Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy

• Published in: Cancers 2022-07, Vol.14 (14), p.3367
• Main Authors: Matsumae, Takayuki, Kodama, Takahiro, Myojin, Yuta, Maesaka, Kazuki, Sakamori, Ryotaro, Takuwa, Ayako, Oku, Keiko, Motooka, Daisuke, Sawai, Yoshiyuki, Oshita, Masahide, Nakabori, Tasuku, Ohkawa, Kazuyoshi, Miyazaki, Masanori, Tanaka, Satoshi, Mita, Eiji, Tawara, Seiichi, Yakushijin, Takayuki, Nozaki, Yasutoshi, Hagiwara, Hideki, Tahata, Yuki, Yamada, Ryoko, Hikita, Hayato, Tatsumi, Tomohide, Takehara, Tetsuo
• Format: Article
• Language: English
• Subjects: Antibodies; Bevacizumab; Biomarkers; Biopsy; Cancer therapies; Catenin; Clinical outcomes; DNA fingerprinting; Genomes; Hepatocellular carcinoma; Hospitals; Hybridization; Immunotherapy; Liver cancer; Mutation; p53 Protein; Patients; PD-L1 protein; Peripheral blood; Prognosis; PTEN protein; RNA-directed DNA polymerase; Survival analysis; Telomerase; Telomerase reverse transcriptase; Tensin; Tumors; Variance analysis; Vascular endothelial growth factor; α-Fetoprotein
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14143367

Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. We investigated the potential of cfDNA/ctDNA as biomarkers for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. We enrolled a multicenter cohort of 85 HCC patients treated with atezolizumab and bevacizumab (Atezo/Bev) between 2020 and 2021. Pretreatment plasma was collected, and cfDNA levels were quantified. Ultradeep sequencing of cfDNA was performed with a custom-made panel for detecting mutations in 25 HCC-related cancer genes. We evaluated the association of cfDNA/ctDNA profiles and clinical outcomes. Patients with high plasma cfDNA levels showed a significantly lower response rate and shorter progression-free survival and overall survival (OS) than those with low cfDNA levels. ctDNA detected in 55% of HCC patients included the telomerase reverse transcriptase (TERT) promoter in 31% of these patients, tumor protein 53 (TP53) in 21%, catenin beta 1 (CTNNB1) in 13% and phosphatase and tensin homolog (PTEN) in 7%. The presence or absence of ctDNA did not predict the efficacy of Atezo/Bev therapy. Twenty-six patients with a TERT mutation had significantly shorter OS than those without. The presence of a TERT mutation and alpha-fetoprotein (AFP) ≥ 400 ng/mL were independent predictors of poor OS according to multivariate Cox proportional hazard analysis and could be used to stratify patients treated with Atezo/Bev therapy based on prognosis. In conclusion, pretreatment cfDNA/ctDNA profiling may be useful for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy.