Prognostic importance of IDH mutations in chondrosarcoma: An individual patient data meta‐analysis

Abstract

Introduction IDH1/2 mutations are prevalent in cartilaginous tumors including chondrosarcoma. This meta‐analysis using individual patient data (IPD) aimed to investigate the clinical and prognostic association of these mutations in chondrosarcoma patients. Methods Two electronic databases including PubMed and Web of Science were searched for relevant data. We included studies providing IPD of chondrosarcoma with available IDH1/2 mutational status for meta‐analysis. Chi‐square and t‐test were performed to compare the groups with and without IDH1/2 mutations. For survival analysis, log‐rank test, and Cox proportional hazards model were used to investigate the association of IDH mutations with patient outcomes. Results Fourteen studies with 488 patients were analyzed. IDH1 and IDH2 mutations were detected in 38.7% and 12.1% of cases, respectively. IDH1/2 mutations were significantly associated with an older age (p = 0.003), tumor origins (p < 0.001), tumor grades (p < 0.001), larger diameter (p = 0.003), relapse (p = 0.014), and patient mortality (p = 0.04). Multivariate Cox regression analysis adjusted for age, gender, tumor grade, and tumor sites confirmed the negative impact of IDH1/2 mutations on patient overall survival (HR = 1.90; 95% CI = 1.06–3.42; p = 0.03). Conclusion Our meta‐analysis demonstrated the distinct characteristics of IDH1/2‐mutated chondrosarcomas in comparison to those without mutations. These mutations could serve as an independent prognostic biomarker to better prognosticate patient outcomes and design appropriate treatment plans.

Clinical usefulness of 2-hydroxyglutarate as a biomarker in IDH-mutant chondrosarcoma

“…Although 2-HG is produced only in mutant IDH, there is conflicting evidence between IDH mutation status and prognosis in chondrosarcoma [5] , [17] , [25] , [26] . Since the prognosis of chondrosarcoma in our cohort was significantly worse in the IDH mutant group (IDH1/2 Mut vs. IDH Wt, P = 0.006; IDH1 Mut vs. IDH Wt, P = 0.030; IDH2 Mut vs. IDH Wt, P < 0.0001) [17] and the recent meta -analysis also showed the negative impact of IDH mutations on patient overall survival [27] , we examined the relationship between intratumoral 2-HG level and prognosis. The prognosis of patients with high-grade (G2, 3) chondrosarcoma without metastasis at initial presentation showed a negative trend in tumors with higher intratumoral 2-HG levels, although the difference was not significant ( Fig.…”

Clinical Characteristics and Prognostic Risk Factors of Parasellar Chondrosarcoma

“…The pathological results also determined that nine patients were negative for the IDH1 mutation, and the IDH1 mutation was undetectable in six patients. IDH1/2 mutations are associated with a low recurrence rate and high mortality [ 43 ]. Thus, evaluating these indicators may improve the prognostic accuracy for parasellar chondrosarcomas.…”

Metabolic Pathways and Targets in Chondrosarcoma

“…Three isoforms of IDH exist: IDH1 (cytoplasmic), IDH2 (mitochondrial-TCA cycle) and IDH3 (mitochondrial-TCA cycle). IDH1 and IDH2 are NADP-dependent enzymes that are mutated in 38-70% of conventional and dedifferentiated chondrosarcoma cases and induce a neomorphic enzymatic activity (6)(7)(8)(9)(10)(11)(12)(13). The mutant forms of IDH1 and IDH2 require a-KG in order to produce a novel metabolite, D-2-hydroxyglutarate (D-2-HG), which becomes a competitive inhibitor in a-KG dependent enzymes and an oncometabolite, which activates hypoxia inducible factor (HIF) (11).…”

“…Interestingly, mutations in IDH in high grade chondrosarcomas have been associated with CDKN2A/2B and TP53 alterations, prolonged relapse-free and metastasis-free survival ( 9 ). In contrast, a meta-analysis revealed that IDH mutations in chondrosarcoma are associated with poor outcomes ( 13 ).…”