Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors.

Abstract

To investigate the presence of <i>ESR1</i> mutations in primary estrogen-receptor-positive (ER⁺) breast cancer treated with extended (>4 weeks) neoadjuvant (presurgical) aromatase inhibitor (NAI) therapy and to identify patients who may gain less benefit from aromatase inhibition (AI) alone based upon on-treatment changes in gene expression. We evaluated ER, progesterone receptor, and Ki67 by immunostaining, <i>ESR1</i> mutations by droplet-digital PCR and expression of over 800 key breast cancer genes in paired pre- and post-NAI tumor samples from 87 ER⁺ breast cancer patients. Cell proliferation and estrogen-regulated genes (ERG) remained suppressed in most tumors indicative of persistent response to NAI. Enrichment of <i>ESR1</i> mutations was found in five tumors and predominantly in patients receiving therapy for >6 months. <i>ESR1</i>-mutant tumors showed increased expression of <i>ESR1</i> transcript and limited suppression of ERGs and proliferation-associated genes in response to NAI. <i>ESR1</i> wild-type tumors with high residual proliferation (Ki67r ≥10%; 15/87 tumors) showed lower <i>ESR1</i>/ER expression pre- and post-therapy and lower ERGs. Tumors with <i>ESR1</i> mutations or Ki67r ≥10% showed less inhibition of estrogen response, cell cycle, and E2F-target genes. Ligand-independent ER signaling, as a result of <i>ESR1</i> mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy.