Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant

Jill M. Spoerke, Steven Gendreau, Kimberly Walter, Jiaheng Qiu, Timothy R. Wilson, Heidi Savage, Junko Aimi, Mika K. Derynck, Meng Chen, Iris T. Chan, Lukas C. Amler, Garret M. Hampton, Stephen Johnston, Ian Krop, Peter Schmid and Mark R. Lackner ()
Additional contact information
Jill M. Spoerke: Genentech, Inc
Steven Gendreau: Genentech, Inc
Kimberly Walter: Genentech, Inc
Jiaheng Qiu: Genentech, Inc
Timothy R. Wilson: Genentech, Inc
Heidi Savage: Genentech, Inc
Junko Aimi: Genentech, Inc
Mika K. Derynck: Genentech, Inc
Meng Chen: Genentech, Inc
Iris T. Chan: Genentech, Inc
Lukas C. Amler: Genentech, Inc
Garret M. Hampton: Genentech, Inc
Stephen Johnston: Royal Marsden NHS Foundation Trust
Ian Krop: Dana-Farber Cancer Institute
Peter Schmid: Barts Cancer Institute, Queen Mary University London
Mark R. Lackner: Genentech, Inc

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract Mutations in ESR1 have been associated with resistance to aromatase inhibitor (AI) therapy in patients with ER+ metastatic breast cancer. Little is known of the impact of these mutations in patients receiving selective oestrogen receptor degrader (SERD) therapy. In this study, hotspot mutations in ESR1 and PIK3CA from ctDNA were assayed in clinical trial samples from ER+ metastatic breast cancer patients randomized either to the SERD fulvestrant or fulvestrant plus a pan-PI3K inhibitor. ESR1 mutations are present in 37% of baseline samples and are enriched in patients with luminal A and PIK3CA-mutated tumours. ESR1 mutations are often polyclonal and longitudinal analysis shows distinct clones exhibiting divergent behaviour over time. ESR1 mutation allele frequency does not show a consistent pattern of increases during fulvestrant treatment, and progression-free survival is not different in patients with ESR1 mutations compared with wild-type patients. ESR1 mutations are not associated with clinical resistance to fulvestrant in this study.

Date: 2016
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DOI: 10.1038/ncomms11579

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