Angiogenesis pathway gene polymorphisms associated with clinical outcome in recurrent ovarian cancer treated with low dose cyclophosphamide and bevacizumab: A California Consortium Trial

Abstract

5017 Background: Despite advances in chemotherapy, ovarian cancer remains a major cause of cancer mortality worldwide. It has therefore become essential to identify novel therapeutic targets, such as angiogenesis which is a complex process regulated by the delicate balance between various local proangiogenic and antiangiogenic proteins. Bevacizumab, a monoclonal antibody binding to VEGF, has shown significant activity in colon, breast, lung and ovarian cancer. There are no established molecular markers to predict response or time to tumor progression for Bevacizumab based chemotherapy. The key enzymes of the VEGF pathway are: Vascular Endothelial Growth Factor (VEGF), VEGF Receptor (VEGFR), Hypoxia Inducible Factor1 (HIF α and β-subunit), Neuropilin1 (NRP), Interleukin-8 (IL-8), Adrenomedullin (AM) and Leptin. Methods: Seventy patients with refractory ovarian cancer were enrolled in a Phase II clinical trial and treated with Cyclophoshamide 50 mg po/Bevacizumab 10 mg/kg IV every 14 days. From 52 patients blood samples were available for gDNA extraction and PCR-RFLP assays. Results: 13 patients had a PR (25%) and 39 were non responders. 31 pts had progressed. Median follow-up of 8.3 months with a median progression-free survival of 6.6 months. Patients who were homozygous A/A or heterozygous A/T genotype at the −251 locus in the IL-8 gene had a lower response rate than those who were T/T (P = 0.047 Fisher’s exact test). Patients with Vegf936 C/C had a median TTP of 6.5 months, pts with any T (T/T, C/T) had a median TTP of 17.2 months. Pts carrying both AM 3’end alleles <14 CA repeats had 3.4 months median TTP, patients with at least one allele >14 showed a median TTP of 6.6 months; for both alleles >14 patients showed 8.7 months of median TPP (P = 0.0006 Log-rank test) Conclusions: Our data suggest for the first time, that IL-8 may be a potential molecular predictor of response to Bevacizumab based chemotherapy. We also demonstrate that both VEGF 936 and the AM 3’ dinucleotide repeat polymorphisms are potential molecular markers for time to tumor progression. A larger prospective study is needed to validate and confirm our preliminary findings. This study was supported by NCI grant NO1 CM 17101. [Table: see text]