Plasma Tie2 trajectories identify vascular response criteria for VEGF inhibitors across advanced biliary tract, colorectal and ovarian cancers

C Zhou; J O'Connor; A Backen; J W Valle; J Bridgewater; C Dive; G C Jayson

doi:10.1016/j.esmoop.2022.100417

Plasma Tie2 trajectories identify vascular response criteria for VEGF inhibitors across advanced biliary tract, colorectal and ovarian cancers

ESMO Open. 2022 Apr;7(2):100417. doi: 10.1016/j.esmoop.2022.100417. Epub 2022 Mar 10.

Authors

C Zhou¹, J O'Connor², A Backen³, J W Valle⁴, J Bridgewater⁵, C Dive¹, G C Jayson⁶

Affiliations

¹ CRUK Manchester Institute Cancer Biomarker Centre, University of Manchester, Manchester, UK.
² Division of Cancer Sciences, University of Manchester, Manchester, UK; Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK.
³ Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK.
⁴ The Christie NHS Foundation Trust, Manchester, UK.
⁵ University College Hospital Macmillan Cancer Centre, Huntley Street, London, UK.
⁶ Division of Cancer Sciences, University of Manchester, Manchester, UK; The Christie NHS Foundation Trust, Manchester, UK. Electronic address: Gordon.Jayson@manchester.ac.uk.

Abstract

Background: Vascular endothelial growth factor inhibitors (VEGFi) are compromised by a lack of validated biomarkers. Previously we showed that changes in the concentration of plasma Tie2 (pTie2) was a response biomarker for bevacizumab. Here, we investigated whether pTie2 can predict response and progression cross-tumour for generic VEGFi treatment.

Patients and methods: Patients (n = 124) with advanced biliary tract cancer (ABC) received cisplatin/gemcitabine with cediranib or placebo (ABC-03 trial). Concentrations of pTie2 were measured longitudinally from before treatment until disease progression. Data from patients with ovarian cancer (n = 92, ICON7 trial) and patients with colorectal cancer (CRC) (n = 70, Travastin trial) were also included.

Results: Cediranib-treated ABC patients were deconvoluted into distinct groups where in one group pTie2 trajectories resembled those seen in placebo-treated patients and in another pTie2 significantly reduced (t-test P = 2.7 × 10^-14). Using the 95% confidence interval for these two groups, we defined a vascular complete response (vCR) as a 24% reduction in pTie2 within 9 weeks; vascular no response (vNR) as a 7% increase in pTie2, and a vascular partial response (between these limits). vCR cediranib-treated patients had significantly improved progression-free survival (8.8 versus 7.5 months, restricted mean ratio 0.73, P = 0.012) and overall survival (18.8 versus 12.1 months, hazard ratio 0.49, P = 0.02). By integrating data across ovarian cancer, CRC and ABC, we show that (i) patients with vNR do not benefit from VEGFi and (ii) Tie2-defined vascular progression occurs sufficiently in advance of radiological progressive disease that changes in treatment could be offered to prevent clinical deterioration.

Conclusion: pTie2 is the first cross-tumour, generic VEGFi, vascular response biomarker to guide optimum use of VEGFi in clinical practice.

Keywords: Tie2; VEGF inhibitor; angiogenesis; bile duct cancer; response biomarker.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biliary Tract* / metabolism
Biomarkers, Tumor
Colorectal Neoplasms* / drug therapy
Female
Humans
Ovarian Neoplasms* / drug therapy
Vascular Endothelial Growth Factor A / therapeutic use

Substances

Biomarkers, Tumor
Vascular Endothelial Growth Factor A

Abstract

Publication types

MeSH terms

Substances

Grants and funding