Predictive tissue biomarkers for bevacizumab-containing therapy in metastatic colorectal cancer: an update

Abstract

Bevacizumab is the first anti-angiogenic agent approved for the treatment of metastatic colorectal cancer. The need for patient selection before initiating therapy necessitates the study of various proteins expressed in metastatic colorectal cancer tissue as candidate predictive markers. Immunohistochemistry is a valuable, commonly available and cost-effective method to assess predictive biomarkers. However, it is subject to variations and therefore requires rigorous protocol standardizations. Furthermore, validated quantification methodologies to study these angiogenic elements have to be applied. Based on their function in tumor angiogenesis and their relation to the mechanism of action of bevacizumab, protein markers were divided in four groups: VEGF A-signaling proteins; other relevant angiogenesis factors; factors regarding the tumor microenvironment and tumor intrinsic markers. Conceivably, nimbly selecting a small but relevant group of therapy-guided patients by the appropriate combination of predictive biomarkers may confer great value to this angiogenic inhibitor.

Keywords:

• anti-angiogenesis
• Avastin^®
• bevacizumab
• immunohistochemistry
• metastatic colorectal cancer
• predictive biomarker
• VEGF inhibitor

Acknowledgements

The authors thank S De Schepper, B Franck and E Van Vré for their suggestions and directions during the writing of the manuscript. L Andries and I Bergwerf assisted with the image acquisition and formatting of the images. The authors thank J Linnegar, E Ross and A Vandebroek for language editing.

Financial & competing interests disclosure

KM Marien, V Croons, C Ung, W Waelput and MM Kockx are employees of HistoGeneX NV, Antwerp, Belgium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Current biomarkers can be categorized in the following groups:

  • – VEGFA-signaling proteins. When VEGFA-binding proteins are overexpressed in a tumor before therapy, the tumor is probably already adapted to cope with the deprivation of VEGFA and will survive bevacizumab therapy; however, overexpression of VEGFA, the target of bevacizumab, does not have predictive value, in part because the different isoforms may not be detected.

  • – Other relevant angiogenesis factors. When these are overexpressed, the tumor cell may redirect its reliance from VEGFA to these factors for vascular supply.

  • – Factors regarding the tumor microenvironment. The tumor may overexpress these factors that interfere with the delivery of chemotherapy and/or bevacizumab. They can also have a synergistic effect.

  • – Tumor intrinsic markers. These may phenotypically and functionally describe the tumor cells and demonstrate indirect links to angiogenesis.

• A meticulously developed, fit-for-purpose immunohistochemistry assay will enable longitudinal assessment and comparisons across large patient sets.

• The specimen origin (primary vs metastatic) is important as well as the timing of the sampling relative to the metastasis (synchronous vs metachronous presentation).

• Study of protein markers requires knowledge of the potentially occurring isoforms and post-translational modifications. Because tumor angiogenesis is a redundant process, multiple markers will be required to predict patient survival after bevacizumab-combining therapy.

Notes