Triple-negative breast cancer: role of specific chemotherapy agents

Abstract

Cytotoxic chemotherapy remains the mainstay of treatment for triple-negative breast cancer (TNBC) despite the promise of new targeted and biologic agents. Many studies have shown significant benefit of chemotherapy in the neoadjuvant, adjuvant, and metastatic treatment of TNBC. Neoadjuvant chemotherapy studies have consistently reported higher response rates in TNBC than non-TNBC, and pathologic complete response has been shown to predict improved long-term outcomes for TNBC. Although the specific adjuvant regimens that may be most effective for TNBC are still being determined, third-generation chemotherapy regimens using dose dense or metronomic polychemotherapy are among the most effective tools presently available. The role of specific chemotherapy agents in the treatment of TNBC remains incompletely defined and warrants careful review to ensure that the most effective therapy is delivered while minimizing unnecessary toxicity. Platinum agents have seen renewed interest in TNBC based on a growing body of preclinical and clinical data suggesting encouraging activity. Taxanes and anthracyclines are active in TNBC and remain important agents but have not shown specific benefit over non-TNBC. Capecitabine has limited reported data in TNBC, but some reports suggest differential activity in TNBC compared with hormone receptor-positive breast cancer. TNBC is itself a heterogeneous group in which subgroups such as BRCA1 mutation carriers may have particular sensitivity to platinum agents and relatively less sensitivity to taxanes. Therefore, the identification of additional molecular biomarkers to predict response to specific chemotherapy is required to further improve treatment strategies with the current menu of chemotherapy options and future combinations with targeted therapies.

Figure 1

Mechanism of p63/p73 mediated platinum sensitivity in triple negative breast cancer. Approximately one-third of triple negative breast cancers express the p53 family members ΔNp63α̣ and TAp73. In proliferating cells ΔNp63α inhibit apoptosis by forming heterodimers with TAp73 and forming homotetramers that bind to the promoters of TAp73 target genes, thereby preventing transcription of proapoptotic genes. Cisplatin treatment induces DNA damage resulting in activation of the c-ABL tyrosine kinase and phosphorylation of TAp73. TAp73 then forms stable homotetramers that bind to TAp73 target genes such as PUMA and NOXA resulting in apoptosis. Expression of -63/p73 in breast cancer cell lines results in 10-100 fold greater sensitivity to platinum chemotherapy.