Emerging strategies to overcome resistance to endocrine therapy for breast cancer.

Endocrine therapy of breast cancer is perhaps the oldest form of effective and well-tolerated targeted cancer systemic treatment, in both the adjuvant and metastatic disease settings. The most commonly used endocrine therapy agents are selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor downregulators. De novo or acquired resistance to these agents is a significant clinical problem. Preclinical and clinical investigations to understand this resistance have yielded significant advances in understanding cell signaling and the possible mechanisms of resistance. These mechanisms of resistance are as diverse as the biology of breast cancer and can arise from alterations in any of the cell signaling pathway components. A growing understanding of these mechanisms has provided rationale for development of strategies to overcome the resistance. Many of these mechanisms of resistance involve adaptive upregulation of alternate signaling pathways, such as growth factor signaling, and cross talk between estrogen receptor and growth factor signaling. Clinical trials are focusing on cotargeting these alternate pathways along with estrogen receptor signaling. It is becoming evident that, as with all cancer therapy, strategies to overcome resistance need to be individualized, and it is important to identify biomarkers to guide the use of these strategies. This manuscript systemically reviews the recent preclinical and clinical trials on the novel and pathway-driven agents that have shown significant promise in enhancing the efficacy and overcoming the resistance in the hormonal treatment of breast cancer. Future directions including biomarker selection and the role of next generation sequencing will be discussed.