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Angiogenic and Antiangiogenic VEGFA Splice Variants in Colorectal Cancer: Prospective Retrospective Cohort Study in
George Pentheroudakis1, Leonidas Mavroeidis1, Kyriaki Papadopoulou2
1Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece; Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece.
Background:
Alternative splicing of vascular endothelial growth factor A (VEGFA) results in VEGFAxxxb antiangiogenic isoforms that fail to activate angiogenesis. Bevacizumab, widely used in patients with metastatic colorectal cancer (CRC), binds both VEGFA and VEGFAxxxb isoforms.
Patients And Methods:
Formalin-fixed, paraffin-embedded primary tumors from metastatic CRC patients treated with first-line FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) + bevacizumab (n = 285) or FOLFIRI only (n = 75) were collected. The relative expression of VEGFA121a, 121b, 145a, 145b, 165a, and 165b was assessed with custom TaqMan-MGB assays and quantitative PCR.
Results:
At a median follow-up of 101.5 months, left-sided primary CRC was a favorable prognosticator (median survival, 29.2 vs. 18.2 months; P = .015). Positive high VEGFA145b was an unfavorable factor for progression-free survival (PFS; hazard ratio [HR] = 1.66; 95% confidence interval [CI], 1.13-2.44; P = .009) in patients who received FOLFIRI + bevacizumab, without prognostic significance in FOLFIRI-only patients (HR = 0.70; 95% CI, 0.34-1.44; P = .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 = .005), especially in those who received bevacizumab (HR = 2.85; 95% CI, 1.31-6.21; P = .008). In patients with right-sided colon primary tumors, isoform 121b correlated with inferior PFS (HR = 1.73; 95% CI, 0.94-3.18; P = .076) and overall survival (OS; HR = 2.0; 95% CI, 1.08-3.72; P = .028). In patients with left-sided primary tumors, positive high 165b correlated with superior PFS (HR = 0.76; 95% CI, 0.59-0.99; P = .044) and OS (HR = 0.68; 95% CI, 0.52-0.90; P = .006). At multivariate analysis, right-sided primary tumor 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-sided but unfavorable in patients with right-sided primary tumors (Pinteraction < .001).
Conclusion:
The antiangiogenic isoform VEGFA145b messenger RNA may predict resistance to bevacizumab. Differences in biological relevance and prognostic significance of various VEGFA isoforms were found for right- versus left-sided primary tumors.
Insights
Vascular Endothelial Growth Factor A (VEGFA) isoform 145b may predict resistance to bevacizumab in metastatic colorectal cancer. Tumor location influences VEGFA isoform prognostic significance, impacting treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Alternative splicing of vascular endothelial growth factor A (VEGFA) produces antiangiogenic VEGFAxxxb isoforms.
- Bevacizumab, a treatment for metastatic colorectal cancer (CRC), targets both proangiogenic and antiangiogenic VEGFA isoforms.
- Understanding VEGFA isoform expression is crucial for predicting treatment response in CRC.
Purpose of the Study:
- To investigate the prognostic and predictive significance of VEGFA splice variants in metastatic colorectal cancer patients.
- To determine if specific VEGFA isoforms correlate with treatment outcomes in patients receiving FOLFIRI plus bevacizumab or FOLFIRI alone.
- To explore the differential impact of VEGFA isoforms based on primary tumor location (right-sided vs. left-sided).
Main Methods:
- Quantitative PCR was used to measure the relative expression of VEGFA121a, 121b, 145a, 145b, 165a, and 165b.
- Tumor samples were from metastatic CRC patients treated with first-line FOLFIRI + bevacizumab (n=285) or FOLFIRI only (n=75).
- Statistical analyses, including hazard ratios and multivariate analysis, were performed to assess prognostic and predictive values.
Main Results:
- High VEGFA145b expression was associated with unfavorable progression-free survival (PFS) in patients receiving bevacizumab, particularly in right-sided tumors.
- VEGFA121b correlated with inferior PFS and overall survival (OS) in right-sided colon cancer patients.
- VEGFA165b expression was associated with superior PFS and OS in left-sided primary tumors, but unfavorable in right-sided tumors.
Conclusions:
- The antiangiogenic VEGFA145b isoform may predict resistance to bevacizumab in metastatic colorectal cancer.
- VEGFA isoform expression has differential biological relevance and prognostic significance depending on primary tumor location.
- Tumor sidedness and specific VEGFA splice variants are important factors in predicting treatment response and survival in CRC.
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