Analysis of the results of whole-exome sequencing of paired samples in patients of the Eurasian population with triple-negative breast cancer and their impact on clinical outcomes.

Abstract

e12605 Background: While standard practice focuses on germline mutations, our study identifies clinically relevant somatic mutations impacting riple-negative breast cancer (TNBC) prognosis, supporting the need for comprehensive exome panels. Using whole-exome sequencing (WES), we analyzed the molecular landscape of Eurasian TNBC patients and its association with clinico-phenotypic features. Methods: We performed WES on paired tumor-blood samples in 80 TNBC patients. The outcome was defined as progression (n = 37, 46%) or remission (n = 43, 54%). Pathological response was assessed using the Residual Cancer Burden (RCB) classification. Detected germline mutations (BRCA1, BRCA2, BARD1, PMS2 and others) and somatic mutations (TP53, PIK3CA, KMT2C and others) were analyzed. Descriptive statistics were calculated for all variables. Categorical variables were compared using the Chi-square or Fisher's exact test; continuous variables using the Mann-Whitney U test. Results: The mean patient age was 53 years. The predominant histological type was invasive ductal carcinoma (91%). Stage distribution: IA (16%), IIA (41%), IIB (16%), IIIA-C (27%). Pathological complete response (pCR, RCB 0) was achieved in 14 of 80 patients (18%). The RCB classification demonstrated a strong association with outcome (p < 0.001): patients with a good response (RCB 0-1) had a progression rate of 5% compared to 58% in patients with a poor response (RCB 2-3). Germline BRCA1 mutation was found in 17/80 patients (21%) and was associated with higher rates of pathological response and a reduced risk of progression. Somatic TP53 mutation was detected in 32/80 patients (40%) and was associated with an increased risk of progression (OR = 3.23, 95% CI: 1.03–10.1, p = 0.044). Our analysis identified patients with the best prognosis (BRCA1+/TP53-: the lowest risk of progression after comprehensive treatment) and the worst prognosis (BRCA1-/TP53+: progression in 67% of cases). Initial group-level analysis of somatic mutations revealed no association (p = 0.7) with disease outcome. Multivariate analysis revealed opposing effects (TP53 mutation was a risk factor for progression, while an opposite effect was observed in patients with somatic PIK3CA mutation), underscoring the importance of analyzing individual mutations. Conclusions: Comprehensive whole-exome analysis in TNBC patients identified clinically significant prognostic factors among both germline (protective BRCA1 mutation) and somatic (TP53 mutation as a risk factor) mutations. Polar prognostic groups were defined: BRCA1+/TP53- (best outcome) and BRCA1-/TP53+ (worst outcome). The results substantiate the necessity of implementing comprehensive genetic profiling that extends beyond the analysis of germline mutations alone for risk stratification and personalization of TNBC therapy.