ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer

Kingston, B. et al. (2023) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, (doi: 10.1158/2159-8290.CD-22-1387) (PMID:37982575) (Early Online Publication)

Abstract

Fulvestrant is used to treat patients with hormone receptor positive advanced breast cancer but acquired resistance is poorly understood. PlasmaMATCH Cohort A (NCT03182634) investigated the activity of fulvestrant in patients with activating ESR1 mutations in circulating tumor DNA (ctDNA). Baseline ESR1 mutations Y537S associated with poor, and Y537C with good outcome. Sequencing of baseline and EOT ctDNA samples (n=69) revealed 3/69 (4%) patients acquired novel ESR1 F404 mutations (F404L, F404I, F404V), in cis with activating mutations. In silico modelling revealed that ESR1 F404 contributes to fulvestrant binding to ERa through a pi-stacking bond, with mutations disrupting this bond. In vitro analysis demonstrated that single F404L, E380Q, and D538G models were less sensitive to fulvestrant, while compound mutations D538G+F404L and E380Q+F404L were resistant. Several oral ERa degraders were active against compound mutant models. We have identified a resistance mechanism specific to fulvestrant, that can be targeted by treatments in clinical development.

• Item Type: Articles
• Additional Information: BK is supported by Cancer Research UK Grant A25161 and Institutional funding from Breast Cancer Now. AP, MTHA, LXS and NCT are supported by funding from Breast Cancer Now. Research support for J.A.K. and Y.H. was provided by the National Institutes of Health (NIH/NCI, 1R01 CA220284) and the Breast Cancer Research Foundation (BCRF-084). SC is supported by NIH Cancer Center Support Grant P30-CA008748 and NIH R01CA245069. This research was funded by Cancer Research UK and Breast Cancer Now, and sequencing of ctDNA was conducted by Guardant Health. The plasmaMATCH trial is funded by Cancer Research UK (CRUK/15/010, C30746/A19505), with additional support from AstraZeneca, Puma Biotechnology, Guardant Health and BioRad. We thank Breast Cancer Now for funding this work as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre. This study represents independent research supported by the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London.
• Keywords: Fulvestrant, acquired resistance, breast cancer.
• Status: Early Online Publication
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MacPherson, Professor Iain
• Authors: Kingston, B., Pearson, A., Herrera-Abreu, M. T., Sim, L.-X., Cutts, R. J., Shah, H., Moretti, L., Kilburn, L. S., Johnson, H., Macpherson, I. R., Ring, A., Bliss, J. M., Hou, Y., Toy, W., Katzenellenbogen, J. A., Chandarlapaty, S., and Turner, N. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Discovery
• Publisher: American Association for Cancer Research
• ISSN: 2159-8274
• ISSN (Online): 2159-8290
• Published Online: 20 November 2023
• Copyright Holders: Copyright © 2023 American Association for Cancer Research
• First Published: First published in Cancer Discovery 2023
• Publisher Policy: Reproduced under a Creative Commons license