肿瘤突变负荷作为错配修复缺陷/微卫星高度不稳定转移性结直肠癌患者接受免疫检查点抑制剂治疗的生物标志物。

Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors.

机构信息

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: https://twitter.com/@paomanca.

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

出版信息

Eur J Cancer. 2023 Jul;187:15-24. doi: 10.1016/j.ejca.2023.03.029. Epub 2023 Mar 31.

DOI:10.1016/j.ejca.2023.03.029

PMID:37099945

Abstract

BACKGROUND

Immune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes.

PATIENTS AND METHODS

We screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers. TMB was tested by Foundation One Next Generation Sequencing assay and correlated with clinical outcomes, in the overall population and according to ICI regimen.

RESULTS

We included 110 patients with dMMR/MSI-H mCRC. Eighty patients received anti-PD-(L)1 monotherapy and 30 received anti-CTLA-4 combinations. Median TMB was 49 mut/Mb (range: 8-251 mut/Mb). The optimal prognostic cut-off for progression-free survival (PFS) stratification was 23 mut/Mb. Patients with TMB ≤23 mut/Mb had significantly worse PFS (adjusted Hazard Ratio [aHR] = 4.26, 95% confidence interval [CI]:1.85-9.82, p = 0.001) and overall survival (OS) (aHR = 5.14, 95% CI: 1.76-14.98, p = 0.003). Using a cut-off optimised for predicting treatment outcome, anti-CTLA-4 combination was associated with a significant PFS/OS benefit versus anti-PD-(L)1 monotherapy in patients with TMB>40 mut/Mb (2-year PFS: 100.0% versus 70.7%, p = 0.002; 2-year OS: 100.0% versus 76.0%, p = 0.025), but not in those with TMB ≤40 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949).

CONCLUSION

Patients with dMMR/MSI-H mCRC and relatively lower TMB value displayed early disease progression when receiving ICIs, whereas patients with the highest TMB values may obtain the maximal benefit from intensified anti-CTLA-4/PD-1 combination.

摘要

背景

免疫检查点抑制剂（ICIs）是错配修复缺陷（dMMR）/微卫星高度不稳定（MSI-H）转移性结直肠癌（mCRC）患者的标准治疗方法。肿瘤突变负担（TMB）是预测治疗结果的有前途的生物标志物。

患者和方法

我们在意大利的三个学术中心筛选了 203 名接受抗 PD-（L）1（抗程序性死亡配体-1）联合或不联合抗细胞毒性 T 淋巴细胞抗原 4（抗 CTLA-4）药物治疗的 dMMR/MSI-H mCRC 患者。通过 Foundation One 下一代测序检测 TMB，并与总体人群以及根据 ICI 方案的临床结果相关联。

结果

我们纳入了 110 名 dMMR/MSI-H mCRC 患者。80 名患者接受抗 PD-（L）1 单药治疗，30 名患者接受抗 CTLA-4 联合治疗。中位 TMB 为 49 个突变/Mb（范围：8-251 个突变/Mb）。无进展生存期（PFS）分层的最佳预后截断值为 23 个突变/Mb。TMB≤23 个突变/Mb 的患者 PFS 明显更差（调整后的危险比[aHR]为 4.26，95%置信区间[CI]：1.85-9.82，p=0.001）和总生存期（OS）（aHR 为 5.14，95%CI：1.76-14.98，p=0.003）。使用优化用于预测治疗结果的截止值，与抗 PD-（L）1 单药治疗相比，抗 CTLA-4 联合治疗在 TMB>40 个突变/Mb 的患者中具有显著的 PFS/OS 获益（2 年 PFS：100.0%对 70.7%，p=0.002；2 年 OS：100.0%对 76.0%，p=0.025），但在 TMB≤40 个突变/Mb 的患者中没有（2 年 PFS：59.7%对 68.6%，p=0.888；2 年 OS：80.0%对 81.0%，p=0.949）。