Abstract P2-03-28: Immune-based gene expression signature determines clinical efficacy of CDK4/6i in HR+HER2- breast cancer

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have emerged as effective treatments for patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer and more recently in adjuvant setting. Trials in neoadjuvant scenario are ongoing. Dedicated research efforts have been undertaken to find predictive biomarkers of response or resistance to these therapies although no molecular biomarkers have reached the clinic so far. Methods. Here, we performed a single-center prospective study to provide insights into the clinical and tumor characteristics determining the efficacy of CDK4/6i in metastatic breast cancer (n=100). Gene expression in tumors was performed using nCounter Breast 360 (BC360TM) panel. Clinical and biological data were correlated using logistic cox regression analysis. Transcriptomic data from NeoPalAna trial (GSE93204) was used as a validation dataset. Results. Taking into account clinical characteristics determining CDK4/6i efficacy, we developed a clinical stratification algorithm that allowed the dichotomic classification of the cohort based on CDK4/6i efficacy. The two resulting efficacy groups were used to identify and characterize the molecular pathways involved in CDK4/6i efficacy through the standardized tissue-based transcriptomic analysis in pre-treatment biopsies. When considering expression signatures implemented into the BC360TM panel, we identified 19 that were differentially expressed, presenting a significant enrichment of overexpressed immune-related signatures in the bad efficacy group (13/19). Multivariate Cox survival analysis indicated that elevated expression levels of the Treg, IFNGamma, PD1 and TIS signatures were independently associated to PFS only in first-line patients, overall suggesting that immune function might be a key factor determining CDK4/6i efficacy. To further delineate the immunologic features determining CDK4/6i efficacy, we evaluated differences in single gene expression in first-line patients, resulting in the identification of a 14-gene group exhibiting at least a 50% significant expression difference between good and bad efficacy groups. Unsupervised consensus clustering, allowed us to further define a 9 immune-gene signature that successfully clustered together 90% of patients from the good efficacy group (19/21). Indeed, mean expression of the 9-gene signature was significantly different between good and bad efficacy groups, both considering first-line patients (p=0,004) or the entire cohort (p=0,003), being always upregulated in the bad efficacy patients. More importantly, multivariate Cox survival analysis indicated that elevated expression levels of the 9-gene signature were associated to poorer PFS and OS independent of treatment line (p=0,033 and p=0,034, respectively), improving predictive capacity compared to the BC360TM signatures. The predictive value of our 9-gene signatures was further confirmed using the data from NeoPalAna clinical trial, where a significant difference in the 9-gene signature expression was also observed between sensitive and resistant tumors (p=0.026). Conclusions: Our results identify a novel 9-gene immune-based signature that predicts CDK4/6i efficacy in breast cancer patients, with easy implementation in daily clinical practice. Overall, our data further strengths the key role of immune response as a valuable predictive factor for CDK4/6i efficacy in breast cancer. Citation Format: Eudald Felip, Sara Cabrero-De las Heras, Edurne Garcia-Vidal, Adrià Bernat-Peguera, Beatriz Cirauqui, Milana Bergamino, Vanessa Quiroga, Iris Teruel, Angelica Ferrando, Anna Pous, Assumpció López, Laia Boronat, Marga Romeu, Ricard Mesía, Pedro Luis Fernández, Bonaventura Clotet, Eva Riveira-Muñoz, Anna Martínez-Cardús, Ester Ballana, Mireia Margelí. Immune-based gene expression signature determines clinical efficacy of CDK4/6i in HR+HER2- breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-28.