Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness an...Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.展开更多
The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic dise...The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic disease,and about two-thirds of the latter will be defined as refractory to radioactive iodine(RAIR)treatment.Since this condition implies 10-year survival rates less than 10% after detection,using available treatments,such as systemic and targeted therapies,have become increasingly relevant.The initiation of these treatments aims to reach stabilization,tumor volume reduction,and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s features.Considering that despite enlarged progression-free survival was proven,multikinase inhibitors remain non-curative,their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction.In this context,molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy,progression free survival,overall survival and adverse events profile.This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC,including approved target therapies as well as those for off-label use,RAI resensitization agents,and immunotherapy.展开更多
基金supported by the Project on InterGovernmental International Scientific and Technological Innovation Cooperation in National Key Projects of Research and Development Plan (No. 2019YFE0106400)the National Natural Science Foundation of China (No. 81771875)。
文摘Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.
文摘The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma(DTC)has exponentially increased.Approximately 10%of patients with DTC exhibit recurrent or metastatic disease,and about two-thirds of the latter will be defined as refractory to radioactive iodine(RAIR)treatment.Since this condition implies 10-year survival rates less than 10% after detection,using available treatments,such as systemic and targeted therapies,have become increasingly relevant.The initiation of these treatments aims to reach stabilization,tumor volume reduction,and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient’s features.Considering that despite enlarged progression-free survival was proven,multikinase inhibitors remain non-curative,their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction.In this context,molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy,progression free survival,overall survival and adverse events profile.This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC,including approved target therapies as well as those for off-label use,RAI resensitization agents,and immunotherapy.
