Abstract PS3-10-21: Should genomic risk guide the use of adjuvant CDK4-6i in N0-N1 HR+ and HER2− early breast cancer?

Abstract Background: Systemic adjuvant treatment for hormone receptor-positive, HER2-negative (HR+,HER2−) breast cancer has been undergoing a major paradigm shift in recent years. On the one hand, multigene prognostic genomic assays (MPGA) have enabled improved selection of patients who are likely to benefit from chemotherapy (CT). On the other hand, the addition of CDK4-6 inhibitors (CDK4-6i) to endocrine therapy (ET) has demonstrated a significant improvement in invasive disease-free survival (iDFS) in high-risk patients, as shown in the MONARCH-E and NATALEE trial (median follow-up of 33.3 months in the last analysis). However, there is currently no standardized definition of high clinical risk (for instance, NATALEE trial included both node negative and positive patients), and correlation between clinicopathological features and genomic risk classification is not consistently observed. This lack of concordance introduces uncertainty regarding the clinical benefit of adding CDK4-6i to ET in this setting. Objectives: The aim of this study is to describe a population of patients with early-stage (N0-N1) HR+,HER2- breast cancer who underwent MPGA (either the Prosigna® or Oncotype DX®) and met the inclusion criteria of the NATALEE trial, with the aim of determining whether the addition of a CDK4-6i to ET provides a clinical benefit in this setting. Methods: This retrospective study included patients diagnosed with early-stage (N0-N1) HR+,HER2- breast cancer between 2014 and 2023 across two hospitals in Málaga, Spain (Hospital Virgen de la Victoria and Hospital Regional Universitario). Efficacy outcomes were iDFS, DDFS and OS. The statistical analysis was performed using the R software (R Core Team. (2019). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Version 3.6.1). Results: 1.508 patients had a genomic platform, of whom 367 met the Natalee inclusion criteria (254 and 113 in the low-intermediate and high risk subgroup, respectively). The most frequent subgroup in both the low-intermediate and high-risk groups according to Prosigna® was T2N0 with Ki67 ≥20% and grade 2 (n = 41 and n = 32, respectively). Regarding Oncotype DX®, the most common low-risk subgroup was T2N0 with Ki67 ≥20% and grade 2 (n = 22), while in the high-risk group, it was T2N1 (n = 13). Among the most relevant clinicopathological features, 14.2%, 53.1%, and 31.3% of patients presented with stage IB, IIA, and IIB disease, respectively; 44.6% had no nodal involvement, 46.3% received adjuvant chemotherapy, and 20% and 10.1% were classified as high risk according to the Prosigna® and Oncotype DX® assays, respectively. Of these high-risk patients, 85.6% and 97.3% received chemotherapy. With a median follow-up of 37.4 months, there were 30 iDFS events (8,2%). The 3-year iDFS rate was 94.9% (95% CI, 92% to 96.8%) in the overall population, 94.8% (95% CI, 91.1% to 97.1%) in the low/intermediate genomic risk subgroup, 95.2% (95% CI 88.8% to 98%) in the high genomic risk subgroup, 94.3% (95% CI 90.8% to 96.5%) in stage II disease, 94.1% in N0 (95% CI, 89% to 97%), and 95.6% (95% CI, 91.2% to 97.7%) in N1 disease. DDFS and OS events occurred in 11 (2.9%) and 12 patients (3.26%) respectively. 3-year OS rates were 98.7% (95% CI 96,7% to 99.5%) in the overall population, 98.2% (95% CI 95.3% to 99.3%) in the low/intermediate genomic risk subgroup and 98.6% (95% CI 90.4% to 99.8%) in the high genomic risk subgroup. Conclusions: Despite the size of our sample, these findings suggest that the use of adjuvant CDK4-6i in N0 or N1 HR+,HER2− breast cancer should be guided not only on clinicopathological features but also on genomic risk, due to the favourable outcomes in low-intermediate risk patients who received ET alone and high-risk patients treated with ET and CT. Therefore, prospective studies are needed to better validate this hypothesis. Citation Format: M. Iglesias Campos, J. Pascual López, A. Sánchez-Muñoz, N. Ribelles Entrena, M. J. Bermejo Pérez, A. Márquez Aragonés, B. Pajares Hachero, M. E. Domínguez Recio, A. Godoy Ortiz, B. Jiménez Rodríguez, F. Carabantes Ocón, T. Díaz Redondo, E. Villar Chamorro, P. Cantizani Maíllo, E. Alba Conejo. Should genomic risk guide the use of adjuvant CDK4-6i in N0-N1 HR+ and HER2− early breast cancer? 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 PS3-10-21.