Treatment algorithms for hormone receptor-positive advanced breast cancer: going forward in endocrine therapy—overcoming resistance and introducing new agents.

Overcoming de novo or acquired endocrine resistance remains critical to further enhancing the benefit of existing endocrine therapies. Recent progress has been made in understanding the molecular biology associated with acquired endocrine resistance, including adaptive "cross-talk" between ER and various growth factor receptor and cell-signaling pathways. Strategies that combine endocrine therapy with targeted inhibitors of growth factor receptors or cell-survival pathways to further enhance first-line response have largely been disappointing, suggesting that any attempts to prevent endocrine resistance by blocking specific pathways from the outset will be futile. In contrast, success has been seen by selecting patients with acquired endocrine resistance and enhancing response to further endocrine therapy by the addition of mTOR antagonists. Numerous other therapeutics are being evaluated in combination with endocrine therapies based on varying levels of preclinical science to support their use, including inhibitors of PI3K, HDAC, Src, IGFR-1, and CDK4/6. Enriching trial recruitment by molecular profiling of different ER+ subtypes will become increasingly important to maximize any additional benefit that these new agents may bring to current endocrine therapies for breast cancer.