Abstract P1-08-31: Putative role of genetic variants of eNOS in survival and toxicity of patients given antiangiogenic therapy
Authors: M Del Re, A Fontana, I Del Re, E Bona, B Salvadori, I Ferrarini, E Landucci, S Fancelli, I Bertolini, A Michelotti, A Falcone, R Danesi
Journal: Cancer Research (2013)

Abstract Background: The development of tumor angiogensis is mainly driven by vascular endothelial growth factor (VEGF), which is strongly overexpressed in many cancers. VEGF induces the expression of the endothelial nitric oxide (NO) synthase (eNOS) and the resultant overproduction of NO may be associated with recruitment of inflammatory cells, disruption of endothelial barrier, edema and impaired drug delivery within tumors (1). Functional polymorphisms in the eNOS gene, including -786C&amp;gt;T and 894G&amp;gt;T, have been associated with impaired production of NO and higher incidence of hypertension (HT) (2), diabetic nephropathy (3) and glaucoma (4). Since suppression of VEGF-eNOS signal transduction by antiangiogenic drugs may normalize tumor vasculature by restoring interstitial fluid pressure and drug distribution in tumors, but may induce HT in patients, the purpose of this study was to examine the association between the major eNOS variants -786C&amp;gt;T and 894G&amp;gt;T with treatment outcome and risk of HT in metastatic breast cancer (MBC) patients given bevacizumab. Methods: Sixty-five MBC patients given bevacizumab as per approved indication were enrolled. Main characteristics were: mean age 49.5 years (range 29-73) at first diagnosis, 53 years (range 34-74) at metastatic progression and PS 0-1. Four subjects with HT and 1 patient with compensated cardiovascular disease were also included. First-line chemotherapy for metastatic disease was taxol plus bevacizumab. Germline DNA was extracted from peripheral blood with the Qiamp Mini Kit (Qiagen, Milano, Italy) and examined for eNOS -786C&amp;gt;T and 894G&amp;gt;T variants by Real Time PCR (Life Sciences 7900HT platform) and automatic sequencing (Life Sciences 3100 Avant). The study was approved by the local Ethics Committee. Results: Genotype frequencies are reported below (Table 1). The presence of -786TT genotype was associated with longer PFS compared with the other genotypes (median PFS 95%CI, CC/CT = 9 vs TT = 12 months, Log-rank [Mantel Cox] test p = 0.0066), but not with any grade of HT. Also the 894GT/TT was associated with longer PFS compaed with the GG homozygous wild-type genotype (median PFS 95%CI, GG = 7,5 vs GT/TT = 10 months, Log-rank [Mantel-Cox] test p = 0,0497). The incidence and severity of HT did not vary among genotypes. Conclusion: Patients bearing deficient eNOS variant did not experience higher risk or severity of HT with respect to the wild-type allele but enjoied a longer PFS. Table 1. Genotype frequenciesSNPFrequencies%Frequencies%Frequencies%-786C&amp;gt;TCCCTTT 37%33.8%26.2%894G&amp;gt;TGGGTTT 41.5%53.8%4.6% References 1. Goel S et al. Physiol Rev 2011;91:1071 2. Niu W, Qi Y. PLoS One 2011;6:e24266 3. Rahimi Z et al. Dis Markers 2013;34:437 4. Awadalla MS et al. Invest Ophtalmol Vis Sci 2013;54:2108. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-31.