Advances in Targeted Therapy for the Prevention of Breast Cancer

Abstract

Although breast cancer mortality has been decreasing for the past 2 decades, breast cancer incidence has stabilized since 2009. Furthermore, while clinical trials have demonstrated that the prevention of some breast cancers is feasible, effective and acceptable preventive strategies for other breast cancers remain elusive. Therefore, the identification of more effective strategies to prevent all types of breast cancer is critical and is contingent upon an increased understanding of the molecular basis of breast tumorigenesis. To this end, recent genomic profiling analyses have established that breast cancer is a heterogeneous disease that comprises 4 molecular subtypes, each of which is characterized by variations in gene expression: 1) luminal tumors express genes associated with breast luminal cells; 2) human epidermal growth factor receptor 2 (HER2) tumors overexpress HER2; 3) basal tumors express genes typically expressed in breast basal cells; and 4) normal-like tumors exhibit an expression profile similar to that of normal breast tissue. The majority of the basal subtype overlaps clinical triple-negative breast cancers (TNBCs), which lack the expression of estrogen receptor (ER), progesterone receptor (PR), and HER2. Likewise, TNBC has been shown to encompass multiple tumor subtypes with disparate gene expression profiles and ontologies: 1) immunomodulatory tumors express immune cell-processing genes; 2) mesenchymal tumors overexpress genes involved in cell motility, differentiation, and growth; 3) mesenchymal stem-like tumors overexpress genes associated with angiogenesis, immune signaling, cell motility, differentiation, and growth but underexpress several claudins; 4) luminal androgen-receptor tumors have hormone signaling pathway enrichment; 5) basal-like 1 tumors have increased expression of cell cycle and cell division pathways; and 6) basal-like 2 tumors have enhanced growth factor signaling pathways. This molecular complexity of TNBC has complicated the development of effective targeted therapies for the treatment and prevention of TNBCs. PREVENTION OF ER-POSITIVE/LUMINAL BREAST CANCERS