George Pentheroudakis1, Vassiliki Kotoula2, George Kouvatseas3, Elpida Charalambous4, Dimitrios Dionysopoulos5, Flora Zagouri6, Angelos Koutras7, Konstantinos Papazisis8, Dimitrios Pectasides9, Epaminontas Samantas10, Meletios A Dimopoulos6, Christos N Papandreou11, George Fountzilas12. 1. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. Electronic address: gpenther@otenet.gr. 2. Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 3. Health Data Specialists Ltd, Athens, Greece. 4. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 5. Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 6. Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece. 7. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece. 8. Third Department of Medical Oncology, Theagenion Cancer Hospital, Thessaloniki, Greece. 9. Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece. 10. Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece. 11. Department of Medical Oncology, University Hospital of Larissa, University of Thessaly School of Medicine, Larissa, Greece. 12. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
Abstract
BACKGROUND: The prognostic utility of vascular endothelial growth factor A (VEGF-A) splice variants in patients with advanced breast cancer treated withbevacizumab has not been studied. PATIENTS AND METHODS: A total of 111 patients with metastatic breast cancer treated with weeklydocetaxel or ixabepilone without bevacizumab (cohort A) and 100 treated with weekly paclitaxel and bevacizumab (cohort B) were studied. Formalin-fixed tumors were macrodissected for reverse transcription quantitative polymerase chain reaction relative quantification of VEGF-A165, -189, and -206 isoforms spliced at exon 8 proximal splice site (VEGF-Axxxa) and at exon 8 distal splice site (VEGF-Axxxb). RESULTS: For high VEGF-Axxxa, the hazard ratios (HRs) for progression were 1.08 (P = .71) in non-bevacizumab-treated patients (cohort A) and 0.66 (P = .22) in bevacizumab-treated patients (cohort B), and the HRs for death were 1.45 (P = .13) and 0.50 (P = .049), respectively. The interaction of VEGF-Axxxa with bevacizumab administration was significant (P = .011) for overall survival (OS). High tissue VEGF-Axxxb was not prognostic in cohort A but was predictive for bevacizumab benefit in cohort B (HR for progression, 0.57 [P = .04]; HR for death, 0.51 [P = .02]). Exploratory analyses done only in cohort B suggested that abundance of VEGFR1 messenger RNA (mRNA) in peripheral blood and low VEGFR2 mRNA in tissue correlated with poor outcome. In multivariate analysis, high tissue mRNA of angiogenic VEGF-Axxxa in the presence of bevacizumab therapy predicted for favorable progression-free survival (HR for progression, 0.39; P = .0227) and OS (HR for death, 0.32; P = .0140). CONCLUSION: Tissue mRNA expression of angiogenic VEGF-Axxxa isoforms was retrospectively associated with adverse prognosis in the absence of bevacizumab and with favorable outcome when bevacizumab was administered in patients with advanced breast cancer.
RCT Entities:
BACKGROUND: The prognostic utility of vascular endothelial growth factor A (VEGF-A) splice variants in patients with advanced breast cancer treated with bevacizumab has not been studied. PATIENTS AND METHODS: A total of 111 patients with metastatic breast cancer treated with weekly docetaxel or ixabepilone without bevacizumab (cohort A) and 100 treated with weekly paclitaxel and bevacizumab (cohort B) were studied. Formalin-fixed tumors were macrodissected for reverse transcription quantitative polymerase chain reaction relative quantification of VEGF-A165, -189, and -206 isoforms spliced at exon 8 proximal splice site (VEGF-Axxxa) and at exon 8 distal splice site (VEGF-Axxxb). RESULTS: For high VEGF-Axxxa, the hazard ratios (HRs) for progression were 1.08 (P = .71) in non-bevacizumab-treated patients (cohort A) and 0.66 (P = .22) in bevacizumab-treated patients (cohort B), and the HRs for death were 1.45 (P = .13) and 0.50 (P = .049), respectively. The interaction of VEGF-Axxxa with bevacizumab administration was significant (P = .011) for overall survival (OS). High tissue VEGF-Axxxb was not prognostic in cohort A but was predictive for bevacizumab benefit in cohort B (HR for progression, 0.57 [P = .04]; HR for death, 0.51 [P = .02]). Exploratory analyses done only in cohort B suggested that abundance of VEGFR1 messenger RNA (mRNA) in peripheral blood and low VEGFR2 mRNA in tissue correlated with poor outcome. In multivariate analysis, high tissue mRNA of angiogenic VEGF-Axxxa in the presence of bevacizumab therapy predicted for favorable progression-free survival (HR for progression, 0.39; P = .0227) and OS (HR for death, 0.32; P = .0140). CONCLUSION: Tissue mRNA expression of angiogenic VEGF-Axxxa isoforms was retrospectively associated with adverse prognosis in the absence of bevacizumab and with favorable outcome when bevacizumab was administered in patients with advanced breast cancer.