Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial

Alison Backen; Andre Lopes; Harpreet Wasan; Daniel H Palmer; Marian Duggan; David Cunningham; Alan Anthoney; Pippa G Corrie; Srinivasan Madhusudan; Anthony Maraveyas; Paul J Ross; Justin S Waters; William P  Steward; Charlotte Rees; Mairead Mcnamara; Sandy Beare; John A Bridgewater; Caroline Dive; Juan Valle

doi:10.1038/s41416-018-0132-8

Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial

Alison Backen, Andre Lopes, Harpreet Wasan, Daniel H Palmer, Marian Duggan, David Cunningham, Alan Anthoney, Pippa G Corrie, Srinivasan Madhusudan, Anthony Maraveyas, Paul J Ross, Justin S Waters, William P Steward, Charlotte Rees, Mairead Mcnamara, Sandy Beare, John A Bridgewater, Caroline Dive, Juan Valle

Research output: Contribution to journal › Article › peer-review

Abstract

Background Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib in addition to cisplatin/gemcitabine [CisGem] improved the response rate but did not improve progression-free survival (PFS) in the ABC-03 study. Minimally-invasive biomarkers predictive of cediranib benefit may improve patient outcomes. Methods Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). Results Samples were available from n=117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P<0.001 and P=0.02, respectively). Conclusions Rising circulating VEGFA levels, in patients with ABC treated with CisGem are associated with a worse PFS and OS; not seen in patients receiving cediranib. Rising levels of markers of tumor burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.

Original language	English
Journal	British Journal of Cancer
Volume	119
DOIs	https://doi.org/10.1038/s41416-018-0132-8
Publication status	Published - 21 Jun 2018

Keywords

angiogenesis
biomarkers
biliary-tract-cancer
cediranib
VEGF

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Backen, A., Lopes, A., Wasan, H., Palmer, D. H., Duggan, M., Cunningham, D., Anthoney, A., Corrie, P. G., Madhusudan, S., Maraveyas, A., Ross, P. J., Waters, J. S., Steward, W. P., Rees, C., Mcnamara, M., Beare, S., Bridgewater, J. A., Dive, C., & Valle, J. (2018). Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial. British Journal of Cancer, 119. https://doi.org/10.1038/s41416-018-0132-8

@article{e2fb8e6d874341dba14eaa94b953c6a0,

title = "Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial",

abstract = "Background Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib in addition to cisplatin/gemcitabine [CisGem] improved the response rate but did not improve progression-free survival (PFS) in the ABC-03 study. Minimally-invasive biomarkers predictive of cediranib benefit may improve patient outcomes. Methods Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). Results Samples were available from n=117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P<0.001 and P=0.02, respectively). Conclusions Rising circulating VEGFA levels, in patients with ABC treated with CisGem are associated with a worse PFS and OS; not seen in patients receiving cediranib. Rising levels of markers of tumor burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation. ",

keywords = "angiogenesis , biomarkers , biliary-tract-cancer , cediranib , VEGF",

author = "Alison Backen and Andre Lopes and Harpreet Wasan and Palmer, {Daniel H} and Marian Duggan and David Cunningham and Alan Anthoney and Corrie, {Pippa G} and Srinivasan Madhusudan and Anthony Maraveyas and Ross, {Paul J} and Waters, {Justin S} and Steward, {William P} and Charlotte Rees and Mairead Mcnamara and Sandy Beare and Bridgewater, {John A} and Caroline Dive and Juan Valle",

year = "2018",

month = jun,

day = "21",

doi = "10.1038/s41416-018-0132-8",

language = "English",

volume = "119",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

}

Backen, A, Lopes, A, Wasan, H, Palmer, DH, Duggan, M, Cunningham, D, Anthoney, A, Corrie, PG, Madhusudan, S, Maraveyas, A, Ross, PJ, Waters, JS, Steward, WP, Rees, C, Mcnamara, M, Beare, S, Bridgewater, JA, Dive, C & Valle, J 2018, 'Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial', British Journal of Cancer, vol. 119. https://doi.org/10.1038/s41416-018-0132-8

TY - JOUR

T1 - Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial

AU - Backen, Alison

AU - Lopes, Andre

AU - Wasan, Harpreet

AU - Palmer, Daniel H

AU - Duggan, Marian

AU - Cunningham, David

AU - Anthoney, Alan

AU - Corrie, Pippa G

AU - Madhusudan, Srinivasan

AU - Maraveyas, Anthony

AU - Ross, Paul J

AU - Waters, Justin S

AU - Steward, William P

AU - Rees, Charlotte

AU - Mcnamara, Mairead

AU - Beare, Sandy

AU - Bridgewater, John A

AU - Dive, Caroline

AU - Valle, Juan

PY - 2018/6/21

Y1 - 2018/6/21

N2 - Background Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib in addition to cisplatin/gemcitabine [CisGem] improved the response rate but did not improve progression-free survival (PFS) in the ABC-03 study. Minimally-invasive biomarkers predictive of cediranib benefit may improve patient outcomes. Methods Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). Results Samples were available from n=117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P<0.001 and P=0.02, respectively). Conclusions Rising circulating VEGFA levels, in patients with ABC treated with CisGem are associated with a worse PFS and OS; not seen in patients receiving cediranib. Rising levels of markers of tumor burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.

AB - Background Advanced biliary tract cancer (ABC) has a poor prognosis. Cediranib in addition to cisplatin/gemcitabine [CisGem] improved the response rate but did not improve progression-free survival (PFS) in the ABC-03 study. Minimally-invasive biomarkers predictive of cediranib benefit may improve patient outcomes. Methods Changes in 15 circulating plasma angiogenesis or inflammatory-related proteins and cytokeratin-18 (CK18), measured at baseline and during therapy until disease progression, were correlated with overall survival (OS) using time-varying covariate Cox models (TVC). Results Samples were available from n=117/124 (94%) patients. Circulating Ang1&2, FGFb, PDGFbb, VEGFC, VEGFR1 and CK18 decreased as a result of therapy, independent of treatment with cediranib. Circulating VEGFR2 and Tie2 were preferentially reduced by cediranib. Patients with increasing levels of VEGFA at any time had a worse PFS and OS; this detrimental effect was attenuated in patients receiving cediranib. TVC analysis revealed CK18 and VEGFR2 increases correlated with poorer OS in all patients (P<0.001 and P=0.02, respectively). Conclusions Rising circulating VEGFA levels, in patients with ABC treated with CisGem are associated with a worse PFS and OS; not seen in patients receiving cediranib. Rising levels of markers of tumor burden (CK18) and potential resistance (VEGFR2) are associated with worse outcomes and warrant validation.

KW - angiogenesis

KW - biomarkers

KW - biliary-tract-cancer

KW - cediranib

KW - VEGF

U2 - 10.1038/s41416-018-0132-8

DO - 10.1038/s41416-018-0132-8

M3 - Article

SN - 0007-0920

VL - 119

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

Circulating biomarkers during treatment in patients with advanced biliary tract cancer receiving cediranib in the UK ABC-03 trial

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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