Abstract PS2-08-07: Differences in Genomic Landscape Between Younger and Older Women with Advanced Breast Cancer

Abstract Background: Despite underrepresentation in clinical trials, the treatment of premenopausal breast cancer is extrapolated from trials focusing on postmenopausal women. The same benefit may not translate given differences in tumor biology, grade, and need for ovarian function suppression. In both younger and older breast cancer patients, there is a need to enhance our understanding of predictive biomarkers for response to targeted therapies. The goal of this study was to evaluate genomic differences between women <50 years of age compared to women >60 years of age with advanced breast cancer. Methods: FFPE blocks of 1,144 advanced breast cancer cases among women <50 and >60 were analyzed by hybrid capture-based comprehensive genomic profiling that evaluated broad types of genomic alterations (GA) including mutations, insertions/deletions, amplifications, homozygous deletions, rearrangements, and fusions. MSI-high (MSI-H) status, tumor mutational burden (TMB), and homologous recombination deficiency signature (HRDsig) were determined from sequencing data. PD-L1 CPS was determined by IHC (Ventana SP142 assay, % of immunocyte/inflammatory cell staining). GA were compared using Fisher’s exact test with the Benjamini-Hochberg multiplicity adjustment. Results: In hormone receptor positive (HR+) and triple negative breast cancer (TNBC) cohorts, non-European genomic ancestry was more prevalent in women <50 vs >60 (HR+ 38.87% vs 15.41% p = <0.001; TNBC 42.14% vs 22.73%, p = 0.004). In HR+ and TNBC cohorts, CDH1 GA were more frequent in those >60 than <50 (HR+ 22.41% vs 8.2% p = 0.002; TNBC 10.4% vs. 2.41% p = 0.09). In the HR+ group, ESR1 GA were more common in the >60 group vs <50 (18.64% vs 8.98% p = 0.06). In the TNBC group, PIK3CA GA were significantly more common in >60 than <50 (31.68% vs 10.84% p = 0.007). In HR+ cancer, PIK3CA GA were also more frequent in older women (>60 49.34% vs <50 36.33%, p = 0.1). BRCA1 and BRCA2 GA were more common in <50 vs >60 in the HR+ cohort (BRCA1 3.52% vs 0.56%, p = 0.07; BRCA2 9.38% vs 3.01% p = 0.03). In the TNBC group, BRCA1 GA were more common in <50 than >60 (15.66% vs 4.95% p = 0.06). HRDsig positivity was significantly more common <50 vs >60 (TNBC 45.68% vs 23.74% p = 0.002; HR+ 15.54% vs 6.24% p = 0.00036). Younger patients were more frequently PD-L1 positive compared to older patients (TNBC 73.39% vs 57.04%, p = 0.2; HR+ 40.14% vs 30.18% p = 0.1). TMB ≥ 10 mut/Mb was more common in women >60 vs < 50 (TNBC 11.68% vs 2.47% p = 0.002; HR+ 8.22% vs 4.15% p = 0.06). Conclusions: Older women were more likely to have targetable GA including ESR1, PIK3CA, and TMB ≥ 10 mut/Mb. Higher prevalence of ESR1 GA in older women may reflect longer history of endocrine therapy use. The prevalence of PIK3CA alterations in older women with TNBC demonstrates a potential area for therapeutic investigation. Younger women had a higher prevalence of BRCA1 and BRCA2 alterations, likely reflecting germline alterations and benefit of PARP inhibitors. Citation Format: N. Casasanta, E. S. Sokol, S. Rengarajan, L. Pusztai, J. S. Ross, M. B. Lustberg. Differences in Genomic Landscape Between Younger and Older Women with Advanced Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-08-07.