The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer

Abstract

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.

Fig. 1

Observed patterns of clonal evolution in mutant-bearing tumors. A primary tumor contains few to no ESR1 mutant-bearing cells. However, it can seed clusters of circulating cells that eventually become mutant-expressing metastases through several different evolutionary patterns. As demonstrated in panel A, circulating cell clusters may bear the same mutation, here Y537S, as the primary tumor. When the circulating cell clusters colonize a distal organ and become a metastatic tumor, they may continue to express the mutation, even increasing in frequency. Treatment with an AI (and possibly a SERD such as Tam, though clinical evidence is lacking) in the metastatic setting may actually cause an increase in mutant frequency. As seen in the BOLERO-2 trial [69], combinatorial treatment in AI + Eve was not effective in Y537S-bearing tumors. In B, the primary tumor seeds circulating cell clusters which lack ESR1 mutations, even in the metastatic tumor. However, hormonal treatment may provide selective pressure for the emergence of ESR1 tumors in the metastatic setting. In this case the mutation is D538G, which does respond to AI + Eve treatment. In C, hormonal therapy again selects for expression of the D538G mutation, and the process of seeding for micrometastases selects for emergence of a second mutation.