Two Single Nucleotide Polymorphisms Associated with Risk for Paclitaxel-related Peripheral Neuropathy


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Peripheral neuropathy is the most common severe toxicity in patients receiving paclitaxel, and mutations in genes affecting drug metabolism, distribution, and elimination are likely to modulate risk for such neurotoxicity. In a recent study, Daniel Hertz, PharmD, and colleagues from the University of North Carolina at Chapel Hill identified two single nucleotide polymorphisms associated with risk of paclitaxel-associated peripheral neuropathy present in genes that have not previously been investigated in paclitaxel pharmacogenetic studies.1

The study included 412 patients with breast cancer who had received paclitaxel-containing regimens. Clinical data, including patient characteristics and toxicity were collected prospectively as part of an observational registry. Blood collected at the time of the diagnosis was genotyped using a platform that interrogates nearly 2,000 known variants in genes associated with drug pharmacokinetic exposure (Affymetrix DMET Plus chip), and associations of single nucleotide polymorphisms with peripheral neuropathy of grade 2 or higher were assessed. Statistical analysis was performed for each single nucleotide polymorphism examined, with the P value for significance being set at P < .001.

Variations in ABCG1 and CYP17A1 Modulate Risk

Older age and African American race may be associated with increased risk of paclitaxel-associated peripheral neuropathy, and diabetes is a risk factor for neuropathy. Among the 412 patients, the median age was 50 years, 26% were African American, and 12% had preexisting diabetes. Overall, the prevalence of grade 2 or higher peripheral neuropathy was 18.5%.

Among 564 single nucleotide polymorphisms interrogated, 2 were associated with peripheral neuropathy. Individuals who were homozygous for the wild-type G allele at the rs3788007 single nucleotide polymorphism in the ABCG1 transporter gene (ABCG1_43706676G>A[Intron]) had a greater than threefold increase in risk of peripheral neuropathy (odds ratio [OR] = 3.54, 95% CI = 1.77–7.72, P = .0003). Patients carrying two copies of the wild-type G allele at the rs6163 single nucleotide polymorphism in the CYP17A1 gene (CYP17A1_195G>T[S65S]) were at approximately one-third of the risk of peripheral neuropathy (OR = 0.35, 95% CI = 0.18-0.66, P = .0008).

Both of these genes have been found to be involved in endogenous steroid biology, which in turn is believed to be involved in the development of neuropathy. In addition, the rs6163 single nucleotide polymorphism was found to be in high linkage disequilibrium (r2 = 0.93) with another single nucleotide polymorphism recently reported to be associated with bortezomib (Velcade)-associated peripheral neuropathy.2

Disclosure: Dr. Hertz reported no potential conflicts of interest.

References

1. Hertz DL, EC Dees, Motsinger-Reif AA, et al: Interrogation of polymorphisms in drug metabolism or transport genes and peripheral neuropathy during paclitaxel treatment. 2012 ASCO Annual Meeting. Abstract 10515. Presented June 5, 2012.

2. Corthals SL, Kuiper R, Johnson DC, et al:  Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients.  Haematologica 96:1728-1732, 2011.



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