Clinicopathologic and Molecular Characterization of Colorectal Cancer in Patients Aged ≥80 years

Renjie Luo,1– 3,* Xiangchao Shi,1– 3,* Zimin Zhao,1– 3,* Xuan Lai,4,* Ziyue Zhang,1– 3 Junwei Wang,1– 3 Yao Ma,1– 3 Wei Fu,1– 3 Fan Zhang,4 Xin Zhou1– 3 1Department of General Surgery, Peking University Third Hospital, Beijing, People’s Republic of China; 2Peking University Third Hospital Cancer Center, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Collaborative Innovation in Gastrointestinal Oncology, Beijing, People’s Republic of China; 4Department of Geriatrics, Peking University Third Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fan Zhang, Department of Geriatrics, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, People’s Republic of China, Email [email protected] Xin Zhou, Department of General Surgery, Peking University Third Hospital, No. 49 North Garden Road, Haidian District, Beijing, 100191, People’s Republic of China, Email [email protected]: With rapid global aging, older colorectal cancer (CRC) patients are increasing, yet their clinical and molecular characteristics remain inadequately characterized. This comparative study systematically analyzed clinical and molecular characteristics of older CRC patients aged 60– 80 years and those aged ≥ 80 years to provide evidence for individualized treatment strategies.Methods: Older CRC patients who underwent radical surgery at Peking University Third Hospital from October 2015 to June 2023 were retrospectively included. Patients were categorized as older-age group (≥ 80 years, n=214) and younger-age group (≥ 60 and < 80 years, n=958). Clinicopathological characteristics and disease-free survival (DFS) were analyzed. Transcriptome sequencing and analysis was performed on 244 primary CRC tissues (53 older-age and 191 younger-age).Results: Among 1172 patients, the older-age group demonstrated distinctive clinical features: reduced chemotherapy receipt, elevated CEA levels, more right-sided tumors, more mucinous adenocarcinomas, larger tumor size, and higher mismatch repair deficiency (dMMR) prevalence (all P< 0.05). DFS was significantly shorter in the older-age group (P< 0.001), with age ≥ 80 years identified as an independent risk factor (HR=1.530, 95% CI: 1.022– 2.290, P=0.039). Transcriptomic analysis revealed unique biological characteristics in the older-age group: upregulation of neural regulation and extracellular matrix remodeling pathways, downregulated immune responses with increased M2 macrophage infiltration, and enrichment of CMS1 and CMS4 molecular subtypes.Conclusion: CRC patients aged ≥ 80 years exhibit higher dMMR rates and shorter DFS, with molecular features of immunosuppression, ECM remodeling, and enhanced neural-tumor interactions, challenging the assumption of slow CRC progression in very older patients. These findings provide basis for personalized treatment strategies in this underrepresented and growing population.Keywords: older patients, colorectal cancer, mismatch repair deficiency, geriatric oncology, prognosis