Triple-negative breast cancer: molecular subtypes and targeted therapy

Triple-negative breast cancers (TNBCs), lacking estrogen receptor expression and human epidermal growth factor receptor 2 amplification, have no effective targeted therapy. Large-scale comprehensive genomic analyses have allowed stratification of TNBCs by molecular features. We will review the recent data regarding the classification of these poor prognosis cancers and the associated potential targeted treatment approaches.

TNBCs are a heterogeneous set of cancers characterized by a diverse set of gene-expression patterns and underlying genomic changes. Mutations in p53 are the only genomic alteration present in the majority of TNBCs. Other potential targetable alterations are only present in small subsets of TNBCs, and include defects in DNA repair present in BRCA1-mutant TNBCs and some sporadic TNBCs. Antiandrogens may be effective for TNBCs that express the androgen receptor and have luminal-like gene-expression features. PI3KCA pathway inhibitors and HSP90 inhibitors may also be effective in a small fraction of TNBCs.

Robust methods to functionally classify TNBCs to determine vulnerable pathways are urgently needed to guide the development of clinical trials. It is quite possible that TNBCs, like non-small cell lung cancer, will be stratified into many individually rare cancer classes, each requiring a distinct treatment approach.