Background
A team from the Cancer Research UK Lung Cancer Centre of Excellence at University College London investigated the prognostic relevance and underlying molecular characteristics of cancer-associated cachexia (CAC) in patients with non-small cell lung cancer (NSCLC). CAC is a complex metabolic syndrome that is often seen in individuals with chronic illnesses such as cancer, and is characterized by progressive loss of skeletal muscle mass, along with significant weight loss etc. This study looked at the relationship of CAC-related physical characteristics with clinical outcomes, as well as undertaking a multiomics analysis of patients using RNAseq to investigate primary tumor tissue and the Olink® Explore 3072 platform for high-throughput protein biomarker discovery to measure plasma proteomics.
Outcome
Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study revealed that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of NSCLC diagnosis had significantly shorter lung cancer-specific survival and overall survival. This finding was also verified using available data from an independent patient cohort. RNAseq in primary NSCLC tumors from individuals who developed CAC showed that gene expression patterns were characterized by enrichment of inflammatory signaling and epithelial–mesenchymal transitional pathways. Differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3.
Exploratory plasma proteomics using Olink Explore in 274 patients revealed that in samples taken at the time of post-surgical disease relapse, 443 proteins had increased expression in patients with CAC. After extensive multiple testing, 12 of these proteins retained statistical significance, including GDF15, HSPA2, KIAA0319, TNFRSF10B and IL1RL1. Furthermore, there was a significant correlation between GDF15 levels in blood and the degree of loss of body composition/weight in relapsed patients, a key finding that was orthogonally verified in a subset of patients using a GDF15 ELISA. This finding could have significant clinical relevance and supports the potential therapeutic targeting of GDF15 in the future management of CAC.
