Circulating cfDNA CD86 methylation is associated with durable response to atezolizumab-bevacizumab in hepatocellular...

/purpose. Although atezolizumab-bevacizumab is approved for unresectable hepatocellular carcinoma (HCC), only a subset of patients attains a durable response (DR). Non-invasive predictors of long-term benefit are lacking. We aimed to assess whether baseline circulating cell-free DNA (cfDNA) quantity combined with cfDNA-derived genetic and methylation profiling could predict prognosis and DR.

We retrospectively analyzed 55 patients with HCC. Baseline cfDNA was dichotomized at the median to evaluate associations with overall survival (OS) and treatment response (objective response rate [ORR], disease control rate [DCR], and DR). In a discovery cohort (n = 17), targeted mutation and methylation profiling on baseline and progression cfDNA was performed. Candidate CpGs were identified by intersecting baseline differential methylation with longitudinal changes, and top hits were validated in an independent cohort (n = 32).

High-cfDNA independently predicted shorter OS (median 13.0 vs. 33.1 months; p = 0.0015) but not ORR, DCR, or DR. Mutation analysis yielded no predictive markers. Integrative methylation profiling identified a locus in CD86 (Chr3:121,795,811) (area under the curve [AUC], 0.903 in discovery); baseline methylation here was associated with DR with an AUC of 0.806 in validation. Patients with high CD86 methylation exhibited higher DR rates and prolonged progression-free survival. Multivariate logistic regression analysis confirmed that high CD86 methylation was independently associated with DR (odds ratio: 6.96, 95% confidence interval: 1.70-28.50; p = 0.0071).

Baseline cfDNA quantity and cfDNA-derived CD86 methylation were associated with clinical outcomes in patients with unresectable HCC treated with atezolizumab-bevacizumab. Prospective validation in larger independent cohorts is warranted before clinical implementation.