963P - Discovery and validation of cfDNA methylation, AFP and ctDNA mutation for the early detection of hepatocellular carcinoma: A multicenter prospective study (ASCEND-Hep)

Background

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Early detection of HCC is critical for timely treatment and a better prognosis. In this prospective study (ASCEND-Hep, NCT04835675), we aimed to explore multi-omics including cell-free DNA (cfDNA) methylation, mutation, and α-fetoprotein (AFP) in early detection of HCC.

Methods

This multicenter study prospectively collected blood samples from patients with HCC and benign liver diseases. Age-matched non-cancer controls were obtained from a previous study. Methylation and mutation were detected through a methylation panel of 161,984 CpG sites and a cancer-associated 168-gene panel, respectively. Models were developed in a training set (cancer: 172; non-cancer: 206) and tested in a validation set (cancer: 117; non-cancer: 140). Then the locked models were validated in an independent validation set (cancer: 158; non-cancer: 637).

Results

In the training set, cfDNA methylation model had a higher area under curve than AFP and mutation alone (P<0.05). In the validation set, the methylation model yielded an overall sensitivity of 92.3% (95% CI, 85.9%–96.4%) at a specificity of 95.0% (90.0%–98.0%). Meanwhile, AFP >400 ng/mL had a sensitivity of 27.3% (18.8%–37.2%) with a specificity of 100.0% (96.5%–100.0%). Combining cfDNA methylation and AFP showed a better performance with a sensitivity of 94.0% (88.1%–97.6%) and a specificity of 95.0% (90.0%–98.0%), while the addition of mutation did not further improve the performance. Consistent results were observed in the independent validation set that the combined model achieved a sensitivity of 90.5% (84.8%–94.6%) at a specificity of 97.3% (95.8%–98.4%). The sensitivity of the combined model in Barcelona Clinic Liver Cancer Classification 0–A was 87.1% (78.0%–93.4%).

Conclusions

cfDNA methylation yielded superior performance than AFP and mutation alone. Our study highlights a potential clinical utility of combining cfDNA methylation and AFP for HCC early detection.

Clinical trial identification

NCT04835675.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Burning Rock Bioengineering Ltd.

Disclosure

All authors have declared no conflicts of interest.