Body composition and lung cancer-associated cachexia in TRACERx

Abstract

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.

Figure 1. Body composition and cancer-specific survival in the TRACERx and BLCS studies.

A Study outline of body composition and downstream analyses. B Distribution of body composition and body mass metrics according to sex at primary diagnosis in the TRACERx cohort (N=651) and C BLCS cohort (N=420); vertical lines indicate mean in female (green) and male (blue) patients. D Lung cancer-specific survival in TRACERx and E BLCS cohorts for body composition at primary diagnosis according to sex-specific bottom 20th percentile (red, <20%), mid 60th percentile (grey, 20%-80%) and upper 20th percentiles (blue, >80%) of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and skeletal muscle (SKM). Hazard ratios and 95% confidence intervals (CI) derived from univariate Cox regression analysis of the <20% group and the 20-80% groups.

Figure 2. Survival outcomes according to changes in body composition between primary diagnosis and first relapse.

A Distribution of losses and gains of body composition and body weight in the TRACERx cohort between primary diagnosis and first tumour recurrence according to sex (N=188). B Dynamics of body composition (N=188) and body weight (N=232) between primary diagnosis (“Baseline”) and first recurrence (“Relapse”), with red lines indicating decrease/loss, blue lines indicating increase/gain, and grey line indicating no changes. C Subgroups of patients according to (co-)presence of SAT loss (defined as ≥20% between baseline and relapse), VAT loss (≥20%) and SKM loss (≥10%). Kaplan-Meier analysis of lung cancer-specific survival according to labelled subgroups.

Figure 3. Tumour genomic and transcriptomic profiles according to cancer cachexia and non-cachexia groups.

A Tumour differential gene expression between patients in the cachexia versus non-cachexia groups, adjusted for number of tumour regions, sex, and histology. B Overlap of differentially expressed genes between the cachexia group and candidate cachexia genes. C Hallmark gene set enrichment in the cachexia (red) versus non-cachexia groups (blue), adjusted for sex and histology. D GISTIC analysis of copy number alterations of cachexia (upper row) and non-cachexia groups (lower row). Y-axes indicate chromosomal positions (1-22), red plots indicate gains, blue plots indicate losses. X-axes indicate q-values. Most significant peaks are indicated on the right of each panel; regions with FDR q≤0.25 (vertical green line) are considered significant. GISTIC G-Scores are plotted on top of each panel.

Figure 4. Differential protein expression and associations between circulating GDF15, body composition and body weight changes, and cancer cachexia.

A Differential plasma proteome of patients in the non-cachexia versus cachexia groups. Red labels indicate significant differential protein expression after adjusting for multiplicity. B Differential plasma protein expression of putative cachexia mediators in the non-cachexia versus cachexia group. C Normalized plasma protein expression of GDF15 in the non-cachexia versus cachexia groups (two-sided Wilcoxon test). D Plasma GDF15 levels in patients at diagnosis (baseline) or first recurrence of NSCLC in the TRACERx cohort (two-sided Wilcoxon test). E Baseline and F recurrence GDF15 levels according to weight change category in the TRACERx cohort (two-sided Wilcoxon test, error bars indicate standard deviation). G-J Spearman correlation of recurrence GDF15 levels and loss/gain of body weight (N=62)(G), subcutaneous adipose tissue (SAT)(H), visceral adipose tissue (VAT) (I), and muscle (J)(N=61). KL Spearman correlation of baseline (K) and recurrence (L) GDF15 levels and GDF15 gene expression as transcripts per million (TPM). All Wilcoxon tests are two-sided and box plots represent lower quartile, median and upper quartile, whiskers extend to a maximum of 1.5 × IQR beyond the box. Points indicate individual data points. Grey shade areas represent 95% confidence intervals. Y-axes represent log10 scales.