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 assessed associations with outcomes. METHODS: RxPONDER enrolled 5,083 women with HR+/HER2- breast cancer, 1-3 positive nodes, and RS ≤ 25, randomized to endocrine therapy ± chemotherapy. 3,102 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 using multivariable Cox models adjusted for clinicopathologic factors and treatment. RESULTS: Among 3,102 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 = 0.003) and Hispanic (p = 0.02) had higher proliferation scores versus NHW women, while Asian women had higher HER2 (p = 0.006) and ER scores (p = 0.028). IDFS differences were not statistically significant for NHB vs. NHW women (HR 1.41; 95% CI 0.98-2.03), whereas Asian women had improved IDFS (HR 0.63; 95% CI 0.43-0.91). 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.