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.