Dataset Information

Somatic mutation profiling in BRCA-negative breast and ovarian cancer patients by multigene panel sequencing.

ABSTRACT: Targeted therapeutic agents such as poly (ADP-ribose) polymerases (PARP) inhibitors have emerged in treating cancers associated with germline BRCA mutations. Recently studies demonstrated the effectiveness of PARP inhibitors in treating patients with somatic BRCA mutations. Somatic mutations in 122 Chinese breast or ovarian cancer patients without BRCA, PTEN and TP53 mutations were screened using multigene sequencing panel. The five most frequent pathogenic or likely pathogenic mutated genes identified in breast cancer patients were PIK3CA (28.6%), TP53 (16.9%), MAP3K1 (14.3%), GATA3 (14.3%) and PTEN (5.2%). The five most frequently mutated genes identified in ovarian patients were TP53 (52.9%), KRAS (23.5%) and PIK3CA (11.8%), BRCA1 (5.9%) and RB1 (5.9%). Somatic PIK3CA and TP53 mutations were common events in both germline BRCA-negative breast and ovarian cancer patients. In contrast, somatic screening of BRCA mutations in BRCA-negative breast cancer patients has limited value. The results highlight the benefit of somatic testing to guide future research directions on other targeted therapies for breast and ovarian malignancies.

SUBMITTER: Kwong A

PROVIDER: S-EPMC7539773 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Somatic mutation profiling in BRCA-negative breast and ovarian cancer patients by multigene panel sequencing.

Kwong Ava A Cheuk Isabella Wy IW Shin Vivian Yvonne VY Ho Cecilia Ys CY Au Chun-Hang CH Ho Dona Ny DN Wong Elaine Yl EY Yu Stephanie Wy SW Chen Jiawei J Chan Karen Kl KK Ngan Hextan Ys HY Chan Tsun-Leung TL Ma Edmond Sk ES

American journal of cancer research 20200901 9

Targeted therapeutic agents such as poly (ADP-ribose) polymerases (PARP) inhibitors have emerged in treating cancers associated with germline BRCA mutations. Recently studies demonstrated the effectiveness of PARP inhibitors in treating patients with somatic BRCA mutations. Somatic mutations in 122 Chinese breast or ovarian cancer patients without BRCA, PTEN and TP53 mutations were screened using multigene sequencing panel. The five most frequent pathogenic or likely pathoge ...[more]

PMID: 33042626

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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.

Project description:IntroductionCompared with breast cancer (BC) in women, BC in men is a rare disease with genetic and molecular peculiarities. Therapeutic approaches for male BC (MBC) are currently extrapolated from the clinical management of female BC, although the disease does not exactly overlap in males and females. Data on specific molecular biomarkers in MBC are lacking, cutting out male patients from more appropriate therapeutic strategies. Growing evidence indicates that Next Generation Sequencing (NGS) multigene panel testing can be used for the detection of predictive molecular biomarkers, including Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI).MethodsIn this study, NGS multigene gene panel sequencing, targeting 1.94 Mb of the genome at 523 cancer-relevant genes (TruSight Oncology 500, Illumina), was used to identify and characterize somatic variants, Copy Number Variations (CNVs), TMB and MSI, in 15 Formalin-Fixed Paraffin-Embedded (FFPE) male breast cancer samples.Results and discussionA total of 40 pathogenic variants were detected in 24 genes. All MBC cases harbored at least one pathogenic variant. PIK3CA was the most frequently mutated gene, with six (40.0%) MBCs harboring targetable PIK3CA alterations. CNVs analysis showed copy number gains in 22 genes. No copy number losses were found. Specifically, 13 (86.7%) MBCs showed gene copy number gains. MYC was the most frequently amplified gene with eight (53.3%) MBCs showing a median fold-changes value of 1.9 (range 1.8-3.8). A median TMB value of 4.3 (range 0.8-12.3) mut/Mb was observed, with two (13%) MBCs showing high-TMB. The median percentage of MSI was 2.4% (range 0-17.6%), with two (13%) MBCs showing high-MSI. Overall, these results indicate that NGS multigene panel sequencing can provide a comprehensive molecular tumor profiling in MBC. The identification of targetable molecular alterations in more than 70% of MBCs suggests that the NGS approach may allow for the selection of MBC patients eligible for precision/targeted therapy.

Dataset Information

Somatic mutation profiling in BRCA-negative breast and ovarian cancer patients by multigene panel sequencing.

Publications

Somatic mutation profiling in <i>BRCA</i>-negative breast and ovarian cancer patients by multigene panel sequencing.

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