Growth differentiation factor 15 (GDF15) predicts relapse free and overall survival in unresected Locally Advanced Non-Small Cell Lung Cancer treated with chemo- radiotherapy.

Abstract Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard-of-care concurrent chemoradiotherapy (cCRT). Methods: Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60-66Gy), with or without metformin (2000mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes. Results: Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively). Conclusions: GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets.