Clinical and Tumor Characteristics of Patients with High Serum Levels of Growth Differentiation Factor 15 in Advanced Pancreatic Cancer

SIMPLE SUMMARY: Growth differentiation factor 15 (GDF-15) is a stress responsive cytokine that mediates food intake, energy consumption, and body weight. We aimed to evaluate whether circulating GDF-15 level could be associated with cachexia symptoms, which include loss of skeletal muscle mass, systemic inflammatory reaction, poor performance status, anorexia, shortened survival time and biological tumor activity in advanced pancreatic cancer (APC). The cut-off for serum GDF-15 was 3356.6 pg/mL, as the mean plus two standard deviations in patients with benign pancreatic disease. APC patients with high serum GDF-15 showed worsened performance, anorexia and elevations of inflammatory and tumor burden, signatures of cachexia, and activation of Akt and JNK in tumor GDF-15-producing pathways. This study identified tumor-driven GDF-15 as a potential cause of cachexia symptoms in APC. ABSTRACT: We aimed to evaluate the association of circulating growth differentiation factor 15 (GDF-15) with cachexia symptoms and the biological activity of advanced pancreatic cancer (APC). Treatment-naïve patients with liver metastasis of APC or with benign pancreatic disease were retrospectively analyzed. Clinical data, blood samples, and biopsy specimens of liver metastasis were collected prior to anti-cancer treatment. Serum GDF-15 levels and multiple protein expressions in lysates extracted from liver metastasis were measured by enzyme-linked immuno-sorbent assay and reverse-phase protein array, respectively. The cut-off for serum GDF-15 was determined as 3356.6 pg/mL, the mean plus two standard deviations for benign pancreatic disease. The high-GDF-15 group was characterized as showing low Karnofsky performance status (KPS) (p = 0.037), poor Eastern Cooperative Oncology Group performance status (ECOG-PS) (p = 0.049), severe appetite loss (p = 0.011), and high serum levels of carbohydrate antigen 19-9 (p = 0.019) and C-reactive protein (p = 0.009). Tumors of the high-GDF-15 group expressed high levels of phosphorylated (p)JNK (p = 0.007) and pAkt (p = 0.040). APC patients with high serum GDF-15 showed signatures of cachexia and activation of the signaling pathways involving Akt and JNK in the tumor. This study indicated circulating GDF-15 could be associated with cachectic symptoms in APC.