循环肿瘤 DNA 的肿瘤突变负担可预测肝癌切除术后的复发：一种新兴的监测生物标志物。

Tumor Mutational Burden From Circulating Tumor DNA Predicts Recurrence of Hepatocellular Carcinoma After Resection: An Emerging Biomarker for Surveillance.

机构信息

Department of Hepato-pancreato-biliary & Liver Transplant Surgery, Cleveland Clinic Foundation, Digestive Diseases and Surgery Institute, Cleveland.

Department of Hematology and Oncology, Cleveland Clinic Foundation, Taussig Cancer Institute, Cleveland, OH.

出版信息

Ann Surg. 2024 Sep 1;280(3):504-513. doi: 10.1097/SLA.0000000000006386. Epub 2024 Jun 11.

DOI:10.1097/SLA.0000000000006386

PMID:38860385

Abstract

OBJECTIVE

Describe the utility of circulating tumor DNA in the postoperative surveillance of hepatocellular carcinoma (HCC).

BACKGROUND

Current biomarkers for HCC like alpha-fetoprotein (AFP) are lacking. Circulating tumor DNA (ctDNA) has shown promise in colorectal and lung cancers, but its utility in HCC remains relatively unknown.

METHODS

Patients with HCC undergoing curative-intent resection from November 1, 2020, to July 1, 2023, received ctDNA testing using the Guardant360 platform. Tumor mutational burden (TMB) is calculated as the number of somatic mutations-per-megabase of genomic material identified.

RESULTS

Forty-seven patients had postoperative ctDNA testing. The mean follow-up was 27 months, and the maximum was 43.2 months. Twelve patients (26%) experienced recurrence. Most (n=41/47, 87.2%) had identifiable ctDNA postoperatively; 55.3% (n=26) were TMB-not detected versus 45.7% (n=21) TMB-detectable. Postoperative identifiable ctDNA was not associated with RFS ( P =0.518). Detectable TMB was associated with reduced RFS (6.9 vs 14.7 mo, P =0.049). There was a higher rate of recurrence in patients with TMB (n=9/21, 42.9%, vs n=3/26, 11.5%, P =0.02). Area under the curve for TMB-prediction of recurrence was 0.752 versus 0.550 for AFP. ROC analysis established a TMB cutoff of 4.8mut/mB for predicting post-operative recurrence ( P =0.002) and RFS ( P =0.025). AFP was not correlated with RFS using the lab-normal cutoff (<11 ng/mL, P =0.682) or the cutoff established by ROC analysis (≥4.6 ng/mL, P =0.494). TMB-high was associated with poorer RFS on cox-regression analysis (hazard ratio=5.386, 95% CI: 1.109-26.160, P =0.037), while microvascular invasion ( P =0.853) and AFP ( P =0.439) were not.

CONCLUSIONS

Identifiable TMB on postoperative ctDNA predicts HCC recurrence and outperformed AFP in this cohort. Perioperative ctDNA may be a useful surveillance tool following curative-intent hepatectomy. Larger-scale studies are needed to confirm this utility and investigate additional applications in HCC patients, including the potential for prophylactic treatment in patients with residual TMB after resection.

摘要

目的

描述循环肿瘤 DNA 在肝细胞癌（HCC）术后监测中的应用。

背景

目前 HCC 的生物标志物，如甲胎蛋白（AFP），存在不足。循环肿瘤 DNA（ctDNA）在结直肠癌和肺癌中显示出了一定的应用前景，但在 HCC 中的应用仍相对未知。

方法

2020 年 11 月 1 日至 2023 年 7 月 1 日，接受根治性切除术的 HCC 患者接受了基于 Guardant360 平台的 ctDNA 检测。肿瘤突变负荷（TMB）计算为每兆碱基基因组材料中鉴定出的体细胞突变数量。

结果

47 例患者进行了术后 ctDNA 检测。平均随访时间为 27 个月，最长为 43.2 个月。12 例（26%）患者出现复发。大多数（n=47，87.2%）患者术后可检测到 ctDNA；55.3%（n=26）为 TMB-未检出，45.7%（n=21）为 TMB-检出。术后可检测到的 ctDNA 与 RFS 无关（P=0.518）。可检测到的 TMB 与降低的 RFS 相关（6.9 个月 vs 14.7 个月，P=0.049）。TMB 患者的复发率更高（n=9/21，42.9%，vs n=3/26，11.5%，P=0.02）。TMB 预测复发的 AUC 为 0.752，而 AFP 为 0.550。ROC 分析确定了 TMB 预测术后复发的截断值为 4.8mut/mB（P=0.002）和 RFS（P=0.025）。使用实验室正常值截断值（<11ng/mL，P=0.682）或 ROC 分析建立的截断值（≥4.6ng/mL，P=0.494）时，AFP 与 RFS 均无相关性。Cox 回归分析显示，TMB 高与 RFS 较差相关（危险比=5.386，95%CI：1.109-26.160，P=0.037），而微血管侵犯（P=0.853）和 AFP（P=0.439）则无相关性。