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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 TERT promoter, CTNNB1, TP53, PIK3CA and NFE2L2 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 TERT promoter, 21.3% in TP53, 13.1% in CTNNB1, 0.4% in PIK3CA and 0.2% in NFE2L2, 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 CTNNB1 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.
- hepatocellular carcinoma
- immunotherapy
Data availability statement
Data are available on reasonable request. Results of tumour sequencing were available in online supplemental data. The study protocol has been published, including details of sample handing and processing. The individual data collected will not be made available due to restrictions from ethics boards.
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Data availability statement
Data are available on reasonable request. Results of tumour sequencing were available in online supplemental data. The study protocol has been published, including details of sample handing and processing. The individual data collected will not be made available due to restrictions from ethics boards.
Footnotes
JZ-R and J-CN are joint senior authors.
X @Zucmanrossi
Correction notice This article has been corrected since it published Online First. All figures have been replaced to improve clarify.
Contributors CC, SI, JZ-R and J-CN designed the study. JZ-R and J-CN obtained funding. MZ, PN, OS, NGC and J-CN recruited the patients and collected the samples. CC, SI, JZ-R and J-CN accessed, curated and verified the data. CC, GC, BN and KH did the laboratory assays. CC, SI, GC, VT, PL-P, J-CN and JZ-R analysed and interpret the data. All authors had access to the raw data reported in the study. CC and J-CN drafted the manuscript. All authors critically revised the manuscript and approved the final version to be published. JZ-R and J-CN had final responsibility for the decision to submit for publication. J-CN is the guarantor of the current manuscript.
Funding This project was supported by INSERM, Institut National du Cancer (INCa) PRTK 2014 MUTHEC, Ligue National contre le Cancer (Equipe labellisée), ANRS CSS7 AAP 2018-1 CITHEC, Association Française pour l’Étude du Foie (AFEF) 2022 projet radio-moléculaire, Agence Nationale De La Recherche (ANR) 2022 SYSTHEC, Agence nationale de recherches sur le sida et les hépatites virales (ANRS) 2023 CSS13 HBV-LIRAGE ECTZ232901, SIRIC CAncer Research in multiple dimensions to accelerate PrEcision Medicine (CARPEM) INCa-DGOS-Inserm-12561. GENIAL (European Union’s Horizon Europe research and innovation programme, grant agreement No 101096312).
Competing interests PN has received honoraria from and/or consults for AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Ipsen and Roche. He received research grants from AstraZeneca, AbbVie, Bristol–Myers Squibb and Eisai. NGC received travel and congress fees, consulting fees or honoraria for lectures, presentations, speakers’ bureaus from Abbvie, Bayer, Gilead, Ipsen, Intercept and Roche. J-CN received research funding from Bayer and Ipsen. CC, SI, GC, MZ, TZH, SR, BN, KH, SS, OS, VT, PL-P and JZ-R have nothing to disclose.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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