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Abstract
IntroductionBevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC). Pre-clinical data showed that the c-MET/VEGFR-2 heterocomplex negates VEGF inhibition through activation of c-MET signalling, leading to a more invasive and metastatic phenotype. We evaluated the clinical significance of c-MET and VEGFR-2 co-localisation and its association with VEGF pathway-related single nucleotide polymorphisms (SNPs) in women participating in the phase 3 trial, ICON7 (ClinicalTrials.gov identifier: NCT00262847).Materials and methodsPatients had FIGO stage I-IIA grade 3/poorly differentiated or clear cell carcinoma or stage IIB-IV epithelial ovarian, primary peritoneal or fallopian tube cancer. Immunofluorescence staining for co-localised c-MET and VEGFR-2 on tissue microarrays and genotyping of germline DNA from peripheral blood leukocytes for VEGFA and VEGFR-2 SNPs was performed. The significance of these biomarkers was assessed against survival.ResultsTissue microarrays from 178 women underwent immunofluorescence staining. Multivariable analysis showed that greater c-MET/VEGFR-2 co-localisation predicted worse OS in patients treated with bevacizumab after adjusting for FIGO stage and debulking surgery outcome (hazard ratio [HR] 1.034, 95% confidence interval [95%CI] 1.010–1.059). Women in the c-MET/VEGFR-2HIGH group treated with bevacizumab demonstrated significantly reduced OS (39.3 versus > 60 months; HR 2.00, 95%CI 1.08–3.72). Germline DNA from 449 women underwent genotyping. In the bevacizumab group, those women with the VEGFR-2 rs2305945 G/G variant had a trend towards shorter PFS compared with G/T or T/T variants (18.3 versus 23.0 months; HR 0.74, 95%CI 0.53–1.03).ConclusionsIn bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes.
Highlights
Bevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC)
Multivariable analysis showed that greater c-MET/VEGFR-2 co-localisation predicted worse overall survival (OS) in patients treated with bevacizumab after adjusting for FIGO stage and debulking surgery outcome
In bevacizumab-treated women diagnosed with EOC, high c-MET/VEGFR-2 co-localisation on tumour tissue and the VEGFR-2 rs2305945 G/G variant, which may be biologically related, were associated with worse survival outcomes
Summary
Bevacizumab improves survival outcomes in women diagnosed with epithelial ovarian cancer (EOC). We evaluated the clinical significance of c-MET and VEGFR-2 co-localisation and its association with VEGF pathway-related single nucleotide polymorphisms (SNPs) in women participating in the phase 3 trial, ICON7 (ClinicalTrials.gov identifier: NCT00262847). Multi-modality first-line therapy includes cytoreductive surgery plus platinum-based chemotherapy, followed by maintenance therapies in certain subgroups [2]. One such maintenance therapy is the anti-angiogenic agent, bevacizumab, a humanised monoclonal antibody directed against vascular endothelial growth factor (VEGF) [3]. Two randomised phase 3 trials, ICON7 and GOG-0218, demonstrated significant improvements in progression-free survival (PFS) using bevacizumab as part of the first-line therapy, with improvements in overall survival (OS) in patients at the highest risk of relapse [4,5,6,7]. While we have identified plasma Tie as the first response biomarker for VEGF inhibitors, we were unable to identify a biomarker that would predict the benefit from bevacizumab [8,9,10]
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