Abstract
FOLFIRI (5-FU, leucovorin, irinotecan) is the first-line chemotherapy for metastatic colorectal cancer (mCRC), but response rates are under 50%. This study aimed to develop a predictive signature for FOLFIRI response in mCRC patients. Firstly, Spearman's rank correlation and Wilcoxon rank-sum test were used to select chemotherapy response genes and gene pairs, respectively. Then, an optimization procedure was used to determine the final signature. A predictive signature consisting of three gene pairs (3-GPS) was identified. In the training set, 3-GPS achieved an accuracy of 0.94. In a validation set of 60 samples, predicted responders had significantly better progression-free survival than the predicted non-responders (HR = 0.47, p = 0.01). A comparable result was observed in an additional validation set of 27 samples (HR = 0.06, p = 0.02). The co-expressed genes of the signature were enriched in pathways associated with the immunotherapy response, and they interacted extensively with FOLFIRI-related genes. Notably, the expression of signature genes significantly correlated with various immune cell types, including plasma cells and memory-resting CD4+ T cells. In conclusion, the REO-based signature effectively identifies mCRC patients likely to benefit from FOLFIRI. Furthermore, these signature genes may play a crucial role in the chemotherapy.