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    c-MET/VEGFR-2 co-localisation impacts on survival following bevacizumab therapy in epithelial ovarian cancer: an exploratory biomarker study of the phase 3 ICON7 trial

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    Authors
    Morgan, Robert David
    Ferreras, C.
    Peset, I.
    Avizienyte, E.
    Renehan, Andrew G
    Edmondson, R. J.
    Murphy, A. D.
    Nicum, S.
    Van Brussel, T.
    Clamp, Andrew R
    Lambrechts, D.
    Zhou, C.
    Jayson, Gordon C
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    Issue Date
    2022
    
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    Abstract
    Introduction Bevacizumab 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 methods Patients 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. Results Tissue 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). Conclusions 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.
    Citation
    Morgan RD, Ferreras C, Peset I, Avizienyte E, Renehan AG, Edmondson RJ, et al. c-MET/VEGFR-2 co-localisation impacts on survival following bevacizumab therapy in epithelial ovarian cancer: an exploratory biomarker study of the phase 3 ICON7 trial [Internet]. Vol. 20, BMC Medicine. Springer Science and Business Media LLC; 2022.
    Journal
    BMC Medicine
    URI
    http://hdl.handle.net/10541/625093
    DOI
    10.1186/s12916-022-02270-y
    Additional Links
    https://dx.doi.org/10.1186/s12916-022-02270-y
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12916-022-02270-y
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