Abstract PS4-11-19: Investigating Genomic and Treatment Heterogeneity in HER2+ and Triple Negative Breast Cancers

Abstract Background: Black women have a higher incidence of aggressive breast cancer subtypes, including both HER2+ and triple negative breast cancers (TNBCs), and this increased incidence contributes to racial disparities in outcomes. Differences in tumor biology and treatment have been well-studied for estrogen receptor (ER) positive/ HER2- disease, but less attention has been given to the interplay of biologic and access differences in explaining racial differences in outcomes of HER2+ and TNBC. We hypothesized that differences in tumor biological features and treatment patterns among ER-negative cancers are important contributors to disparate outcomes. Methods: The Carolina Breast Cancer Study Phase 3 (diagnosed 2008-2013) included clinical and molecular data from 391 women with TNBC and 451 women with HER2+ breast cancer (305 HR+/HER2+, 144 HR-/HER2+; 2 missing HR status). For TNBC cases, days between diagnosis and first course therapy were abstracted from medical records. For HER2+ cases, receipt and time to receipt of trastuzumab were abstracted along with receipt of endocrine therapy (for HR+/HER2+ cases). RNA expression was assessed for a panel of 219 genes including PAM50 subtype, immune response, p53 status and proliferation on the NanoString platform. Within each clinical subtype (HER2+ or TNBC) we applied consensus clustering to identify de novo genomic subtypes. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between self-reported race, trastuzumab/endocrine therapy receipt in HER2+ cases only, and molecular subtypes using logistic and multinomial logistic regression. Differences in time to therapy were assessed by Wilcoxon tests. Separately in HER2+ cases and TNBCs, we used Cox regression to estimate unadjusted race-, treatment- and subtype-specific hazard ratios (HRs) and 95% CIs of recurrence over 10 years of follow up. Results: Among TNBCs, we observed substantial gene expression heterogeneity, including three subtypes: 1) one ‘Immunogenic’ type with high expression of immune genes, 2) one ‘Luminal/Androgen Receptor (LAR)’ with higher proportions of Luminal A/B tumors and higher expression of estrogen signaling genes, and 3) one ‘Basal-like (BL)’ group with higher expression of proliferation genes. Black women with TNBC were significantly less likely than non-Black women to present in the Immunogenic (39% vs 43%; OR= 0.67, 95% CI = 0.45 - 0.98) and LAR classes (20% vs 27%; OR = 0.57, 95% CI = 0.38 - 0.86) relative to the BL class, and had longer median time to first treatment (26 vs 18 days, p 0.001). However, there was no difference in risk of recurrence by race among TNBCs (HR = 1.06, 95% CI = 0.65, 1.73). In contrast, Black women with HER2+ disease had a significantly higher risk of recurrence than non-Black HER2+ women (HR = 1.79, 95% CI = 1.08, 2.98), with differences most pronounced among HR-/HER2+s (HR = 2.71, 95% CI = 1.08, 6.84). A similar proportion (89% Black vs. 88% non-Black) of HER2+ cases received guideline-concordant trastuzumab, with no association between race and trastuzumab receipt (OR = 1.16, 95% CI = 0.65 - 2.07) nor between race and time to trastuzumab receipt (Black women mean = 73 days vs non-Black mean= 61 days, p = 0.15). Likewise, 90% of both Black and non-Black HR+/HER2+ cases received endocrine therapy, with no association between race and endocrine receipt in this subgroup. Conclusions: Black women with HER2+ breast cancers experienced worse prognosis, despite similar guideline-concordant treatment receipt and treatment timeliness. Discontinuation of trastuzumab and other treatment differences and/or access issues merit further consideration to understand HER2+ disparities. We did not find evidence of racial disparities in outcomes among TNBCs, but TNBCs have meaningful biological heterogeneity in outcomes. Citation Format: S. C. Van Alsten, C. Clayhold, K. E. Reeder-Hayes, K. A. Hoadley, M. A. Troester. PS4-11-19: Investigating Genomic and Treatment Heterogeneity in HER2+ and Triple Negative Breast Cancers 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 PS4-11-19.