The first identification of potential genetic biomarkers for taxane-induced peripheral neuropathy was reported at the 2011 ASCO Annual Meeting by researchers from Indiana University in Indianapolis.¹

The presence of two single nucleotide polymorphisms (SNPs), or common genetic variations, residing in two genes—RWDD3 and TECTA—was associated with an increased risk of developing neuropathy in a cohort of patients with breast cancer enrolled in the Eastern Cooperative Oncology Group clinical trial E5103. Neuropathy was reported by 60% of persons with two copies of the variant allele, said Bryan P. Schneider, MD, Associate Professor of Medicine at Indiana University Melvin and Bren Simon Cancer Center, at a preconference media briefing.

“If these findings can be replicated, this may allow physicians to know prior to recommending therapy whether the patient is at an inordinate risk for developing taxane-induced neuropathy. This may allow for better counseling, use of alternative drugs or schedules, or omission of taxanes in the appropriate setting,” Dr. Schneider commented.

Researchers conducted a genome-wide association study of 2,204 patients with breast cancer enrolled in E5103, a phase III study of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and weekly paclitaxel for 12 weeks, with or without bevacizumab (Avastin). More than 1.2 million SNPs were evaluated per subject.

Principal Findings

Interim toxicity data at a median of 15 months identified 613 patients with grade 2–4 neuropathy occurring at any time point during or after treatment. Significant clinical predictors of neuropathy included increasing age (P = .0004) and African-American race (P = 2.3 × 10^-11). In addition, six SNPs with minor allele frequency (MAF) > 5% were associated with neuropathy.

The strongest association was found for an SNP in RWDD3. The incidence among homozygous wild-type subjects (ie, no SNPs) was 27%; this rose to 40% among persons heterozygous for the SNP and to 60% among those homozygous for the variant (HR = 1.5; P = 8.5 × 10^-8).

“The study evaluated the risk with weekly paclitaxel, but we are planning to validate these findings in a trial looking at a variety of schedules of paclitaxel as well as docetaxel,” Dr. Schneider said.

Mark Kris, MD, Chair of the ASCO Cancer Communications Committee, commented on the value of moving beyond clinical factors to employ a more refined means of predicting neuropathy risk. “I am excited to see these data…This study represents one of the first times that molecular biology has melded into the area of supportive care,” he noted. ■

Financial Disclosure: Dr. Schneider reported that he is on the advisory board for Genentech. Dr. Kris reported no potential conflicts of interest.

Reference

1. Schneider BP, Li L, Miller K et al: Genetic associations with taxane-induced neuropathy by genome wide association study (GWAS) in E5103. J Clin Oncol 29(15 suppl):Abstract 1000, 2011.