Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality
in individuals with non-small cell lung cancer. Key features of CAC include alterations
in body composition and body weight. Here, we explore the association between body
composition and body weight with survival and delineate potential biological processes
and mediators that contribute to the development of CAC. Computed tomography-based
body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell
lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the
bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area
at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific
survival and overall survival. This finding was validated in 420 individuals in the
independent Boston Lung Cancer Study. Individuals classified as having developed CAC
according to one or more features at relapse encompassing loss of adipose or muscle
tissue, or body mass index-adjusted weight loss were found to have distinct tumor
genomic and transcriptomic profiles compared with individuals who did not develop
such features. Primary non-small cell lung cancers from individuals who developed
CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal
transitional pathways, and differentially expressed genes upregulated in these tumors
included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3.
In an exploratory proteomic analysis of circulating putative mediators of cachexia
performed in a subset of 110 individuals from TRACERx, a significant association between
circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was
identified at relapse, supporting the potential therapeutic relevance of targeting
GDF15 in the management of CAC.