Plasma-only circulating tumor DNA analysis detects minimal residual disease and predicts early relapse in hepatocellular carcinoma patients undergoing curative resection

Yuyan Xu; Jianpeng Cai; Kaihang Zhong; Yaohong Wen; Lei Cai; Guolin He; Hangyu Liao; Cheng Zhang; Shunjun Fu; Tingting Chen; Jinping Cai; Xuefeng Zhong; Chunzhu Chen; Mengli Huang; Yuan Cheng; Mingxin Pan

doi:10.3389/fonc.2023.1119744

Plasma-only circulating tumor DNA analysis detects minimal residual disease and predicts early relapse in hepatocellular carcinoma patients undergoing curative resection

Front Oncol. 2023 Mar 7:13:1119744. doi: 10.3389/fonc.2023.1119744. eCollection 2023.

Authors

Affiliations

¹ Department of Hepatobiliary Surgery II, General Surgery Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
² Department of Pancreatobiliary Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
³ Medical Affairs, 3D Medicines, Inc., Shanghai, China.

Abstract

Background: Minimal residual disease (MRD) is considered an essential factor leading to relapse within 2 years (early relapse) after radical surgery, which is challenging to be detected by conventional imaging. Circulating tumor DNA (ctDNA) provides a novel approach for detecting MRD and predicting clinical outcomes. Here, we tried to construct a fixed panel for plasma-only ctDNA NGS to enable tumor-uninformed MRD detection in hepatocellular carcinoma (HCC).

Methods: Here, we performed the followings: (i) profiling genomic alteration spectrum of ctDNA from the Chinese HCC cohort consisting of 493 individuals by NGS; (ii) screening of MRD monitoring genes; and (iii) performance evaluation of MRD monitoring genes in predicting early relapse in the ZJZS2020 cohort comprising 20 HCC patients who underwent curative resection.

Results: A total of 493 plasma samples from the Chinese HCC cohort were detected using a 381/733-gene NGS panel to characterize the mutational spectrum of ctDNA. Most patients (94.1%, 464/493) had at least one mutation in ctDNA. The variants fell most frequently in TP53 (45.1%), LRP1B (20.2%), TERT (20.2%), FAT1 (16.2%), and CTNNB1 (13.4%). By customized filtering strategy, 13 MRD monitoring genes were identified, and any plasma sample with one or more MRD monitoring gene mutations was considered MRD-positive. In the ZJZS2020 cohort, MRD positivity presented a sensitivity of 75% (6/8) and a specificity of 100% (6/6) in identifying early postoperative relapse. The Kaplan-Meier analysis revealed a significantly short relapse-free survival (RFS; median RFS, 4.2 months vs. NR, P=0.002) in the MRD-positive patients versus those with MRD negativity. Cox regression analyses revealed MRD positivity as an independent predictor of poor RFS (HR 13.00, 95% CI 2.60-69.00, P=0.002).

Conclusions: We successfully developed a 13-gene panel for plasma-only MRD detection, which was effective and convenient for predicting the risk of early postoperative relapse in HCC.

Keywords: circulating tumor DNA; early relapse; hepatocellular carcinoma; minimal residual disease; plasma-only.

Grants and funding

This research was supported by a grant from the National Natural Science Foundation of China (No.82072627) and the Guangdong Basic and Applied Basic Research Foundation of China (No. 2021B1515230011).