P101 - Biomarkers for Predicting Therapeutic Response to Preoperative Chemoradiotherapy in Rectal Cancer

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Purpose/Background: Preoperative chemoradiotherapy (PCRT) is an essential treatment for locally advanced rectal cancer (LARC), aiming to downstage tumors and increase the likelihood of sphincter-preserving surgery. Despite its effectiveness, there is variability in patient response, making it crucial to identify predictive biomarkers. Recent studies suggest that molecular changes induced by PCRT may play a significant role in patient outcomes, but clinically relevant markers remain scarce. This study aims to investigate gene expression changes and develop predictive molecular signatures for PCRT response in LARC patients.

Methods/Interventions: Formalin-fixed paraffin-embedded (FFPE) tissue samples from 102 LARC patients treated with PCRT and subsequent surgery were collected. RNA was extracted, and gene expression was analyzed using the nCounter platform. The data were normalized and subjected to Gene Set Enrichment Analysis (GSEA) and Non-negative Matrix Factorization (NMF) analysis using 770 genes across 35 pathways. These analyses were aimed at identifying distinct molecular clusters. A Sankey plot was used to visualize associations between responder groups and identified clusters. The molecular signatures were validated using external datasets (GSE139255, TCGA-COADREAD), and predictive modeling was performed using Bayesian Compound Covariate Predictor (BCCP).

Results/Outcomes: Gene expression analysis revealed significant differences between Tumor Regression Grade (TRG) groups. Pathway enrichment analysis showed that immune response, DNA damage repair, and apoptosis pathways were more active in patients with complete and near-complete responses. NMF analysis of 770 genes identified two distinct molecular clusters, with most responders associated with the K2 cluster. The identified gene expression signatures were validated using external datasets, confirming their predictive accuracy. Key genes involved in immune activation, cell cycle regulation, and apoptosis were notably enriched in the responder group, suggesting these pathways as crucial determinants of favorable PCRT responses.

Conclusion/Discussion: This study identified molecular markers that can predict the response to preoperative chemoradiotherapy in LARC patients. Immune response, DNA damage repair, and apoptosis pathways were significantly more active in responders, indicating that these molecular processes play a key role in treatment success. These findings highlight the potential for personalized treatment strategies based on molecular profiles, suggesting new molecular targets to optimize PCRT outcomes in LARC patients.