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

Publication ,  Journal Article
Hertz, DL; Owzar, K; Lessans, S; Wing, C; Jiang, C; Kelly, WK; Patel, J; Halabi, S; Furukawa, Y; Wheeler, HE; Sibley, AB; Lassiter, C ...
Published in: Clin Cancer Res
October 1, 2016

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

October 1, 2016

Volume

22

Issue

19

Start / End Page

4890 / 4900

Location

United States

Related Subject Headings

  • Taxoids
  • Prostatic Neoplasms, Castration-Resistant
  • Prednisone
  • Polyneuropathies
  • Polymorphism, Single Nucleotide
  • Pharmacogenomic Testing
  • Oncology & Carcinogenesis
  • Middle Aged
  • Mice, Knockout
  • Mice, Inbred C57BL
 

Citation

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Chicago
ICMJE
MLA
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Hertz, D. L., Owzar, K., Lessans, S., Wing, C., Jiang, C., Kelly, W. K., … McLeod, H. L. (2016). Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy. Clin Cancer Res, 22(19), 4890–4900. https://doi.org/10.1158/1078-0432.CCR-15-2823
Hertz, Daniel L., Kouros Owzar, Sherrie Lessans, Claudia Wing, Chen Jiang, William Kevin Kelly, Jai Patel, et al. “Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.Clin Cancer Res 22, no. 19 (October 1, 2016): 4890–4900. https://doi.org/10.1158/1078-0432.CCR-15-2823.
Hertz DL, Owzar K, Lessans S, Wing C, Jiang C, Kelly WK, et al. 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):4890–900.
Hertz, Daniel L., et al. “Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.Clin Cancer Res, vol. 22, no. 19, Oct. 2016, pp. 4890–900. Pubmed, doi:10.1158/1078-0432.CCR-15-2823.
Hertz DL, Owzar K, Lessans S, Wing C, Jiang C, Kelly WK, Patel J, Halabi S, Furukawa Y, Wheeler HE, Sibley AB, Lassiter C, Weisman L, Watson D, Krens SD, Mulkey F, Renn CL, Small EJ, Febbo PG, Shterev I, Kroetz DL, Friedman PN, Mahoney JF, Carducci MA, Kelley MJ, Nakamura Y, Kubo M, Dorsey SG, Dolan ME, Morris MJ, Ratain MJ, McLeod HL. 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.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

October 1, 2016

Volume

22

Issue

19

Start / End Page

4890 / 4900

Location

United States

Related Subject Headings

  • Taxoids
  • Prostatic Neoplasms, Castration-Resistant
  • Prednisone
  • Polyneuropathies
  • Polymorphism, Single Nucleotide
  • Pharmacogenomic Testing
  • Oncology & Carcinogenesis
  • Middle Aged
  • Mice, Knockout
  • Mice, Inbred C57BL