A health-system-scale, episode-resolved multimodal atlas of cancer cachexia

Cancer cachexia is a wasting syndrome with outsized impact on morbidity and mortality, yet its drivers and systemic consequences remain poorly defined. In this study, we repurposed longitudinal clinicogenomic data from 52,236 patients with cancer profiled by MSK-IMPACT (2010-2024) at Memorial Sloan Kettering Cancer Center to define episode-resolved trajectories of consensus-defined cachectic weight loss and linked these events to outcomes, serology and tumor genotypes. Cachectic episodes clustered near periods of disease progression and were associated with inferior outcomes in nearly all cancer types. Across diverse malignancies, cachectic weight loss episodes exhibited a consistent serologic signature characterized by lower albumin and hemoglobin and higher levels of liver enzymes. Numerous somatic tumor genotypes, including TP53 mutation across several diseases, were also associated with more frequent onset of cachectic episodes. Motivated by these observations, we developed a multivariate model to predict impending risk of cachectic weight loss in patients with lung, colorectal and prostate cancer, validated in an independent, external cohort from Dana-Farber Cancer Institute (n = 5,785). Routine clinicogenomic data are, therefore, a scalable resource for discovery in cancer cachexia.