1. Angiogenic and Antiangiogenic VEGFA Splice Variants in Colorectal Cancer: Prospective Retrospective Cohort Study in Patients Treated With Irinotecan-Based Chemotherapy and Bevacizumab
- Author
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Christina Bamia, Epaminontas Samantas, Georgia Kafiri, Dimitrios Bafaloukos, George Fountzilas, Sofia Chrisafi, Ioannis Efstratiou, Dimitrios Pectasides, Kyriaki Papadopoulou, Iliada Bombolaki, George Pentheroudakis, Thomas Makatsoris, Leonidas Mavroeidis, Georgia-Angeliki Koliou, Kyriakos Chatzopoulos, Kalliopi Petraki, Helen P. Kourea, George Papatsibas, Vassiliki Kotoula, Pavlos Papakostas, and Davide Mauri
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Oncology ,Colorectal cancer ,Leucovorin ,Angiogenesis Inhibitors ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Protein Isoforms ,Prospective Studies ,Hazard ratio ,Gastroenterology ,Middle Aged ,Prognosis ,Primary tumor ,Bevacizumab ,Gene Expression Regulation, Neoplastic ,Oxaliplatin ,Survival Rate ,Vascular endothelial growth factor ,030220 oncology & carcinogenesis ,FOLFIRI ,Female ,030211 gastroenterology & hepatology ,Fluorouracil ,Colorectal Neoplasms ,medicine.drug ,medicine.medical_specialty ,Irinotecan ,03 medical and health sciences ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Capecitabine ,Aged ,Retrospective Studies ,business.industry ,medicine.disease ,Alternative Splicing ,chemistry ,Drug Resistance, Neoplasm ,Angiogenesis Inducing Agents ,Camptothecin ,business ,Follow-Up Studies - Abstract
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 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.
- Published
- 2019