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Abstract：
Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients.
摘要：
缺乏错配修复（dMMR）途径/微卫星不稳定性（MSI）的大肠癌（CRC）的特征是高突变负荷和肿瘤微环境中免疫细胞的浸润。与这些发现一致，临床试验表明，免疫检查点抑制剂（ICIs）在dMMR/MSI转移性CRC（mCRC）患者中具有显着的活性，最近,在接受新辅助治疗的早期疾病的CRC患者中。然而,尽管高反应率和持久的临床益处，一小部分mCRC患者，高达30%,当用单剂抗程序性细胞死亡1（PD-1）抗体治疗时，显示进行性疾病。本文讨论了在使用ICIs治疗时与dMMR/MSImCRC患者早期进展相关的三个主要原因，即，误诊,假性进展和肿瘤异质性。虽然假性进展可能不会起到相关作用，来自临床研究的数据表明，一些在ICIs上快速进展的dMMR/MSICRC病例可能被误诊，强调正确诊断的重要性。更重要的是,证据表明，dMMR/MSImCRC是一组对ICIs敏感性不同的异质性肿瘤。因此,我们提出了新的诊断和治疗策略,以改善dMMR/MSICRC患者的预后.
