Cancer-associated cachexia remains a primary focus of clinical research, with increasing attention on molecular targets such as Growth Differentiation Factor 15 (GDF-15). A recent Phase 2 trial showed that GDF-15 inhibition via ponsegromab improved body weight and physical activity, reinforcing its role as a key driver. While other targets are in development, evidence linking GDF-15 to muscle mass remains inconclusive, and gastric and colorectal cancers are underrepresented in these clinical studies. This landscape underscores the need to investigate the clinical implications of elevated GDF-15 levels across specific oncological populations.

To investigate associations between body composition, radiodensity, and adipose tissue glucose uptake (via PET/CT) with plasma GDF-15 levels in gastric and colorectal cancer patients.

This prospective study included patients with gastric/gastroesophageal junction (GEJ) adenocarcinoma (n=67; 42 analyzed for GDF-15) and colorectal cancer (n=46; 38 analyzed for GDF-15). Data were managed via REDCap. Preoperative serum was analyzed for GDF-15 using Luminex®. Body composition was assessed by CT; cachexia followed GLIM (gastric) or Fearon (colorectal) criteria. Statistical analysis in Jamovi 2.3 included Shapiro-Wilk, × 2, Student’s t/Mann-Whitney U, and Spearman’s rank correlation (p<0.05).

In the Gastric/GEJ cohort the median age was 63; 56.7% were male. Mean BMI was 24.5 (±5.05) kg/m²; however, cachexia (35.9%), sarcopenia (40.9%), and myosteatosis (39.4%) were prevalent. Cachectic patients had significantly higher GDF-15 (1028 ± 663 vs. 655 ± 293 pg/mL; p = 0.034). GDF-15 correlated with sarcopenia (rho=0.270, p=0.009), myosteatosis (rho=0.293, p=0.030), and negatively with skeletal muscle attenuation (rho=-0.451, p=0.003). No significant association was found with PET/CT glucose uptake (mean SUV) in visceral adipose tissue (VAT) (p=0.441), subcutaneous adipose tissue (SAT) (p=0.911), or muscle (p=0.072). In the Colorectal cohort the mean age was 62.5; 54.3% male. Mean BMI was 28.6 (± 5.1) kg/m²; cachexia (67.4%), myosteatosis (78.9%), and low muscularity (39.5%) were identified. GDF-15 levels did not differ by cachexia status (p=0.554) but were significantly higher in patients with weight loss (795 ± 400 vs. 404 ± 281pg/mL; p = 0.012). VAT area was significantly larger in patients with GDF-15 >1000 pg/mL (230 ± 35 vs. 136 ± 72, p = 0.017). No association was found with PET/CT uptake in VAT (p=0.774) or SAT (p=0.518).

GDF-15 was associated with cachexia and musculoskeletal impairment in gastric cancer, and with weight loss and visceral adiposity in colorectal cancer. The lack of correlation with PET/CT glucose uptake suggests GDF-15 influences tissue wasting independent of glucose metabolic alterations in these settings. These results highlight GDF-15 as a potential target for personalized therapeutic interventions in gastrointestinal oncology.