Chronic Inflammatory Comprehensive Signature Predicts Oxaliplatin and 5-Fluorouracil Benefit in Early Colorectal Cancer

Yue Peng,1,2 Rong Shang,1,2 Zhi-Jie Wang,1,2 Qiu-Ying Ye,3,4 Xiao-Yan Tang,1,2 Xue-Xin Cheng,1,2 Hou-Qun Ying1,4,5 1Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 3Department of Medical Technology, Jiangxi Medical College, Shangrao, Jiangxi, People’s Republic of China; 4Department of Laboratory Medicine, Central Hospital of Shangrao City, Shangrao, Jiangxi, People’s Republic of China; 5Shangrao Medical Center of The Second Affiliated Hospital of Nanchang University, Shangrao, Jiangxi, People’s Republic of ChinaCorrespondence: Hou-Qun Ying, Department of Clinical Laboratory, Immunity and Inflammation Key Laboratory of Jiangxi Province, The Second Affiliated Hospital of Nanchang University, No. 1 of Minde Road, Nanchang, 330006, People’s Republic of China, Tel/Fax +86 0791-86297662, Email [email protected]: Precision delivery of adjuvant chemotherapy (ACT) improves healthcare efficiency and postoperative quality of life in stage II–III colorectal cancer (CRC). However, there remains an unmet need for identifying biomarkers that can predict therapeutic responses to 5-fluorouracil (5-FU) and oxaliplatin.Methods: We analyzed three independent cohorts (1676 stage II–III surgical cases) to evaluate the prognostic role of 12 inflammatory indices. A novel Chronic Inflammatory Comprehensive Signature (CICS) was developed using multivariable Cox regression. Three-year recurrence-free survival (RFS) and overall survival (OS) were compared between CICS-stratified subgroups (CICS-L vs CICS-H) receiving 5-FU- or oxaliplatin-based ACT.Results: Two novel inflammatory ratios (FPSIIR, FPSIRIR) and six composite scores (FPSIIS, FPSIRIS, FPSIRS, FASIIS, FASIRS, FASIRIS) independently predicted prognosis across all three cohorts (all plog-rank< 0.05). The CICS demonstrated an AUC of 0.690 for outcome prediction, increasing to 0.724 when combined with CEA-CA19-9. CICS-H patients exhibited reduced chemosensitivity to both agents, with therapeutic benefits primarily confined to the CICS-L subgroup. Comparable favorable RFS was observed in stage II CICS-L patients undergoing 5-FU monotherapy or oxaliplatin-based ACT versus non-ACT treatments (97.73% vs 91.02% vs 91.46%, plog-rank=0.33). Superior survival outcomes and a lower recurrence rate were observed in stage II CICS-H patients receiving 5-FU compared to those receiving oxaliplatin-based ACT. Consistent oxaliplatin benefits were observed in CICS-H and CICS-L patients compared to 5-FU-treated cases in the stage III subgroup. Optimal ACT regimens for patients with CICS-L and CICS-H differ in different stages. The CICS strategy can help patients select a more optimal ACT regimen (RR=0.47, 95% CI=0.35– 0.62, p< 0.01) and enhance therapeutic efficacy (HR=0.70, 95% CI=0.53– 0.92 for RFS; HR=0.70, 95% CI=0.47– 0.97 for OS in stage III CRC).Conclusion: CICS-quantified cancer-derived inflammation inversely correlates with the therapeutic responsiveness to 5-FU/oxaliplatin. A CICS-guided strategy maximizes survival outcomes while precision-deescalating chemotherapy use without compromising outcomes, establishing a biomarker-driven paradigm for personalized postoperative management of CRC.Keywords: chronic inflammatory comprehensive signature, CEA-CA19-9-CICS score, oxaliplatin, 5-fluorouracil, colorectal cancer