Therapeutic strategies for the treatment of endocrine resistant hormone receptor positive advanced breast cancer

HR+ breast cancers are defined by the prominence of signaling pathways dependent on the estrogen receptor. Endocrine therapy is the standard treatment for these advanced diseases. Resistance to these treatments, called hormone resistance, appears invariably with biological mechanisms that have led to the development of therapeutic opportunities. An exhaustive literature review was carried out concerning the biology of the hormone resistance pathways, the therapeutic options before the era of CDK4/6 inhibitors, the rise of CDK4/6 inhibitors and the therapeutic prospects in a situation of hormone resistance. Various biological abnormalities have been identified in the mechanisms of hormone resistance such as changes in the estrogen receptor, mutations in the ESR1 gene, aberrant activation of the PI3K pathway or cell cycle deregulations. Historical strategies for circumventing this hormone resistance have been based on hormonal manipulation, on the development of new endocrine therapy such as fulvestrant (selective estrogen receptor inhibitor, SERD), on combinations of treatments such as everolimus, a mTOR inhibitor. This strategy combining endocrine therapy and targeted therapy has led to the development of combinations with CDK4/6 inhibitors which have now become a standard treatment in the hormone resistance phase. The future of this therapeutic era remains to be written with new combinations of hormone therapy and targeted therapy such as PI3K inhibitors or even with the positioning of new SERDs in clinical development.