Better Together: Targeted Combination Therapies in Breast Cancer.

Recent discoveries both in cell proliferation and survival mechanisms and new antineoplastic agents have led to deep change in the breast cancer treatment paradigm. Nonetheless, all of the progress in knowledge and strategy has not been enough to overcome mechanisms of escape and resistance put in place by the tumor cells. New targeted agents mean new possibilities for combinations, a viable option to try to stop compensatory pathways of tumor growth activated in response to therapeutics. The main challenges in designing a combined therapy come from the variety of subtypes of breast cancer (luminal A, luminal B, HER2-enriched, and basal-like) and from the multitude of pathways each subtype can exploit. Recent research has focused on dual blockade of HER2 (trastuzumab-lapatinib; trastuzumab-pertuzumab) and concomitant blockade of the endocrine driver and other pathways such as the PI3K/AKT/mTOR pathway (everolimus-exemestane), HER2 (trastuzumab/lapatinib-endocrine therapy) and the cell cycle through cyclin-dependent kinase inhibition (letrozole-palbociclib). This combined and personalized approach to treatment needs a profound knowledge of the mechanisms leading to proliferation in each tumor subtype. Deepening our understanding of tumor growth is mandatory to keep improving the efficacy of combination therapy.