Translating the Molecular Message of Triple-Negative Breast Cancer into Targeted Therapy

摘要

Triple-negative breast cancer (TNBC) has a poor prognosis with limited treatment options. Genomic analysis of TNBCs offers the opportunity to decode TNBC into biologically relevant subtypes with unique molecular targets. With further research, these findings may be translated into effective targeted therapeutic options. In this issue of Clinical Cancer Research, Burstein and colleagues (1) describe the findings of a genomic analysis of triple-negative breast cancer (TNBC). TNBC has been conventionally described as breast cancer that does not express the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), although recent studies suggest that TNBC is actually quite heterogeneous (2). Using DNA and RNA profiling of 198 TNBC tumors, Burstein and colleagues (1) describe four subtypes of TNBCs with prognostic significance, identified by specific gene amplifications, termed luminal-androgen receptor (LAR), mesenchymal (MES), basal-like immune-suppressed (BLIS), and basal-like immune-activated (BLIA; ref. 1). LAR tumors express the androgen receptor (AR), ER (although ER negative by immunohistochemistry), prolactin, and cell-surface mucin (MUC-1), whereas the MES subtype is characterized by insulin-like growth factor 1 (IGFI), prostaglandin F receptor, and c-Kit. The BLIS subgroup showed Sry-related HMG box (SOX) transcription factors as well as V-set domain-containing T-cell activation inhibitor 1 (VTCN1), whereas signal transducer and activators of transcription (STAT), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and cytokines were noted in the BLIA group. The authors conclude that TNBC can be categorized as four subtypes based on discrete molecular markers, which then can be used to identify potentially effective targeted agents. How do we apply these data to the clinic? TNBC is a difficult to treat subtype of breast cancer, with a high propensity for systemic metastases and poor survival. Chemotherapy resistance is common, and, to date, there are no effective alternative treatments.