Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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.

People
Kingston, Belinda
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Pearson, Alex
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

Ring, Alistair and Kilburn, Lucy S. and Pearson, Alex and Moretti, Laura and Afshari-Mehr, Angelica and Wardley, Andrew M. and Gurel, Bora and MacPherson, Iain R. and Riisnaes, Ruth and Baird, Richard D. and Martin, Sue and Roylance, Rebecca and Johnson, Hannah and Ferreira, Ana and Winter, Matthew C. and Dunne, Kathryn and Copson, Ellen and Hickish, Tamas and Burcombe, Russell and Randle, Kat and Serra, Violeta and Llop-Guevara, Alba and Bliss, Judith M. and Turner, Nicholas C. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29 (23). pp. 4751-4759. ISSN 1078-0432

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Herrera-Abreu, Maria Teresa
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Sim, Li-Xuan
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Cutts, Rosalind J.
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Shah, Heena
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Moretti, Laura
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

Ring, Alistair and Kilburn, Lucy S. and Pearson, Alex and Moretti, Laura and Afshari-Mehr, Angelica and Wardley, Andrew M. and Gurel, Bora and MacPherson, Iain R. and Riisnaes, Ruth and Baird, Richard D. and Martin, Sue and Roylance, Rebecca and Johnson, Hannah and Ferreira, Ana and Winter, Matthew C. and Dunne, Kathryn and Copson, Ellen and Hickish, Tamas and Burcombe, Russell and Randle, Kat and Serra, Violeta and Llop-Guevara, Alba and Bliss, Judith M. and Turner, Nicholas C. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29 (23). pp. 4751-4759. ISSN 1078-0432

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Kilburn, Lucy S.
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

Ring, Alistair and Kilburn, Lucy S. and Pearson, Alex and Moretti, Laura and Afshari-Mehr, Angelica and Wardley, Andrew M. and Gurel, Bora and MacPherson, Iain R. and Riisnaes, Ruth and Baird, Richard D. and Martin, Sue and Roylance, Rebecca and Johnson, Hannah and Ferreira, Ana and Winter, Matthew C. and Dunne, Kathryn and Copson, Ellen and Hickish, Tamas and Burcombe, Russell and Randle, Kat and Serra, Violeta and Llop-Guevara, Alba and Bliss, Judith M. and Turner, Nicholas C. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29 (23). pp. 4751-4759. ISSN 1078-0432

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Johnson, Hannah
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

Ring, Alistair and Kilburn, Lucy S. and Pearson, Alex and Moretti, Laura and Afshari-Mehr, Angelica and Wardley, Andrew M. and Gurel, Bora and MacPherson, Iain R. and Riisnaes, Ruth and Baird, Richard D. and Martin, Sue and Roylance, Rebecca and Johnson, Hannah and Ferreira, Ana and Winter, Matthew C. and Dunne, Kathryn and Copson, Ellen and Hickish, Tamas and Burcombe, Russell and Randle, Kat and Serra, Violeta and Llop-Guevara, Alba and Bliss, Judith M. and Turner, Nicholas C. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29 (23). pp. 4751-4759. ISSN 1078-0432

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Macpherson, Iain R.
Author

Maldonado, Horacio and Dreger, Marcel and Bedgood, Lara D. and Kyriakou, Theano and Wolanska, Katarzyna I. and Rigby, Megan E. and Marotta, Valeria E. and Webster, Justine M. and Wang, Jun and Rusilowicz-Jones, Emma V. and Marshall, John F. and Coulson, Judy M. and MacPherson, Iain R. and Hurlstone, Adam and Morgan, Mark R. (2024) A trafficking regulatory subnetwork governs α V β 6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance. Science Advances, 10 (49): eadk9944. ISSN 2375-2548

Hanna, Daire and Merrick, Sophie and Ghose, Aruni and Devlin, Michael John and Yang, Dorothy D. and Phillips, Edward and Okines, Alicia and Chopra, Neha and Papadimatraki, Elisavet and ROSS, KIRSTY and MacPherson, Iain and Boh, Zhuang Y. and Michie, Caroline O. and Swampillai, Angela and Gupta, Sunnia and Robinson, Tim and Germain, Lewis and Twelves, Chris and Atkinson, Charlotte and Konstantis, Apostolos and Riddle, Pippa and Cresti, Nicola and Naik, Jay D. and Borley, Annabel and Guppy, Amy and Schmid, Peter and Phillips, Melissa (2024) Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom. British Journal of Cancer, 130 (12). pp. 1916-1920. ISSN 0007-0920

