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Precision Medicine and Imaging

Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers

Dan Høgdall, Colm J. O'Rourke, Christian Dehlendorff, Ole F. Larsen, Lars H. Jensen, Astrid Z. Johansen, Hien Dang, Valentina M. Factor, Mie Grunnet, Morten Mau-Sørensen, Douglas V.N.P. Oliveira, Dorte Linnemann, Mogens K. Boisen, Xin W. Wang, Julia S. Johansen and Jesper B. Andersen
Dan Høgdall
1Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
2Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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  • For correspondence: Danhog01@regionh.dk
Colm J. O'Rourke
2Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Christian Dehlendorff
3Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
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Ole F. Larsen
1Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
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Lars H. Jensen
4Department of Oncology, University Hospital of Southern Denmark, Vejle, Denmark.
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Astrid Z. Johansen
1Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
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Hien Dang
5Division of Surgical Research, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Valentina M. Factor
6Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
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Mie Grunnet
7Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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Morten Mau-Sørensen
7Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
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Douglas V.N.P. Oliveira
2Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Dorte Linnemann
8Department of Pathology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
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Mogens K. Boisen
1Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
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Xin W. Wang
9Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA.
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Julia S. Johansen
1Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
10Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
11Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Jesper B. Andersen
2Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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DOI: 10.1158/1078-0432.CCR-19-2700 Published November 2020
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Abstract

Purpose: Biliary tract cancer (BTC) is a heterogeneous group of rare gastrointestinal malignancies with dismal prognosis often associated with inflammation. We assessed the prognostic value of IL6 and YKL-40 compared with CA19-9 before and during palliative chemotherapy. We also investigated in mice whether IL6R inhibition in combination with gemcitabine could prolong chemosensitivity.

Experimental Design: A total of 452 Danish participants with advanced (locally advanced and metastatic) BTC were included from six clinical trials (February 2004 to March 2017). Serum CA19-9, IL6, and YKL-40 were measured before and during palliative treatment. Associations between candidate biomarkers and progression-free survival (PFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression. Effects of inhibiting IL6R and YKL-40 were assessed in vitro, and of IL6R inhibition in vivo.

Results: High pretreatment levels of CA19-9, IL6, and YKL-40, and increasing levels during treatment, were associated with short PFS and OS in patients with advanced BTC. IL6 provided independent prognostic information, independent of tumor location and in patients with normal serum CA19-9. ROC analyses showed that IL6 and YKL-40 were predictive of very short OS (OS < 6 months), whereas CA19-9 was best to predict OS > 1.5 years. Treatment with anti-IL6R and gemcitabine significantly diminished tumor growth when compared with gemcitabine monotherapy in an in vivo transplant model of BTC.

Conclusions: Serum IL6 and YKL-40 are potential new prognostic biomarkers in BTC. IL6 provides independent prognostic information and may be superior to CA19-9 in certain contexts. Moreover, anti-IL6R should be considered as a new treatment option to sustain gemcitabine response in patients with BTC.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:5655–67

  • Received August 16, 2019.
  • Revision received April 23, 2020.
  • Accepted August 17, 2020.
  • Published first September 15, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers
Dan Høgdall, Colm J. O'Rourke, Christian Dehlendorff, Ole F. Larsen, Lars H. Jensen, Astrid Z. Johansen, Hien Dang, Valentina M. Factor, Mie Grunnet, Morten Mau-Sørensen, Douglas V.N.P. Oliveira, Dorte Linnemann, Mogens K. Boisen, Xin W. Wang, Julia S. Johansen and Jesper B. Andersen
Clin Cancer Res November 1 2020 (26) (21) 5655-5667; DOI: 10.1158/1078-0432.CCR-19-2700

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Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers
Dan Høgdall, Colm J. O'Rourke, Christian Dehlendorff, Ole F. Larsen, Lars H. Jensen, Astrid Z. Johansen, Hien Dang, Valentina M. Factor, Mie Grunnet, Morten Mau-Sørensen, Douglas V.N.P. Oliveira, Dorte Linnemann, Mogens K. Boisen, Xin W. Wang, Julia S. Johansen and Jesper B. Andersen
Clin Cancer Res November 1 2020 (26) (21) 5655-5667; DOI: 10.1158/1078-0432.CCR-19-2700
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