Medical Oncology Unit, ASST Bergamo Ovest, Treviglio (BG), Italia.
Medical Oncology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italia.
JAMA Oncol. 2020 Jul 1;6(7):1068-1071. doi: 10.1001/jamaoncol.2020.1046.
The mismatch repair (MMR) pathway plays a crucial role in repairing DNA replication errors in normal and cancer cells. Defects in DNA MMR proteins that determine the microsatellite instability-high (MSI-H) condition lead to the accumulation of mutations and the generation of neoantigens, which may stimulate the antitumor immune response. Clinical trials have demonstrated that MSI-H status is associated with long-term benefit in patients treated with immune checkpoint inhibitors (ICIs).
To evaluate the activity of ICIs in terms of overall response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) in patients with MSI-H cancers.
Published articles that evaluated ICIs in the treatment of advanced MSI-H tumors from inception to December 2019 were identified by searching the PubMed, EMBASE, and Cochrane Library databases.
Prospective or retrospective studies, published in the English language, providing outcome data with ICIs in patients with MSI-H cancer were selected.
Author and year of publication, type of studies, diseases included, median follow up, type of ICI, median OS ,and PFS, ORR, DCR and 1-, 2-, and 3-year OS were retrieved. Analysis was performed in December 2019.
The primary outcome of interest was ORR. Secondary end points were median PFS, median OS, pooled rate of patients alive at 1, 2 ,and 3 years, and pooled rate of patients that attained disease control rate ([DCR] calculated as the sum of stable disease rate and ORR).
Overall, 939 patients (14 studies) were analyzed mainly in pretreated settings. The pooled ORR was 41.5% (95% CI, 34.9%-48.4%). The pooled DCR was 62.8% (95% CI, 54.5%-70.3%). Pooled median PFS was 4.3 months (95% CI, 3-6.8 months). The pooled median OS was 24 months (95% CI, 20.1-28.5 months). The pooled 1- and 2-year OS were 75.6% (95% CI, 61.8%-85.5%) and 56.5% (95% CI, 46%-66.4%), respectively. Because only 1 study provided 3-year OS data, a formal pooled analysis for 3 years was not possible.
In this meta-analysis of patients with pretreated MSI-H cancer, ICIs were associated with high activity independent of tumor type and drug used. Among molecular biomarkers for selection of treatment, MMR proteins may have a predictive value for the activity of immunotherapy.
错配修复（MMR）途径在修复正常和癌细胞中的 DNA 复制错误方面起着至关重要的作用。决定微卫星不稳定高（MSI-H）状态的 DNA MMR 蛋白缺陷导致突变的积累和新抗原的产生，这可能会刺激抗肿瘤免疫反应。临床试验表明，MSI-H 状态与接受免疫检查点抑制剂（ICI）治疗的患者的长期获益相关。
评估 ICI 在 MSI-H 癌症患者中的总体反应率（ORR）、疾病控制率（DCR）、总生存期（OS）和无进展生存期（PFS）方面的活性。
从开始到 2019 年 12 月，通过搜索 PubMed、EMBASE 和 Cochrane 图书馆数据库，确定了评估 ICI 治疗晚期 MSI-H 肿瘤的已发表文章。
选择了以英文发表的、提供了在 MSI-H 癌症患者中使用 ICI 的结果数据的前瞻性或回顾性研究。
检索了作者和出版年份、研究类型、纳入的疾病、中位随访时间、ICI 类型、中位 OS 和 PFS、ORR、DCR 以及 1 年、2 年和 3 年 OS 的生存率。分析于 2019 年 12 月进行。
主要研究终点为 ORR。次要终点为中位 PFS、中位 OS、1、2 和 3 年时的患者总生存率和疾病控制率（DCR）的汇总率[DCR 计算为稳定疾病率和 ORR 的总和]。
共分析了 939 名患者（14 项研究），主要在预处理环境下进行。汇总的 ORR 为 41.5%（95%CI，34.9%-48.4%）。汇总的 DCR 为 62.8%（95%CI，54.5%-70.3%）。汇总的中位 PFS 为 4.3 个月（95%CI，3-6.8 个月）。汇总的中位 OS 为 24 个月（95%CI，20.1-28.5 个月）。汇总的 1 年和 2 年 OS 分别为 75.6%（95%CI，61.8%-85.5%）和 56.5%（95%CI，46%-66.4%）。由于只有 1 项研究提供了 3 年 OS 数据，因此无法对 3 年进行正式的汇总分析。
在这项针对预处理后 MSI-H 癌症患者的荟萃分析中，ICI 与肿瘤类型和药物无关，具有较高的活性。在用于选择治疗的分子生物标志物中，MMR 蛋白可能对免疫治疗的活性具有预测价值。
