American Association for Cancer Research
10780432ccr191129-sup-220135_2_supp_5713004_pw9zxg.docx (15.94 kB)

SUPPLEMENTARY FIGURE AND TABLE LEGENDS from Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors

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journal contribution
posted on 2023-03-31, 21:00 authored by Mariana Ferreira Leal, Ben P. Haynes, Eugene Schuster, Belinda Yeo, Maria Afentakis, Lila Zabaglo, Vera Martins, Richard Buus, Andrew Dodson, Maggie C.U. Cheang, Ian E. Smith, Lesley-Ann Martin, Mitch Dowsett




To investigate the presence of ESR1 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, ESR1 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 ESR1 mutations was found in five tumors and predominantly in patients receiving therapy for >6 months. ESR1-mutant tumors showed increased expression of ESR1 transcript and limited suppression of ERGs and proliferation-associated genes in response to NAI. ESR1 wild-type tumors with high residual proliferation (Ki67r ≥10%; 15/87 tumors) showed lower ESR1/ER expression pre- and post-therapy and lower ERGs. Tumors with ESR1 mutations or Ki67r ≥10% showed less inhibition of estrogen response, cell cycle, and E2F-target genes. Ligand-independent ER signaling, as a result of ESR1 mutation or reduced ER dependence, identified after extended NAI therapy, can guide early selection of patients who would benefit from combination therapy.