Evaluation of CYP3A5, VEGF-a, and VEGFR2 polymorphisms as markers of sunitinib toxicity.

Abstract

10546 Background: Sunitinib (Sun) is a multitargeted tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma (RCC), GIST and pancreatic neuroendocrine tumors (pNETs). It is known that a polymorphism in Sun metabolizing gene CYP3A5, was associated with an increased risk of dose reductions due to toxicity (tox). Additionally, polymorphisms in VEGF-A and VEGFR2 were suggested to increase the risk of hypertension (HT) during treatment (García-Donas, et al. Lancet Oncol 2011). These data have not been validated so far. We aim to assess the value of these polymorphisms as markers of tox using a wide range of solid tumors treated with Sun. Methods: In this non-interventional and retrospective study, DNA was collected from 28 patients with different pathologies (16 pNETs, 5 medullary thyroid carcinomas, 2 NETs of the lung, 2 undifferentiated follicular carcinomas, 1 undifferentiated papillar carcinoma, 1 GIST, and 1 carcinoid of the rectum) treated with Sun in a daily practice setting. Genotyping for CYP3A5*1 allele (rs776746), VEGF-A -2578C>A (rs699947) and VEGFR2 Q472H (rs1870377) was performed. Associations between the genotypes and Sun dose reductions and HT were performed using univariable analyses. Results: In agreement with previous reports, we found that VEGF-A rs699947 conferred a statistically significant increased risk of developing HT during treatment (HR=9.8, 95%CI=1.2-82.0, P=0.034). CYP3A5*1 high metabolizing allele showed a trend towards the increase in the risk of Sun dose reductions due to tox (HR=2.4, 95%CI=0.8-6.8, P=0.11) with a median time to dose reduction of 7.0 months for wild type homozgygous patients and 4.6 months for heterozygous patients. A trend was also found on the relation between VEGF-A rs699947 A/A patients (HR=3.8, 95%CI=0.8-16.8, P=0.080) and dose reduction risk. No significant associations were found for VEGFR2 rs1870377. Conclusions: The present study suggests that VEGF-A rs699947 is a risk factor for Sun HT and has a role in other tox leading to dose reductions. Similarly, CYP3A5*1 shows a trend towards an increased risk of Sun dose reductions. If confirmed, these markers could be used to identify a subset of patients with an increased risk of Sun toxicity.