Circulating metabolites and physical performance are predictors of overall survival in metastatic lung cancer patients

Background: Skeletal muscle atrophy and low physical performance are associated with disease progression and higher mortality rates in multiple pathological conditions. Here, we determined whether body composition and physical performance would predict mortality in metastatic non-small cell lung cancer (NSCLC) patients. In addition, we defined whether plasma samples from NSCLC patients would directly affect the homeostasis of skeletal muscle cells. Methods: The prospective cohort included 55 metastatic NSCLC patients and seven age-matched control subjects. We assessed clinical characteristics, body composition, cancer cachexia, and quality of life (QoL). We determined physical performance with a series of functional tests. We analyzed skeletal muscle and adipose tissue areas. Finally, we evaluated the overall survival rate, and additional blood samples were collected from a subcohort of eighteen patients for further studies in cell culture and metabolomic analysis. Results: We found that physical performance, not body composition, was associated with overall survival in this cohort. Moreover, incubation with plasma derived from NSCLC patients with low physical performance impaired the metabolism and proliferation of primary human myotubes. Unbiased metabolomics revealed several metabolites differentially expressed in the plasma of NSCLC patients with low physical performance compared to healthy control subjects, with serine and N2,N2-dimethylguanosine (M22G) being the most reduced and increased metabolites, respectively. Conclusion: These novel findings confirm physical performance as a significant predictor of overall survival in metastatic NSCLC patients and provide insights into cancer-induced circulating factors that can directly affect skeletal muscle homeostasis and prognosis.