Brain Neural Progenitors are New Predictive Biomarkers for Breast Cancer Hormonotherapy

Heterogeneity of the tumor microenvironment (TME) is one of the major causes of treatment resistance in breast cancer. Among TME components, nervous system role in clinical outcome has been underestimated. Identifying neuronal signatures associated with treatment response will help to characterize neuronal influence on tumor progression and identify new treatment targets. The search for hormonotherapy-predictive biomarkers was implemented by supervised machine learning (ML) analysis on merged transcriptomics datasets from public databases. ML-derived genes were investigated by pathway enrichment analysis, and potential gene signatures were curated by removing the variables that were not strictly nervous system specific. The predictive and prognostic abilities of the generated signatures were examined by Cox models, in the initial cohort and seven external cohorts. Generated signature performances were compared with 14 other published signatures, in both the initial and external cohorts. Underlying biological mechanisms were explored using deconvolution tools (CIBERSORTx and xCell). Our pipeline generated two nervous system-related signatures of 24 genes and 97 genes (NervSign24 and NervSign97). These signatures were prognostic and hormonotherapy-predictive, but not chemotherapy-predictive. When comparing their predictive performance with 14 published risk signatures in six hormonotherapy-treated cohorts, NervSign97 and NervSign24 were the two best performers. Pathway enrichment score and deconvolution analysis identified brain neural progenitor presence and perineural invasion as nervous system-related mechanisms positively associated with NervSign97 and poor clinical prognosis in hormonotherapy-treated patients. Transcriptomic profiling has identified two nervous system–related signatures that were validated in clinical samples as hormonotherapy-predictive signatures, meriting further exploration of neuronal component involvement in tumor progression. SIGNIFICANCE: The development of personalized and precision medicine is the future of cancer therapy. With only two gene expression signatures approved by FDA for breast cancer, we are in need of new ones that can reliably stratify patients for optimal treatment. This study provides two hormonotherapy-predictive and prognostic signatures that are related to nervous system in TME. It highlights tumor neuronal components as potential new targets for breast cancer therapy.