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

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Embargo End Date

ICR Authors

Smith, Ian
 Buus, Richard
 Martin, Lesley-Ann
 Cheang, Chon
 Dowsett, Mitch

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

Document Type

Journal Article

Date

2019-12

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

Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 25 (24), pp. 7485 - 7496

DOI

10.1158/1078-0432.ccr-19-1129

URI

https://repository.icr.ac.uk/handle/internal/3438

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

ISSN

1078-0432

eISSN

1557-3265

Collections

Breast Cancer Research
Clinical Studies
Molecular Pathology

Research Team

Genomic Analysis – Clinical Trials
Medicine (RMH Smith Cunningham)
Endocrinology

Notes