Guinter MA, Gapstur SM, McCullough ML, et al. - Given colorectal cancer (CRC) etiology may be influenced by energy balance-associated factors such as body mass index (BMI), diet, and physical activity, via inter-connected metabolic pathways, but there is less clarity regarding their combined impact, so, researchers undertook this study wherein they derived three energy balance scores, applying reduced rank regression, that link lifestyle factors with combinations of pre-diagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A1c (HbA1c) in participants (n = 2,498) in the Cancer Prevention Study-II Nutrition Cohort. They determined links of each score with CRC incidence and by tumor molecular phenotypes, applying Cox proportional hazards regression. BMI, physical activity, screen time, and 14 food groups were incorporated into the derived scores, and these scores explained 5.1 to 10.5% of the variation in biomarkers. The hazard ratio and 95% confidence interval for quartile 4 vs 1 of the HbA1c + C-peptide-based score and CRC was estimated to be 1.30 (1.15, 1.47), the hsCRP-based score was 1.35 (1.19, 1.53), and the hsCRP, C-peptide, and HbA1c-based score was estimated to be 1.35 (1.19, 1.52). Overall, the findings lend further support to the hypotheses that part of the link between many energy balance-related modifiable factors and CRC risk is mediated by systemic biomarkers of metabolic health—inflammation and abnormal glucose homeostasis.