Abstract IA10: Angiopoietin/Tie2 as predictive biomarkers for bevacizumab in ovarian cancer

Abstract

Abstract Ovarian cancer1 is the commonest cause of gynecological cancer death in the West accounting for approximately 7,000 lives in the UK and 22,000 women in the US each year. Surgery and platinum-based chemotherapy have remained the principal treatment modalities for several decades but in the last few years critical improvements in therapy have been made. These have been based on the implementation of PARP inhibitors in patients whose disease harbors BRCA gene mutations and the deployment of anti-angiogenic agents. Several trials have validated the tumor vasculature as a target in the treatment of ovarian cancer, through the addition of VEGF pathway inhibitors to cytotoxic chemotherapy followed by single agent VEGF inhibitors until a year after chemotherapy or until progression. Trials have been carried out in the first line2-4, second line platinum sensitive5 setting and in the platinum-resistant setting6 with the general observation that the addition of VEGF inhibitors to treatment improves progression free survival (PFS) and, in a pre-planned subgroup analysis of one trial, an improvement in overall survival (OS). ICON72 was a first line randomized, controlled trial in which over 1500 patients with FIGO stage Ic to IV ovarian cancer were randomly allocated to receive treatment with carboplatin and paclitaxel or the same regimen supplemented with the anti-VEGF monoclonal antibody, bevacizumab, which was continued for a year in total. The results demonstrated an improvement in PFS in patients at high risk of progression and an overall survival advantage in the same group. Patients with early stage disease did not benefit. VEGF inhibitors have improved PFS in a statistically significant manner in multiple clinical trials yet the effects remain clinically somewhat modest. Taken in conjunction with their moderate toxicity and expense, there was a clear need to identify predictive biomarkers that would allow oncologists to prescribe these agents to the patients most likely to benefit. We therefore validated a multiplex ELISA assay7 to quantify the concentration of several angiogenesis-related molecules in plasma samples taken from patients before treatment, on treatment and at progression. Examining pre-treatment concentrations of plasma angiogenesis-related molecules, while taking into account established clinical prognostic factors, we detected and validated a biomarker signature in which we showed that patients with supra-median concentrations of Ang1 and infra-median concentrations of Tie2 benefitted from bevacizumab. We have now extended this analysis to the blood samples taken from patients on treatment and at the development of progressive disease. The data show that the plasma concentration of Tie2 decreases during treatment with bevacizumab but that this is not seen in patients receiving treatment with cytotoxic therapy alone suggesting that plasma Tie2 is potentially a marker of vascular response. In keeping with this hypothesis, we saw an increase in Tie2 concentrations in patients developing progressive disease and have developed a model to combine changes in Ang1, Tie2 and Ca-125 to determine if these parameters can be used as early detectors of progressive disease. Such a tool would be useful in determining when to stop VEGF inhibitors and/or to change anti-angiogenic therapy to drugs with an alternative anti-vascular mode of action. Acknowledgements: This work was funded by Cancer Research UK and the ICON7 trial was overseen by the MRC (UK) Clinical Trials Unit. Roche (Basel, Switzerland) funded the international sample collection.