Immune Gene Signature as a Predictor of CDK4/6 Inhibitor Response in HR+/HER2– Breast Cancer

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Abstract

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are a standard treatment for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). However, reliable predictive biomarkers for treatment efficacy remain an unmet clinical need. Methods: A cohort of HR+/HER2– ABC patients (n=100) treated with CDK4/6i was characterized from both a clinical and molecular perspective. Pre-treatment tumor biopsies underwent transcriptomic profiling using the nCounter Breast 360™ panel. Gene set enrichment and pathway analyses were employed to identify differentially expressed genes (DEGs) and associated pathways across efficacy groups. Correlations between clinical, transcriptomic, and treatment outcomes were assessed using logistic and Cox regression models. The NeoPalAna dataset served as an external validation cohort. Results: A clinical stratification algorithm, integrating known determinants of CDK4/6i efficacy from pivotal trials, enabled the classification of patients into two balanced efficacy groups. Transcriptomic analysis revealed an overexpression of immune-related signatures in poor responders (14/18), notably the interferon-gamma (IFN-γ) signature, which remained independently associated with progression-free survival (PFS) in multivariate analyses. DEG analysis and unsupervised consensus clustering further delineated immune function as a key determinant of treatment response, accurately classifying 90% of first-line responders (19/21; p=0.004) based on immune gene expression. A refined transcriptomic analysis identified KIMA, a 9-gene immune signature, as significantly enriched in patients with poor responses across both first-line and later treatment lines (p=0.0048 and p=0.0022, respectively). Elevated KIMA expression was independently correlated with inferior PFS and overall survival (OS) in multivariate Cox regression analyses (p=0.033 and p=0.034). Receiver operating characteristic (ROC) curve analysis, as measured by the area under the curve (AUC), confirmed the superior predictive performance of KIMA compared to the predefined BC360™ immune signature. Finally, KIMA was validated in the NeoPalAna cohort of patients receiving neoadjuvant palbociclib (p=0.026). Conclusions: These findings highlight the pivotal role of the immune microenvironment in modulating CDK4/6i efficacy. The KIMA signature emerges as a novel and robust predictive biomarker, offering a refined tool for tailoring therapeutic strategies in HR+/HER2– breast cancer. Its integration into clinical decision-making frameworks could enhance patient stratification and optimize treatment outcomes.

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