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Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis.

ABSTRACT: Germline BRCA1 and BRCA2 mutations confer an increased lifetime risk for breast cancer and ovarian cancer. Several studies have investigated prognosis among BRCA1/2 mutation carriers and noncarriers, but the prognostic impact on outcomes of breast cancer patients has not been determined. The aim of this study was to determine the prognosis of TNBC patients with and without BRCA1/2 germline mutation. Among 502 patients diagnosed with TNBC between 2005 and 2008, 124 patients with a strong family history of breast cancer or ovarian cancer as well as TNBC patients diagnosed under 45 years were referred to the Genetic Counseling Unit for genetic counselling and genetic tests. In 30 (24%) of them, the BRCA1/2 mutation was detected (the most common 5382insC in 18 (60%) patients). The median follow-up of the entire group was 60 months. BRCA1/2 mutation carriers were statistically significantly younger at TNBC diagnosis compared with nonmutation patients (41 vs 47 years, respectively). Patients with the BRCA1/2 mutation had smaller tumors (stage I: 47% vs 24.5% in noncarriers), but there was no significant difference in the regional nodal status (58.5-63% with cN0). Contralateral breast cancer developed in 26.5% of BRCA1/2 mutation carriers and in 14% of noncarriers. Other primary cancers were also slightly more common in BRCA1/2 mutation carriers (16.5% vs 9.5%). The performed analysis did not show any significant differences between the groups in recurrence-free survival (p=0.312). There was no significant difference between patients with or without BRCA1/2 mutation as regards overall survival (p=0.649) and the risk of TNBC death (p=0.333). The survival from detection of metastases was similar in two groups (p=0.865). Our study demonstrated that the BRCA1 mutation does not affect TNBC patients' outcomes.

SUBMITTER: Pogoda K

PROVIDER: S-EPMC7165358 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis.

Pogoda Katarzyna K Niwińska Anna A Sarnowska Elżbieta E Nowakowska Dorota D Jagiełło-Gruszfeld Agnieszka A Siedlecki Janusz J Nowecki Zbigniew Z

Journal of oncology 20200127

Germline BRCA1 and BRCA2 mutations confer an increased lifetime risk for breast cancer and ovarian cancer. Several studies have investigated prognosis among BRCA1/2 mutation carriers and noncarriers, but the prognostic impact on outcomes of breast cancer patients has not been determined. The aim of this study was to determine the prognosis of TNBC patients with and without BRCA1/2 germline mutation. Among 502 patients diagnosed with TNBC between 2005 and 2008, 124 pat ...[more]

PMID: 32322271

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Project description:We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70-216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding ("stem") clone at diagnosis, which persisted over time, from which all other clones ("subclone") were derived ("branching evolution"), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone.SignificanceIn germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.

Project description:Objective:To compare the efficacy of platinum- and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer (TNBC) and analyze the relationship between their efficacy and BRCA gene status. Methods:Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology, Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy. A total of 114 patients had BRCA1/2 gene tested by next generation sequencing (NGS) using peripheral blood, and we analyzed the correlation between their efficacy and BRCA1/2 gene status. Results:Non-platinum-based chemotherapy (NPCT) was administered to 129 and platinum-based chemotherapy (PBCT) to 91 study patients. The clinical benefit rate (CBR) and median progression-free survival (PFS) were not statistically different between NPCT and PBCT groups. The median overall survival (OS) was 30.0 and 22.5 months for PBCT and NPCT group, respectively [P=0.090, hazard ratios (HR)=0.703]. BRCA status was assessed in 114 patients, 14 of whom had deleterious germline BRCA1/2 (gBRCA) mutations (seven in each group). In PBCT group, the CBR was 85.7% and 35.1% for patients with and without deleterious gBRCA mutations, respectively (P=0.039). The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious gBRCA mutations, respectively (P=0.001, P=0.161, respectively). Patients in PBCT group had significantly greater rates of grade 3-4 anemia (5.5%vs. 0%) and thrombocytopenia (8.8% vs. 0%), whereas palmar-plantar erythrodysesthesia (12.4% vs. 0%) and peripheral neuropathy (8.6% vs. 1.1%) occurred more frequently in NPCT group. Conclusions:Platinum-based regimens are more effective in patients with deleterious gBRCA mutations, but no difference in patients without BRCA gene mutations, so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect. And we recommend that patients with advanced TNBC should have BRCA gene test.

Dataset Information

Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis.

Publications

Effects of <i>BRCA</i> Germline Mutations on Triple-Negative Breast Cancer Prognosis.

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