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

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Høgdall, Dan ; O'Rourke, Colm J ; Dehlendorff, Christian ; Larsen, Ole F ; Jensen, Lars H ; Johansen, Astrid Z ; Dang, Hien ; Factor, Valentina M ; Grunnet, Mie ; Mau-Sørensen, Morten ; Oliveira, Douglas V N P ; Linnemann, Dorte ; Boisen, Mogens K ; Wang, Xin W ; Johansen, Julia S ; Andersen, Jesper B. / Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers. I: Clinical Cancer Research. 2020 ; Bind 26, Nr. 21. s. 5655-5667.

Bibtex

@article{b4202c6daa4546bba37ab4bbf92b840e,
title = "Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers",
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.",
author = "Dan H{\o}gdall and O'Rourke, {Colm J} and Christian Dehlendorff and Larsen, {Ole F} and Jensen, {Lars H} and Johansen, {Astrid Z} and Hien Dang and Factor, {Valentina M} and Mie Grunnet and Morten Mau-S{\o}rensen and Oliveira, {Douglas V N P} and Dorte Linnemann and Boisen, {Mogens K} and Wang, {Xin W} and Johansen, {Julia S} and Andersen, {Jesper B}",
note = "{\circledC}2020 American Association for Cancer Research.",
year = "2020",
month = "11",
day = "1",
doi = "10.1158/1078-0432.CCR-19-2700",
language = "English",
volume = "26",
pages = "5655--5667",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research (A A C R)",
number = "21",

}

RIS

TY - JOUR

T1 - Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers

AU - Høgdall, Dan

AU - O'Rourke, Colm J

AU - Dehlendorff, Christian

AU - Larsen, Ole F

AU - Jensen, Lars H

AU - Johansen, Astrid Z

AU - Dang, Hien

AU - Factor, Valentina M

AU - Grunnet, Mie

AU - Mau-Sørensen, Morten

AU - Oliveira, Douglas V N P

AU - Linnemann, Dorte

AU - Boisen, Mogens K

AU - Wang, Xin W

AU - Johansen, Julia S

AU - Andersen, Jesper B

N1 - ©2020 American Association for Cancer Research.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-19-2700

DO - 10.1158/1078-0432.CCR-19-2700

M3 - Journal article

VL - 26

SP - 5655

EP - 5667

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 21

ER -

ID: 61014121