Early Enrichment of ESR1 Mutations and the Impact on Gene Expression in Presurgical Primary Breast Cancer Treated with Aromatase Inhibitors.
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Authors
Leal, MF
Haynes, BP
Schuster, E
Yeo, B
Afentakis, M
Zabaglo, L
Martins, V
Buus, R
Dodson, A
Cheang, MCU
Smith, IE
Martin, L-A
Dowsett, M
Haynes, BP
Schuster, E
Yeo, B
Afentakis, M
Zabaglo, L
Martins, V
Buus, R
Dodson, A
Cheang, MCU
Smith, IE
Martin, L-A
Dowsett, M
Document Type
Journal Article
Date
2019-12-15
Date Accepted
2019-09-09
Abstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
Citation
Clin Cancer Res, 2019
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
Research Team
Genomic Analysis – Clinical Trials
Medicine (RMH Smith Cunningham)
Endocrinology
Medicine (RMH Smith Cunningham)
Endocrinology