Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, U.S.A.
Merck & Co., Inc., Kenilworth, NJ, U.S.A.
Anticancer Res. 2021 Jun;41(6):2985-2992. doi: 10.21873/anticanres.15080.
BACKGROUND/AIM: The majority of colorectal cancer (CRC) cases, which are microsatellite stable (MSS) and do not harbor mismatch repair deficiency/microsatellite instability, are resistant to immunotherapy. Identification of patients with exceptional responses in MSS CRC and predictive biomarkers is an unmet need that needs to be addressed.
We report three cases of MSS CRC with durable clinical benefit from immunotherapy with anti-PD-1 checkpoint inhibitors. Two cases bear a POLE P286R mutation, which has been associated with lack of immunotherapy response in MSS CRC. Two cases bear alterations in Ataxia-Telangiectasia Mutated (ATM) which may contribute to observed responses, including interaction with a co-administered intratumoral stimulator of interferon genes (STING) pathway agonist in one patient.
Novel DNA damage repair alterations, including mutations in ATM, can provide insight into additional mechanisms by which genomic alterations can sensitize MSS CRC to diverse immunotherapies.
背景/目的：大多数结直肠癌（CRC）病例为微卫星稳定（MSS）且不具有错配修复缺陷/微卫星不稳定，对免疫治疗有抗性。鉴定 MSS CRC 中具有特殊反应的患者和预测生物标志物是一个未满足的需求，需要加以解决。
我们报告了三例 MSS CRC 患者，他们接受抗 PD-1 检查点抑制剂免疫治疗后获得了持久的临床获益。两例存在 POLE P286R 突变，该突变与 MSS CRC 中免疫治疗反应缺失相关。两例存在共济失调毛细血管扩张突变（ATM）改变，这可能有助于观察到的反应，包括在一名患者中与联合使用的肿瘤内干扰素基因刺激物（STING）通路激动剂的相互作用。
新的 DNA 损伤修复改变，包括 ATM 突变，可以深入了解基因组改变使 MSS CRC 对多种免疫疗法敏感的其他机制。
