肝癌患者在不同肿瘤分期和治疗中的循环肿瘤 DNA。

Circulating tumour DNA in patients with hepatocellular carcinoma across tumour stages and treatments.

机构信息

Cordeliers Research Center, INSERM, Paris Cité University, "Functional Genomics of Solid Tumors" Team, Ligue Nationale Contre le Cancer Accredited Team, Labex OncoImmunology, Sorbonne Université, Université Paris Cité, Paris, France.

Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, Florence, Italy.

出版信息

Gut. 2024 Oct 7;73(11):1870-1882. doi: 10.1136/gutjnl-2024-331956.

DOI:10.1136/gutjnl-2024-331956

PMID:39054058

Abstract

OBJECTIVE

Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. We aim to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC).

DESIGN

We analysed 772 plasmas from 173 patients with HCC collected at the time of diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154) and during follow-up (n=116). For controls, 56 plasmas from patients with chronic liver disease without HCC were analysed. All samples were analysed for cell free DNA (cfDNA) concentration, and for mutations in promoter, , , and by sequencing and droplet-based digital PCR. Results were compared with 232 corresponding tumour samples.

RESULTS

In patients with active HCC, 40.2% of the ctDNA was mutated vs 14.6% in patients with inactive HCC and 1.8% in controls (p<0.001). In active HCC, we identified 27.5% of mutations in promoter, 21.3% in , 13.1% in , 0.4% in and 0.2% in most of the times similar to those identified in the corresponding tumour. CtDNA mutation rate increased with advanced tumour stages (p<0.001). In 103 patients treated by percutaneous ablation, the presence and number of mutations in the ctDNA before treatment were associated with higher risk of death (p=0.001) and recurrence (p<0.001). Interestingly, cfDNA concentration and detectable mutations increased 24 hours after a locoregional treatment. Among 356 plasmas collected in 53 patients treated by systemic treatments, we detected mutations at baseline in 60.4% of the cases. In patients treated by atezolizumab-bevacizumab, persistence of mutation in ctDNA was associated with radiological progression (63.6% vs 36.4% for disappearance, p=0.019). In two patients progressing under systemic treatments, we detected the occurrence of mutations in in the plasma that was subclonal in the tumour for one patient and not detectable in the tumour for the other one.

CONCLUSION

ctDNA offers dynamic information reflecting tumour biology. It represents a non-invasive tool useful to guide HCC clinical management.

摘要

目的

循环肿瘤 DNA（ctDNA）是一种有前途的癌症无创生物标志物。本研究旨在评估 ctDNA 在肝细胞癌（HCC）患者中的动态变化。

设计

我们分析了 173 名 HCC 患者的 772 份血浆，这些患者在诊断或治疗时（n=502）、局部治疗后 24 小时（n=154）和随访时（n=116）采集了血浆。另外，还分析了 56 份来自无 HCC 慢性肝病患者的血浆作为对照。所有样本均通过测序和液滴式数字 PCR 分析游离 DNA（cfDNA）浓度和、、、启动子的突变。结果与 232 个相应肿瘤样本进行了比较。

结果

在活动性 HCC 患者中，ctDNA 突变率为 40.2%，而在非活动性 HCC 患者和对照组中分别为 14.6%和 1.8%（p<0.001）。在活动性 HCC 患者中，我们发现 27.5%的启动子突变、21.3%的突变、13.1%的突变、0.4%的突变和 0.2%的突变，这些突变在大多数情况下与相应肿瘤中的突变相似。ctDNA 突变率随肿瘤分期的进展而增加（p<0.001）。在 103 名接受经皮消融治疗的患者中，治疗前 ctDNA 中的存在和突变数量与更高的死亡风险（p=0.001）和复发风险（p<0.001）相关。有趣的是，局部治疗后 24 小时 cfDNA 浓度和可检测的突变增加。在 53 名接受系统治疗的患者中，我们在 356 份血浆中检测到基线时的突变，在 60.4%的病例中检测到突变。在接受阿特珠单抗-贝伐珠单抗治疗的患者中，ctDNA 中的突变持续存在与影像学进展相关（消失的患者中 63.6% vs 36.4%，p=0.019）。在两名接受系统治疗进展的患者中，我们在血浆中检测到一个患者肿瘤中为亚克隆的和另一个患者肿瘤中无法检测到的突变。