Therapeutic landscape in mutational triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is a heterogeneous disease with aggressive behavior and poor prognosis. Genomic sequencing has detected a distinctive mutational portrait of both the germline and somatic alterations in TNBC, which is staggeringly different from other breast cancer subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. However, for other predisposition genes, studies concerning the risk and penetrance to TNBC are relatively scarce. Very few recurrent mutations, including TP53 and PI3KCA mutations, together with a long tail of individually rare mutations occur in TNBC. These combined effects of genomic alterations drive TNBC progression. Given the complexity and heterogeneity of TNBC, clinical interpretation of the genomic alterations in TNBC may pave a new way for the treatment of TNBC. In this review, we summarized the germline and somatic mutation profiles of TNBC and discussed the current and upcoming therapeutic strategies targeting the mutant proteins or pathways to enable tailored-therapeutics.

Keywords: Germline; Mutation; Somatic; TNBC; Therapeutic.

Fig. 1

TNBC: The current and upcoming therapeutic strategies targeting the mutant proteins or pathways to enable tailored-therapeutics. Therapeutics target at genetic alterations include defects in DNA damage repair, TP53 mutations, activation of PI3K pathway, EGFR amplification/mutations, activation of RAF-MEK signaling, and Rb loss. These genetic alterations were summarized in the white boxes of the diagram. Potential therapeutic strategies were depicted in red boxes