Association of VEGF-A splice variant mRNA expression with outcome in bevacizumab-treated patients with metastatic breast cancer.
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.


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).


CONCLUSIONS
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.
Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. Electronic address: gpenther@otenet.gr.
George
G
Pentheroudakis
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.
Vassiliki
V
Kotoula
Health Data Specialists Ltd, Athens, Greece.
George
G
Kouvatseas
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
Elpida
E
Charalambous
Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.
Dimitrios
D
Dionysopoulos
Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece.
Flora
F
Zagouri
Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
Angelos
A
Koutras
Third Department of Medical Oncology, Theagenion Cancer Hospital, Thessaloniki, Greece.
Konstantinos
K
Papazisis
Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece.
Dimitrios
D
Pectasides
Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece.
Epaminontas
E
Samantas
Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece.
Meletios A
MA
Dimopoulos
Department of Medical Oncology, University Hospital of Larissa, University of Thessaly School of Medicine, Larissa, Greece.
Christos N
CN
Papandreou
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.
George
G
Fountzilas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008875:Middle Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D034261:Epothilones / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D016016:Proportional Hazards Models; D020033:Protein Isoforms / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D000077143:Docetaxel; D034261:Epothilones; C430592:ixabepilone; D017239:Paclitaxel; D020033:Protein Isoforms; D012333:RNA, Messenger; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human
Anti-angiogenesis; Chemotherapy; Predictive factors; Prognostic factors; Survival