In this review we summarize the use of PARP inhibitors in various tumor types, as well as possible approaches for overcoming resistance to PARP inhibitors.

BRCA1/2 mutations and risk-reducing bilateral salpingo-oophorectomy among Latinas: The UPTAKE study.

Bilateral salpingo-oophorectomy (BSO) is a risk management approach with strong evidence of mortality reductionfor women with germline mutations in the tumor suppressor genes BRCA1 and BRCA2 (BRCA1/2). Few studies to date have evaluated uptake of BSO in women from diverse racial and ethnic backgrounds who carry BRCA1/2 mutations. The objective of the UPTAKE study was to explore rates and predictors of risk-reducing BSO among Latinas affected and unaffected with breast cancer who had a deleterious BRCA1/2 mutation. We recruited 100 Latina women with deleterious BRCA1/2 mutations from community hospitals, academic health systems, community, and advocacy organizations. Women completed interviews in Spanish or English. We obtained copies of genetic test reports for participants who provided signed medical release. After performing threefold cross-validation LASSO for variable selection, we used multiple logistic regression to identify demographic and clinical predictors of BSO. Among 100 participants, 68 had undergone BSO at the time of interview. Of these 68, 35 were US-born (61% of all US-born participants) and 33 were not (77% of the non-US-born participants). Among Latinas with BRCA1/2 mutations, older age (p=0.004), personal history of breast cancer (p=0.003), higher income (p=0.002), and not having a full-time job (p=0.027) were identified as variables significantly associated with uptake of BSO. Results suggest a high rate of uptake of risk-reducing BSO among a sample of Latinas with BRCA1/2 mutations living in the US. We document factors associated with BSO uptake in a diverse sample of women. Relevant to genetic counseling, our findings identify possible targets for supporting Latinas' decision-making about BSO following receipt of a positive BRCA1/2 test.

304 Poster - BRCA variant classification of ClinVar submitter content from ENIGMA, ARUP laboratories and German cancer consortium compared to MH BRCA® and correlation with response to PARP inhibition in MH GUIDE®

Background: Germline mutations in BRCA1 and BRCA2 genes confer a high risk for the hereditary breast and/or ovarian cancer (HBOC) syndrome, whereas both germline and somatic mutations are predictive biomarkers for PARP inhibition. MH BRCA® classifies variants based on ACMG guidelines. Clinical interpretation of NGS results by MH GUIDE® provides clinicians with treatment recommendations to cancer based on expert curated biomarker knowledge.

Utilization of maintenance therapy for platinum-sensitive recurrent ovarian cancer

Objective: Maintenance therapy can extend progression-free survival (PFS) in platinum-sensitive recurrent ovarian cancer. Patients with a somatic or germline BRCA mutation have greater clinical benefit with maintenance PARP inhibitor (PARPi) than those with wildtype. Roughly 50% of patients eligible for maintenance therapy do not receive it, and variation in prescribed therapy (bevacizumab [BEV] vs PARPi) exists. Our objective was to analyze institutional utilization of maintenance therapy in platinum-sensitive recurrent ovarian cancer.

Germline BRCA Mutation and Clinical Outcomes in Breast Cancer Patients Focusing on Survival and Failure Patterns: A Long-Term Follow-Up Study of Koreans.

Background and Objectives: This study aimed to evaluate the effect of a BRCA mutation on survival and failure patterns, focusing on the risk of ipsilateral recurrence and contralateral breast cancer in patients. Materials and Methods: We retrospectively reviewed medical records of 300 patients with breast cancer who underwent genetic screening for BRCA1/2 genes and were treated at Samsung Medical Center between 1 January 2000 and 31 December 2010. Ultimately, clinical outcomes of 273 patients were analyzed. Results: The median follow-up duration was 102 months (range, 1 to 220 months). Patients with BRCA1/2-mutated tumors had a shorter 10-year disease-free survival (DFS) rate compared to those with non-mutated tumors (62.8% vs. 80.0%, p = 0.02). Regarding failure patterns, patients with BRCA1/2-mutated tumors showed a higher incidence of contralateral breast cancer than those with non-mutated tumors (BRCA1/2 non-mutated vs. mutated tumors: 4.9% vs. 26.0%, p < 0.001). BRCA mutation status remained a significant prognostic factor for contralateral breast recurrence-free survival (HR: 4.155; 95% CI: 1.789–9.652; p = 0.001). Korean patients with a BRCA mutation showed inferior DFS compared to those without a BRCA mutation. Conclusions: BRCA mutation status is a strong predictor of recurrence in contralateral breast cancer. Strategies such as prophylactic treatment and active surveillance should be discussed with breast cancer patients who have a BRCA mutation.

