Editor’s Note:
Circulating tumor DNA (ctDNA) refers to free tumor DNA fragments located in peripheral circulation. These free nucleic acids not only provide a comprehensive view of tumor genetics but also indirectly reflect tumor progression, heterogeneity, and invasive ability. They represent a promising non-invasive biomarker in cancer treatment. Dr. Claudia Campani from the University of Paris delivered an oral presentation at the 17th International Liver Cancer Association Annual Meeting (ILCA 2023) (Abstract No.: O-04). The study aimed to assess the dynamic changes in ctDNA levels in hepatocellular carcinoma (HCC) patients across different tumor stages and during anti-cancer treatments. The findings highlighted the significant clinical relevance of monitoring ctDNA levels for HCC patients. Dr. Claudia Campani was honored with the “Young Investigator” award by the ILCA conference.
The study enrolled 173 HCC patients and 56 patients with chronic liver disease but no HCC, collecting 832 blood plasma samples for research. The team quantified cell-free DNA (cfDNA) levels, screened relevant mutations in TERT promoter, CTNNB1, TP53, PIK3CA, and NFE2L2 through ultra-deep second-generation sequencing, searched for TERT promoter mutations via Droplet Digital PCR (ddPCR), and sequenced 39 driver genes from 241 tumor tissue samples. Statistical analysis was conducted using Mann-Whitney, Kruskal-Wallis tests, and chi-square tests, Fisher’s exact test, and McNemar’s test.
Of the 173 HCC patients, 82% were male with a median age of 63. 73% had cirrhosis. HCC-related etiologies included: chronic hepatitis B (28%), chronic hepatitis C (42%), non-alcoholic fatty liver disease (26%), and alcoholic fatty liver (40%). Patients were classified by tumor stage as: BCLC 0 (23%), BCLC A (44%), BCLC B (21%), and BCLC C (12%).
Tumor sequencing revealed mutations in TERT promoter (71%), TP53 (28%), CTNNB1 (27%), ATM (14.95%), ARID1A (13.4%), ARID2 (8%), NFE2L2 (2%), and PIK3CA (2%). In the 56 plasma samples from patients without HCC, 8 mutations in TP53, 1 mutation in CTNNB1 were identified, while TERT, PIK3CA, and NFE2L2 had no mutations.
Out of 776 plasma samples from HCC patients, 502 were from active HCC cases, 158 were taken 24 hours after localized treatment, and 116 were from inactive HCC patients. Analysis showed significantly higher cfDNA levels in active HCC patients compared to inactive ones (0.27 ng/µL vs. 0.16 ng/µL, P<0.001). In the 502 samples from active HCC patients, 45.8% had tumor-associated mutations. Specific mutations observed in circulating DNA included: TP53 (29.37%), TERT promoter (27.51%), CTNNB1 (13.10%), PIK3CA (0.41%), and NFE2L2 (0.21%). 24.3% of active HCC patients had normal serum AFP levels.
It was found that the mutation rate of cfDNA significantly increased with tumor stage: BCLC 0 at 16.4%, BCLC A at 24.8%, BCLC B at 41.6%, and BCLC C at 58% (P<0.0001). In the 116 plasma samples from inactive HCC patients, 26 samples (22%) had cfDNA mutations; in 21 of those, the mutations matched those previously observed in blood samples or tumor tissues from the same patient.
Additionally, researchers compared baseline plasma samples of HCC patients with those taken 24 hours post-localized treatment. The post-treatment samples showed significantly elevated cfDNA levels (0.19 ng/µL vs. 0.63 ng/µL, P<0.001) and mutation rates (31% vs. 44%, P<0.001).
Lastly, the team compared 179 plasma samples from 50 advanced HCC patients treated with a combination of atezolizumab and bevacizumab. At baseline, 49% of patients showed cfDNA mutations, and 24% had normal serum AFP levels. All radiological responses in HCC patients correlated with the disappearance of baseline cfDNA mutations by 12 weeks of treatment. Conversely, continued cfDNA mutations post-treatment significantly correlated with radiological progression (P=0.005).
This study indicates that ctDNA provides dynamic insights into tumor biology. As a non-invasive tool, ctDNA testing aids in guiding clinical treatment and management for HCC patients.
Reference: Claudia Campani, Sandrine Imbeaud, Marianne Ziol, et al. Dynamic evolution of circulating tumor DNA in patients with hepatocellular carcinoma across tumor stages and treatment. ILCA 2023 Abstract O-04.
TAG: ILCA 2023, Commentary, HCC
