{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:28:13Z","timestamp":1791224893138,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T00:00:00Z","timestamp":1657497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP22fk0210074 (T.K.)"],"award-info":[{"award-number":["JP22fk0210074 (T.K.)"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP22fk0210091 (T.K.)"],"award-info":[{"award-number":["JP22fk0210091 (T.K.)"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["JP22fk0310524 (T.K.)"],"award-info":[{"award-number":["JP22fk0310524 (T.K.)"]}]},{"name":"Japan Agency for Medical Research and Development (AMED)","award":["20H03661"],"award-info":[{"award-number":["20H03661"]}]},{"DOI":"10.13039\/501100001691","name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","doi-asserted-by":"publisher","award":["JP22fk0210074 (T.K.)"],"award-info":[{"award-number":["JP22fk0210074 (T.K.)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","doi-asserted-by":"publisher","award":["JP22fk0210091 (T.K.)"],"award-info":[{"award-number":["JP22fk0210091 (T.K.)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","doi-asserted-by":"publisher","award":["JP22fk0310524 (T.K.)"],"award-info":[{"award-number":["JP22fk0310524 (T.K.)"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Ministry of Education, Culture, Sports, Science, and Technology, Japan","doi-asserted-by":"publisher","award":["20H03661"],"award-info":[{"award-number":["20H03661"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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) \u2265 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.<\/jats:p>","DOI":"10.3390\/cancers14143367","type":"journal-article","created":{"date-parts":[[2022,7,11]],"date-time":"2022-07-11T21:57:53Z","timestamp":1657576673000},"page":"3367","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy"],"prefix":"10.3390","volume":"14","author":[{"given":"Takayuki","family":"Matsumae","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6250-1324","authenticated-orcid":false,"given":"Takahiro","family":"Kodama","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Myojin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"},{"name":"Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Maesaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1580-607X","authenticated-orcid":false,"given":"Ryotaro","family":"Sakamori","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Takuwa","sequence":"additional","affiliation":[{"name":"Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Oku","sequence":"additional","affiliation":[{"name":"Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Motooka","sequence":"additional","affiliation":[{"name":"Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Sawai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Ikeda Municipal Hospital, Ikeda 563-0025, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahide","family":"Oshita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Ikeda Municipal Hospital, Ikeda 563-0025, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tasuku","family":"Nakabori","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka 541-8567, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuyoshi","family":"Ohkawa","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, Osaka International Cancer Institute, Osaka 541-8567, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka Police Hospital, Osaka 543-0035, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Mita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka 540-0006, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiichi","family":"Tawara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka 558-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Yakushijin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka General Medical Center, Osaka 558-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasutoshi","family":"Nozaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Rosai Hospital, Amagasaki 660-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Kansai Rosai Hospital, Amagasaki 660-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9116-7054","authenticated-orcid":false,"given":"Yuki","family":"Tahata","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoko","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayato","family":"Hikita","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohide","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuo","family":"Takehara","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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