Abstract PS3-09-20: Not all pN1 ER-pos HER2-neg breast cancers are equal: why careful patient selection is key for adjuvant ribociclib

Abstract Introduction: For patients with high-risk ER-pos, HER2-neg breast cancer, adding abemaciclib (2 years) or ribociclib (3 years) to standard endocrine therapy improves invasive disease-free survival (IDFS). We hypothesize that not all patients who meet the eligibility criteria of the NATALEE trial will derive a clinically meaningful benefit from 3 years of adjuvant ribociclib. Previously, we demonstrated that patients with grade 3 pT2N0 tumors have a high risk of recurrence and might benefit from this additional treatment. Contrarily, patients with a pT0-2N1 tumor with more favorable tumor biology (grade 1-2), might have a low risk of recurrence irrespective of adjuvant treatment with a CDK4/6 inhibitor. The RxPONDER trial showed that 2497 patients with pN1, genomically low-risk tumors achieved a 94% 5-year distant disease-free survival (DDFS) with endocrine therapy alone. Here, we present real-world outcomes for patients with grade 1-2, pT0-2N1, ER-pos, HER2-neg tumors. Methods: We retrospectively reviewed the UZ Leuven-database of patients with early-stage ER-pos, HER2-neg breast cancer who underwent surgery between 2000 and 2023. All patients included met the NATALEE trial eligibility criteria for adjuvant ribociclib following local therapy. Eligibility (Cohort 1) was defined as stage III disease (AJCC 8th edition) or stage II including either pN1 or pT2-3N0 tumors with grade 3, or grade 2 tumors with Ki-67 >20% and/or a MammaPrint high-risk profile. We assessed both IDFS and DDFS in this NATALEE-eligible population and compared (Cohort 1) to a predefined lower-risk subgroup (Cohort 2), characterized as patients with stage II, pT0-2N1, grade 1 or 2 tumors (excluding pT1N1mi). Kaplan-Meier curves were used for the estimation of the DDFS and IDFS for both cohorts. Analyses have been performed using SPSS software. The 4-year outcome was chosen in accordance with the ESMO 2024 updated analysis of NATALEE with a 44.2 median follow-up. Results: We identified 3980 patients eligible for adjuvant ribociclib according to NATALEE-criteria (Cohort 1); 66,8% were stage II and 1357 of them met the lower-risk subgroup criteria (Cohort 2). Median age at diagnosis was 58 years for both cohorts and median follow-up time was 17,6 years for Cohort 1 and 18,8 years for Cohort 2. Analysis showed a 4-year IDFS for Cohort 1 of 87,6% as compared to 93,5% for patients for Cohort 2. DDFS was 86.4 % and 94.5% respectively. At 10 years of follow-up the absolute difference in DDFS increased to 9,9% (70,1% vs. 80,0%). Discussion: We found that lower-risk, NATALEE eligible patients, already have an encouraging 4-year IDFS and DDFS. These data emphasize the need for careful patient selection, to derive a clinically meaningful benefit, balancing efficacy against potential toxicity. Citation Format: B. Salaets, A. Deblander, L. De Sutter, K. Van Baelen, M. Van Houdt, N. Willers, T. Baert, A. Baten, F. Derouane, G. Floris, S. Han, H. Janssen, I. Nevelsteen, C. Remmerie, A. Smeets, J. Verhoeven, Y. Van Herck, C. Van Ongeval, C. Weltens, H. Wildiers, P. Neven. Not all pN1 ER-pos HER2-neg breast cancers are equal: why careful patient selection is key for adjuvant ribociclib [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 PS3-09-20.