Circulating Growth Differentiation Factor 15 as a Biomarker in Patients with Unresected Locally Advanced Non-Small Cell Lung Cancer Treated with Chemo-Radiotherapy with or without Metformin

Abstract

Growth differentiation factor 15 (GDF15) is a member of the TGFβ family suggested to have prognostic value in cancer. Plasma GDF15 levels are elevated in humans during cellular stress, chronic diseases, and cancer and in response to cytotoxic (chemotherapy and radiation) or metabolic (metformin) therapies. Currently, the effect of combined metformin and cytotoxic treatment on circulating GDF15 is not known, and it is unclear whether GDF15 can serve as a biomarker in patients receiving such therapy. To examine this question, we analyzed circulating GDF15 levels in stage IIIA or IIIB NSCLC patients that participated in the randomized phase II clinical trial OCOG-ALMERA (NCT02115464). In OCOG-ALMERA patients were randomized to treatment with concurrent platinum-based chemotherapy and chest radiotherapy (60-66 Gy), with or without consolidation chemotherapy (CRT) or the same treatment plus metformin (2000mg/d). Dosimetric parameters and survival outcomes were collected by the trial. EDTA Plasma was collected from patients at baseline, 2 weeks into CRT treatment, at completion of CRT and 6 months after treatment initiation and assayed for GDF15 using an ELISA method. Statistical analyses were conducted to explore potential associations between plasma GDF15 with survival and dosimetric parameters. Fifteen patients from the metformin arm and 18 from the control arms provided EDTA plasma for this analysis. Average baseline GDF15 levels for all participants were elevated compared to those reported for healthy individuals. Baseline plasma GDF15 was statistically prognostic for RFS and OS (hazard ratio = 1.19, 95% CI = 1.06 to 1.34, p = 0.005). GDF15 levels increased during CRT treatment reaching the highest value at the end of cytotoxic therapy. Addition of metformin to CRT treatment was associated with further increase in circulating GDF15 (p<0.001). Plasma GDF15 levels at 2 weeks of CRT were positively correlated with size of the radiotherapy clinical target volume and volumes of esophagus and heart receiving high dose radiotherapy. This work suggests that GDF15 may be a promising prognostic marker to predict response to standard chemoradiation therapy in NSCLC. Future studies should aim to validate these results in larger datasets and examine whether GDF15 may have value as early biomarker of radiation toxicity in lung cancer patients.