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

  • Author(s): Hertz, Daniel L
  • Owzar, Kouros
  • Lessans, Sherrie
  • Wing, Claudia
  • Jiang, Chen
  • Kelly, William Kevin
  • Patel, Jai
  • Halabi, Susan
  • Furukawa, Yoichi
  • Wheeler, Heather E
  • Sibley, Alexander B
  • Lassiter, Cameron
  • Weisman, Lois
  • Watson, Dorothy
  • Krens, Stefanie D
  • Mulkey, Flora
  • Renn, Cynthia L
  • Small, Eric J
  • Febbo, Phillip G
  • Shterev, Ivo
  • Kroetz, Deanna L
  • Friedman, Paula N
  • Mahoney, John F
  • Carducci, Michael A
  • Kelley, Michael J
  • Nakamura, Yusuke
  • Kubo, Michiaki
  • Dorsey, Susan G
  • Dolan, M Eileen
  • Morris, Michael J
  • Ratain, Mark J
  • McLeod, Howard L
  • et al.
Abstract

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.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.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).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.

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