CYP3A5 and ABCB1 polymorphisms as predictors for sunitinib outcome in metastatic renal cell carcinoma.
BACKGROUND
In our exploratory studies, we associated single nucleotide polymorphisms (SNPs) in candidate genes with the efficacy and toxicities of sunitinib in metastatic renal cell carcinoma (mRCC).


OBJECTIVE
To see whether previously reported associations of SNPs with sunitinib-induced toxicities and efficacy in mRCC can be confirmed in a large cohort of patients.


METHODS
The mRCC patients treated with sunitinib and a DNA sample available were pooled from three exploratory studies conducted in the United States, Spain, and the Netherlands. A total of 22 SNPs and 6 haplotypes in 10 candidate genes related to the pharmacokinetics and pharmacodynamics of sunitinib were selected for association testing.


METHODS
SNPs and haplotypes were tested for associations with toxicity, dose reductions, progression-free survival (PFS), overall survival (OS), and best objective response.


CONCLUSIONS
A total of 333 patients were included. We confirmed 2 of the 22 previously reported SNP associations. The presence of CYP3A5*1 was associated with dose reductions (odds ratio: 2.0; 95% confidence interval [CI], 1.0-4.0, p=0.039). The presence of CGT in the ABCB1 haplotype was associated with an increased PFS (hazard ratio: 1.9; 95% CI, 1.3-2.6; p<0.001) and remained significant after Bonferroni correction. These associations are consistent with prior observations.


CONCLUSIONS
The confirmation of previously reported associations between polymorphisms in CYP3A5 and ABCB1 with sunitinib toxicity and efficacy, respectively, indicates that genotyping of these genetic variants will be useful for guiding sunitinib treatment. A prospective validation study is needed to confirm our findings on ABCB1 and CYP3A5 genetic polymorphisms.


RESULTS
We confirmed that variants in genes involved in processing sunitinib through the body have an effect on sunitinib treatment outcome. These findings confirm the potential of testing for these genetic variants to improve individual patient care for patients with metastatic renal cell carcinoma treated with sunitinib.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands; Dutch working group focusing on sunitinib-induced toxicity (SUTOX consortium), The Netherlands.
Meta H M
MH
Diekstra
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands; Dutch working group focusing on sunitinib-induced toxicity (SUTOX consortium), The Netherlands.
Jesse J
JJ
Swen
Dutch working group focusing on sunitinib-induced toxicity (SUTOX consortium), The Netherlands; Department of Medical Oncology, VU University Medical Centre, Amsterdam, The Netherlands.
Epie
E
Boven
Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; Spanish Oncology Genitourinary Group (SOGUG), Madrid, Spain.
Daniel
D
Castellano
Dutch working group focusing on sunitinib-induced toxicity (SUTOX consortium), The Netherlands; Department of Clinical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.
Hans
H
Gelderblom
Dutch working group focusing on sunitinib-induced toxicity (SUTOX consortium), The Netherlands; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Ron H J
RH
Mathijssen
Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; ISCIII Centre for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
Cristina
C
Rodríguez-Antona
Spanish Oncology Genitourinary Group (SOGUG), Madrid, Spain; Oncology Unit, Clara Campal Comprehensive Cancer Centre, Madrid, Spain.
Jesus
J
García-Donas
Department of Solid Tumour Oncology, Cleveland Clinic Foundation (CCF) Taussig Cancer Institute, Cleveland, OH, USA.
Brian I
BI
Rini
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, The Netherlands; Dutch working group focusing on sunitinib-induced toxicity (SUTOX consortium), The Netherlands. Electronic address: H.J.Guchelaar@lumc.nl.
Henk-Jan
HJ
Guchelaar
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006239:Haplotypes; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D009820:Ohio; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012307:Risk Factors; D013030:Spain; D000077210:Sunitinib; D013997:Time Factors; D016896:Treatment Outcome
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D000077210:Sunitinib
Association analysis; Biomarker; Metastatic renal cell carcinoma; Pharmacogenetics; Single nucleotide polymorphism; Sunitinib