Prognostic impact of homologous recombination deficiency in advanced breast cancer treated with trastuzumab deruxtecan.

e13046 Background: Trastuzumab deruxtecan (T-DXd) has redefined the treatment paradigm of HER2-positive or HER2-low advanced breast cancer (ABC). While homologous recombination deficiency (HRD) is prevalent in up to 70% of triple-negative breast cancers and approximately 15% of hormone receptor-positive/HER2-negative cancers, its prevalence and prognostic significance in HER2-positive or HER2-low ABC treated with T-DXd remains unclear. Methods: Whole-genome sequencing (WGS) was conducted on tumor samples from 31 patients with HER2-positive or HER2-low ABC treated with T-DXd. HRD scores (range: 0–1) were calculated using a proprietary algorithm integrating HRD-associated genomic features, such as mutational signatures and copy number alterations. Tumors with an HRD score ≥0.7 were classified as HRD. Tumor samples were obtained before T-DXd treatment in 27 cases and during treatment in 4 cases. Results: Of the cohort, 18 (58%) had HER2-positive and 13 (42%) had HER2-low tumors, with 26 (81%) being hormone receptor-positive. The majority of patients (71%) received T-DXd in the fourth or later line of therapy. WGS was performed on primary tumors from 18 (58%) patients and metastatic tumors from 13 (42%) patients. HRD was identified in 5 (19%) patients. Of these, 3 (60%) were HER2-low, while homologous recombination-proficient tumors were predominantly HER2-positive (16/26, 62%). All hormone receptor-negative tumors (n = 5) were homologous recombination-proficient. HRD tumors were primarily basal (n = 1) or luminal B (n = 4) subtypes, while 13 (50%) of homologous recombination-proficient tumors were HER2-enriched, as determined by whole-transcriptome sequencing-based intrinsic subtyping. Patients with HRD tumors had significantly shorter progression-free survival compared to those with homologous recombination-proficient tumors (median PFS: 3.3 vs. 16.1 months; hazard ratio: 4.56; 95% CI: 1.45–14.36; P = 0.009). One HRD patient had a germline BRCA1 mutation, while a germline BRCA2 mutation was found in a patient with a homologous recombination-proficient tumor. Other HRD tumors harbored somatic mutations in BRCA1 (n = 1) and BRCA2 (n = 1) and disruptive structural variations (SVs) in BRCA1 (n = 1) and BRIP1 (n = 2). Somatic mutations or SVs involving BRCA2 (n = 2), PALB2 (n = 2), RAD51B (n = 5), and BRIP1 (n = 1) were also identified but were not associated with HRD. Conclusions: HRD is present in a subset of HER2-positive or HER2-low ABC and is associated with significantly worse outcomes following T-DXd treatment. This highlights the need for alternative therapeutic strategies for this vulnerable patient population, such as combining T-DXd with PARP inhibitors. Our findings suggest that HRD in these tumors is driven by complex genomic and epigenomic alterations, rather than a single-gene defects in homologous recombination repair.