Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma

M H Diekstra; A Belaustegui; J J Swen; E Boven; D Castellano; H Gelderblom; R H Mathijssen; J García-Donas; C Rodríguez-Antona; B I Rini; H-J Guchelaar

doi:10.1038/tpj.2015.100

Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma

Pharmacogenomics J. 2017 Jan;17(1):42-46. doi: 10.1038/tpj.2015.100. Epub 2016 Jan 26.

Authors

M H Diekstra^{1

2}, A Belaustegui³, J J Swen^{1

2}, E Boven^{2

4}, D Castellano^{5

6}, H Gelderblom^{2

7}, R H Mathijssen^{2

8}, J García-Donas^{6

9}, C Rodríguez-Antona^{10

11}, B I Rini¹², H-J Guchelaar^{1

2}

Affiliations

¹ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
² Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands.
³ Department of Clinical Pharmacy, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain.
⁴ Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
⁵ Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
⁶ Spanish Oncology Genitourinary Group, Madrid, Spain.
⁷ Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
⁸ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
⁹ Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain.
¹⁰ Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, Madrid, Spain.
¹¹ ISCIII Center for Biomedical Research on Rare Diseases, Madrid, Spain.
¹² Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.

PMID: 26810136
DOI: 10.1038/tpj.2015.100

Abstract

The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients. We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2.4, 95% confidence interval: 1.1-5.2, P=0.021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib.

Publication types

Multicenter Study
Observational Study

MeSH terms

Adult
Aged
Aged, 80 and over
Angiogenesis Inhibitors / adverse effects*
Carcinoma, Renal Cell / drug therapy*
Carcinoma, Renal Cell / enzymology
Carcinoma, Renal Cell / secondary
Chi-Square Distribution
Cytochrome P-450 CYP3A / genetics*
Cytochrome P-450 CYP3A / metabolism
Disease-Free Survival
Europe
Female
Gene Frequency
Genetic Predisposition to Disease
Heterozygote
Homozygote
Humans
Hypertension / chemically induced
Hypertension / enzymology
Hypertension / genetics*
Indoles / adverse effects*
Kidney Neoplasms / drug therapy*
Kidney Neoplasms / enzymology
Kidney Neoplasms / pathology
Logistic Models
Male
Middle Aged
Multivariate Analysis
Odds Ratio
Ohio
Pharmacogenomic Variants*
Phenotype
Polymorphism, Single Nucleotide*
Proportional Hazards Models
Protein Kinase Inhibitors / adverse effects*
Pyrroles / adverse effects*
Retrospective Studies
Risk Factors
Sunitinib
Time Factors
Treatment Outcome

Substances

Angiogenesis Inhibitors
Indoles
Protein Kinase Inhibitors
Pyrroles
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Sunitinib