Alternate (distal) splicing of VEGF-A isoforms results in production of VEGF-Axxxb anti-angiogenic proteins that fail to activate the angiogenic cascade. Bevacizumab, widely used in patients with metastatic colorectal cancer (mCRC), binds both VEGFA and VEGFAxxxb isoforms.
Formalin-fixed paraffin-embedded primary tumours from mCRC patients treated in 1st line with FOLFIRI+Bevacizumab (Nbev=285) or FOLFIRI only (Nchem=75) were collected, mRNA was extracted, amplified and quantified with qRT-PCR (Taqman-MGB-assays) for the relative expression of VEGF-A 121a, 121b, 145a, 145b, 165a, 165b mRNA transcripts.
At a median follow-up of 101.5 months, patients with left-sided (L-CRC) compared to those with right-sided primaries (R-CRC) had longer overall survival (OS) [median OS: 29.2 vs. 18.2 months, p = 0.015]. High VEGFA 145b mRNA expression was an unfavourable factor for PFS (HR = 1.66,95% CI 1.13-2.44, p = 0.009) in Nbev patients, with no prognostic significance in Nchem patients (HR = 0.70, 95% CI 0.34-1.44, p = 0.33). The adverse PFS prognostic effect of 145b was more pronounced in R-CRC patients (HR = 2.62, 95% CI 1.35-5.12, p = 0.005), especially when bevacizumab-treated (HR = 2.85, 95% CI 1.31-6.21, p = 0.008). High VEGFA 121b was adversely prognostic for PFS (HR = 2.48, 95% CI 1.23-5.04, p = 0.012) , OS (HR = 2.00, 95% CI 1.08-3.72, p = 0.028) in right, but not left colon, while high 165b was a favourable prognosticator in left sided disease ( PFS HR = 0.76, 95% CI 0.59-0.99, p = 0.044, OS HR 0.68, 95% CI 0.52-0.90, p = 0.006). At multivariate analysis, right-sided primary was associated with inferior PFS (HR = 1.28, 95% CI 1.00-1.64, p = 0.051) and OS (HR = 1.33, 95% CI 1.02-1.73, p = 0.037), while high 145b mRNA expression consistently retained predictive significance for lack of PFS benefit from bevacizumab therapy (HR = 1.71, 95% CI 1.16-2.53, p = 0.007).
In a cohort of mCRC patients treated with bevacizumab, RQ of VEGF-A 145b mRNA, an anti-angiogenic isoform, may predict for resistance to bevacizumab, without prognostic utility in patients not exposed to the antibody. Differences in biological relevance of various VEGF-A isoforms were shown for right versus left-sided primaries.
Clinical trial identification
Legal entity responsible for the study
Hellenic Cooperative Oncology Group (HeCOG).
E. Samantas, G. Fountzilas: Advisory board: Roche. T. Makatsoris: Honoraria, advisory role: Roche. P. Papakostas: Advisory role: Roche. A. Psyrri: Consultation, honoraria: Roche. All other authors have declared no conflicts of interest.