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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This work was supported by a grant from Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP; 15/22814-5). WN and CRRA received fellowships from FAPESP (16/20187-6, 19/17009-7; 14/03016-8; 16/01478-0). PCB was supported by a grant from Conselho Nacional de Pesquisa e Desenvolvimento (CNPq; 308071/2021-2). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human Research Ethics Committee at the University of Sao Paulo (CEP-FMUSP; protocol: 2.286.563) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript