A plasma proteomic signature of cancer-related sarcopenia implicates the IGFBP axis in muscle dysfunction

Cancer-related sarcopenia is associated with poor clinical outcomes but remains difficult to define and quantify in routine oncology practice. Current assessments rely on imaging and functional scales that are time-consuming and provide limited biological insight. We aimed to identify a plasma proteomic signature of cancer-related sarcopenia and to uncover circulating mediators involved in its pathophysiology.

Patients were included from two cohorts of the MATCH-R study (NCT02517892): a discovery cohort of advanced cancer patients treated with immunotherapy and an independent validation cohort of metastatic castration-resistant prostate cancer (mCRPC) patients treated with androgen-receptor pathway inhibitors. External validation was performed in the TRACERx cohort of non-small cell lung cancer. Skeletal muscle index at third lumbar vertebra (L3) was quantified using imaging, and ECOG performance status served as a functional proxy. Plasma proteomics was performed using the Olink Explore platform. An extreme gradient boosting (XGBoost) model was trained on a high-contrast subset using a neuromuscular-focused protein panel and validated across cohorts. Functional effects of candidate mediators were assessed in differentiating human myoblasts.

The model generated a continuous sarcopenia probability (SP) score that correlated with muscle mass and functional status and consistently stratified overall survival across cohorts. A reduced four-protein model retained comparable performance, supporting translational applicability. Proteins associated with SP included insulin-like growth factor binding protein 1 and 2 (IGFBP1, IGFBP2), and interleukin-6 (IL6). IGFBP1 and IGFBP2 impaired myoblast differentiation, while IL6 induced IGFBP1 expression in liver cells.

Plasma proteomics enables scalable and biologically informed assessment of cancer-related sarcopenia, identifies tumor-host mediators of muscle dysfunction, and supports objective patient stratification for therapeutic intervention.