A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101

Abstract

Purpose: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity.

Experimental design: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects.

Results: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 × 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy.

Conclusions: A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.

Figure 1. The EPHA5 rs7349683 C>T and FGD4 rs10771973 G>A polymorphisms are associated with an increased probability of developing paclitaxel-induced Grade 2 or greater sensory peripheral neuropathy

The probability of the first instance of Grade 2 or greater neuropathy as a function of cumulative paclitaxel dose (corrected for body surface area) is shown for each genotype. Results are shown for A) rs7239683 (per allele HR = 1.63; 95% CI 1.34 – 1.98; P = 9.6 × 10⁻⁷) and B) rs10771973 (per allele HR, 1.57; 95% CI, 1.30 – 1.91; P = 2.6 × 10⁻⁶) in the discovery set. The number of individuals with each genotype is noted in parentheses.

Figure 2. Association of FZD3 SNP rs7001034 with sensory peripheral neuropathy

The minor allele frequency of rs7001034 in the European discovery cohort is expressed as a function of maximal grade of sensory peripheral neuropathy in 855 individuals.