Liver and Bile
Gut. 2024;73(11):1870–1882
Circulating tumour DNA in patients with hepatocellular carcinoma across tumour stages and treatments
Objective: Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. The aim of this study was to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC).
Design: The authors 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 versus 14.6% in patients with inactive HCC and 1.8% in controls (p < 0.001). In active HCC, they 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, the authors 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 2 patients progressing under systemic treatments, they detected the occurrence of mutations in CTNNB1 in the plasma that was subclonal in the tumour for 1 patient and not detectable in the tumour for the other one.
Conclusion: Circulating tumour DNA (ctDNA) offers dynamic information reflecting tumour biology. It represents a non-invasive tool useful to guide clinical management of hepatocellular carcinoma.