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

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%; p<.0001), BRCA2 (22.8% vs 1.1%; p<.0001) and RAD21 (25.1% vs 14.6%; p<.0001). When compared to HRDsig- cases, HRDsig+ cases had more frequent PTEN GA (16.3% vs 9.9%; p<.0001) MTAP loss (5.6% vs 2.7%; p<.0001), and TMB >10 mutations/Mb (12.7% vs 9.3%; p=.015). HRDsig- ABC cases had more frequent PIK3CA GA (47.6% vs 20.4%; p<.0001), ERBB2 (10.9% vs 6.0%; p<.0001), ESR1 (11.0% vs 5.3%; p<.0001) and CDH1 (24.6% vs 6.5%; p<.0001). MSI-H status (0.3% vs 0.8%) and PD-L1 low 1-49% (36.1% vs 30.1%) were similar in both groups (NS). Conclusions: Among older adults with ABC, HRDsig+ status was identified in over 10% of patients undergoing CGP. Those with HRDSig+ more frequently had GAs in tumor suppressor genes involved in HRD, including TP53, BRCA1, BRCA2 , and RAD21. The association of HRDSig+ with high TMB could provide the rationale for future trials with combination of PARP inhibitors with immunotherapy. HRD signature status and associated genomic alterations in older women with advanced breast cancer. HRDsig positive(N=662) HRDsig negative(N=5559) P-value MSI-H 0.3% 0.8% NS TMB>10 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