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Title: Early enrichment of ESR1 mutations and the impact on gene expression in pre-surgical primary breast cancer treated with aromatase inhibitors.
Authors: Leal, Mariana F;Haynes, Benjamin P;Schuster, Eugene F;Yeo, Belinda;Afentakis, Maria;Zabaglo, Lila;Martins, Vera;Buus, Richard;Dodson, Andrew;Cheang, Maggie C U;Smith, Ian E;Martin, Lesley-Ann;Dowsett, Mitch
Affiliation: Endocrinology, Institute of Cancer Research
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Academic Department of Biochemistry, The Royal Marsden Hospital/The Institute of Cancer Research
Ralph Lauren Centre for Breast Cancer Research, Institute of Cancer Research
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital
Breast Cancer Research, Institute of Cancer Research
Department of Academic Biochemistry, Royal Marsden Hospital
Clinical Trials and Statistics Unit (ICR-CTSU), Institute of Cancer Research
Medicine- Breast Unit, The Royal Marsden Hospital/The Institute of Cancer Research
The Breast Cancer Now Toby Robins Breast Cancer Research Centre, Institute of Cancer Research
Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital
Issue Date: 23-Sep-2019
EDate: 2019-09-23
Citation: Clinical cancer research : an official journal of the American Association for Cancer Research 2019; online first: 23 September
Abstract: To investigate the presence of ESR1 mutation in primary oestrogen-receptor positive breast cancer (ER+BC) treated with extended (>4 weeks) neoadjuvant (pre-surgical) 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 BC genes in paired pre- and post-NAI tumour samples from 87 ER+BC patients. Cell proliferation and oestrogen-regulated genes (ERGs) remained suppressed in most tumours indicative of persistent response to NAI. Enrichment of ESR1 mutations was found in five tumours and predominantly in patients receiving therapy for >6 months. ESR1 mutant tumours showed increased expression of ESR1-transcript and limited suppression of ERGs and proliferation associated genes in response to NAI. ESR1 wild-type tumours with high residual proliferation (Ki67r≥10%; 15/87 tumours) showed lower ESR1/ER expression pre- and post-therapy and lower ERGs Tumours with ESR1 mutations or Ki67r≥10% showed less inhibition of oestrogen-response, cell-cycle and E2F-target genes. Ligand-independent ER-signalling, 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.
DOI: 10.1158/1078-0432.CCR-19-1129
ORCID: 0000-0003-4375-2563
PubMed URL: 31548345
ISSN: 1078-0432
Type: Journal Article
Appears in Collections:Journal articles

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