Histopathological characterization of the tubal fimbria reveals a subgroup of BRCA1 mutation carriers with tumor-promoting gene-set enrichment

Objective: Fallopian tube secretory epithelial cells have been implicated as the origin of high-grade serous ovarian cancer (HGSOC). Most ovarian cancers are diagnosed in postmenopausal women, although it is unclear how postmenopausal conditions contribute to cancer formation. Germline BRCA1 mutations are associated with a 40% lifetime risk of ovarian cancer. This high-risk population is characterized by early onset of disease and predominant serous histology. The events that lead to secretory cell transformation are unknown.

Cost-minimization analysis of germline and somatic testing strategies for BRCA mutations in women with newly diagnosed epithelial ovarian cancer

Objective: The SOLO1 trial made it a priority to identify BRCA germline and somatic mutations in women with newly diagnosed epithelial ovarian cancer in order to determine candidates for olaparib maintenance. It is also important to differentiate between germline and somatic mutations because of the potential for cascade testing in relatives. Three testing strategies can be employed: (1) test all patients for germline mutations with reflex somatic testing if germline testing is negative; (2) test all tumors for somatic mutations with reflex germline testing if somatic testing is positive; or (3) perform simultaneous germline and somatic testing.

Trends in germline and somatic BRCA1/2 testing before and after SOLO1

Objective: In October 2018, the SOLO-1 trial showed maintenance olaparib compared to placebo had a 70% lower risk of disease progression or death among women with newly diagnosed, advanced epithelial ovarian cancer (EOC) with germline or somatic BRCA1 and BRCA2 mutation. Our study objective was to determine whether patterns of genetic and genomic testing in patients with advanced EOC at our institution changed after SOLO1 trial announcement.

Development of novel biomarkers for early detection of high-grade serous ovarian cancer in high-risk women using exosomal miRNAs

Objective: The aim of this study was to identify unique circulating exosomal miRNA signatures in high-grade serous ovarian cancer (HGSC) patients with germline BRCA1 or BRCA2 mutations and determine the performance of each candidate miRNA in combination with CA-125 for early detection of ovarian cancer.

Efficacy and safety of oral poly (ADP-ribose) polymerase inhibitor fluzoparib in patients with BRCA1/2 mutations and recurrent ovarian cancer

Objective: Fluzoparib is a potent orally administered poly(ADP-ribose) polymerase (PARP) inhibitor. The safety and tolerability of fluzoparib has been evaluated in a phase 1 trial (NCT02575651). In this study, we aim to characterize the efficacy and safety of fluzoparib in patients with germline BRCA1 or BRCA2 mutations and recurrent ovarian cancer who had received ≥2 prior lines of chemotherapy.

Cost-effectiveness analysis of olaparib as a maintenance monotherapy for patients with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation: A United States payer perspective

Objective: A phase 3 clinical trial (SOLO1) demonstrated that olaparib as maintenance provided significant improvement in progression-free survival (PFS) in patients with newly diagnosed advanced ovarian cancer and a germline or somatic BRCA mutation. This study evaluates the cost-effectiveness of olaparib as a first-line maintenance therapy versus routine surveillance from a U.S. third-party payer perspective.

Exploring the relationship between homologous recombination score and progression-free survival in BRCA wildtype ovarian carcinoma: Analysis of veliparib plus carboplatin/paclitaxel in the velia study

Objective: The phase 3 VELIA trial demonstrated that veliparib dosed concurrently with carboplatin and paclitaxel and continued as maintenance monotherapy resulted in significantly better progression-free survival (PFS) compared to carboplatin and paclitaxel alone in patients with newly diagnosed advanced high-grade serous ovarian carcinoma (HGSC). VELIA enrolled patients without regard to germline or somatic BRCA mutations (BRCAm), homologous recombination deficiency (HRD), or platinum sensitivity, providing a unique opportunity to evaluate the prognostic and predictive role of the HRD assay.

314 Poster - Prevalence of germline BRCA pathogenic variants in a monoinstitutional cohort of patients with triple negative breast cancer

Triple negative (TN) breast cancer (BC) is an uncommon and aggressive subtype of BC associated with early disease recurrence and short survival. In literature, prevalence of BRCA mutations in TNBC patients may vary from 9 to 32%. The prevalence of BRCA germline mutations has been systematically evaluated in this setting of patients at our center.