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Clinical Trial
. 2014 Aug;14(4):336-42.
doi: 10.1038/tpj.2014.2. Epub 2014 Feb 11.

Polygenic Inheritance of Paclitaxel-Induced Sensory Peripheral Neuropathy Driven by Axon Outgrowth Gene Sets in CALGB 40101 (Alliance)

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Free PMC article
Clinical Trial

Polygenic Inheritance of Paclitaxel-Induced Sensory Peripheral Neuropathy Driven by Axon Outgrowth Gene Sets in CALGB 40101 (Alliance)

A Chhibber et al. Pharmacogenomics J. .
Free PMC article

Abstract

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

Conflict of interest statement

Conflict of Interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Distribution of sensory peripheral neuropathy in the study population
The distribution of the highest reported grade of sensory peripheral neuropathy is shown for 849 unrelated genetic Europeans from the paclitaxel arm of CALGB 40101. Toxicity is measured using the NCI-CTCAE Scale v2.
Figure 2
Figure 2. Heritability estimates for severity and onset of paclitaxel-induced sensory peripheral neuropathy for SNPs in genic and intergenic regions
Total genomic variance for both severity and onset of neuropathy was partitioned onto genic and intergenic regions. The error bars denote the SE for the heritability estimates.
Figure 3
Figure 3. Heritability estimates for severity of paclitaxel-induced sensory peripheral neuropathy for SNPs in selected GO biological pathways
Heritability was estimated for sets of SNPs within all pathways contained within the GO Axonogenesis pathway. Results are shown (heritability ± SE) for those pathways with significant (P < 0.05) heritability signals. The heritability estimates for the intersection between and union of the Axon Extension and Regulation of Axonogenesis are also shown.

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