POLE 和 POLD1 校对缺陷 (POLE/D1pd) 定义了超突变转移性结直肠癌 (mCRC；超过 100 mut/Mb) 的罕见亚型。缺乏有关 POLE/D1pd mCRC 中免疫检查点抑制剂 (ICIs) 活性和功效的疾病特异性数据，并且尚不清楚结果是否可能与错配修复缺陷 (dMMR)/微卫星不稳定性高 (MSI-H) 不同使用 ICI 治疗的 mCRC。在这项全球研究中，我们收集了 27 名携带 POLE/D1 突变（导致校对缺陷）的 mCRC 患者，并单独使用抗程序性细胞死亡配体 1/- 抗细胞毒性 T 淋巴细胞抗原 4 药物进行治疗。我们收集了 POLE/D1pd mCRC ICI 后的临床病理学和基因组特征、反应和生存结果，并将其与接受 ICI 治疗的 610 名 dMMR/MSI-H mCRC 患者进行比较。在 7241 名 CRC 的独立队列中进行了进一步的基因组分析，以确定 POLE 和 POLD1pd 分子谱和突变特征。POLE/D1pd 与年龄较小、男性、较少 RAS/BRAF 驱动突变以及右侧结肠占主导地位相关癌症。与 dMMR/MSI-H mCRC 患者相比，POLE/D1pd mCRC 患者的总体缓解率 (ORR) 显着更高（89% 对比 54%；P = 0.01）。中位随访 24.9 个月（四分位距：11.3-43.0 个月）后，与 dMMR/MSI-H mCRC 患者相比，POLE/D1pd 患者表现出显着优越的无进展生存期 (PFS) [风险比 (HR) = 0.24，95% 置信区间 (CI) 0.08-0.74，P = 0.01] 和优越的总生存 (OS)（HR = 0.38，95% CI 0.12-1.18，P = 0.09）。在包括 DNA 修复缺陷类型的多变量分析中，POLE/D1pd 与显着改善的 PFS（HR = 0.17，95% CI 0.04-0.69，P = 0.013）和 OS（HR = 0.24，95% CI 0.06-0.98， P = 0.047）。分子分析显示 POLE/D1pd 肿瘤具有较高的肿瘤突变负荷 (TMB)。在两种亚型中均观察到反应，并且与 POLE/D1pd 特征的强度相关。与 dMMR/MSI-H mCRC 患者相比，POLE/D1pd mCRC 患者在肿瘤反应和生存方面对 ICI 治疗表现出更有利的结果。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs.In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures.POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature.Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.