BRCA1 -Mutated Estrogen Receptor–Positive Breast Cancer Shows BRCAness, Suggesting Sensitivity to Drugs Targeting Homologous Recombination Deficiency
Published version of a preprint
Abstract
Purpose: As estrogen receptor–positive (ER+) breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER-negative (ER−) BRCA1-mutated breast cancer, it has been suggested that these tumors are “sporadic” and not BRCA1 driven. With the introduction of targeted treatments specific for tumors with a nonfunctioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors. Experimental Design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER− tumors, 36 BRCA2-mutated ER+-associated tumors, and 182 sporadic ER+ tumors. Results: The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER− breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wild-type BRCA1 allele was observed. In addition, clinicopathologic variables in BRCA1-mutated ER+ cancer were also more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1-mutated ER− cancers. Conclusions: As BRCA1-mutated ER+ tumors show a BRCAness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER+ breast cancer. Clin Cancer Res; 23(5); 1236–41. ©2016 AACR.
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These cases were predicted to be good candidates for platinum-based chemotherapy or PARP inhibitors, including 12 tumours that would not otherwise meet this recommendation (grade 2, ER/PR-positive, or invasive lobular carcinoma).
“These cases would be predicted to be good candidates for platinum-based chemotherapy or PARPi, and included 12 tumours that would not otherwise fall into this recommendation of treatment (i.e. histological grade-2, ER/PR-positive [31], or invasive lobular carcinoma).”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [31]
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- Authors
- Lips, E. H., Debipersad, R. D., Scheerman, C. E., Mulder, L., Sonke, G. S., van der Kolk, L. E., Wesseling, J., Hogervorst, F. B. L., & Nederlof, P. M.
- Affiliations
- The Netherlands Cancer Institute (NL)
- 4Department of Clinical Genetics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Venue
- Clinical Cancer Research
- Published
- 2017-02-28
- Volume
- 23
- Issue
- 5
- Pages
- 1236-1241
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2519999109
- Cited by
- 22
- References
- 23
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 5 · 2018: 3
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- BRCA1 mutation, estrogen receptor-positive breast cancer, BRCAness, homologous recombination deficiency, BRCA2 mutation, loss of heterozygosity, BRCA1 promoter methylation, copy number alterations, genomic profiling, targeted therapy, sporadic breast cancer
- MeSH terms
- Adult, Aged, Breast Neoplasms, Female, Humans, Middle Aged, Mutation, Receptors, Estrogen, Biomarkers, Tumor, BRCA1 Protein, Loss of Heterozygosity, BRCA2 Protein, DNA Copy Number Variations, Homologous Recombination, Carcinogenesis
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