Tackling endocrine resistance in ER-positive HER2-negative advanced breast cancer: A tale of imprecision medicine

- Optimal treatment after endocrine failure in advanced breast cancer is not clearly defined.
- Combinations of endocrine agents have met with mixed results.
- PI3K/mTOR inhibition has modest efficacy; no biomarkers have been identified.
- CDK4/6 inhibitors significantly prolong PFS, but not OS, in randomized trials.
- Biomarkers are critical for the integration of novel combinations in clinical practice.

The selection of patients with advanced breast cancer as appropriate for endocrine manipulation according to hormone receptor status is a successful strategy. Unfortunately, the emergence of resistance is inevitable and subsequent treatment is not well defined. Numerous mechanisms have been implicated in the development of resistance; central among them is the activation of compensatory signaling pathways. Despite the rationale that supports combining agents targeting these pathways with hormonal therapies in an attempt to delay or even reverse endocrine resistance, most clinical trials have failed to demonstrate improved outcomes. Although the inhibition of the PI3K/mTOR pathway and of CDK 4/6 function has led to meaningful prolongations of progression free survival, no overall survival gains have been reported yet. Considering the associated toxicity and costs, genomic-driven trials are eagerly needed in order to refine management strategies and achieve a truly personalized approach for this patient subgroup.