Integrative Multiomic Profiling of Triple-Negative Breast Cancer for Identifying Suitable Therapies

Triple-negative breast cancer (TNBC) is a heterogeneous disease that carries the poorest prognosis of all breast cancers. Although novel TNBC therapies in development are frequently targeted toward tumors carrying a specific genomic, transcriptomic, or protein biomarker, it is poorly understood how these biomarkers are correlated.

To better understand the molecular features of TNBC and their correlation with one another, we performed multimodal profiling on a cohort of 95 TNBC. Our approach involved quantifying tumor-infiltrating lymphocytes through hematoxylin and eosin staining, assessing the abundance of retinoblastoma, androgen receptor, and PDL1 proteins through IHC, 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.

Levels of RB1 mRNA and RB proteins are better correlated with markers of retinoblastoma functionality than RB1 mutational status. Luminal androgen receptor tumors clustered into two groups with transcriptomes that cluster with either basal or mesenchymal tumors. Tumors classified as PDL1-positive by the presence of immune or tumor cells showed similar biological characteristics. HER2-low TNBC showed no distinct biological phenotype when compared with HER2-zero. The majority of TNBC were classified as basal or HER2-enriched by PAM50, the latter showing significantly improved overall survival.

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.