Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel Induced Neuropathy
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 x 10 8, adjusted P 5.88 x 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. (c)2016 AACR.
Clinical Cancer Research