SNPs associated with activity and toxicity of cabazitaxel in patients with advanced urothelial cell carcinoma

Pharmacogenomics. 2016 Apr;17(5):463-71. doi: 10.2217/pgs.15.186. Epub 2016 Mar 29.

Abstract

Aim: We aimed to identify SNPs associated with cabazitaxel toxicity and response within a Phase II clinical trial using this compound in advanced transitional cell carcinoma after progression to a platinum-based regimen.

Patients & methods: Eleven SNPs in CYP3A4, CYP3A5, CYP2C8, ABCB1 and TUBB1 were genotyped in 45 patients.

Results: CYP3A5 rs776746 A allele was associated with protection against gastrointestinal toxicity (odds ratio: 0.06, 95% CI: 0.007-0.63, p = 0.018) and with reduced progression-free survival (hazard ratio: 5.1, 95% CI: 1.7-15.1, p = 0.0038, multivariable analysis). ABCB1 SNPs were associated with total number of grade 3-4 toxicity events (p-values of 0.009, 0.041 and 0.043, respectively).

Conclusion: Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

Keywords: SNPs; biomarkers; cabazitaxel; genitourinary transitional cell carcinoma; pharmacogenetics.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Transitional Cell / drug therapy*
  • Carcinoma, Transitional Cell / genetics
  • Carcinoma, Transitional Cell / pathology
  • Cytochrome P-450 CYP2C8 / genetics
  • Cytochrome P-450 CYP3A / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Polymorphism, Single Nucleotide
  • Taxoids / adverse effects
  • Taxoids / therapeutic use*
  • Tubulin / genetics
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / pathology
  • Urothelium / pathology*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • TUBB1 protein, human
  • Taxoids
  • Tubulin
  • cabazitaxel
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A