Energy Balance-Related Factors and Direct Tumor-Adipocyte Contact in Colorectal Cancer: Etiology Insights from the Population-Based Netherlands Cohort Study

BACKGROUND: Stroma AReactive Invasion Front Areas (SARIFA) are a histopathologic biomarker characterized by a direct tumor-adipocyte interaction at the tumor invasion front. While the tumor promoting effect of tumor-adipocyte interactions has often been linked to obesity, it is unclear whether pre-diagnostic energy balance-related factors are differentially associated with the risk of SARIFA-positive versus SARIFA-negative colorectal cancers (CRC). METHODS: We analyzed data from the Netherlands Cohort Study, including 120,852 participants and 1,826 incident CRC cases with known SARIFA status. Multivariable-adjusted Cox regression was used to estimate associations between baseline pre-diagnostic BMI, lower-body clothing size as a proxy for waist circumference, and non-occupational physical activity and colon and rectal cancer risk by SARIFA status. RESULTS: In men, BMI was more strongly associated with risk of SARIFA-positive colon cancer (HR per 5 kg/m²: 1.57, 95%CI 1.20-2.07) than SARIFA-negative tumors (HR: 1.22, 95%CI 1.01-1.48), with similar patterns for lower-body clothing size. In women, weaker associations were observed but estimates were again higher for SARIFA-positive tumors than SARIFA-negative tumors. Physical activity was inversely associated with SARIFA-positive colon cancer in women (HR per 30 min/day: 0.92, 95%CI 0.85-1.01), but not SARIFA-negative tumors, with no clear SARIFA-specific patterns in men or for rectal cancer. CONCLUSIONS: Findings suggest a stronger role of body fatness in the development of SARIFA-positive than SARIFA-negative colon cancer, and provide novel evidence warranting confirmation in other molecular pathological epidemiology studies. IMPACT: This study extends previous epidemiological findings by suggesting that adiposity may influence colon cancer development, resulting in a specific tumor-stroma interaction phenotype.