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Updated: Jul 30, 2025
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
Published on: February 17, 2011
Mutations in Homologous Recombination Genes and Loss of Heterozygosity Status in Advanced-Stage Breast Carcinoma
Brooke B Bartow1, Gene P Siegal1, Ceren Yalniz2
1Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Abstract:
Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) have demonstrated antitumor activity in cancers with a homologous recombination deficiency (HRD) and have recently been approved by the FDA for the treatment of germline BRCA1/2-mutation-associated breast cancer. PARPis have also been found to be efficacious in BRCA wild-type (BRCAwt) lesions with high genomic loss of heterozygosity (LOH-high). The goal of this study was to retrospectively investigate the tumor mutations in homologous recombination (HRR) genes and the LOH score in advanced-stage breast carcinomas (BCs). Sixty-three patients were included in our study, 25% of whom had HRR gene mutations in their tumors, including 6% BRCA1/2 and 19% non-BRCA-containing gene mutations. An HRR gene mutation was associated with a triple-negative phenotype. Twenty-eight percent of the patients had an LOH-high score, which, in turn, was associated with a high histological grade, a triple-negative phenotype, and a high tumor mutational burden (TMB). Among the six patients who received PARPi therapy, one had a tumor with a PALB2 mutation other than BRCA and had a clinical partial response. Twenty-two percent of the LOH-low tumors had BRCAwt-HRR gene mutations, compared with 11% of the LOH-high tumors. Comprehensive genomic profiling revealed a subset of breast cancer patients with a BRCAwt-HRR gene mutation that would be missed by an LOH test. The necessity of next-generation sequencing coupled with HRR gene analysis for PARPi therapy requires further investigation in clinical trials.
Insights
Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) show promise in breast cancer treatment. Comprehensive genomic profiling, including homologous recombination repair (HRR) gene analysis, is crucial for identifying patients who may benefit from PARPi therapy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) are effective in homologous recombination deficiency (HRD) cancers, including FDA-approved treatments for germline BRCA1/2-mutation-associated breast cancer.
- PARPis also show efficacy in BRCA wild-type (BRCAwt) tumors with high genomic loss of heterozygosity (LOH-high).
Purpose of the Study:
- To retrospectively investigate tumor homologous recombination repair (HRR) gene mutations and loss of heterozygosity (LOH) scores in advanced-stage breast carcinomas (BCs).
- To evaluate the utility of comprehensive genomic profiling versus LOH testing for identifying patients eligible for PARPi therapy.
Main Methods:
- Retrospective analysis of tumor samples from 63 advanced-stage breast carcinoma patients.
- Assessment of homologous recombination repair (HRR) gene mutations and loss of heterozygosity (LOH) scores.
- Correlation of genomic findings with clinical phenotypes, including triple-negative status, histological grade, and tumor mutational burden (TMB).
Main Results:
- 25% of patients had HRR gene mutations (6% BRCA1/2, 19% non-BRCA).
- HRR gene mutations were associated with a triple-negative phenotype.
- 28% of patients had LOH-high scores, linked to high histological grade, triple-negative phenotype, and high TMB.
- One patient with a PALB2 mutation (non-BRCA) achieved a partial response to PARPi therapy.
- BRCAwt-HRR gene mutations were found in 22% of LOH-low tumors versus 11% of LOH-high tumors, indicating potential missed diagnoses by LOH testing alone.
Conclusions:
- A subset of breast cancer patients with BRCAwt-HRR gene mutations may be missed by LOH testing alone.
- Next-generation sequencing combined with HRR gene analysis is essential for comprehensive patient selection for PARPi therapy.
- Further clinical trials are needed to validate the necessity of comprehensive genomic profiling for PARPi treatment selection.
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