Abstract P5-17-06: The deficient eNOS c.894G&gt;T genotype is not associated with increased severity of hypertension and proteinuria in breast cancer patients receiving bevacizumab
Authors: Del Re M , Ferrarini I , Fontana A , Santoro M , Bona E , Del Re I , Stasi I , Bertolini I , Laurà F , Landucci E , Salvadori B , Falcone A , Danesi R 
Published: August 2014

Background. Tumor angiogenesis is a complex process involving a wide array of effector molecules and stromal cells. In tumor tissue, vasculature is structurally and functionally abnormal, causing elevated interstitial pressure and irregular perfusion. The expression of vascular endothelial growth factor (VEGF), the most important angiogenic factor, is enhanced in many tumors. VEGF may induce nitric oxide (NO) production via up-regulation of the endothelial NO synthase (eNOS, NOS3) and the resultant overproduction of NO is associated with vasodilation and edema within tumors (Goel S et al. Physiol Rev 2011;91:1071). eNOS plays an important physiologic role in maintaining blood pressure homeostasis and vascular integrity by providing constitutive release of NO in endothelial cells. Functional variants of the eNOS gene, including the single-nucleotide polymorphism rs1799983 (c.894G&gt;T, p. Asp298Glu) at codon 298, have been associated with reduced function of eNOS and higher incidence of hypertension (HT) (Niu W, Qi Y. PLoS One 2011;6:e24266).

Purpose. Since suppression of VEGF-eNOS axis by anti-angiogenic therapies is considered a causative factor of HT in patients, the purpose of this study was to examine whether the major eNOS non-synonymous variant c.894G&gt;T may be associated with increased risk of developing hypertension (HT) and proteinuria (PU) in breast cancer patients treated with bevacizumab.

Patients and methods. Forty-one metastatic breast cancer patients given bevacizumab as per standard of care were enrolled. Main characteristics were: median age 49.5 years (range 29–73) at first diagnosis, 53 years (range 34–74) at metastatic disease; PS 0–1 in all patients; 4 subjects with hypertension and 1 patient with compensated cardiovascular disease at diagnosis. Twenty-six subjects had received neoadjuvant or adjuvant chemotherapy based on anthracycline and taxane; first-line chemotherapy for metastatic disease was paclitaxel plus bevacizumab for all patients; 14 subjects received hormone-therapy for metastatic disease (range 1–5 lines). Germline DNA was extracted from peripheral blood and used to screen patients for eNOS c.894G&gt;T variant by automatic sequencing. The study was approved by the local Ethics Committee.

Results. Three patients (7.3%) were homozygous variant c.894TT, 12 (29.3%) homozygous wild-type c.894GG and the remaining 26 (63.4%) were heterozygous c.894GT. The c.894TT patients had no HT or PU at baseline and developed grade (G) 1, 2, 2 HT, respectively, and in one case PU during treatment. G1, 2 and 3 HT developed in 4, 5 and 2 c.894GG subjects, respectively, while PU was observed in 7/12 (58%) patients. The full range of HT grades and PU were observed in heterozygous subjects. Thirty-seven patients achieved one of the following: partial remission, minimal response or stable disease upon treatment with bevacizumab in combination with chemotherapy; 3 subjects had progressive disease and 1 was not evaluable.

Conclusions. The presence of the mutant T allele of c.894G&gt;T is not associated with increased severity of HT and PU; therefore, bevacizumab can be administered at no increased risk in TT patients with respect to the wild-type GG population.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-17-06.