Agnew, Sommer and Crawford, Megan and MacPherson, Iain and Shiramizu, Victor and Fleming, Leanne (2024) The impact of symptom clusters on endocrine therapy adherence in patients with breast cancer. Breast, 75: 103731. ISSN 0960-9776

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Ring, Alistair
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

Ring, Alistair and Kilburn, Lucy S. and Pearson, Alex and Moretti, Laura and Afshari-Mehr, Angelica and Wardley, Andrew M. and Gurel, Bora and MacPherson, Iain R. and Riisnaes, Ruth and Baird, Richard D. and Martin, Sue and Roylance, Rebecca and Johnson, Hannah and Ferreira, Ana and Winter, Matthew C. and Dunne, Kathryn and Copson, Ellen and Hickish, Tamas and Burcombe, Russell and Randle, Kat and Serra, Violeta and Llop-Guevara, Alba and Bliss, Judith M. and Turner, Nicholas C. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29 (23). pp. 4751-4759. ISSN 1078-0432

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Bliss, Judith M.
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

Ring, Alistair and Kilburn, Lucy S. and Pearson, Alex and Moretti, Laura and Afshari-Mehr, Angelica and Wardley, Andrew M. and Gurel, Bora and MacPherson, Iain R. and Riisnaes, Ruth and Baird, Richard D. and Martin, Sue and Roylance, Rebecca and Johnson, Hannah and Ferreira, Ana and Winter, Matthew C. and Dunne, Kathryn and Copson, Ellen and Hickish, Tamas and Burcombe, Russell and Randle, Kat and Serra, Violeta and Llop-Guevara, Alba and Bliss, Judith M. and Turner, Nicholas C. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29 (23). pp. 4751-4759. ISSN 1078-0432

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Hou, Yingwei
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Toy, Weiyi
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Katzenellenbogen, John A.
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Chandarlapaty, Sarat
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

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Turner, Nicholas C.
Author

Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C. (2024) ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer. Cancer Discovery, 14 (2). pp. 274-289. ISSN 2159-8274

Ring, Alistair and Kilburn, Lucy S. and Pearson, Alex and Moretti, Laura and Afshari-Mehr, Angelica and Wardley, Andrew M. and Gurel, Bora and MacPherson, Iain R. and Riisnaes, Ruth and Baird, Richard D. and Martin, Sue and Roylance, Rebecca and Johnson, Hannah and Ferreira, Ana and Winter, Matthew C. and Dunne, Kathryn and Copson, Ellen and Hickish, Tamas and Burcombe, Russell and Randle, Kat and Serra, Violeta and Llop-Guevara, Alba and Bliss, Judith M. and Turner, Nicholas C. (2023) Olaparib and celarasertib (AZD6738) in patients with triple negative advanced breast cancer: results from Cohort E of the plasmaMATCH trial (CRUK/15/010). Clinical Cancer Research, 29 (23). pp. 4751-4759. ISSN 1078-0432

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Title:
ESR1 F404 mutations and acquired resistance to fulvestrant in ESR1 mutant breast cancer
Creators:
Kingston, Belinda and Pearson, Alex and Herrera-Abreu, Maria Teresa and Sim, Li-Xuan and Cutts, Rosalind J. and Shah, Heena and Moretti, Laura and Kilburn, Lucy S. and Johnson, Hannah and Macpherson, Iain R. and Ring, Alistair and Bliss, Judith M. and Hou, Yingwei and Toy, Weiyi and Katzenellenbogen, John A. and Chandarlapaty, Sarat and Turner, Nicholas C.
Identification Number:
10.1158/2159-8290.CD-22-1387
Date:
1 February 2024
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
American Association for Cancer Research
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.
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https://pub.demo35.eprints-hosting.org/id/eprint/369
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
Date Deposited:
11 Jun 2025 16:37
Revision:
16
Last Modified:
12 Jun 2025 09:45
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