Genomic characterization reveals distinct mutational landscapes and therapeutic implications between different molecular subtypes of triple negative breast cancer

Abstract Background Triple-negative breast cancer (TNBC) has high heterogeneity, poor prognosis, and limited treatment success. Recently, an immunohistochemistry (IHC)-based surrogate classification for the “Fudan University Shanghai Cancer Center (FUSCC) subtyping” has been developed and is considered more suitable for clinical application. Here, the genetics and potential therapeutic targets for TNBC molecular subtypes classified by the surrogate classification were investigated. Methods Seventy-one paraffin-embedded sections of surgically resected TNBC were classified into four molecular subtypes using the IHC-based surrogate classification. Genomic analysis was performed by targeted next-generation sequencing (NGS). The specificity of the subtypes was explored by bioinformatics, including survival analysis, multivariate Cox regression, pathway enrichment, Pyclone analysis, mutational signature analysis and PHIAL analysis. Results In total, 71 TNBC specimens were examined. AKT1 and BRCA1 mutations were identified as independent prognostic factors. Clear heterogeneity was observed in somatic mutations, key mutation pathways, evolutionary and mutational signatures, and copy number variations in the molecular subtypes. Importantly, 70 (98.5%) samples harbored putative clinically relevant alterations. The luminal androgen receptor (LAR) subtype was associated with mutations in PIK3CA and PI3K pathways, which are potentially sensitive to PI3K pathway inhibitors. The basal-like immune-suppressed (BLIS) subtype was characterized by high genomic instability and the specific possession of signature 19 while patients in the immunomodulatory (IM) subtype belonged to the PD-L1 ≥ 1% subgroup with enrichment in Notch signaling, suggesting a possible benefit of immune checkpoint inhibitors and Notch inhibitors. Moreover, mesenchymal-like (MES) tumors displayed enrichment in the receptor tyrosine kinase (RTK)-RAS pathway and potential sensitivity to RTK pathway inhibitors. Conclusions TNBC molecular subtypes encompass distinct genomic landscapes that show specific heterogeneities. The findings suggest potential treatment targets and prognostic factors, indicating the possibility of stratified therapy in the future.