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

PLoS One. 2015 Aug 5;10(8):e0134102. doi: 10.1371/journal.pone.0134102. eCollection 2015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adolescent
  • Adult
  • Aged
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use
  • Asian People / genetics
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / ethnology
  • Carcinoma, Renal Cell / genetics
  • Disease-Free Survival
  • Drug-Related Side Effects and Adverse Reactions / genetics
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Haplotypes
  • Humans
  • Indoles / adverse effects
  • Indoles / therapeutic use*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / ethnology
  • Kidney Neoplasms / genetics
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Polymorphism, Single Nucleotide*
  • Pyrroles / adverse effects
  • Pyrroles / therapeutic use*
  • Singapore
  • Sunitinib
  • Treatment Outcome
  • Young Adult
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • Indoles
  • Pyrroles
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Sunitinib

Grants and funding

This work is supported by the Institute of Bioengineering and Nanotechnology (Biomedical Research Council, Agency for Science, Technology and Research, Singapore), funding granted to MHT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.