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

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

  • Cancer Discov. 2023 Nov 20. doi: 10.1158/2159-8290.CD-22-1387.
Belinda Kingston 1,  Alex Pearson 1,  Maria Teresa Herrera-Abreu 1,  Li-Xuan Sim 1,  Rosalind J Cutts 2,  Heena Shah 1,  Laura Moretti 3,  Lucy S Kilburn 3,  Hannah Johnson 3,  Iain R Macpherson 4,  Alistair Ring 5,  Judith M Bliss 1,  Yingwei Hou 6,  Weiyi Toy 7,  John A Katzenellenbogen 6,  Sarat Chandarlapaty 7,  Nicholas C Turner 8
Affiliations

Affiliations

  • 1 Institute of Cancer Research, London, United Kingdom.
  • 2 Institute of Cancer Research and The Royal Marsden Hospital, London, United Kingdom.
  • 3 Institute of Cancer Research, Sutton, United Kingdom.
  • 4 University of Glasgow, Glasgow, United Kingdom.
  • 5 Royal Marsden Hospital, Surrey, United Kingdom.
  • 6 University of Illinois Urbana-Champaign, Urbana, IL, United States.
  • 7 Memorial Sloan Kettering Cancer Center, New York, New York, United States.
  • 8 Royal Marsden NHS Foundation Trust, London, United Kingdom.
PMID: 37982575 DOI: 10.1158/2159-8290.CD-22-1387
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.

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