Enhancing Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: Cotargeting Signaling Pathways.

Overcoming primary or secondary endocrine resistance in breast cancer remains critical to further enhancing the benefit of existing therapies such as tamoxifen or an aromatase inhibitor (AI). Much progress has been made in understanding the molecular biology associated with secondary endocrine resistance. Cotargeting the estrogen receptor, together with various key intracellular proliferation and cell survival signaling pathways, has been explored as a strategy either to treat endocrine resistance once it develops in the second-line setting or to enhance first-line endocrine responsiveness by preventing secondary resistance from developing via blockade of specific pathways from the outset. While attempts to improve endocrine therapy by adding growth factor inhibitors have been disappointing, success resulting in new drug approvals has been seen in secondary endocrine resistance by treating patients with the mTOR antagonist everolimus in combination with the AI exemestane and, more recently, in the first-line setting, by the addition of the CDK 4/6 inhibitor palbociclib to the AI letrozole. Numerous other therapeutics are being evaluated in combination with endocrine therapies based on supportive preclinical evidence, including inhibitors of PI3K, Akt, HDAC, Src, IGFR-1, and FGFR. Appropriate clinical trial design and patient selection based on prior therapy exposure, together with predictive biomarkers derived through real-time molecular profiling, are needed to enrich future trials and maximize any additional benefit that cotargeting may bring to current endocrine therapies for estrogen receptor-positive breast cancer.