IDH Mutations in Chondrosarcoma Correlate with Patient Survival in De-Differentiated but Not Conventional Subtypes

Background: Chondrosarcoma is the second most common bone tumor in adults with an average incidence of 0.1-0.3 individuals per 100,000 per year. These tumors are often resistant to chemotherapy and radiation, and surgical excision is a mainstay of current treatment. However, survival in the setting of metastatic disease is still poor, and research is needed to identify prognostic biomarkers and potential therapeutic targets. Several studies have examined the role of IDH mutations in chondrosarcoma, but the results vary widely. The goal of this analysis was to aggregate individual patient data from these studies and conduct a high-powered analysis of the impact of IDH mutations on survival outcomes in chondrosarcoma. Methods: Chondrosarcoma studies that included data on the IDH mutation status of tumors were queried, and the individual datasets reporting patient and tumor variables were extracted. The data from these studies were added to the internal dataset from the authors' home institution. Two-sample tests for equality of proportions were used to assess the distribution of sample characteristics between groups. Univariate Kaplan-Meier (KM) curves and multivariate Cox Proportional Hazards (CPH) models were used to assess the relationship between tumor IDH mutations and five and ten-year patient overall survival (OS). Results: The final cohort included 1152 patients sourced from 21 studies and the authors' internal dataset. IDH mutations were more common in higher grade tumors and were more likely to be found in individuals over 60 years old. Patients with IDH mutant tumors had shorter five-year OS in univariate KM analysis when analyzing all chondrosarcomas combined. However, multivariate CPH models accounting for age and tumor grade, found that the effect of IDH mutation was isolated to patients with dedifferentiated tumors only. Patients with IDH mutant dedifferentiated tumors displayed significantly shorter five-year OS (HR: 1.99, p = 0.02) relative to patients with IDH wild-type (WT) dedifferentiated tumors. The primary predictor of five-year OS in the conventional chondrosarcoma cohort was tumor grade, regardless of IDH mutation status (HR: 2.72, p < 0.005). Discussion: IDH mutations are relatively common in cartilaginous neoplasms (including benign tumors), with the literature reporting rates as high as 50% in chondrosarcomas. Prior studies have investigated the link between IDH1/2 mutation status, tumor grade and overall survival, with mixed results on the effect of IDH mutation on survival. Vuong et al. performed a meta-analysis in 2021 and found that IDH mutation was associated with older patient age, larger tumor size, higher tumor grade, and increased risk of death compared to WT tumors. Our analysis, which builds on the Vuong et al. study, indicates that IDH status itself is not independently predictive of overall survival in conventional chondrosarcoma, however, it does correlate with survival in dedifferentiated tumors. Further analysis is needed to investigate the potential correlation of IDH mutations in higher grade tumors and patients of older age.