# Circulating Inflammatory and Mitochondrial Biomarkers Associated with Cachexia in Advanced Non-Small Cell Lung Cancer

## TL;DR

This study identifies blood biomarkers linked to cachexia in advanced lung cancer patients, showing different patterns at early and later stages of the condition.

## Contribution

The study reveals distinct inflammatory and mitochondrial biomarker profiles associated with cachexia progression in non-small cell lung cancer.

## Key findings

- Early cachexia is linked to elevated GDF-15 and IL-15 levels in blood samples.
- Later-stage cachexia correlates with increased circulating mitochondrial DNA.
- Lower body mass index was observed in cachectic patients at both study timepoints.

## Abstract

Cancer-associated cachexia is a common and serious condition in patients with advanced lung cancer, leading to unintentional weight loss, muscle wasting, and poor quality of life. Currently, there are no reliable blood-based biomarkers to identify patients who are at risk of developing cachexia. In this study, we analyzed blood samples from patients with stage IV non-small cell lung cancer to determine whether inflammatory proteins and mitochondrial DNA levels in the blood were associated cachexia development and progression. We found that cachectic patients exhibit distinct changes in the blood biomarkers at different stages of the disease. Early cachexia is associated with higher levels of inflammatory proteins GDF-15 and IL-15, while cachexia later in the disease course was associated with increased circulating mitochondrial DNA. Larger studies are needed to confirm these results and assess their clinical utility.

Background: Cancer-associated cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and/or adipose tissue loss and affects approximately 40% of patients with non-small cell lung cancer (NSCLC). However, reliable circulating biomarkers for early detection and risk stratification remain undefined. Based on prior observations linking elevated circulating mitochondrial DNA (mtDNA) to cachexia, we hypothesized that mtDNA and inflammatory protein levels in plasma could predict cachexia onset and trajectories. Methods: We evaluated 27 patients with stage IV NSCLC enrolled in the SeroNet-CORALE cohort with plasma samples collected between 2020 and 2023. Forty biomarkers were quantified at two timepoints (T1 and T2) using a multiplexed MesoScale Discovery platform. Associations between log2-transformed biomarker levels and cachexia status were assessed using Firth’s penalized logistic regression. Results: Among 27 patients (65% female; mean age 65 ± 10 years; 89% adenocarcinoma histology), cachectic patients exhibited lower body mass index at both time points (T1: 21.0 ± 2.0 vs. 27.0 ± 7.0; T2: 21.8 ± 4.9 vs. 25.2 ± 4.9). 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), whereas IL-4 had a protective association (OR 0.09; 95% CI 0.00–0.66; p = 0.013). At T2, cachexia was associated with higher mtDNA levels (OR 2.13; 95% CI 1.07–7.69; p = 0.022) and lower levels of IL-15, IL12/IL23p40, and MDC. Conclusions: Distinct inflammatory and mitochondrial biomarkers tracked cachexia evolution in advanced NSCLC, with early GDF-15/IL-15 elevations and later increases in circulating mtDNA. Larger longitudinal studies are warranted to validate these findings and define their clinical relevance.