Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists

Abstract

Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer (MBC) and found some of them to promote estrogen-independent activation of the receptor. The degree to which all recurrent mutants can drive estrogen-independent activities and reduced sensitivity to ER antagonists like fulvestrant is not established. In this report, we characterize the spectrum of ESR1 mutations from over 900 patients. ESR1 mutations were detected in 10%, with D538G being the most frequent (36%), followed by Y537S (14%). Several novel, activating mutations were also detected (e.g. L469V, V422del, Y537D). While many mutations lead to constitutive activity and reduced sensitivity to ER antagonists, only select mutants such as Y537S caused a magnitude of change associated with fulvestrant resistance in vivo. Correspondingly, tumors driven by Y537S, but not D5358G, E380Q or S463P were less effectively inhibited by fulvestrant than more potent and bioavailable antagonists including AZD9496. These data point to a need for antagonists with optimal pharmacokinetic properties to realize clinical efficacy against certain ESR1 mutants.

Genomic profiling of ER + breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance

“…Table S9). In addition to and consistent with a recent report (33), we showed that V422del activates estrogen-independent ERα transcription approximately two-fold (Suppl. Fig.…”

“…Importantly, these mutants have been shown to be transcriptionally active in the absence of estrogen. To date, ERα p.V422del has only been reported in a single case of endometrial cancer in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (32) and most recently, by Toy, et al (33). Secondary analysis of FoundationOne™-profiled breast tumors revealed 10 additional tumors that harbor ERα V422del (Suppl.…”

“…S8A & S8B), as recently reported by Toy, et al . (33). Further investigation is necessary to confirm a causal association of ERα V422del with resistance to anti-estrogen therapy.…”

Are We Ready to Use ESR1 Mutations in Clinical Practice

“…In addition, affinity studies showed that the LBD-mutated receptors have a decreased affinity for estradiol (E2). Finally, several studies showed co-activator binding to mutant ER in ligand-independent conditions [15,16]. Together, these observations provide a mechanistic explanation for the ligand-independent activity.…”

“…The majority of these samples were ER+ metastatic tumors, with 95 patients found to have a somatic ESR1 mutation. Not surprisingly, 85 of the 95 patients had ER+ metastatic disease [15].…”