Next generation sequencing reveals CCNE1 amplification as an independent prognostic factor for triple negative breast cancer (TNBC) patients.

Abstract

558 Background: Triple negative breast cancer (TNBC) has the worst prognosis among breast cancer due to the heterogeneity as well as lack of better therapeutic approach. It remains controversial whether BRCA status is the predictor of survival in TNBC. Besides, both germline and somatic mutation may contribute to the prognosis. This study is to explore the potential predictors and therapeutic targets based on genetic data and clinicopathological parameters. Methods: Seventy-five TNBC patients were enrolled with approximately 2:1 based on BRCA status. Genetic data was analysed by comprehensive genomic profiling 508 key cancer related genes. DAVID was applied to perform pathway enrichment analysis of significant enriched genetic alterations. Cox regression model was applied to evaluate disease-free survival (DFS) and overall survival (OS). Immuno-chemistry (IHC) was used to validate clinically meaningful genetic alteration. Results: In this study, 27 germline mutations were detected, including 26 homologous recombination repair (HRR) pathway gene mutations and 1 mismatch repair gene mutation among them 16 BRCA1 mutations and 5 BRCA2 mutations were found. Germline HRR including BRCA1/2 mutation marginally affected DFS ( p = 0.0624 and 0.15, respectively). We found 480 somatic genetic alterations including 110 copy number variations (CNV). The median value of TMB was determined to be 4.1 Muts/Mb which divided 74 TNBC patients into TMB-low (TMB-l) and TMB-high (TMB-h) group. TMB-l group had inferior DFS to TMB-h ( p = 0.0457). CCNE1 (with 5% frequency) copy number gain was specifically enriched in TMB-l group but mutually exclusive with BRCA1/2 mutation. TNBC with CCNE1 gain displayed worse DFS ( p< 0.0001). Cox multivariate regression analysis indicated CCNE1 gain was an independent risk factors for DFS [HR = 13.48 (95% CI 2.62-69.23), p= 0.002)]. Pathway analysis indicated CCNE1 harmed prognosis through regulation of transcription in G1/S phase. Expression of cyclin E1 was validated by IHC, which would be presented later. Conclusions: Comprehensive genomic profiling disclosed various potential prognostic markers for TNBC by integrating clinical characters. Especially, amplified CCNE1 may be a potential prognostic marker and therapeutic target. [Table: see text]