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

Autor:	Leal MF; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom. mleal@icr.ac.uk.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Haynes BP; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom., Schuster E; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Yeo B; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom., Afentakis M; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom., Zabaglo L; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Martins V; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Buus R; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Dodson A; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom., Cheang MCU; Clinical Trials and Statistic Unit, The Institute of Cancer Research, Sutton, United Kingdom., Smith IE; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom.; Breast Unit, The Royal Marsden NHS Foundation Trust, London, United Kingdom., Martin LA; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom., Dowsett M; Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital NHS Trust, London, United Kingdom.; The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Dec 15; Vol. 25 (24), pp. 7485-7496. Date of Electronic Publication: 2019 Sep 23.
DOI:	10.1158/1078-0432.CCR-19-1129
Abstrakt:	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. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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