Recurrence Score gene group components and outcomes in the RxPONDER trial (SWOG S1007)

Background: The RxPONDER trial has guided adjuvant chemotherapy use in node-positive HR+/HER2– breast cancer; however, prior analyses showed poorer outcomes among non-Hispanic Black (NHB) women compared with non-Hispanic White (NHW) women despite similar 21-gene Recurrence Score (RS) results. This suggests contributors to disparities may not be captured by the composite RS. We evaluated RS gene group components—proliferation, estrogen receptor (ER), HER2 (GRB7), and invasion—by ethnicity, body mass index, and menopausal status, and we assessed associations with outcomes. Methods: RxPONDER enrolled 5083 women with HR+/HER2– breast cancer, 1-3 positive nodes, and RS ≤25, randomly assigned to endocrine therapy ± chemotherapy. In total, 3102 participants with ethnicity and gene expression data were included. RS components were compared across subgroups, and associations with invasive disease-free survival (IDFS) and distant recurrence-free interval were evaluated by using multivariable Cox models adjusted for clinicopathological factors and treatment. Results: Among 3102 women (70.2% NHW, 15.5% Hispanic, 9.5% Asian, 4.7% NHB), RS distributions were similar across groups and prognostic overall. Tumors from NHB (P-=-.003) and Hispanic women (P-=-.02) had higher proliferation scores vs NHW women, and Asian women had higher HER2 (P-=-.006) and ER scores (P-=-.028). IDFS differences were not statistically significant for NHB vs NHW women (hazard ratio [HR] = 1.41, 95% CI = 0.98 to 2.03), whereas Asian women had improved IDFS (HR = 0.63, 95% CI = 0.43 to 0.91). Conclusions: Despite similar overall RS distributions, component pathways vary by ethnicity and may contribute to outcome differences. These findings support evaluating gene-specific biology beyond composite scores to better understand disparities and refine risk stratification. Trial Registration: ClinicalTrials.gov: NCT01272037. © The Author(s) 2026. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/pages/standard-publication-reuse-rights)