Highlights
- •N08CA studied 138 patients undergoing neurotoxic paclitaxel chemotherapy.
- •Polyneuropathy phenotyped by serial patient reported outcomes using CIPN20.
- •Gene ARHGEF10 found to be associated with paclitaxel polyneuropathy.
- •Study validates result of previous report in the paclitaxel trial N08C1.
- •Toxic neuropathies such as from paclitaxel may have a genetic component.
Abstract
The predisposition of patients to develop polyneuropathy in response to toxic exposure
may have a genetic basis. The previous study Alliance N08C1 found an association of
the Charcot–Marie–Tooth disease (CMT) gene ARHGEF10 with paclitaxel chemotherapy induced peripheral neuropathy (CIPN) related to the
three non-synonymous, recurrent single nucleotide variants (SNV), whereby rs9657362
had the strongest effect, and rs2294039 and rs17683288 contributed only weakly.
In the present report, Alliance N08CA was chosen to attempt to replicate the above
finding. N08CA was chosen because it is the methodologically most similar study (to
N08C1) performed in the CIPN field to date. N08CA enrolled patients receiving the
neurotoxic chemotherapy agent paclitaxel. Polyneuropathy was assessed by serial repeat
administration of the previously validated patient reported outcome instrument CIPN20.
A study-wide, Rasch type model was used to perform extreme phenotyping in n = 138 eligible patients from which “cases” and “controls” were selected for genetic
analysis of SNV performed by TaqMan PCR.
A significant association of ARHGEF10 with CIPN was found under the pre-specified primary endpoint, with a significance
level of p = 0.024. As in the original study, the strongest association of a single SNV was seen
for rs9657362 (odds ratio = 3.56, p = 0.018). To further compare results across the new and the previous study, a statistical
“classifier” was tested, which achieved a ROC area under the curve of 0.60 for N08CA
and 0.66 for N08C1, demonstrating good agreement.
Retesting of the primary endpoint of N08C1 in the replication study N08CA validated
the association of ARHGEF10 with CIPN.
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Published online: June 26, 2015
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© 2015 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
