Department of Musculoskeletal Oncology and Rehabilitation, National Cancer Center Hospital, Tokyo, Japan; Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
Department of Orthopaedic Surgery, Showa University, Tokyo, Japan.
J Orthop Sci. 2022 Nov;27(6):1315-1322. doi: 10.1016/j.jos.2021.07.024. Epub 2021 Sep 14.
Mutant isocitrate dehydrogenase (IDH) in chondrosarcoma produces the oncometabolite 2-hydroxyglutarate (2-HG) and contributes to malignant progression, and is therefore a potential therapeutic target for chondrosarcoma. Robust historical control data are important in clinical trials of rare cancers such as chondrosarcoma in order to show a clear benefit of new drugs. However, it remains controversial whether IDH mutation status is associated with the clinical outcome of chondrosarcoma, and this hinders the development of mutant IDH inhibitors in clinical trials.background METHODS: We investigated the relationship between IDH gene status and clinicopathological data in 38 chondrosarcoma patients from whom frozen tumor samples were obtained at the time of biopsy or surgery. Targeted next-generation sequencing was also performed to compare genetic alterations between patients with and without IDH mutations.
The results revealed 15 cases (40%) of heterozygous IDH1 mutations and five cases (13%) of IDH2 mutations. IDH-mutant chondrosarcoma was associated with worse overall survival than IDH-wild-type chondrosarcoma (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). IDH mutation was also a significant poor prognostic factor both in univariate (P = 0.026) and multivariate (P = 0.048) analyses. Targeted next-generation sequencing revealed that characteristic mutations in chondrosarcoma, including TP53 and COL2A1, were more common in the IDH-mutant group than in the IDH-wild-type group.results CONCLUSION: This study is the first to report in detail the characteristics and clinical courses of IDH-mutant chondrosarcoma patients in Japan. Our data suggested that IDH-mutant chondrosarcomas might have a worse prognosis than that of IDH-wild-type chondrosarcoma, possibly through the more aggressive characters after metastasis. This information will be useful for designing clinical trials of mutant IDH inhibitors for treatment of advanced chondrosarcoma.
软骨肉瘤中的突变异柠檬酸脱氢酶（IDH）产生致癌代谢物 2-羟基戊二酸（2-HG），并促进恶性进展，因此是软骨肉瘤的潜在治疗靶点。在临床试验中，对于软骨肉瘤等罕见癌症，稳健的历史对照数据非常重要，以便清楚地显示新药的益处。然而，IDH 突变状态是否与软骨肉瘤的临床结果相关仍存在争议，这阻碍了突变 IDH 抑制剂在临床试验中的开发。
我们研究了 38 名软骨肉瘤患者的 IDH 基因状态与临床病理数据之间的关系，这些患者在活检或手术时获得了冷冻肿瘤样本。还进行了靶向下一代测序，以比较 IDH 突变患者和无突变患者之间的遗传改变。
结果显示，15 例（40%）存在杂合 IDH1 突变，5 例（13%）存在 IDH2 突变。与 IDH 野生型软骨肉瘤相比，IDH 突变型软骨肉瘤的总生存率更差（IDH1/2Mut 与 IDH Wt，P=0.006；IDH1Mut 与 IDH Wt，P=0.030；IDH2Mut 与 IDH Wt，P<0.0001）。在单因素（P=0.026）和多因素（P=0.048）分析中，IDH 突变也是一个显著的不良预后因素。靶向下一代测序显示，软骨肉瘤的特征性突变，包括 TP53 和 COL2A1，在 IDH 突变组中比在 IDH 野生型组中更为常见。
本研究首次详细报告了日本 IDH 突变型软骨肉瘤患者的特征和临床过程。我们的数据表明，IDH 突变型软骨肉瘤的预后可能比 IDH 野生型软骨肉瘤更差，这可能是由于转移后的侵袭性更强。这些信息对于设计治疗晚期软骨肉瘤的突变 IDH 抑制剂的临床试验将是有用的。
