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Abstract：
BACKGROUND: The recognition of distinct molecular subgroups within cholangiocarcinoma (CC), along with the increasing availability of targeted therapies, suggests that further characterization of the prevalence and prognosis of frequently occurring subgroups may assist with the development of more effective treatment approaches for the management of CC. A systematic review was performed to investigate the prevalence of isocitrate dehydrogenase 1 (IDH1) mutations (mIDH1) in patients with CC, the possible clinical and prognostic significance of mIDH1, and the presence of co-mutations in tumors with mIDH1.
METHODS: This review was conducted using the Cochrane dual-reviewer methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol (PRISMA-P) guidelines. Searches were performed in Embase, MEDLINE, the Cochrane Central Trials Register and Database of Systematic Reviews, and other Cochrane Library assets using terms for CC and mIDH1 with no language or date restrictions for articles published up to December 31, 2017. Searches were also performed of abstracts presented at the following conferences in 2016 and 2017: American Society of Clinical Oncology (ASCO), ASCO-Gastrointestinal Cancers Symposium (ASCO-GI), the European Society for Medical Oncology (ESMO), and ESMO-Asia. Screening was performed separately by two reviewers and cross-checked. Any discrepancies between reviewers were resolved by a senior researcher. Data from all selected references were recorded in a data extraction grid.
RESULTS: A total of 46 publications met the inclusion criteria and were included in the systematic review. Of these publications, 45 reported the frequency of mIDH1 among a total sample of 5,393 patients with CC. mIDH1 was enriched in intrahepatic CC (ICC), with 552 (13.1%; 95% CI, 12.1-14.2) of the 4,214 patients with ICC having the mutation compared with 9 (0.8%; 95% CI, 0.4-1.5%) of the 1,123 patients with extrahepatic CC (ECC). The percentage of females with mIDH1 CC (66.2%; 95% CI, 57.7-73.7%) was higher than in the overall CC population (44.4%). The frequency of mIDH1 in patients with ICC reported in individual studies ranged from 4.5-55.6%, and a significantly higher frequency was reported in non-Asian centers compared with Asian centers (weighted mean, 16.5% vs. 8.8%; P<0.001). The prevalence of mIDH1 in patients with ICC at USA centers was 18.0% (95% CI, 16.4-19.8%). Eleven publications reported the prevalence of co-mutations in patients with mIDH1 ICC, with the most frequent being AT-rich interactive domain-containing protein 1A (ARID1A) (22.0%), BRCA1-associated protein 1 (BAP1) (15.5%), and PBRM1 (13.3%). Eight publications investigated the possible prognostic significance of mIDH1. None of the studies reported a statistically significant association between mIDH1 and overall survival (OS), progression-free survival (PFS), or time to progression.
CONCLUSIONS: This systematic review substantiates the prevalence of mIDH1 in CC and further characterizes clinical, pathologic, and genetic covariates within this sub-population. Co-mutation data may inform future studies of mechanisms of response and resistance to mIDH1-targeted therapies.
METHODS: This review was conducted using the Cochrane dual-reviewer methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol (PRISMA-P) guidelines. Searches were performed in Embase, MEDLINE, the Cochrane Central Trials Register and Database of Systematic Reviews, and other Cochrane Library assets using terms for CC and mIDH1 with no language or date restrictions for articles published up to December 31, 2017. Searches were also performed of abstracts presented at the following conferences in 2016 and 2017: American Society of Clinical Oncology (ASCO), ASCO-Gastrointestinal Cancers Symposium (ASCO-GI), the European Society for Medical Oncology (ESMO), and ESMO-Asia. Screening was performed separately by two reviewers and cross-checked. Any discrepancies between reviewers were resolved by a senior researcher. Data from all selected references were recorded in a data extraction grid.
RESULTS: A total of 46 publications met the inclusion criteria and were included in the systematic review. Of these publications, 45 reported the frequency of mIDH1 among a total sample of 5,393 patients with CC. mIDH1 was enriched in intrahepatic CC (ICC), with 552 (13.1%; 95% CI, 12.1-14.2) of the 4,214 patients with ICC having the mutation compared with 9 (0.8%; 95% CI, 0.4-1.5%) of the 1,123 patients with extrahepatic CC (ECC). The percentage of females with mIDH1 CC (66.2%; 95% CI, 57.7-73.7%) was higher than in the overall CC population (44.4%). The frequency of mIDH1 in patients with ICC reported in individual studies ranged from 4.5-55.6%, and a significantly higher frequency was reported in non-Asian centers compared with Asian centers (weighted mean, 16.5% vs. 8.8%; P<0.001). The prevalence of mIDH1 in patients with ICC at USA centers was 18.0% (95% CI, 16.4-19.8%). Eleven publications reported the prevalence of co-mutations in patients with mIDH1 ICC, with the most frequent being AT-rich interactive domain-containing protein 1A (ARID1A) (22.0%), BRCA1-associated protein 1 (BAP1) (15.5%), and PBRM1 (13.3%). Eight publications investigated the possible prognostic significance of mIDH1. None of the studies reported a statistically significant association between mIDH1 and overall survival (OS), progression-free survival (PFS), or time to progression.
