Body composition and lung cancer-associated cachexia in TRACERx

Abstract

Cancer-associated cachexia (CAC) is a major determinant of morbidity and mortality in patients with non-small cell lung cancer (NSCLC). 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 possible biological processes and mediators that contribute to the development of CAC. Computed tomography-based (CT) body composition analysis of 651 patients in TRACERx suggested that patients with low skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, represented by the bottom 20 th percentile, had significantly shorter lung cancer-specific survival (LCSS) and overall survival (OS). This finding was validated in 420 patients in the independent Boston Lung Cancer Study. In a longitudinal subset of 272 patients in TRACERx who experienced disease relapse, loss of adipose tissue, skeletal muscle, or body weight in the interval between diagnosis and relapse, was significantly associated with shorter LCSS and OS. Patients with one or more features encompassing loss of adipose or muscle tissue, or BMI-adjusted weight loss according to specific thresholds were classified as having developed CAC and were found to have distinct tumour genomic and transcriptomic profiles compared with patients who did not develop such features at relapse. Primary NSCLCs from patients in the CAC group were characterised by enrichment of inflammatory signalling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumours included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3 . In an exploratory analysis of putative circulating cachexia mediators performed in a subset of 256 baseline and relapse plasma samples from TRACERx, proteomic analysis revealed a significant association between circulating GDF15 and loss of body weight, skeletal muscle, and adipose tissue at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy

“…Overall, these findings are consistent with prior reports that strongly associate muscle mass wasting with cancer outcomes . A recent study by the TRACERx consortium also observed that SM loss at follow-up is associated with worse OS in patients with early-stage NSCLC treated with surgery . These unfavorable outcomes were observed in association with poor prognostic syndromes, such as cancer cachexia and muscle wasting, associated with decreases in protein synthesis and increases in protein degradation.…”

“…These unfavorable outcomes were observed in association with poor prognostic syndromes, such as cancer cachexia and muscle wasting, associated with decreases in protein synthesis and increases in protein degradation. The TRACERx study reported that patients with early-stage NSCLC with cancer cachexia by BC profiling exhibit an increased expression of metalloproteinases, providing a possible mechanistic explanation for the processes contributing to tumor-induced SM wasting . These results underscore the importance of monitoring changes in SM mass as a prognostic factor for patients receiving systemic therapy for advanced NSCLC, particularly among male individuals.…”

Association between the Static and Dynamic Lung Function and CT-Derived Thoracic Skeletal Muscle Measurements–A Retrospective Analysis of a 12-Month Observational Follow-Up Pilot Study

“…There was also considerable variability in the exacerbation frequency per year within the study group, although an overall reduction in exacerbations compared to baseline was noted. Future studies could be improved by including a broader range of COPD traits, such as chronic bronchitis, phlegm production, static and dynamic hyperinflation [ 42 ], and inflammatory and genetic markers, as seen in lung cancer studies, which have been associated with cancer cachexia [ 69 ] and include muscle strength (leg or hand grip) and exercise capacity.…”

Assessment of lipolysis biomarkers in adipose tissue of patients with gastrointestinal cancer

“…Our study has some limitations, including the relatively small sample size and the type of adipose tissue analyzed (SAT); more comprehensive analyses should be performed also on visceral adipose tissue, known to be implicated in several metabolic alterations [ 1 ]. However, SAT is reliable for this type of investigation in humans [ 33 ], especially for studying metabolic alterations during cancer [ 6 , 7 , 10 ], and is easy to obtain without major complications.…”

“…During cancer, several metabolic alterations occur and lead to peripheral tissue abnormalities, mainly represented by muscle and adipose tissue atrophy [ 1 , 2 ]. Importantly, both loss of muscularity and adipose tissue have been shown to significantly impact clinical outcomes among cancer patients [ 3 , 4 ].…”