ABSTRACT
Title
VEGF-A polymorphisms are associated with clinical response and progression free survival in advanced hormone-refractory prostate cancer patients treated with a metronomic cyclophosphamide, dexamethasone and celecoxib schedule.
Authors
P. Orlandi1, A. Fontana2, A. Fioravanti1, B. Canu1, T. Di Desidero1, L. Galli2, L. De Rosa2, A. Falcone2, R. Danesi1, G. Bocci1.
1Div. of Pharmacology, Dept. of Internal Medicine, University of Pisa, Italy;
2Dept. of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy.
1Div. of Pharmacology, Dept. of Internal Medicine, University of Pisa, Italy;
2Dept. of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy.
Abstract
The aim of this study was to evaluate,for the first time,the association between angiogenesis-related gene polymorphisms and clinicalresponse in advanced hormone-refractory prostate cancer patients treated with metronomic cyclophosphamide (50mg/day), celecoxib (400 mg/day) and dexamethasone (1mg/day) an antiangiogenic therapy.Forty three prostate cancer patients were enrolled in a phase II clinical trial and genomic DNA was available from 43 blood samples. DNA was extracted by QIAamp DNA Blood Mini kit (Qiagen). Three SNPs on VEGF-A gene were analyzed: -2578A/C, -634C/G and +936C/T; the allelic discrimination was performed in Real-Time PCR Taqman platform. The Hardy-Weinberg equilibrium and linkage disequilibrium tests between loci was calculated using Arlequin 3.1 and PHASE. The three SNPs of VEGF-A were in Hardy-Weinberg equilibrium. The SNPs of the promoter region were in linkage disequilibrium, whereas the +936C/T segregated independently of the others. In order to demonstrate the possible association between VEGF-A genotypes and clinical response (decrease of PSA level), the data were analyzed with the Fisher exact test. The association between VEGF-A genotypes and progression free survival (PFS) or overall survival (OS) was analyzed with the Kaplan Meier curves.
Metronomic cyclophosphamide plus celecoxib and dexamethasone schedule was overall very well tolerated. Indeed, no grade 3-4 haematological or non-haematological toxicities were observed among the 43 assessable patients. Seven patients (16,3%) developed a NCI-CTC grade 2 anaemia and 6 patients (14%) grade 2 thrombocytopenia, while only 1 patient showed grade 2 neutropenia and anorexia (2,3%). Neither major cardiovascular events no toxicity-related deaths were observed. Overall 20 patients (46%) experienced a reduction in PSA levels from baseline (from 9% to 99% of decrease) and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. After a median follow-up of 30 months (95%CI 26.43-33.65months), the median PFS and median OS were 5.26 months (95%CI 2.42-7.32 months) and 17.39 months (95%CI 13.10-21.68 months), respectively.
Interestingly, in non-responder patients the -634CC VEGF-A genotype frequency was 11.63% whereas no patients with CC genotype was retrieved in the responder’s group (P=0.0485). Furthermore,also the -2578C/A VEGF-A polymorphism was linked to the clinical response. Indeed, comparing the responders and non-responders with -2578CC vs -2578AC/AA genotypes, we demonstrated that the 2578CC genotype was significantly more frequent (18.60% vs. 2.33%) in the non-responder patients with a P value of 0.0212. With regard to PFS, patients harbouring the -634CC VEGF-A genotype had a median PFS of 2.2 months (95%CI 0.45-3.95 months)whereas patients with genotype -634CG/GG VEGF-A had a median PFS of 6.25 months (95%CI 3.28-8.62 months)with a calculated P=0.0042. Interestingly, the only patient carrying the 936TT VEGF-A genotype had a PFS of 0.46 months and an OS of 3.94 monthswhereas the rest of the population with the genotype 936CT/CC VEGF-A had a median PFS of 5.26 months and a median OS of 17.98 months.
In conclusion, there are relevant associations among VEGF-A gene polymorphisms and both clinical response and PFS in patients treated with this antiangiogenic metronomic schedule. These data could represent the molecular bases for future randomized clinical studies and personalized therapies.
Metronomic cyclophosphamide plus celecoxib and dexamethasone schedule was overall very well tolerated. Indeed, no grade 3-4 haematological or non-haematological toxicities were observed among the 43 assessable patients. Seven patients (16,3%) developed a NCI-CTC grade 2 anaemia and 6 patients (14%) grade 2 thrombocytopenia, while only 1 patient showed grade 2 neutropenia and anorexia (2,3%). Neither major cardiovascular events no toxicity-related deaths were observed. Overall 20 patients (46%) experienced a reduction in PSA levels from baseline (from 9% to 99% of decrease) and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. After a median follow-up of 30 months (95%CI 26.43-33.65months), the median PFS and median OS were 5.26 months (95%CI 2.42-7.32 months) and 17.39 months (95%CI 13.10-21.68 months), respectively.
Interestingly, in non-responder patients the -634CC VEGF-A genotype frequency was 11.63% whereas no patients with CC genotype was retrieved in the responder’s group (P=0.0485). Furthermore,also the -2578C/A VEGF-A polymorphism was linked to the clinical response. Indeed, comparing the responders and non-responders with -2578CC vs -2578AC/AA genotypes, we demonstrated that the 2578CC genotype was significantly more frequent (18.60% vs. 2.33%) in the non-responder patients with a P value of 0.0212. With regard to PFS, patients harbouring the -634CC VEGF-A genotype had a median PFS of 2.2 months (95%CI 0.45-3.95 months)whereas patients with genotype -634CG/GG VEGF-A had a median PFS of 6.25 months (95%CI 3.28-8.62 months)with a calculated P=0.0042. Interestingly, the only patient carrying the 936TT VEGF-A genotype had a PFS of 0.46 months and an OS of 3.94 monthswhereas the rest of the population with the genotype 936CT/CC VEGF-A had a median PFS of 5.26 months and a median OS of 17.98 months.
In conclusion, there are relevant associations among VEGF-A gene polymorphisms and both clinical response and PFS in patients treated with this antiangiogenic metronomic schedule. These data could represent the molecular bases for future randomized clinical studies and personalized therapies.