Baseline serum cortisol as a prognostic biomarker for immune checkpoint inhibitor therapy in advanced gastric cancer

Background Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced gastric cancer (AGC), but only a subset of patients benefit. Validated prognostic biomarkers for ICI efficacy in AGC remain limited, and the role of endogenous cortisol—an immunosuppressive steroid hormone—in modulating ICI response is unclear. Methods This single-center retrospective study enrolled 134 AGC patients who received anti-PD-1 antibody therapy at the Fourth Hospital of Hebei Medical University between January 2019 and September 2023. Baseline serum cortisol and adrenocorticotropic hormone (ACTH) levels were measured via electrochemiluminescence immunoassay. Patients were stratified into low- and high-cortisol groups using a cutoff of 193.95 nmol/L. The primary/secondary endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR); disease control rate (DCR) was also analyzed. Survival analyses were performed using Kaplan-Meier curves (log-rank test) and Cox proportional hazards models. Results The entire cohort had a median PFS of 7.0 months (95% CI: 5.44–8.63) and median OS of 14.5 months (95% CI: 13.59–15.34), with an ORR of 15.7% (95% CI: 9.4–21.9%) and DCR of 79.1% (95% CI: 72.1–86.1%). Baseline serum cortisol showed an AUC of 0.673 (95% CI: 0.58–0.77) for OS prediction with a cutoff of 193.95 nmol/L, while ACTH had an AUC of 0.561 (95% CI: 0.46–0.66) at 25.09 pg/mL. Compared with the high-cortisol group, the low-cortisol group had a significantly higher DCR (93.9% vs. 74.3%, P = 0.016), longer median PFS (10.3 vs. 5.7 months, P = 0.047), and longer median OS (17.4 vs. 13.4 months, P = 0.014). Multivariate analysis confirmed high baseline cortisol as an independent prognostic factor for poorer OS (HR=2.03, 95% CI: 1.20–4.00, P = 0.035) and showed a trend toward significance for shorter PFS (HR=1.64, 95% CI: 1.00–2.69, P = 0.050). In subgroup analysis of 112 microsatellite stability (MSS)/microsatellite instability-low (MSI-L) patients, high cortisol remained independently associated with shorter PFS (HR=1.77, 95% CI: 1.02–3.06, P = 0.042). Conclusions Baseline serum cortisol levels are significantly associated with ICI efficacy in AGC patients, with high baseline cortisol correlating with poorer DCR, PFS, and OS. This study identifies baseline serum cortisol as a promising prognostic biomarker for ICI response in AGC, supporting further exploration of stress hormone signaling in immunotherapy optimization.