Integrative multi-omic profiling of triple-negative breast cancer for identifying suitable therapies.

ABSTRACT

PURPOSE: Triple-negative breast cancer (TNBC) is a heterogenous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted towards tumors carrying a specific genomic, transcriptomic, or protein biomarker, how these biomarkers are correlated is poorly understood. EXPERIMENTAL DESIGN: To better understand the molecular features of TNBC and their correlation with one another, we performed multi-modal profiling on a cohort of 95 TNBCs. Our approach involved quantifying tumor-infiltrating lymphocytes through H&E staining, assessing the abundance of retinoblastoma (Rb), androgen receptor (AR), and PD-L1 proteins through immunohistochemistry, and carrying out transcriptomic profiling using the Nanostring BC360 platform, targeted DNA sequencing on a subset of cases, as well as evaluating associations with overall survival. RESULTS: Levels of RB1 mRNA and RB protein are better correlated with markers of Rb functionality than is RB1 mutational status. Luminal AR tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PD-L1-positive by presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared to HER2-zero. The majority of TNBCs classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival. CONCLUSIONS: Our study contributes new insights into biomarker utility for identifying suitable TNBC therapies and the intercorrelations between genomic, transcriptomic, protein, and cellular biomarkers. Additionally, our rich data resource can be used by other researchers to explore the interplay between DNA, RNA, and protein biomarkers in TNBC.