Risk stratification and age-related disparities with abemaciclib responses in early ER-positive/HER2-negative breast cancer.

Abstract

e12527 Background: Adjuvant abemaciclib improves outcomes in high-risk hormone receptor–positive, HER2-negative early breast cancer. However, the prognostic relevance of individual monarchE eligibility criteria and age-related differences in treatment decisions and outcomes remain poorly understood in real-world settings. Methods: We analyzed three complementary datasets: the SEER registry, the METABRIC genomic cohort, and a Japanese multi-institutional real-world cohort. Patients were classified using a four-tier system adapted from the monarchE trial (NCT03155997): Group 1, lymph node–negative; Group 2, 1–3 positive nodes with low grade and tumor size < 5 cm; Group 3, 1–3 positive nodes with high grade or tumor size ≥5 cm; and Group 4, ≥4 positive nodes. Molecular characteristics were evaluated in the METABRIC cohort using gene set variation analysis (GSVA). Patients were stratified by age into adolescent and young adult (AYA, 15–39 years), perimenopausal (40–54), menopausal (55–64), and older (≥65) groups. Disease-specific survival (DSS) was analyzed using Kaplan–Meier methods and Cox proportional hazards models, including interaction analyses between age and risk group. Results: The monarchE-based risk classification consistently stratified DSS in both SEER and METABRIC cohorts. Group3 patients exhibited significantly worse DSS compared with Group2 patients, underscoring than even within N1 disease, biological risk features strongly affect prognosis. In the METABRIC analysis, transcriptomic differences between groups reflected variations in proliferation-related and cell-cycle pathways, consistent with the pathological criteria of the monarchE trial. In the Japanese real-world cohort, abemaciclib initiation increased with nodal burden, 40% in Group 3 and 72% in Group 4, suggesting that treatment decisions were largely driven by nodal count rather than histologic or molecular features. Elderly patients were markedly less likely to receive abemaciclib, despite showing comparable or slightly inferior DSS relative to younger patients. Importantly, interaction analyses revealed no significant age-by-biology synergy, indicating that tumor aggressiveness is largely independent of age. The slightly inferior DSS observed in older patients appears not to be attributable to intrinsic tumor biology. AYA patients showed poorer outcomes compared to other age groups in Group 4. Conclusions: Our findings validate the prognostic relevance of the monarchE-based risk classification, demonstrating that high-risk N1 patients represent a clinically distinct subgroup. In addition, older patients were less likely to receive intensive therapy despite comparable disease aggressiveness, which may partly explain their inferior DSS. These results highlight the need for risk- and age-adapted treatment strategies in early-stage breast cancer.