Research Papers:

Tumour vasculature immaturity, oxidative damage and systemic inflammation stratify survival of colorectal cancer patients on bevacizumab treatment

Sinead A. Noonan, Maria E. Morrissey, Petra Martin, Monika Biniecka, Shane Ó’Meachair, Aoife Maguire, Miriam Tosetto, Blathnaid Nolan, John Hyland, Kieran Sheahan, Diarmuid O’Donoghue, Hugh Mulcahy, David Fennelly and Jacintha O’Sullivan _

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Oncotarget. 2018; 9:10536-10548. https://doi.org/10.18632/oncotarget.24276

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Sinead A. Noonan1,*, Maria E. Morrissey2,*, Petra Martin1, Monika Biniecka3, Shane Ó’Meachair4, Aoife Maguire5, Miriam Tosetto1, Blathnaid Nolan1, John Hyland1, Kieran Sheahan1, Diarmuid O’Donoghue1, Hugh Mulcahy1, David Fennelly1 and Jacintha O’Sullivan2

1Centre for Colorectal Disease, St. Vincent’s University Hospital, University College Dublin, Dublin, Ireland

2Trinity Translational Medicine Institute (TTMI), Department of Surgery, Trinity College Dublin, St James’s Hospital, Dublin, Ireland

3Education and Research Centre, St. Vincent’s University Hospital, University College Dublin, Dublin, Ireland

4Centre for Health Decision Science (CHeDS), School of Computer Science and Statistics, Trinity College Dublin, Dublin, Ireland

5Department of Histopathology, St. James’s Hospital, Dublin, Ireland

*These authors have contributed equally to this work

Correspondence to:

Jacintha O’Sullivan, email: [email protected]

Keywords: bevacizumab; predictive biomarkers; metastatic colorectal cancer; vasculature; inflammation

Abbreviations: mCRC: Metastatic colorectal cancer; VEGF: vascular endothelial growth factor; FFPE: formalin-fixed, paraffin-embedded; TMA: tissue microarrays; OS: overall survival

Received: September 08, 2017     Accepted: January 02, 2018     Published: January 19, 2018


Despite treatment of patients with metastatic colorectal cancer (mCRC) with bevacizumab plus chemotherapy, response rates are modest and there are no biomarkers available that will predict response. The aim of this study was to assess if markers associated with three interconnected cancer-associated biological processes, specifically angiogenesis, inflammation and oxidative damage, could stratify the survival outcome of this cohort.

Levels of angiogenesis, inflammation and oxidative damage markers were assessed in pre-bevacizumab resected tumour and serum samples of mCRC patients by dual immunofluorescence, immunohistochemistry and ELISA.

This study identified that specific markers of angiogenesis, inflammation and oxidative damage stratify survival of patients on this anti-angiogenic treatment. Biomarkers of immature tumour vasculature (% IMM, p=0.026, n=80), high levels of oxidative damage in the tumour epithelium (intensity of 8-oxo-dG in nuclear and cytoplasmic compartments, p=0.042 and 0.038 respectively, n=75) and lower systemic pro-inflammatory cytokines (IL6 and IL8, p=0.053 and 0.049 respectively, n=61) significantly stratify with median overall survival (OS).

In summary, screening for a panel of biomarkers for high levels of immature tumour vasculature, high levels of oxidative DNA damage and low levels of systemic pro-inflammatory cytokines may be beneficial in predicting enhanced survival outcome following bevacizumab treatment for mCRC.

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