Endocrine Resistance: What Do We Know?

Adjuvant therapy with antiestrogens targeting estrogen receptor α (ER) signaling prevents disease recurrence in many patients with early-stage ER+ breast cancer. However, a significant number of cases exhibit de novo or acquired endocrine resistance. While other clinical subtypes of breast cancer (HER2+, triple-negative) have disproportionately higher rates of mortality, ER+ breast cancer is responsible for at least as many deaths because it is the most common subtype. Therefore, identifying mechanisms that drive endocrine resistance is a high clinical priority. A large body of experimental evidence indicates that oncogenic signaling pathways underlie endocrine resistance, including growth factor receptor tyrosine kinases (HER2, epidermal growth factor receptor [EGFR], fibroblast growth factor receptor 1/2 [FGFR], insulin-like growth factor-1 receptor [IGF-1R]/ insulin receptor [InsR]), PI3K/AKT/ mTOR, MAPK/ERK, Src, CDK4/CDK6, and ER itself. Combined targeting of ER and such pathways may be the most effective means to combat antiestrogen resistance, and clinical trials testing such strategies show promising results. Herein, we discuss pathways associated with endocrine resistance, biomarkers that may be useful to predict response to targeted agents, and avenues for further exploration to identify strategies for the treatment of patients with endocrine-resistant disease.