(P 148) ISOCITRATE DEHYDROGENASE MUTATIONS IN CHONDROSARCOMA: A META-ANALYSIS

Objective: 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. Researchers are exploring targeted therapies that could one day enhance chondrosarcoma treatment. One such target is the isocitrate dehydrogenase (IDH) gene, which has been implicated in the pathogenesis of other malignancies. 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 in chondrosarcoma.

Methods: Individual patient data (IPD) from 21 studies that examined IDH mutations in chondrosarcoma was collected. The data from these studies was added to an internal set of 21 patients at 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 IDH mutation status and five-year overall survival (OS).

Results: The final sample contained 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 significantly shorter five-year OS in univariate KM analysis when looking at both conventional and dedifferentiated chondrosarcoma. However, multivariate CPH models accounting for age, sex, tumor grade, and IDH status found that this effect was isolated to patients with dedifferentiated tumors. Patients with IDH mutant dedifferentiated tumors displayed significantly shorter five-year OS (HR: 1.99, p = 0.02) relative to patients with IDH WT dedifferentiated tumors. The primary predictor of five-year OS in the conventional chondrosarcoma cohort was tumor grade (HR: 2.72, p < 0.005), and this effect was amplified when high-grade and low-grade tumors were grouped (HR: 11.20, p = 0.02).

Conclusion: IDH mutations are relatively common in cartilage forming 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 OS. Literature has been somewhat mixed overall, with some studies suggesting that IDH mutation is correlated with poor survival and others finding no such effect. 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 does influence OS, but this effect may be isolated to patients with dedifferentiated tumors. When tumor grade was accounted for, there was no significant effect of IDH mutation status on OS in conventional chondrosarcoma. Further analysis is needed to investigate the role that IDH mutations play in the development of metastatic/locally recurrent disease.