Introduction: Cancer cachexia (CC) is a major contributor to morbidity and mortality in patients with non-small cell lung cancer (NSCLC). It is characterized by loss of skeletal muscle (SM) tissue with or without adipose tissue loss. This analysis reports on the characteristics and outcomes of patients recruited into the prospective TRACERx study, who presented with or subsequently developed features of CC during follow-up.

Approach: Using longitudinal CT imaging, total, subcutaneous and visceral adipose tissue (TAT, SAT, VAT) and SM volumes were manually quantified at the 3rd lumbar vertebrae level. Body weight was measured every 3-6 months and grouped according to BMI-adjusted weight loss grades. Multi-region primary tumour tissue was collected at the time of surgical resection and subjected to whole exome and RNA sequencing.

Results: Patients in the TRACERx 421 cohort who presented with low SAT volume at diagnosis, represented by the lower 20% percentile of the cohort, had significantly shorter lung-cancer specific survival (LCSS) and overall survival (OS) compared with patients in the 80% percentile (3-y LCSS 61% vs 81%, p<0.001; 3-y OS 57% vs 69%, p=0.02). Patients presenting with low VAT had a significantly shorter LCSS (3-y-LCSS 66% vs 79%, p=0.01), but not OS (3-y OS 60% vs 69%). Low SM volume was not associated with LCSS or OS. However, loss of SM volume of ≥20% between diagnosis and disease relapse was associated with significantly reduced LCSS and OS (3-y LCSS 30% vs 49%, p=0.02; 3-y OS 26% vs 45%, p=0.03). Based on a multivariable model, low SAT volume at diagnosis and SM loss were independent prognostic factors for LCSS, but not OS. In addition, BMI-adjusted weight loss was associated with shorter OS and LCSS (3-y OS 7% for patients with weight loss grade 4 vs 54% in patients with stable weight, p<0.001 [LCSS 8% vs 61%, p<0.001]). Preliminary genomic data from patients with disease recurrence and with (n=47) or without (n=107) features of CC, defined as SAT or muscle loss >20% or weight loss grade 4, demonstrated distinct copy number alteration and differential gene expression profiles.

Conclusion: In patients with early-stage NSCLC, both altered body composition and weight loss in keeping with CC was associated with poor survival outcomes. In particular, low SAT volume at diagnosis and loss of SM between diagnosis and relapse were independent prognostic factors for LCSS. Ongoing analyses in TRACERx will continue to investigate the potential tumour-intrinsic mediators of CC.

Citation Format: Othman Al-Sawaf, Marcin Skrzypski, Jakob Weiss, Takahiro Karasaki, Nicolai Juul Birkbak, Francisco Zambrana, Alexander Frankell, Thomas B. Watkins, Carlos Martinez Ruiz, Selvaraju Veeriah, Cristina Naceur-Lombardelli, TRACERx Consortium, Nicholas McGranahan, Hugo Aerts, Charles Swanton, Mariam Jamal-Hanjani. Features of cancer cachexia in non-small cell lung cancer: Insights from the prospective TRACERx study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5818.