A new therapeutic strategy using cell-free DNA that predicts drug resistance of atezolizumab+bevacizumab for the treatment of advanced hepatocellular carcinoma.

[Background] Atezolizumab+bevacizumab (atezo+bev) therapy was indicated for unresectable HCC as the first combined immunotherapy. Compared with existing molecular-targeted drugs (MTAs), significant prolongation of OS and PFS was observed in atezo+bev therapy. However, there are some cases with poor effect, and thus, the timing of switching to conventional MTAs is critical. There is an urgent need to develop a biomarker for early determination of atezo+bev resistance.
[Aim] The aim of this study is to analyze cell-free DNA (cfDNA) as a biomarker for early diagnosis of drug resistance of atezo+bev.
[METHODS] Among unresectable HCC patients, 10 cases with CR/PR and 10 cased with PD on atezo+bev were registered. CfDNAs from serum were analyzed using digital PCR before administration of atezo+bev.
[Results] In HCC patients, 45% for TERT mutations and 40% for β-catenin mutations were detected in serum cfRNAs. The percentages of TERT and β-catenin mutations in PD cases were significantly higher than those in CR/PR cases.
[Discussion] In the analyses of gene mutation using cfDNA in serum before administration of atezo+bev, both TERT and β-catenin had a significant correlation in resistance. By quantifying cfDNA mutations in pre-administration serum, it was possible to predict the resistance of atezo+bev.
[Conclusion] CfDNA was suggested to be effective as a biomarker for diagnosing the resistance of atezo+bev.