GDF-15 in oropharyngeal squamous cell carcinoma (OPSCC): Association of an HPV-dependent biomarker with malnutrition and low skeletal muscle.

6110 Background: GDF15 is a stress-response cytokine implicated in systemic inflammation and cancer-related wasting. We assessed whether baseline circulating GDF15 captures an HPV-stratified nutritional/body composition phenotype and whether longitudinal GDF15 changes relate to treatment outcome in OPSCC. Methods: We analyzed a prospective cohort of OPSCC patients (pts) undergoing curative intent treatment (CIT; surgery and radiotherapy RT-based) with available baseline plasma GDF15. HPV status was defined by dual detection (p16 INK4a and HPV DNA). Baseline nutritional status (Patient Generated Subjective Global Assessment), symptom burden (nutrition-impact composite score), body mass index (BMI), and CT-derived skeletal muscle index (SMI) were analyzed when available. Response assessment was performed 8-12 weeks after CIT, classifying cases as no evidence of disease (NED) vs evidence of disease (ED). Longitudinal GDF15 was analyzed using linear mixed-effects models (LMEN) (random intercept) including interactions of time with response status and induction chemotherapy. Results: We included 138 pts (HPVnegative − n=82; HPVpositive + n=56). Stage III–IV was more frequent in HPV- vs HPV+ (85.4% vs 30.4%; p<0.001) and ECOG 0 less common (9.8% vs 51.8%; p<0.0001). RT-based treatment predominated (85.5%) mainly chemoradiotherapy ± induction (82.6%). Baseline GDF15 was higher in HPV- vs HPV+ (median 1591 vs 803 pg/mL; p<0.001). HPV− pts showed worse nutritional phenotype: lower BMI (22.7 vs 27.2 kg /m²; p=0.001), more severe malnutrition (37.8% vs 7.1%; p<0.001), higher symptom burden (1.90±0.94 vs 1.39±0.71; p=0.002) and higher sarcopenia (34.1% vs 16.1%; p=0.029). In pts with CT body composition (n=89), SMI was lower in HPV− vs HPV+ (45.6 vs 53.6 cm²/m²; p=0.010). Baseline GDF15 differed by nutritional status (p=0.014) and was associated with symptom burden and SMI (both p<0.05). In LMEN, GDF15 increased significantly from baseline to end of treatment (β=2264 pg/mL; p<0.001). Baseline HPV positivity was independently associated with lower GDF15 (β=−980 pg/mL; p<0.001). At the end of treatment, NED was associated with lower GDF15 compared with ED (β=−1141 pg/mL; p=0.011). Induction chemotherapy showed no significant effect on GDF15 change (β=−448 pg/mL at end of treatment; p=0.22). No significant interaction between time and baseline HPV status was observed (p=0.26) indicating comparable longitudinal trajectories of GDF15 in HPV+ and HPV-pts. Conclusions: Baseline GDF15 is strongly HPV-dependent and reflects a multidimensional nutritional and muscle phenotype. GDF15 increases during CIT and lower end-of-treatment GDF15 is independently associated with NED, whereas induction chemotherapy does not significantly modify GDF15 change.