Angiogenic and anti-angiogenic VEGFA splice variants in colorectal cancer: A prospective retrospective cohort study in patients treated with irinotecan-based chemotherapy and bevacizumab

Abstract Background Alternative splicing of VEGFA results in VEGFAxxxb anti-angiogenic isoforms that fail to activate angiogenesis. Bevacizumab, widely used in patients with metastatic colorectal cancer (mCRC), binds both VEGFA and VEGFAxxxb isoforms. Patients and Methods Formalin-fixed paraffin-embedded primary tumors from mCRC patients treated with 1 st line FOLFIRI+Bevacizumab (Nbev=285) or FOLFIRI only (Nchem=75) were collected. The relative expression of VEGFA isoforms 121a, 121b, 145a, 145b, 165a, and 165b was assessed with custom Taqman-MGB assays and qRT-PCR. Results At a median follow-up of 101.5 months, left-sided primary (L-CRC) was a favorable prognosticator [median survival: 29.2 vs. 18.2 months, p=0.015]. Positive high VEGFA145b was an unfavorable factor for PFS (HR=1.66, 95% CI 1.13-2.44, p=0.009) in Nbev patients, without prognostic significance in Nchem patients (HR=0.70, 95% CI 0.34-1.44, p=0.33). The adverse effect on PFS of 145b was more pronounced in patients with right-sided colon cancer (HR=2.62, 95% CI 1.35-5.12, p=0.005), especially in bevacizumab-treated (HR=2.85, 95% CI 1.31-6.21, p=0.008). In patients with right-sided colon primaries, 121b correlated with inferior PFS (HR 1.73, 95% CI 0.94-3.18, p=0.076) and OS (HR 2.0, 95% CI 1.08-3.72, p=0.028). In patients with left-sided primaries, positive high 165b correlated with superior PFS (HR 0.76, 95% CI 0.59-0.99, p=0.044) and 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), while 145b consistently retained predictive significance for lack of benefit in PFS with bevacizumab (HR=1.71, 95% CI 1.16-2.53). Multivariate analysis for OS showed that VEGFA165b expression was favorable in patients with left, but unfavorable in patients with right-sided primaries (interaction p Conclusions The antiangiogenic isoform VEGFA145b mRNA may predict for resistance to bevacizumab. Differences with biological relevance and prognostic significance of various VEGFA isoforms were shown for right versus left-sided primaries.