Overweight BMI compromises survival and correlates with aggressive phenotypes in early-onset but not late-onset rectal cancer patients

Abstract Background The incidence of early-onset colorectal cancer (EOCRC) is rising globally, presenting unique clinical challenges due to its aggressive nature compared to late-onset cases. While obesity is a known risk factor for carcinogenesis, its prognostic significance specifically on the EOCRC population remains underexplored. We hypothesized that the association of metabolic dysregulation with tumor aggressiveness and survival may depend on the age of onset. Methods A total of 324 patients with stage II/III rectal cancer from the FOWARC trial were stratified by BMI (using the Asian overweight cut-off of 24 kg/m²) and age of onset (early-onset <50 years vs. late-onset ≥50 years). The clinicopathologic characteristics, treatment response, complications, and survival outcomes were compared. Results The prognostic profile was heterogeneous between patients with high and low BMI. Notably, age had opposing prognostic value in the two groups. In the early-onset subgroups, patients with high BMI exhibited more prevalent aggressive phenotypes, including T4 stage, MRF+, elevated tumor length/thickness, and pretreatment CEA. However, in the late-onset subgroups, those phenotypes were less in the patients with high BMI. For short-term outcome, the incidence of pathological complete response after neoadjuvant treatment and complications was similar between two groups. In the early-onset subgroups, the overall (P = 0.003) and disease-free (P = 0.001) survival outcomes were significantly worse in the patients with high BMI compared to those with low BMI. However, this difference was not observed in the late-onset subgroups. Conclusion The association of overweight and obesity with aggressive tumor phenotypes and poor survival outcomes is specifically observed in early-onset rectal cancer, which highlights the need for BMI-specific therapeutic strategies and weight management interventions in these vulnerable cases.