Division of Lower GI Surgery, Department of Gastroenterological Surgery, Hyogo Medical University, Nishinomiya.
Department of Biostatistics, Clinical Research Center, Shizuoka Cancer Center, Sunto-gun.
Ann Oncol. 2024 Nov;35(11):1015-1025. doi: 10.1016/j.annonc.2024.08.2240. Epub 2024 Sep 16.
The prognostic role of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection and its utility for postsurgical risk stratification has been reported in colorectal cancer. In this study, we explored the use of ctDNA-based MRD detection in patients with colorectal liver metastases (CLM), for whom the survival benefit of adjuvant chemotherapy (ACT) after surgical resection remains unclear.
Patients with CLM without extrahepatic disease from the GALAXY study (UMIN000039205) were included. The disease-free survival (DFS) benefit of ACT was evaluated in MRD-positive and -negative groups after adjusting for age, gender, number, and size of liver metastases, RAS status, and previous history of oxaliplatin for primary cancer. ctDNA was detected using a personalized, tumor-informed 16-plex polymerase chain reaction-next-generation sequencing (mPCR-NGS) assay. ctDNA-based MRD status was evaluated 2-10 weeks after curative surgery, before the start of ACT.
Among 6061 patients registered in GALAXY, 190 surgically resected CLM patients without any preoperative chemotherapy were included with a median follow-up of 24 months (1-48 months). ctDNA positivity in the MRD window was 32.1% (61/190). ACT was administered to 25.1% (48/190) of patients. In the MRD-positive group, 24-month DFS was higher for patients treated with ACT [33.3% versus not reached, adjusted hazard ratio (HR): 0.07, P < 0.0001]; whereas no benefit of ACT was seen in the MRD-negative group (24-month DFS: 72.3% versus 62.2%, adjusted HR: 0.68, P = 0.371). Multivariate analysis showed that the size of liver metastases (HR: 3.94, P = 0.031) was prognostic of DFS in the MRD-positive group. In the MRD-negative group, however, none of the clinicopathological factors were prognostic of DFS.
Our data suggest that ACT may offer notable clinical benefits in MRD-positive patients with CLM. MRD status-based risk stratification could be potentially incorporated in future clinical trials for CLM.
循环肿瘤 DNA（ctDNA）基于分子残留疾病（MRD）检测的预后作用及其在结直肠癌术后风险分层中的应用已得到报道。在这项研究中，我们探讨了 ctDNA 基于 MRD 检测在结直肠癌肝转移（CLM）患者中的应用，对于这些患者，手术切除后辅助化疗（ACT）的生存获益仍不明确。
本研究纳入了来自 GALAXY 研究（UMIN000039205）的无肝外疾病的 CLM 患者。在调整年龄、性别、肝转移数量和大小、RAS 状态和原发性癌症奥沙利铂既往史后，评估了 MRD 阳性和阴性组患者 ACT 的无病生存率（DFS）获益。使用个性化、基于肿瘤的 16 重聚合酶链反应-下一代测序（mPCR-NGS）检测进行 ctDNA 检测。在根治性手术后 2-10 周进行 ctDNA 基于 MRD 状态评估，在 ACT 开始之前。
在 GALAXY 登记的 6061 名患者中，纳入了 190 名接受根治性手术切除的 CLM 患者，其中中位随访时间为 24 个月（1-48 个月）。MRD 窗口期的 ctDNA 阳性率为 32.1%（61/190）。25.1%（48/190）的患者接受了 ACT。在 MRD 阳性组中，接受 ACT 治疗的患者 24 个月 DFS 更高[33.3%与未达到，调整后的风险比（HR）：0.07，P<0.0001]；而在 MRD 阴性组中，ACT 未见获益[24 个月 DFS：72.3%与 62.2%，调整后的 HR：0.68，P=0.371]。多变量分析显示，肝转移的大小（HR：3.94，P=0.031）是 MRD 阳性组 DFS 的预后因素。然而，在 MRD 阴性组中，无任何临床病理因素与 DFS 相关。
我们的数据表明，ACT 可能为 CLM 中 MRD 阳性患者提供显著的临床获益。MRD 状态为基础的风险分层可能被纳入未来的 CLM 临床试验中。
