Establishment And Application Of A Predictive Model For Gefitinib-Induced Severe Rash Based On Pharmacometabolomic Profiling And Polymorphisms Of Transporters In Non-Small Cell Lung Cancer
TRANSLATIONAL ONCOLOGY(2021)
摘要
Background: Rash is a well-known predictor of survival for patients with gefitinib therapy with non-small cell lung cancer (NSCLC). However, whether patients with more severe rash obtain the more survival benefits from gefitinib is still unknown, and predicted model for severe rash is needed.Methods: The relationship between gefitinib-induced rash and progression free survival (PFS) was primarily explored in the retrospective cohort. The association between rash and gefitinib/metabolites concentration and genetic polymorphisms were determined by pharmacometabolomic and pharmacogenomics methods in the exploratory cohort and validated in an external cohort.Results: The survival for patients with rash was significantly higher than that of patients without rash ( p = 0.0002, p = 0.0089), but no difference was found between grade 1/2 or grade 3/4. Only the concentration of gefitinib, but not its metabolites, was found to be associated with severe rash, and the cutoff value of gefitinib was 204.6 ng/mL conducted by ROC curve analysis (AUC= 0.685). A predictive model for severe rash was established: gefitinib concentration (OR = 11.523, 95% CI = 2.898-64.016, p = 0.0016), SLC22A8 rs4149179(CT vs CC, OR = 3.156, 95% CI = 0.958-11.164, p = 0.0629), SLC22A1 rs4709400(CG vs CC, OR = 10.267, 95% CI = 2.067-72.465, p = 0.0087; GG vs CC, OR = 5.103, 95% CI = 1.032-33.938, p = 0.061). This model was confirmed in the validation cohort with an excellent predictive ability (AUC = 0.749, 95% CI = 0.710-0.951).Conclusions: Our finding demonstrated that the incidence, not the severity, of gefitinib-induced rash predicted improved survival, the gefitinib concentration and polymorphisms of SLC22A8 and SLC22A1 were recommended to manage severe rash.
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关键词
Gefitinib, Pharmacometabolomic, Rash, Non-small cell lung cancer, Metabolites, Polymorphisms
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