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May 29, 2026

Homologous recombination deficiency signature (HRDsig+) in older women with advanced breast cancer (ABC).

Key Points

This research aims to determine the frequency of homologous recombination deficiency signature (HRDsig+) in older women with advanced breast cancer (ABC).
Comprehensive genomic profiling was performed on 6,221 patients aged 65 and older with advanced breast cancer.
Assessment of genomic alterations included base substitutions, short insertions, deletions, and copy number variations.
HRDsig status was measured through large-scale copy number changes and DNA repair errors.
662 (10.6%) of 6,221 cases were HRDsig+, indicating significant genomic alterations associated with DNA repair.
HRDsig+ cases had higher rates of BRCA1 (13.7% vs 1.2%), BRCA2 (22.8% vs 1.1%), and RAD21 (25.1% vs 14.6%) alterations, all with p<.0001.
HRDsig+ showed a higher frequency of tumor mutation burden (TMB >10 mutations/Mb) at 12.7% compared to 9.3% in HRDsig- cases (p=0.015).

Abstract

1121 Background: The identification of homologous recombination deficiency (HRD) may expand targeted therapy options in the management of advanced breast cancer (ABC). However, the frequency of positive HRD signature (HRDsig+) status in older women with ABC is not widely known. We explored the prevalence of HRDsig+ status, and its co-occurrence with other genomic alterations (GAs). Methods: Comprehensive genomic profiling (CGP) was performed on 6,221 cases of patients ≥ 65 years old with ABC to assess GA including base substitutions, short insertions and deletions, copy number changes and rearrangements and fusions. Microsatellite instability (MSI) status, tumor mutation burden (TMB), genomic ancestry, and trinucleotide signature were determined from the sequencing data. HRDsig status, provided as a clinical service, was determined by measuring large scale copy number changes and DNA repair errors. Results: Of the 6,221 cases, 662 (10.6%) were HRDsig+. Compared to the HRDsig- cases, HRDsig+ cases more frequently had genomic alterations (GA) associated with DNA repair, including BRCA1 (13.7% vs 1.2%; p10 mutations/Mb (12.7% vs 9.3%; p=.015). HRDsig- ABC cases had more frequent PIK3CA GA (47.6% vs 20.4%; p10 mut/Mb 12.7% 9.3% 0.015 PD-L1 low positive (1-49%) 36.1% 30.1% NS BRCA1 13.7% 1.2% <.0001 BRCA2 22.8% 1.1% <.0001 ERBB2 6.0% 10.9% <.0001 ESR1 5.3% 11.0% <.0001 PIK3CA 20.4% 47.6% <.0001 TP53 73.1% 40.4% <.0001

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