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 ¼ 154) and African American (n ¼ 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 ¼ 2.6 Â 10 À6] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P ¼ 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P ¼ 6.7 Â 10 À3 ) 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 paclitaxelinduced 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.

Targeted Sequencing Reveals Low-Frequency Variants in EPHA Genes as Markers of Paclitaxel-Induced Peripheral Neuropathy

“…and EPHA4-rs17348202) (10,11) and subsequent studies further supported the association of EPHA5, EPHA6 and EPHA8 polymorphisms (9, 18). Non-synonymous coding variants, potentially affecting protein function, are expected to have stronger effects on neuropathy than common regulatory variants (28).…”

“…The patient genetic background has been proposed to play a relevant role in the susceptibility for suffering neuropathy (5). In this regard, paclitaxel pharmacokinetic (6, 7) and pharmacodynamic (8,9) pathways have been included in studies of candidate genes and, more recently genome-wide association studies (GWAS) have been performed (10,11).…”

“…CYP2C8*3 (12)(13)(14), CYP3A4*22 (7), TUBB2A rs909964 and rs909965 (8,9)) influence neuropathy risk, while genome wide genotyping has uncovered novel genes (10,11). A GWAS by our group (11) suggested that the EPHA gene family, which plays a key role in the development of nervous system and in nerve injury repair (15)(16)(17), was a key player for paclitaxel neuropathy susceptibility.…”

Replication of Genetic Polymorphisms Reported to Be Associated with Taxane-Related Sensory Neuropathy in Patients with Early Breast Cancer Treated with Paclitaxel

“…A secondary analysis was undertaken that used a time-toevent approach (2) in which an event is described as the first incidence of TRSN grade !2 and time was defined as cumulative paclitaxel dose (mg/m 2 ) at the event. For patients not experiencing any event, the total study paclitaxel drug exposure was used.…”

“…Reported rates of taxane-related sensory neuropathy (TRSN) are variable depending on factors such as the dose of taxane given, concomitant neurotoxic drugs, and preexisting comorbidities. The prevalence of National Cancer Institute common toxicity criteria for adverse events (NCI CTCAE) grade 2 neuropathy is 50% to 80% in patients with stage I to III breast cancer (2)(3)(4) whereas the prevalence of grade 3 or grade 4 neuropathy is 5% to 30% (2,5). Longer-term neurotoxicity complications (beyond 2 years postchemotherapy) have also been reported (6).…”