Management of breast cancer with targeted agents: importance of heterogenicity

Breast cancer is a heterogeneous disease with different molecular drivers regulating its growth, survival and response to therapy. Breast cancer is divided in three major subtypes based on the pattern of expression of hormone receptors and HER2: luminal tumors (or HR positive), HER2 amplified tumors, and the remaining subtypes being collectively referred to as triple-negative breast cancer. While tumors within these subtypes have similar gene-expression patterns, clinical outcomes, and response to therapy, this division is far from perfect and subgroups within these groups are beginning to be identified. In terms of therapy, an increasingly rational drug development effort has resulted in agents against new molecular targets that are active against only those tumors with the targeted molecular alteration or phenotype. These agents include receptor and non-receptor tyrosine kinase inhibitors (HER1, HER2, HER3, insulin-like growth factor receptor, c-met, fibroblast growth factor receptor and HSP 90 inhibitors), intracellular signaling pathways (PI3K, AKT, mTOR), angiogenesis inhibitors and agents that interfere with DNA repair (PARP inhibitors). Thus, the overall management of breast cancer will increasingly require an understanding of breast cancer heterogeneicity, the biological nature of any given tumor as well the existence of increased personalized treatment options.