After nearly 20 years of research, it is now established that mutations within the
estrogen receptor (ER) gene, ESR1, frequently occur in metastatic
breast cancer and influence response to
hormone therapy. Though early studies presented differing results, sensitive sequencing techniques now show that ESR1 mutations occur at a frequency between 20 and 40% depending on the assay method. Recent studies have focused on several "hot spot mutations," a cluster of mutations found in the
hormone-binding domain of the ESR1 gene. Throughout the course of treatment,
tumor evolution can occur, and ESR1 mutations emerge and become enriched in the metastatic setting. Sensitive techniques to continually monitor mutant burden in vivo are needed to effectively treat patients with mutant ESR1. The full impact of these mutations on
tumor response to different
therapies remains to be determined. However, recent studies indicate that mutant-bearing
tumors may be less responsive to specific hormonal
therapies, and suggest that
aromatase inhibitor (AI)
therapy may select for the emergence of ESR1 mutations. Additionally, different mutations may respond discretely to targeted
therapies. The need for more preclinical mechanistic studies on ESR1 mutations and the development of better agents to target these mutations are urgently needed. In the future, sequential monitoring of ESR1 mutational status will likely direct personalized therapeutic regimens appropriate to each
tumor's unique mutational landscape.