Serum GDF15 as a potential biomarker for treatment response and survival in patients with resectable locally advanced gastric cancer undergoing neoadjuvant chemotherapy.

Background: Patients with locally advanced gastric cancer (LAGC) typically require neoadjuvant chemotherapy (NAC) to reduce tumor burden and improve surgical resectability. However, treatment responses to NAC vary substantially among individuals. This study investigated the potential value of baseline serum growth differentiation factor 15 (GDF15) for identifying patients at risk of poor treatment response and unfavorable survival outcomes among patients with LAGC receiving NAC. Methods: We retrospectively identified 318 eligible patients with LAGC who received NAC and enrolled 30 healthy controls. Serum GDF15 levels were measured by ELISA. In the unmatched cohort, the median baseline serum GDF15 concentration (2,147.3 pg/mL), determined before PSM, was used as a fixed cutoff to define the GDF15-L and GDF15-H groups (n = 159 each). After 1:1 PSM, 256 patients (n = 128 per group) were included in the matched analyses. Comparative analyses included baseline characteristics, CT images, preoperative endoscopic biopsy specimens and postoperative pathological features. Survival outcomes (OS and DFS) were assessed via Kaplan-Meier analysis. Multivariate Cox regression identified prognostic factors, and a prognostic nomogram was constructed. Results: High GDF15 expression correlated with advanced age (P = 0.045), poor tumor differentiation (P = 0.040), and elevated serum CA72-4 (P = 0.028). The GDF15-L group demonstrated superior median OS (58.1 vs. 54.0 months, P = 0.031) and DFS (47.1 vs. 26.9 months, P = 0.002) compared to GDF15-H counterparts. Preoperative endoscopic biopsy demonstrated a positive correlation between tissue GDF15 expression and serum GDF15 levels, while post-NAC imaging indicated greater tumor regression in the GDF15-L group. The GDF15-L group exhibited a higher pathological complete response (pCR) rate in postoperative pathological features (P < 0.001) while the GDF15-H group exhibited increased positive lymph nodes (P = 0.018) and a higher incidence of newly detected distant metastasis during or after NAC (P = 0.024). Multivariate analysis identified high GDF15 expression (P = 0.021) and high CAP degree (P = 0.022) as independent risk factors for OS, with younger age being protective (P = 0.016). Based on these factors, a prognostic nomogram was constructed to predict 1-year, 3-year, and 5-year OS and DFS. Conclusion: Low baseline serum GDF15 levels were associated with favorable radiological and pathological responses and prolonged survival in patients with LAGC receiving NAC. Baseline serum GDF15 may help identify patients at increased risk of poor response and unfavorable prognosis and may therefore serve as a potential biomarker for pretreatment risk stratification. However, because all patients received NAC, these findings do not establish that GDF15 predicts differential benefit from NAC, and prospective validation is required.