Association of ABCB1 and FLT3 Polymorphisms with Toxicities and Survival in Asian Patients Receiving Sunitinib for Renal Cell Carcinoma

Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corr...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2015-08, Vol.10 (8), p.e0134102
Main Authors: Chu, Ying-Hsia, Li, Huihua, Tan, Hui Shan, Koh, Valerie, Lai, Johnathan, Phyo, Wai Min, Choudhury, Yukti, Kanesvaran, Ravindran, Chau, Noan Minh, Toh, Chee Keong, Ng, Quan Sing, Tan, Puay Hoon, Chowbay, Balram, Tan, Min-Han
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Asian Continental Ancestry Group - genetics
ATP Binding Cassette Transporter, Sub-Family B - genetics
Bioengineering
Biomarkers
Cancer therapies
Carcinoma, Renal Cell - drug therapy
Carcinoma, Renal Cell - ethnology
Carcinoma, Renal Cell - genetics
Care and treatment
Cell survival
Disease-Free Survival
Dosage and administration
Drug dosages
Drug-Related Side Effects and Adverse Reactions - genetics
Enzyme inhibitors
FDA approval
Female
fms-Like Tyrosine Kinase 3 - genetics
Gene Frequency
Genes
Genetic Predisposition to Disease - ethnology
Genetic Predisposition to Disease - genetics
Genotype
Genotypes
Haplotypes
Humans
Indoles - adverse effects
Indoles - therapeutic use
Inhibitor drugs
Kidney cancer
Kidney Neoplasms - drug therapy
Kidney Neoplasms - ethnology
Kidney Neoplasms - genetics
Leukemia
Leukopenia
Male
Medical research
Metastases
Metastasis
Middle Aged
Minority & ethnic groups
Nanotechnology
Neoplasm Metastasis
Neutropenia
Oncology
Patients
Pharmacology
Platelet-derived growth factor
Polymorphism, Single Nucleotide
Population
Populations
Protein-tyrosine kinase
Pyrroles - adverse effects
Pyrroles - therapeutic use
Renal cell carcinoma
Risk factors
Singapore
Studies
Sunitinib
Survival
Toxicity
Treatment Outcome
Tyrosine
Vascular endothelial growth factor
Young Adult
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Sunitinib is a tyrosine kinase inhibitor used as first-line treatment for metastatic renal cell carcinoma (mRCC). Asian ethnicity has been previously associated with lower clearance and greater toxicities for sunitinib treatment, relative to Caucasian ethnicity. Research focusing on identifying corresponding biomarkers of efficacy and toxicity has been hitherto conducted in Caucasian populations, and few of the reported associations have been externally validated. Our work thus aims to investigate candidate biomarkers in Asian patients receiving sunitinib, comparing the observed genotype effects with those reported in Caucasian populations. Using data from 97 Asian mRCC patients treated with sunitinib, we correlated 7 polymorphisms in FLT3, ABCB1, VEGFR2, ABCG2 and BIM with patient toxicities, response, and survival. We observed a stronger association of FLT3 738T genotype with leucopenia in our Asian dataset than that previously reported in Caucasian mRCC patients (odds ratio [OR]=8.0; P=0.03). We observed significant associations of FLT3 738T (OR=2.7), ABCB1 1236T (OR=0.3), ABCB1 3435T (OR=0.1), ABCB1 2677T (OR=0.4), ABCG2 421A (OR=0.3) alleles and ABCB1 3435, 1236, 2677 TTT haplotype (OR=0.1) on neutropenia. Primary resistance (OR=0.1, P=0.004) and inferior survival (progression-free: hazard ratio [HR]=5.5, P=0.001; overall: HR=5.0, P=0.005) were associated with the ABCB1 3435, 1236, 2677 TTT haplotype. In conclusion, ABCB1 and FLT3 polymorphisms may be helpful in predicting sunitinib toxicities, response and survival benefit in Asian mRCC patients. We have also validated the association between FLT3 738T and sunitinib-induced leucopenia previously reported in Caucasian populations, but have not validated other reported genetic associations.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0134102