Direct comparison of five serum biomarkers in early diagnosis of hepatocellular carcinoma

Cancer Management and Research Dovepress open access to scientific and medical research ORIGINAL RESEARCH Cancer Management and Research downloaded from https://www.dovepress.com/ by 37.59.46.207 on 13-Jul-2018 For personal use only. Open Access Full Text Article Direct comparison of five serum biomarkers in early diagnosis of hepatocellular carcinoma This article was published in the following Dove Press journal: Cancer Management and Research Hongda Chen,1,* Yue Zhang,1,2,* Siwen Li,3,* Ni Li,1 Yuhan Chen,4 Bei Zhang,3 Chunfeng Qu,1 Huiguo Ding,4 Jian Huang,3,5 Min Dai1 National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; 2Office of Scientific Research, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China; 3Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China; 4Department of Gastrointestinal and Hepatology, Beijing You’ An Hospital Affiliated to Capital Medical University, Beijing, China; 5National Clinical Research Center of Digestive Diseases, Beijing, China 1 *These authors contributed equally to this work Correspondence: Min Dai National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuannanli 17, Beijing 100021, China Tel +86 10 8778 7394 Email Jian Huang Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis,Yong’an Road 95, Beijing 100050, China Tel +86 10 6313 9310 Email Introduction Liver cancer is the sixth most commonly diagnosed cancer worldwide and the second leading cause of cancer-related death.1,2 Hepatocellular carcinoma (HCC) accounts for 70–90% of all new liver cancer cases, largely in association with chronic hepatitis B virus (HBV) infection.1–4 Stage at diagnosis is the most important prognostic factor, with a 5-year overall survival rate of 50–70% at early stages and less than 5% at advanced stages. Therefore, diagnosis of HCC at a curative stage and surveillance of non-malignant chronic liver diseases carrying a risk of HCC are key to improving the poor prognosis of HCC. Abdominal ultrasonography is the main recommended tool in HCC diagnosis and surveillance.3,5 However, abdominal ultrasonography presents rather limited sensitivity 1947 submit your manuscript | www.dovepress.com Cancer Management and Research 2018:10 1947–1958 Dovepress © 2018 Chen et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/CMAR.S167036 Powered by TCPDF (www.tcpdf.org) Background: Although a number of serum biomarkers for detection of hepatocellular carcinoma (HCC) have been explored, their exact diagnostic value remains unclear. We aimed to conduct a direct comparison of five representative serum biomarkers for detecting HCC and to derive multi-marker prediction algorithms. Patients and methods: In total, 846 patients were recruited from three hospitals in China, including 202 HCC patients, 226 liver cirrhosis patients, 215 chronic hepatitis B virus-infected patients, and 203 healthy volunteers. Serum levels of alpha-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), des-gamma-carboxyprothrombin (DCP), squamous cell carcinoma antigen, and centromere protein F autoantibody were measured by ELISA. The diagnostic performances of individual biomarkers and multi-marker combinations were evaluated by receiver operating characteristics analysis. The bootstrapping method was adopted to adjust for potential overfitting of all diagnostic indicators. Results: DCP exhibited the best diagnostic performance, with areas under the curve (AUC) for detecting HCC of 0.82 (95% CI 0.64–0.80) and sensitivity of 65.2% (95% CI 63.3–82.1%) at 90% specificity. Of note, DCP showed similar diagnostic efficacy for detecting AFP-positive and AFP-negative HCC. After a comprehensive search for multi-marker combinations, a twomarker prediction algorithm including AFP and DCP was constructed and yielded an AUC of 0.87 (95% CI 0.68–0.84) for detecting HCC. In addition, the combination showed good ability in discriminating early-stage HCC and decompensated liver cirrhosis, with an AUC of 0.81 (95% CI 0.75–0.86). Conclusion: DCP could be a complementary biomarker in the early diagnosis of HCC. The constructed multi-marker prediction algorithms could contribute toward distinguishing HCC from non-malignant chronic liver diseases. Keywords: early detection, liver cirrhosis, prediction model Dovepress Cancer Management and Research downloaded from https://www.dovepress.com/ by 37.59.46.207 on 13-Jul-2018 For personal use only. Chen et al in detecting HCC and is further hampered by inter- and intraobserver variability.6 Alpha-fetoprotein (AFP) is currently the best established serum biomarker for the diagnosis of HCC.7,8 However, the diagnostic performance of AFP in detecting HCC is suboptimal, with sensitivities of 41–65% and specificities of 80–90% at a commonly used cutoff value of 20 ng/ mL.9,10 In particular, much lower sensitivity was observed in detecting early-stage HCC and smaller tumors.9 Therefore, the identification of effective and reliable non-invasive biomarkers for diagnosis and surveillance of HCC is urgently needed and is of high clinical and public health relevance. To date, a number of serum biomarkers carrying diagnostic potential for detecting HCC have been identified,11,12 such as lens culinaris agglutinin-reactive AFP (AFP-L3),13,14 des-gamma carboxyprothrombin (DCP),15,16 squamous cell carcinoma antigen (SCCA),17,18 and centromere protein F autoantibody (anti-CENPF).19 Although these biomarkers have been evaluated in several studies, the diagnostic performance varied greatly across studies, and evidence of a direct comparison of the diagnostic performance of multiple biomarkers in the same population is sparse, especially for Chinese populations.7,8 In addition, promising results were commonly reported in some studies which tried to combine different biomarkers and constructed multi-marker prediction models.7,8,14 However, some results should be interp (...truncated)