CONCLUSIONS: This systematic review substantiates the prevalence of mIDH1 in CC and further characterizes clinical, pathologic, and genetic covariates within this sub-population. Co-mutation data may inform future studies of mechanisms of response and resistance to mIDH1-targeted therapies.
摘要：
背景：胆管癌（CC）中不同分子亚群的识别，随着靶向治疗的日益普及，提示对频繁发生的亚组的患病率和预后的进一步表征可能有助于开发更有效的治疗方法来管理CC.进行了系统评价以调查CC患者异柠檬酸脱氢酶1（IDH1）突变（mIDH1）的患病率。mIDH1的可能的临床和预后意义，以及mIDH1肿瘤中是否存在共突变。
方法：本综述使用Cochrane双重审查方法和系统评价和荟萃分析方案（PRISMA-P）指南的首选报告项目进行。搜索是在Embase中进行的，MEDLINE,Cochrane中央试验登记册和系统审查数据库，和其他CochraneLibrary资产使用CC和mIDH1的术语，对截至2017年12月31日发表的文章没有语言或日期限制。还对2016年和2017年在以下会议上发表的摘要进行了搜索：美国临床肿瘤学会（ASCO），ASCO-胃肠道癌症研讨会（ASCO-GI），欧洲医学肿瘤学会（ESMO），和ESMO-Asia。筛选由两名评审员分别进行并交叉检查。审稿人之间的任何差异都由高级研究员解决。将来自所有选择的参考的数据记录在数据提取网格中。
结果：共有46篇出版物符合纳入标准，被纳入系统综述。在这些出版物中,45例报告了在总共5,393例CC患者中mIDH1的频率。mIDH1在肝内CC（ICC）中富集，与552（13.1％;95％CI，12.1-14.2）的4,214例ICC具有突变，而9（0.8％;95％CI，0.4-1.5％）的1,123例肝外CC（ECC）。患有mIDH1CC的女性百分比（66.2％；95％CI，57.7-73.7％）高于整个CC人群（44.4％）。在个别研究中报告的ICC患者中mIDH1的频率范围为4.5-55.6％，与亚洲中心相比，非亚洲中心的频率明显更高(加权平均值，16.5%与8.8%;P<0.001)。美国中心ICC患者mIDH1的患病率为18.0%（95%CI，16.4-19.8%）。11种出版物报道了mIDH1ICC患者的共突变患病率，最常见的是富含AT的含相互作用域的蛋白1A（ARID1A）（22.0%），BRCA1相关蛋白1（BAP1）（15.5%），和PBRM1（13.3%）。八篇出版物研究了mIDH1的可能预后意义。没有一项研究报告mIDH1与总生存期（OS）之间存在统计学上的显着关联。无进展生存期（PFS），或进步的时间。
结论：本系统综述证实了mIDH1在CC中的患病率，并进一步表征了临床，病理性,和这个亚群中的遗传协变量。共突变数据可能为未来对mIDH1靶向疗法的反应和抗性机制的研究提供信息。
方法：本综述使用Cochrane双重审查方法和系统评价和荟萃分析方案（PRISMA-P）指南的首选报告项目进行。搜索是在Embase中进行的，MEDLINE,Cochrane中央试验登记册和系统审查数据库，和其他CochraneLibrary资产使用CC和mIDH1的术语，对截至2017年12月31日发表的文章没有语言或日期限制。还对2016年和2017年在以下会议上发表的摘要进行了搜索：美国临床肿瘤学会（ASCO），ASCO-胃肠道癌症研讨会（ASCO-GI），欧洲医学肿瘤学会（ESMO），和ESMO-Asia。筛选由两名评审员分别进行并交叉检查。审稿人之间的任何差异都由高级研究员解决。将来自所有选择的参考的数据记录在数据提取网格中。
结果：共有46篇出版物符合纳入标准，被纳入系统综述。在这些出版物中,45例报告了在总共5,393例CC患者中mIDH1的频率。mIDH1在肝内CC（ICC）中富集，与552（13.1％;95％CI，12.1-14.2）的4,214例ICC具有突变，而9（0.8％;95％CI，0.4-1.5％）的1,123例肝外CC（ECC）。患有mIDH1CC的女性百分比（66.2％；95％CI，57.7-73.7％）高于整个CC人群（44.4％）。在个别研究中报告的ICC患者中mIDH1的频率范围为4.5-55.6％，与亚洲中心相比，非亚洲中心的频率明显更高(加权平均值，16.5%与8.8%;P<0.001)。美国中心ICC患者mIDH1的患病率为18.0%（95%CI，16.4-19.8%）。11种出版物报道了mIDH1ICC患者的共突变患病率，最常见的是富含AT的含相互作用域的蛋白1A（ARID1A）（22.0%），BRCA1相关蛋白1（BAP1）（15.5%），和PBRM1（13.3%）。八篇出版物研究了mIDH1的可能预后意义。没有一项研究报告mIDH1与总生存期（OS）之间存在统计学上的显着关联。无进展生存期（PFS），或进步的时间。
结论：本系统综述证实了mIDH1在CC中的患病率，并进一步表征了临床，病理性,和这个亚群中的遗传协变量。共突变数据可能为未来对mIDH1靶向疗法的反应和抗性机制的研究提供信息。
