Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.
Publication/Presentation Date
10-1-2016
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
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.
Volume
22
Issue
19
First Page
4890
Last Page
4900
ISSN
1557-3265
Published In/Presented At
Hertz, D. L., Owzar, K., Lessans, S., Wing, C., Jiang, C., Kelly, W. K., Patel, J., Halabi, S., Furukawa, Y., Wheeler, H. E., Sibley, A. B., Lassiter, C., Weisman, L., Watson, D., Krens, S. D., Mulkey, F., Renn, C. L., Small, E. J., Febbo, P. G., Shterev, I., … McLeod, H. L. (2016). Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy. Clinical cancer research : an official journal of the American Association for Cancer Research, 22(19), 4890–4900. https://doi.org/10.1158/1078-0432.CCR-15-2823
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
27143689
Department(s)
Administration and Leadership
Document Type
Article