Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism That Increases Risk of Docetaxel-Induced Neuropathy

Clin Cancer Res. 2016 Oct 1;22(19):4890-4900. doi: 10.1158/1078-0432.CCR-15-2823. Epub 2016 May 3.

Abstract

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.

Experimental design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.

Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10-8, adjusted P = 5.88 × 10-7). siRNA knockdown of VAC14 in stem cell-derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).

Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890-900. ©2016 AACR.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Bevacizumab / administration & dosage
  • Bevacizumab / adverse effects
  • Docetaxel
  • Double-Blind Method
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Pharmacogenomic Testing
  • Polymorphism, Single Nucleotide
  • Polyneuropathies / chemically induced*
  • Polyneuropathies / genetics
  • Prednisone / administration & dosage
  • Prednisone / adverse effects
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Taxoids / administration & dosage
  • Taxoids / adverse effects*

Substances

  • Membrane Proteins
  • Taxoids
  • VAC14 protein, human
  • Docetaxel
  • Bevacizumab
  • Prednisone