The Role of Germline BRCA1 Founder Mutations and Somatic TP53 Mutations in the Triple-Negative Breast Cancer Subtype. Summary of the Doctoral Thesis

Abstract

Triple-negative breast cancer is a heterogeneous clinicopathological entity defined as an oestrogen (ER), progesterone (PR) and HER2/neu negative breast cancer that is characterized by agressive clinical behavior with high recurrence and deaths rate, especially in the first five years after diagnosis. In previous studies a strong relationship between BRCA1 mutation-associated tumors and triple-negative breast cancers has been manifested, approximately 57–88% of all BRCA1-related tumours are triple-negative or/and basal-like. 60–88% of triple-negative / basal-like or BRCA1-related breast cancers have TP53 mutations. However, inconsistent and limited data are available regardless the prognostic and predictive implication of BRCA1 germline mutations and TP53 sporadic mutations in the triple-negative breast cancer subgroup. Therefore, the aim of our study was to investigate the prognostic significance of carrying a two germline BRCA1 founder mutations (4153delA and 5382insC) and somatic TP53 mutations in patients with triple-negative breast cancer. The study was designed as a combined prospective-retrospective cohort. In the prospective part of the study invasive breast cancer patients were tested for germline BRCA1 founder mutations and clinical data were prospectively obtained. In the retrospective part of the study an analysis of somatic TP53 mutations was retrospectively performed in the triple-negative breast cancer group and correlation between somatic TP53 mutations and clinical outcomes were retrospectively analysed. The evidence from our study suggests that germline BRCA1 founder mutations (4153delA and 5382insC) carriers have statistically significantly improved prognosis relative to non-carriers. We showed that positive BRCA1 mutation status statistically significantly reduce the risk of distant recurrence and breast cancer-specific death and is an independent prognostic factor for lower distant recurrence risk. In addition we showed that sporadic deleterious TP53 mutations could be used as prognostic factor of worse distant recurrence-free survival in the triple-negative breast cancer group.