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Hormone receptor positive, HER2 negative metastatic breast cancer: Future treatment landscape. Endocrine therapy is an established and effective treatment strategy for hormone receptor positive metastatic breast cancer. The clinical utility of endocrine therapy is lost over time due to evolving changes in tumor biology and the development of endocrine resistance. Many agents targeting the intracellular signaling pathways associated with endocrine resistance are in development. Encouraging early results have been seen for agents which directly target the estrogen receptor (ER), inhibitors of co-signaling pathways, inhibitors of ER chaperones, ER antagonists able to inhibit mutated or otherwise activated ERs, and modulators of histone acetylation restoring synthesis of ER signaling components. Following our systematic review of treatments with established benefits in this supplement, we review some of the more promising new strategies for overcoming endocrine resistance, looking at the impact on disease control and quality of life for women with hormone receptor positive, HER2 negative breast cancer. We also examine the biomarkers that may guide selection of the best therapy for the individual.