Germline breast cancer susceptibility gene mutations and breast cancer outcomes

Abstract

Background: It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis.

Methods: The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic.

Results: We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29-4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40-6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64-6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22-3.51; P = 0.007).

Conclusions: Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.

Keywords: BRCA1 & BRCA2; Breast cancer; Breast cancer prognosis; Cancer susceptibility gene; Next generation sequencing.

Fig. 1

Distribution of the 20 breast cancer susceptibility genes. Genes not shown (PTEN, CDH1, STK11, NF1, NBN, MLH1, MSH2, MSH6, CHEK2) are those without identified pathogenic mutations in the study cohort

Fig. 2

Kaplan-Meier estimates of disease-free survival (a), freedom from breast cancer recurrence (b), freedom from distant recurrence of breast cancer (c), and overall survival (d), according to BRCA mutation carrier status. The 5-year and 10-year values are based on Kaplan–Meier estimates of the time to an event. The hazard ratios are for breast cancer recurrence or death (a), any recurrence (b), distant recurrence (c), and death from any cause (d), respectively, based on Cox proportional hazards univariate analysis