Dynamic inflammatory biomarkers are associated with cancer cachexia in a prospective lung cancer cohort

Background: Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle loss that affects approximately 40-50% of patients with non-small cell lung cancer (NSCLC)Despite its clinical impact, reliable biomarkers for early detection and risk stratification remain poorly defined. Methods: In this prospective longitudinal study,we conducted an analysis of 27 patients with stage IV NSCLC from the SeroNet-CORALE cohort with at least two plasma samples collected between 2020-2023. Cachexia was defined according to international consensus criteria (weight loss >5% or >2% with BMI<20 kg/m2 over 6 months). We quantified 40 biomarkers using MesoScale Discovery platforms, including inflammatory cytokines, chemokines, metabolic hormones, angiogenic factors, and mitochondrial DNA. Firth penalized logistic regression models were used to evaluate associations between log2-transformed biomarker levels and cachexia status, with adjustment for age, sex, race, and treatment exposures. Results: We enrolled lung cancer patients (65% female, mean age 65±10 years) with predominantly adenocarcinoma histology (89 percent), and the proportion classified as cachectic was 22 percent at diagnosis and 20 percent and 19 percent at the subsequent timepoints. Cachectic patients showed consistently lower BMI (21.0±2.0 vs 27.0±7.0 at T1; 21.8±4.9 vs 25.2±4.9 at T2). At T1, cachexia was strongly associated with elevated GDF15 (OR: 4.29, 95% CI: 1.04-29.74, p=0.044) and IL-15 (OR: 43.83, 95% CI: 2.39->999, p=0.007), while IL-4 demonstrated protective effects (OR: 0.09, 95% CI: 0.00-0.66, p=0.013). By T2, the biomarker profile had shifted, with significant associations emerging for elevated mtDNA (OR: 2.13, 95% CI: 1.07-7.69, p=0.022) and reduced levels of IL-5 (OR: 0.17, p=0.011), IL12/IL23p40 (OR: 0.44, p=0.010), and MDC (OR: 0.26, p=0.006). Longitudinal analysis revealed that baseline inflammatory biomarkers were associated with future cachexia risk. Elevated MCP-1 at baseline showed a strong, though non-significant, trend toward association with increased odds of cachexia at the 6-month follow-up (OR: 3.72, 95% CI: 0.91-42.70, p=0.070). In contrast, higher levels of MDC (OR: 0.19, 95% CI: 0.02-0.77, p=0.016) and TARC (OR: 0.28, 95% CI: 0.04-0.96, p=0.041) at baseline were significantly associated with reduced odds of cachexia at the subsequent timepoint. Conclusion: This exploratory study reveals temporal variations in inflammatory profiles associated with cancer cachexia. While requiring validation in larger cohorts, the distinct biomarker patterns at different timepoints suggest cachexia biology may evolve from initial cytokine activation to later-stage mitochondrial and immune dysregulation. The association between baseline biomarkers and future cachexia development warrants cautious interpretation but may inform future research directions.