GDF-15 levels and clinical correlates in head and neck cancer patients: Developing a risk model for cachexia.

Abstract

6099 Background: Cachexia is a challenging complication of cancer and its treatment, associated with an increased risk of death. Growth differentiation factor 15 (GDF15) is a known driver of cachexia in lung, pancreatic and colorectal cancer. However, we lack information about GDF15 role and temporal dynamics in patients with head and neck squamous cell carcinoma (HNSCC) receiving curative treatments. Here, we aimed to quantify circulating GDF15 in HNC patients and determine the relationship with indicators of cachexia and other prominent clinical correlates, namely oral mucositis (OM). Methods: Adults diagnosed with HNSCC, scheduled to receive definitive platinum based chemoradiotherapy (CRT), were recruited from four tertiary hospitals in Australia and Italy. Cachexia was determined using a variety of clinical parameters, including weight, grip strength, and upper arm circumference (UAC). OM was assessed using the World Health Organization (WHO) mucositis scale (grade 0-4). GDF15 was quantified in serially-collected serum using a commercial ELISA. All measures were assessed at baseline, week 3, end of treatment (EOT) and 3 months after treatment end. Results: Fifty-nine patients (pts) were enrolled, predominantly male (71%) with a mean age of 64+/-8 years. Main subsite of disease was oropharynx (44 cases, 75%), of whom 68% were HPV positive. Treatment was delivered with definitive intent in 90% of the cases. Median dose of RT was 70 Gy (66-70). At EOT, 77.3% of the pts met the diagnostic criteria for cachexia, with an average weight loss of 8.6% over the course of treatment. This was accompanied by a 7.7% and 5.6% average reduction in grip strength and UAC, respectively. Notably, these reductions continued beyond treatment cessation, with an average baseline weight loss of 9.8% after 3 months. Aligning with these outcomes, serum GDF15 levels were highly elevated following CRT compared to baseline (2.6 fold, P<0.0001), and correlated with reductions in weight (R 2 =0.168, P=0.0002), UAC (R 2 =0.1516, P<0.0001), grip strength (R 2 =0.1332, P<0.0001), as well as OM severity (R 2 =0.1013, P<0.0009). Conclusions: These data reveal that highly elevated GDF15 production correlates with OM and cachexia, providing strong clinical rationale to explore the biological basis of this new symptom cluster, as well as identifying a new clinical cohort that may benefit from GDF15 targeting agents.