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

Robert D Morgan, Cristina Ferreras, Isabel Peset, Egle Avizienyte, Andrew G Renehan, Richard J Edmondson, Alexander D Murphy, Shibani Nicum, Thomas Van Brussel, Andrew R Clamp, Diether Lambrechts, Cong Zhou, Gordon C Jayson, Robert D Morgan, Cristina Ferreras, Isabel Peset, Egle Avizienyte, Andrew G Renehan, Richard J Edmondson, Alexander D Murphy, Shibani Nicum, Thomas Van Brussel, Andrew R Clamp, Diether Lambrechts, Cong Zhou, Gordon C Jayson

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.

Keywords: Bevacizumab; Epithelial ovarian cancer; VEGFR-2, Single-nucleotide polymorphisms; c-MET.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
A Kaplan-Meier estimates of overall survival in patients (n = 87) treated with carboplatin/paclitaxel plus bevacizumab (experimental group). Patients are dichotomised by their median average expression of c-MET/VEGFR-2 into c-MET/VEGFR-2HIGH (n = 42) and c-MET/VEGFR-2LOW (n = 45) groups. The median OS was 39.3 months for c-MET/VEGFR-2HIGH and >60 months c-MET/VEGFR-2LOW (HR 2.00, P = 0.03). B Kaplan-Meier estimates of overall survival in patients (n=90) treated with carboplatin/paclitaxel (control group). Patients are dichotomised by their median average expression of c-MET/VEGFR-2 into c-MET/VEGFR-2HIGH (n = 46) and c-MET/VEGFR-2LOW (n = 44) groups. Both groups had a median OS > 60 months.
Fig. 2
Fig. 2
A Kaplan-Meier estimates of progression-free survival in patients (n = 231) treated with carboplatin/paclitaxel plus bevacizumab (experimental group). Patients are separated into two groups: those with the VEGFR-2 rs2305945 G/G variant (n = 93) and those with the VEGFR-2 rs2305945 G/T or T/T variant (n = 138). The median PFS was 18.2 months for those patients with the VEGFR-2 rs2305945 G/G variant and 23.0 months for those with the VEGFR-2 rs2305945 G/T or T/T variant (HR 0.74, P = 0.07). B Kaplan-Meier estimates of progression-free survival in patients (n = 214) treated with carboplatin/paclitaxel (control group). Patients are separated into two groups: those with the VEGFR-2 rs2305945 G/G variant (n = 83) and those with the VEGFR-2 rs2305945 G/T or T/T variant (n = 131). The median PFS was 21.2 months for those patients with the VEGFR-2 rs2305945 G/G variant and 15.6 months for those with the VEGFR-2 rs2305945 G/T or T/T variant (HR 1.14, P = 0.48)

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