Pretreatment Serum GDF-15 and Features of Clinical Vulnerability in Advanced Pancreatic Ductal Adenocarcinoma

Background: This study aimed to define the clinical significance of pretreatment serum growth differentiation factor-15 (GDF-15), including its associations with clinical vulnerability, survival, and chemotherapy outcomes in advanced pancreatic ductal adenocarcinoma (PDAC). Methods: Pretreatment serum samples were prospectively collected from 80 patients with locally advanced or metastatic PDAC. GDF-15 was measured using an enzyme-linked immunosorbent assay and analyzed continuously and according to the cohort median. Associations with clinicopathological characteristics and overall survival (OS) were evaluated in the overall cohort. Treatment effectiveness, delivery, and safety were additionally assessed among 68 patients who received systemic chemotherapy. Results: The median GDF-15 concentration was 362.6 pg/mL. Higher GDF-15 was associated with poor performance status, involvement of multiple metastatic organ sites, an elevated neutrophil-to-lymphocyte ratio, and hypoalbuminemia. Eleven of the 12 patients unable to receive chemotherapy because of clinical deterioration had high GDF-15. The high GDF-15 group had shorter OS than the low GDF-15 group in the overall cohort (median, 6.1 vs. 13.9 months; hazard ratio [HR] = 1.96; 95% CI, 1.23–3.13; p = 0.002). The association between continuous GDF-15 and OS was attenuated and no longer statistically significant after multivariable adjustment (HR per doubling = 1.22; 95% CI, 0.97–1.52; p = 0.085). Among treated patients, progression-free survival and objective response did not differ significantly between groups, whereas high GDF-15 was associated with shorter OS (median, 8.7 vs. 14.2 months; HR = 1.72; 95% CI, 1.02–2.90; p = 0.025) and treatment duration (median, 3.2 vs. 6.3 months; p = 0.007). Relative dose intensity and subsequent treatment rates were similar. Febrile neutropenia occurred exclusively in the high GDF-15 group, which also accounted for four of five treatment-related deaths. Conclusions: Elevated pretreatment GDF-15 was associated with limited treatment fitness and inferior survival in patients with advanced PDAC, without clear evidence of intrinsic chemotherapy resistance. GDF-15 may represent a potential marker of systemic vulnerability in advanced PDAC, although its clinical utility requires external validation.