Medical Oncology Unit, University Hospital and University of Cagliari, SS 554 km 4500 Bivio Per Sestu, 09042, Monserrato, Cagliari, Italy.
Genetic and Genomic Laboratory, Pediatric Children Hospital A. Cao ASL8, Cagliari, Italy.
Sci Rep. 2023 Mar 16;13(1):4397. doi: 10.1038/s41598-023-31538-3.
Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.
免疫检查点抑制剂 (ICI) 在错配修复缺陷或高微卫星不稳定性 (dMMR-MSI-H) 的转移性结直肠癌 (mCRC) 中显示出疗效。不幸的是，患者的亚组并没有从免疫治疗中获益。尾相关同源盒转录因子 2 (CDX-2) 似乎会影响免疫治疗的敏感性，促进趋化因子 (C-X-C 基序) 配体 14 (CXCL14) 的表达。因此，我们研究了 CDX-2 作为 MSI-H mCRC 患者预后预测标志物的作用。我们回顾性收集了 2019 年至 2021 年间接受 ICI 治疗的 14 例 MSI-H mCRC 患者的数据。主要终点是 12 个月无进展生存期 (PFS) 率。次要终点是总生存期 (OS)、PFS、客观缓解率 (ORR) 和疾病控制率 (DCR)。CDX-2 阳性患者 12 个月时的 PFS 率为 81%，而 CDX-2 阴性患者为 0%（p=0.0011）。CDX-2 阳性组的中位 PFS 未达到 (NR)，而 CDX-2 阴性组为 2.07 个月（95%CI 2.07-10.8）（p=0.0011）。CDX-2 阳性患者的中位 OS 为 NR，而 CDX-2 阴性患者为 2.17 个月（95%置信区间 [CI] 2.17-18.7）（p=0.026）。所有 CDX-2 阳性患者均达到疾病缓解，其中 1 例完全缓解。在 CDX-2 阴性患者中，1 例患者疾病稳定，另 1 例患者疾病进展迅速（ORR：100% vs 0%，p=0.0005；DCR：100% vs 50%，p=0.02）。12 名患者接受了一线 pembrolizumab 治疗（11 名 CDX-2 阳性，1 名 CDX-2 阴性），未达到中位 PFS，而 2 名患者（1 名 CDX-2 阳性，1 名 CDX-2 阴性）接受了三线 pembrolizumab 治疗，中位 PFS 为 10.8 个月（95%CI，10.8-12.1；p=0.036）。尽管我们的研究报告了小群体的结果，但 CDX-2 在 CRC 中的预后作用似乎得到了证实，并可能在确定对免疫治疗更敏感的人群方面发挥有前途的预测作用。调节 CDX-2 阴性患者的 CDX-2/CXCL14 轴可能有助于克服对免疫治疗的原发性耐药。
Zotero 插件
