Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Lancet Gastroenterol Hepatol. 2024 Jul;9(7):609-619. doi: 10.1016/S2468-1253(24)00091-8. Epub 2024 May 9.
Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating the combination of TIL and MSI status identified distinct colorectal cancer subtypes with unique prognostic associations. However, these studies were often limited by sample size, particularly for MSI-high (MSI-H) tumours, and there is no comprehensive summary of the available evidence. We aimed to review the literature to compare the survival outcomes associated with the subtypes derived from the integrated MSI-TIL classification in patients with colorectal cancer.
In this systematic review and network meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library without language restrictions, for articles published between Jan 1, 1990, and March 13, 2024. Patient cohorts comparing different combinations of TIL (high or low) and MSI status (MSI or microsatellite stable [MSS]) in patients with surgically resected colorectal cancer were included. Studies were excluded if they focused on neoadjuvant therapy or on other immune markers such as B cells or macrophages. Methodological quality assessment was done with the Newcastle-Ottawa scale; data appraisal and extraction was done independently by two reviewers. Summary estimates were extracted from published reports. The primary outcomes were overall survival, disease-free survival, and cancer-specific survival. A frequentist network meta-analysis was done to compare hazard ratios (HRs) and 95% CI for each outcome. The MSI-TIL subgroups were prognostically ranked based on P-score, bias, magnitude, and precision of associations with each outcome. The protocol is registered with PROSPERO (CRD42023461108).
Of 302 studies initially identified, 21 studies (comprising 14 028 patients) were included in the systematic review and 19 (13 029 patients) in the meta-analysis. Nine studies were identified with a low risk of bias and the remaining ten had a moderate risk of bias. The MSI-TIL-high (MSI-TIL-H) subtype exhibited longer overall survival (HR 0·45, 95% CI 0·34-0·61; I=77·7%), disease-free survival (0·43, 0·32-0·58; I=61·6%), and cancer-specific survival (0·53, 0·43-0·66; I=0%), followed by the MSS-TIL-H subtype for overall survival (HR 0·53, 0·41-0·69; I=77·7%), disease-free survival (0·52, 0·41-0·64; I=61·6%), and cancer-specific survival (0·55, 0·47-0·64; I=0%) than did patients with MSS-TIL-low tumours (MSS-TIL-L). Patients with the MSI-TIL-L subtype had similar overall survival (0·88, 0·66-1·18; I=77·7%) and disease-free survival (0·93, 0·69-1·26; I=61·6%), but a modestly longer cancer-specific survival (0·72, 0·57-0·90; I=0%) than did the MSS-TIL-L subtype. Results from the direct and indirect evidence were strongly congruous.
The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer.
German Research Council (HO 5117/2-2).
微卫星不稳定性 (MSI) 状态和肿瘤浸润淋巴细胞 (TIL) 是结直肠癌的既定预后因素。以前评估 TIL 和 MSI 状态联合的研究确定了具有独特预后关联的不同结直肠癌亚型。然而，这些研究通常受到样本量的限制，特别是对于 MSI 高 (MSI-H) 肿瘤，并且没有对现有证据的全面总结。我们旨在回顾文献，比较结直肠癌患者中基于 MSI-TIL 综合分类的亚型相关的生存结果。
在这项系统评价和网络荟萃分析中，我们在没有语言限制的情况下搜索了 PubMed、Embase、Scopus 和 Cochrane 图书馆，以查找 1990 年 1 月 1 日至 2024 年 3 月 13 日期间发表的文章。患者队列比较了手术切除的结直肠癌患者中 TIL（高或低）和 MSI 状态（MSI 或微卫星稳定 [MSS]）的不同组合。如果研究集中于新辅助治疗或其他免疫标志物（如 B 细胞或巨噬细胞），则将其排除在外。使用纽卡斯尔-渥太华量表进行方法学质量评估；数据评估和提取由两名评审员独立进行。从已发表的报告中提取总结估计值。主要结局是总生存、无病生存和癌症特异性生存。使用频率主义网络荟萃分析比较每个结局的危险比 (HR) 和 95%置信区间。根据 P 分数、偏倚、大小和与每个结局的关联精度对 MSI-TIL 亚组进行预后排名。该方案在 PROSPERO（CRD42023461108）中注册。
在最初确定的 302 项研究中，有 21 项研究（包括 14028 名患者）被纳入系统评价，19 项研究（包括 13029 名患者）被纳入荟萃分析。9 项研究被确定为低风险偏倚，其余 10 项研究为中度风险偏倚。MSI-TIL-H 亚型的总生存（HR 0.45，95%CI 0.34-0.61；I=77.7%）、无病生存（0.43，0.32-0.58；I=61.6%）和癌症特异性生存（0.53，0.43-0.66；I=0%）更长，其次是 MSS-TIL-H 亚型的总生存（HR 0.53，0.41-0.69；I=77.7%）、无病生存（0.52，0.41-0.64；I=61.6%）和癌症特异性生存（0.55，0.47-0.64；I=0%），而 MSS-TIL-L 肿瘤患者的 MSS-TIL-H 肿瘤患者的总生存（0.88，0.66-1.18；I=77.7%）和无病生存（0.93，0.69-1.26；I=61.6%）相似，但癌症特异性生存（0.72，0.57-0.90；I=0%）略长。直接证据和间接证据的结果高度一致。
这项网络荟萃分析的结果表明，只有 TIL-H 结直肠癌患者观察到更好的生存，无论 MSI 或 MSS 状态如何。应进一步探索综合 MSI-TIL 分类作为早期结直肠癌临床决策的预测工具。
德国研究委员会（HO 5117/2-2）。
