Pure estrogen receptor antagonists potentiate capecitabine activity in ESR1-mutant breast cancer.

Journal

NPJ breast cancer
ISSN: 2374-4677
Titre abrégé: NPJ Breast Cancer
Pays: United States
ID NLM: 101674891

Informations de publication

Date de publication:
08 Jun 2024
Historique:
received: 21 12 2023
accepted: 23 05 2024
medline: 9 6 2024
pubmed: 9 6 2024
entrez: 8 6 2024
Statut: epublish

Résumé

The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

Identifiants

DOI: 10.1038/s41523-024-00647-1 PMID: 38851818
pubmed: 38851818
doi: 10.1038/s41523-024-00647-1
pii: 10.1038/s41523-024-00647-1
doi:

Types de publication

Journal Article

Langues

eng

Pagination

42

Subventions

Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : RO1 CA237414-04

Informations de copyright

© 2024. The Author(s).

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Auteurs

Albert Grinshpun (A)

Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-3351-5719

Douglas Russo (D)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
ORCID: 0000-0002-2502-1540

Wen Ma (W)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

Ana Verma (A)

Harvard Medical School, Boston, MA, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Francisco Hermida-Prado (F)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

Shira Sherman (S)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0001-5717-2987

Giorgio Gaglia (G)

Harvard Medical School, Boston, MA, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Sheheryar Kabraji (S)

Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-5315-7103

Gregory Kirkner (G)

Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Melissa E Hughes (ME)

Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Nancy U Lin (NU)

Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

Zachary Sandusky (Z)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

Agostina Nardone (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

Cristina Guarducci (C)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-3234-564X

Quang-De Nguyen (QD)

Harvard Medical School, Boston, MA, USA.
Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Sandro Santagata (S)

Harvard Medical School, Boston, MA, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0002-7528-9668

Zsuzsanna Nagy (Z)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

Rinath Jeselsohn (R)

Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, USA. Rinath_jeselsohn@dfci.harvard.edu.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Rinath_jeselsohn@dfci.harvard.edu.
Harvard Medical School, Boston, MA, USA. Rinath_jeselsohn@dfci.harvard.edu.
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. Rinath_jeselsohn@dfci.harvard.edu.
ORCID: 0000-0001-7996-7529

Classifications MeSH