State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China.
Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China.
Hepatol Int. 2022 Aug;16(4):868-878. doi: 10.1007/s12072-022-10348-1. Epub 2022 Jun 8.
Circulating tumor DNA (ctDNA) can be useful in tumor diagnosis and surveillance. However, its value in hepatocellular carcinoma (HCC) patients receiving curative resection remains unknown. Here, we aim to determine the prognostic value of ctDNA in HCC patients.
A prospective cohort enrolled 258 HCC patients who underwent curative liver resection from April 1, 2019, to September 31, 2020. Blood samples were collected before surgery for the detection of ctDNA.
The number of total mutant genes in ctDNA was associated with early tumor relapse (HR = 2.2, p < 0.001). We defined a gene set consisting of APC, ARID1A, CDKN2A, FAT1, LRP1B, MAP3K1, PREX2, TERT and TP53 as high-risk genes (HRGs) associated with early recurrence. Patients were classified into low-, median- and high-risk levels based on the number of mutant genes in the HRGs. High-risk patients had worse recurrence free survival, especially single-tumor patients (HR = 13.0, p < 0.001). The risk level and TNM stage were independently associated with tumor recurrence. A preoperative recurrence estimation nomogram based on those two factors was constructed and demonstrated good accuracy with a C index of 0.76 (95% CI 0.70-0.82). Patients preserved FAT1 or LRP1B variants but without TP53 variants had worse progression free survival for receiving lenvatinib combined with immune checkpoint inhibitors after recurrence (HR = 17.1, p < 0.001). Furthermore, RNA sequencing data revealed that ctDNA status was associated with tumor immune infiltration.
Preoperative serum ctDNA can be a practical noninvasive approach to predict recurrence after surgery and response to systemic therapies. ctDNA-guided HCC management should be recommended.
循环肿瘤 DNA（ctDNA）可用于肿瘤诊断和监测。然而，其在接受根治性切除的肝细胞癌（HCC）患者中的价值尚不清楚。在此，我们旨在确定 ctDNA 在 HCC 患者中的预后价值。
前瞻性队列纳入了 2019 年 4 月 1 日至 2020 年 9 月 31 日期间接受根治性肝切除术的 258 例 HCC 患者。手术前采集血液样本检测 ctDNA。
ctDNA 中的总突变基因数量与早期肿瘤复发相关（HR=2.2，p<0.001）。我们定义了一个由 APC、ARID1A、CDKN2A、FAT1、LRP1B、MAP3K1、PREX2、TERT 和 TP53 组成的基因集为与早期复发相关的高风险基因（HRG）。根据 HRG 中突变基因的数量，患者被分为低、中、高危水平。高危患者无复发生存率较差，尤其是单发肿瘤患者（HR=13.0，p<0.001）。风险水平和 TNM 分期与肿瘤复发独立相关。基于这两个因素构建了一个术前复发估计列线图，具有 0.76（95%CI 0.70-0.82）的良好准确性。在复发后接受仑伐替尼联合免疫检查点抑制剂治疗的患者中，保留 FAT1 或 LRP1B 变异但无 TP53 变异的患者无进展生存期更差（HR=17.1，p<0.001）。此外，RNA 测序数据显示，ctDNA 状态与肿瘤免疫浸润相关。
术前血清 ctDNA 是预测术后复发和对系统治疗反应的一种实用的非侵入性方法。应推荐 ctDNA 指导的 HCC 管理。
