关键词: 免疫检查点抑制剂, 甲状腺毒症, 甲状腺功能减退症, 生物标记, 肿瘤, 生存分析, 代谢疾病, 真实世界研究

Abstract:

Objective To investigate the influencing factors of immune-related thyroid dysfunction （irTD） and its impact on survival prognosis in patients with advanced malignant tumors， and to analyze the regulatory role of metabolic factors. Methods A total of 70 patients with advanced tumors who received immunotherapy at the Third Affiliated Hospital of Kunming Medical University from January 1， 2018 to January 31， 2024 were selected as the study subjects. Based on the occurrence of thyroid dysfunction after immune checkpoint inhibitors （ICIs） treatment， patients were divided into the irTD group （n=53） and the non-irTD group （n=17）. The relevant indicators of the patients in the irTD group before and after immunotherapy were compared. Receiver operator characteristic （ROC） curves were plotted to evaluate the predictive efficacy of each indicator for irTD in advanced tumor patients after ICIs treatment. Multivariate logistic regression was used to identify the risk factors for irTD in tumor patients after ICIs treatment. Kaplan-Meier survival curves were plotted for survival analysis， and the log-rank test was performed. A stratified Cox proportional hazards regression model was used to evaluate the influencing factors of prognosis in patients with advanced tumors. Results In tumor patients with irTD， serum levels before and after immunotherapy were as follows： thyroid-stimulating hormone （TSH） was 3.24 （2.16， 4.01） and 12.20 （0.03， 73.55） μIU/ml； thyroglobulin antibody （TGAb） was 19.87 （12.82， 216.00） and 29.47 （15.92， 436.80） IU/ml； thyroid peroxidase antibody （TPOAb） was 4.04 （2.00， 130.43） and 42.28 （2.00， 400.00） IU/ml； and thyroglobulin （TG） was 5.67 （1.48， 17.81） and 22.80 （2.55， 52.15） ng/ml， with statistically significant differences （Z=4.36， P<0.001； Z=4.81， P<0.001； Z=4.64， P<0.001； Z=4.30， P<0.001）. ROC curve analysis showed that baseline TSH， TGAb， TPOAb， and suppressor T （Ts） cell levels had areas under the curve （AUCs） for predicting irTD after immunotherapy of 0.663， 0.704， 0.737， and 0.691， respectively， but pairwise comparisons revealed no significant differences in predictive efficacy （all P>0.05）. Multivariate analysis identified TSH≥1.87 μIU/ml （OR=4.12， 95%CI： 1.10-15.46， P=0.036） and baseline antibody positivity （OR=10.68， 95%CI： 1.21-94.43， P=0.033） as independent risk factors for irTD after immunotherapy in tumor patients. Survival analysis showed that the median overall survival （mOS） was 29 months in the irTD group and 22 months in the non-irTD group， with 1-year overall survival （OS） rates of 88.5% and 76.0%， respectively， with a statistically significant difference （χ²=4.85， P=0.028）. The subgroup analysis showed that in patients aged ≥65 years， receiving first-line therapy， with comorbid hyperlipidemia， without hyperuricemia， without diabetes， without combined surgery， with combined targeted therapy， with C-reactive protein-albumin-lymphocyte score ≤3， body mass index （BMI）<18.5 kg/m² or 18.5 kg/m²≤BMI<24 kg/m²， the mOS in the irTD group was significantly longer than that in the non-irTD group （all P<0.05）. The mOS for patients with lung adenocarcinoma， lung squamous cell carcinoma， small cell lung cancer， and other histological subtypes in the irTD group was 43， 29， 18， and 15 months， respectively， with a statistically significant difference （χ²=8.67， P=0.034）. However， pairwise comparisons showed that there were no statistically significant differences after Bonferroni correction （all adjusted P>0.008 3）. Multivariate analysis revealed that among all patients receiving ICI treatment， sex （HR=0.39， 95%CI： 0.18-0.84， P=0.016）， treatment line （HR=0.33， 95%CI： 0.13-0.85， P=0.021）， occurrence of irTD （HR=0.43， 95%CI： 0.19-0.95， P=0.037）， and surgery （HR=4.38， 95%CI： 1.26-10.55， P=0.017） were all independent influencing factors for OS. Among patients who developed irTD， further subgroup analysis stratified by TSH level showed that all Eastern Cooperative Oncology Group performance status score （HR=0.19， 95%CI： 0.05-0.83， P=0.027）， BMI grade （HR=0.54， 95%CI： 0.29-0.98， P=0.043）， and TSH>100 μIU/ml （HR=0.04， 95%CI： 0.00-0.60， P=0.021） were independent influencing factors for OS in this population. Conclusions Baseline TSH≥1.87 μIU/ml and elevated thyroid autoantibodies are independent predictors of irTD in patients with advanced tumors. The occurrence of irTD is associated with prolonged mOS， and this survival benefit persists in patients with comorbid hyperlipidemia， as well as in those without hyperuricemia or diabetes， suggesting that metabolic status may influence the prognostic value of irTD. Among patients with irTD， TSH>100 μIU/ml is an independent protective factor for OS.

Key words: Immune checkpoint inhibitors, Thyrotoxicosis, Hypothyroidism, Biomarkers, tumor, Survival analysis, Metabolic diseases, Real-world study