Serum glycan as a prognostic marker in patients with advanced hepatocellular carcinoma treated with sorafenib

Authors

  • Koji Miyahara M.D.,

    1. Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Kazuhiro Nouso M.D., Ph.D.,

    1. Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
    2. Department of Molecular Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Yasuhiro Miyake M.D., Ph.D.,

    1. Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Shinichiro Nakamura M.D., Ph.D.,

    1. Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Shuntaro Obi M.D., Ph.D.,

    1. Division of Hepatology, Kyoundo Hospital, Tokyo, Japan
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  • Maho Amano Ph.D.,

    1. Field of Drug Discovery Research, Faculty of Advanced Life Science & Graduate School of Life Science, Hokkaido University, Sapporo, Japan
    2. Medicinal Chemistry Pharmaceuticals, Sapporo, Japan
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  • Kazuko Hirose Ph.D.,

    1. Field of Drug Discovery Research, Faculty of Advanced Life Science & Graduate School of Life Science, Hokkaido University, Sapporo, Japan
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  • Shin-Ichiro Nishimura Ph.D.,

    1. Field of Drug Discovery Research, Faculty of Advanced Life Science & Graduate School of Life Science, Hokkaido University, Sapporo, Japan
    2. Medicinal Chemistry Pharmaceuticals, Sapporo, Japan
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  • Kazuhide Yamamoto M.D., Ph.D.

    1. Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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  • Supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI 23590976) and partly by a grant for “Development of Systems and Technology for Advanced Measurement and Analysis (SENTAN)” and “The Matching Program for Innovations in Future Drug Discovery and Medical Care” from the Japan Science and Technology Agency and the Ministry of Education, Culture, Science, and Technology, Japan.

  • Potential conflict of interest: Dr. Yamamoto received grants from Bayer Yakuhin.

To the Editor:

We read with interest the article by Kamiyama et al.[1] on whole-serum N-glycan profiling in hepatocellular carcinoma (HCC) patients who underwent hepatectomy. The authors demonstrated that these glycans were differentially expressed in HCC patients compared with healthy controls; both G2890 (m/z value, 2,890.052) and G3560 (m/z value, 3,560.295) were recurrent and prognostic factors, respectively. To determine whether these two serum glycans could be clinical markers for advanced HCC patients and their levels in patients with chronic hepatitis (CH), we investigated serum N-glycan profiles using the same method used by Kamiyama et al. in 85 consecutive HCC patients treated with sorafenib, 41 patients with CH B or C, and 459 healthy volunteers.

Mean serum levels (SDs) of G2890 were 2.60 (1.50), 0.85 (0.60), and 1.04 (0.41) pmol/mL (P < 0.0001), and the levels of G3560 were 0.42 (0.37), 0.05 (0.06), and 0.09 (0.06) pmol/mL (P < 0.0001) in HCC, CH, and healthy volunteers, respectively. Changes in the levels of the two glycans did not correlate with CH virus infection but with the presence of HCC.

Of the 61 glycans detected, 15 glycans, including G2890 and G3560, were elevated in patients with progressive disease 6 weeks after starting sorafenib. Comparing overall survival (OS) between patients with high and low values of these 15 glycans, only G2890 correlated with poor OS in univariate analysis using Cox's proportional hazard model, while G3560 showed a borderline correlation (Table 1). Multivariate analysis with known prognostic factors revealed that high levels of G2890 (hazard ratio, 1.88; 95% confidence interval, 1.04-3.48), as well as Eastern Cooperative Oncology Group performance status (ECOG PS)[1, 2] and Child-Pugh (B), were identified as independent risk factors for survival.

Table 1. Risk Factors for Overall Survival in Hepatocellular Carcinoma Patients Treated With Sorafenib
VariablesUnivariate AnalysisMultivariate Analysis
HR95% CIPHR95% CIP
  1. Only variables that demonstrated P < 0.1 in univariate analysis were analyzed in the multiple logistic regression model. G3560 was excluded in multivariate analysis to avoid the multicollinearity with G2890.

  2. a

    Monosaccharide composition: rhombus, sialic acid; triangle, fucose; square, N-acetyl glucosamine; open circle, galactose; closed circle, mannose.

  3. Abbreviations: AFP-L3, lens culinaris agglutinin-reactive α-fetoprotein; ECOG PS, Eastern Cooperative Oncology Group performance status; MVI, macroscopic vascular invasion.

Clinical parameters      
ECOG PS (1,2)3.321.80-5.90<0.0013.812.01-7.01<0.001
Child-Pugh grade (B)3.982.02-7.46<0.0013.701.84-7.12<0.001
MVI (present)2.031.15-3.530.0141.440.80-2.550.219
AFP-L3 (>30%)1.690.96-2.970.0671.650.92-2.980.090
Glycan markers [Monosaccharide compositiona]      
G2890 (>median)
image
1.961.12-3.490.0171.881.04-3.480.036
G3560 (>median)
image
1.650.96-2.900.072---

We have yet to identify the ligands of G2890 and the biological effects in HCC patients; however, our findings support and expand the results by Kamiyama et al.: serum G2890 is a novel diagnostic and prognostic factor in HCC patients treated with sorafenib, as was observed in surgically treated patients.

  • Koji Miyahara, M.D.1

  • Kazuhiro Nouso, M.D., Ph.D.1,2

  • Yasuhiro Miyake, M.D., Ph.D.1

  • Shinichiro Nakamura, M.D., Ph.D.1

  • Shuntaro Obi, M.D., Ph.D.3

  • Maho Amano, Ph.D.4,5

  • Kazuko Hirose, Ph.D.4

  • Shin-Ichiro Nishimura, Ph.D.4,5

  • Kazuhide Yamamoto, M.D., Ph.D.1

  • 1Department of Gastroenterology & Hepatology

  • Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences

  • Okayama, Japan

  • 2Department of Molecular Hepatology

  • Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences

  • Okayama, Japan

  • 3Division of Hepatology

  • Kyoundo Hospital, Tokyo, Japan

  • 4Field of Drug Discovery Research

  • Faculty of Advanced Life Science & Graduate School of Life Science

  • Hokkaido University

  • Sapporo, Japan

  • 5Medicinal Chemistry Pharmaceuticals

  • Sapporo, Japan

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