ESR1 Mutations Not Implicated in Fulvestrant Resistance

ESR1 mutations, which are believed to convey aromatase inhibitors (AIs) resistance in ER-positive, metastatic breast cancer, are not associated with tumor resistance to fulvestrant (Faslodex), reported researchers from Genentech in the journal Nature Communications. 

“ESR1 mutation allele frequency does not show a consistent pattern of increase during fulvestrant treatment, and progression-free survival (PFS) is not different in patients with ESR1 mutations compared with wild-type patients,” reported Genentech’s  Jill M. Spoerke and colleagues. “Our study does not provide any evidence that patients with plasma mutations in ESR1 have differential PFS with fulvestrant treatment, compared with patients without ESR1 mutation, suggesting ESR1 mutations in aggregate may not be associated with innate or acquired resistance to fulvestrant.”

Previous research has shown that ESR1 mutations appear to convey resistance to AIs, the coauthors noted. To assess ESR1 mutations’ effects on fulvestrant, the researchers assayed circulating tumor DNA (ctDNA) in samples archived from clinical trial participants with ER-positive metastatic breast cancer. The patients had been randomly assigned to receive either fulvestrant or fulvestrant plus a pan-PI3K inhibitor.

“ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumors,” the authors reported. “ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behavior over time.”

ESR1 mutations were “very infrequently” detected in metastatic ctDNA samples that had been collected before AI therapy, but occurred more frequently in samples collected after AI therapy had begun, the researchers noted. This finding is consistent with prior research that suggests ESR1 mutations are found “exclusively” among patients with ER-positive breast cancer treated with AI.

“Recent studies have highlighted the ability of mutational analysis of ctDNA to serve as a potential surrogate for antitumor activity and for therapeutic monitoring,” the authors noted.