ESR1 F404 Mutations and Acquired Resistance to Fulvestrant in ESR1-Mutant Breast Cancer.
Date
2024-02-08ICR Author
Author
Kingston, B
Pearson, A
Herrera-Abreu, MT
Sim, L-X
Cutts, RJ
Shah, H
Moretti, L
Kilburn, LS
Johnson, H
Macpherson, IR
Ring, A
Bliss, JM
Hou, Y
Toy, W
Katzenellenbogen, JA
Chandarlapaty, S
Turner, NC
Type
Journal Article
Metadata
Show full item recordAbstract
UNLABELLED: 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 are associated with poor outcomes and Y537C with good outcomes. Sequencing of baseline and EOT ctDNA samples (n = 69) revealed 3/69 (4%) patients acquired novel ESR1 F404 mutations (F404L, F404I, and F404V), in cis with activating mutations. In silico modeling revealed that ESR1 F404 contributes to fulvestrant binding to estrogen receptor-alpha (ERα) 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, whereas compound mutations D538G + F404L and E380Q + F404L were resistant. Several oral ERα 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. SIGNIFICANCE: Novel F404 ESR1 mutations may be acquired to cause overt resistance to fulvestrant when combined with preexisting activating ESR1 mutations. Novel combinations of mutations in the ER ligand binding domain may cause drug-specific resistance, emphasizing the potential of similar drug-specific mutations to impact the efficacy of oral ER degraders in development. This article is featured in Selected Articles from This Issue, p. 201.
Collections
Research team
Molecular Oncology
Clin Trials & Stats Unit
Language
eng
Date accepted
2023-11-16
License start date
2023-11-20
Citation
Cancer Discovery, 2023,
Publisher
AMER ASSOC CANCER RESEARCH