Abstract PS2-07-14: Characterization of long-term responders to first-line CDK4/6 inhibitors in HR+/HER2- advanced breast cancer

Abstract Background: CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) have reshaped first-line treatment of HR+/HER2- metastatic breast cancer (MBC), achieving median progression-free survival (PFS) of 24-33 months in pivotal trials. However, real-world outcomes vary: while some progress early, others achieve long-term control. As triplet therapies and escalation strategies emerge, identifying predictors of prolonged benefit is key to refine patient selection. We aimed to characterize clinical, molecular and pathological factors associated with sustained benefit in this setting. Methods: We analyzed 166 patients (pts) with HR+/HER2- MBC treated with first-line CDK4/6i between March 2014 and April 2022 at Clinic Barcelona Comprehensive Cancer Center, with a minimum follow-up (FU) of 36 months. Clinical and molecular characteristics were compared between long-term responders (LR, defined as PFS ≥36 months) and non-long responders (nLR). Comparisons were performed using chi-square or Fisher’s exact tests. Survival was analyzed using the Kaplan-Meier method. Odds ratios (ORs) for factors associated with LR were estimated using univariate and multivariate logistic regression. Intrinsic subtype (IS) was determined at baseline using a research-based PAM50 assay in 123 pts. Gene expression data from the Breast Cancer 360™ nCounter panel were available for 119 pts. Statistical significance was set at p≤0.05. Results: Median FU was 60.5 months (95% CI: 54.0-67.43). Median PFS and overall survival (OS) for the cohort were 21.9 months (95% CI: 18.3-26.5) and 57.9 months (95% CI: 44.8-74.6), respectively. By data cutoff, 133 pts (80.1%) had progression and 87 (52.4%) had died. Of the total, 53 (31.9%) classified as LR. Most pts received ribociclib (104, 62.7%), followed by palbociclib (58, 34.9%) and abemaciclib (4, 2.4%), with no significant differences in CDK4/6i type between LR and nLR groups (p=0.626). IS distribution differed significantly (p=0.038): 32 (82.1%) of LR were luminal vs. 53 (63.1%) in nLR, and 7 (17.9%) vs. 31 (36.9%) were non-luminal. Specifically, Luminal A (LUMA) was more frequent in LR (51.3% vs. 31.0%, p=0.045), while HER2-enriched tumors were less frequent (5.1% vs. 19.0%, p=0.054). Endocrine-resistant tumors (defined as relapse during adjuvant ET or within 12 months after its completion) were less common in LR (p=0.009), and liver metastases were significantly less frequent in LR (7.6% vs. 38.9%, p<0.001). Higher progesterone receptor (PR) (>20%) was more common in LR (43.4% vs. 21.2%, p=0.005). In univariate analysis, endocrine resistance (OR 0.30, p=0.003), liver metastases (OR 0.13, p<0.001), PR >20% (OR 2.77, p=0.011), Luminal IS (OR 2.67, p=0.038), and LUMA (OR 2.35, p=0.031) were significantly associated with LR. In multivariate analysis including endocrine resistance, liver metastases, PR >20% and luminal IS, only liver metastases remained independently associated with a lower probability of being LR (OR 0.16, p=0.023). The remaining variables were not independently significant, likely reflecting overlapping biological information related to hormone sensitivity and luminal phenotype. Multivariate logistic regression models adjusted for endocrine resistance, liver metastases, PAM50 subtype, and PR >20%, identified multiple immune-related genes (including HLA-A, HLA-B, HLA-C, HLA-E, CD274, STAT1, CCL5, CXCL10, TAP1, PSMB10, and GZMA) independently associated with LR, highlighting the potential contribution of immune-related pathways to durable benefit from CDK4/6i. Conclusions: In HR+/HER2- MBC, long-term benefit from first-line CDK4/6i was associated with absence of liver metastasis, hormone-sensitivity, luminal features, and upregulation of immune-related genes, highlighting a potential role of the tumor immune microenvironment in durable response. Citation Format: I. Garcia-Fructuoso, O. Martínez-Sáez, M. Romero Vaquerano, R. Gómez-Bravo, F. Schettini, S. Cobo, E. Sanfeliu, B. Adamo, È. Seguí, B. Walbaum, M. González-Rodríguez, M. Bergamino, O. Castillo, P. Blasco, P. Galván, M. Muñoz, C. Núria, T. Pascual, M. Vidal Losada, A. Prat, F. Brasó-Maristany. Characterization of long-term responders to first-line CDK4/6 inhibitors in HR+/HER2- advanced 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 PS2-07-14.