Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199

Bryan P. Schneider, Lang Li, Milan Radovich, Fei Shen, Kathy D. Miller, David A. Flockhart, Guanglong Jiang, Gail Vance, Laura Gardner, Matteo Vatta, Shaochun Bai, Dongbing Lai, Daniel Koller, Fengmin Zhao, Anne O'Neill, Mary Lou Smith, Elda Railey, Carol White, Ann Partridge, Joseph SparanoNancy E. Davidson, Tatiana Foroud, George W. Sledge

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Purpose: Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. Experimental Design: We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. Results: When evaluating for grade 3?4 TIPN, 120 SNPs had a P value of 10-4 from patients of European descent (EA) in ECOG- 5103. Thirty candidate SNPs were subsequently tested in ECOG- 1199 and SNP rs3125923 was found to be significantly associated with grade 3?4 TIPN (P = 1.7 × 10-3; OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2?4 TIPN (HR, 2.1; P = 5.6 × 10-16) and grade 3?4 TIPN(HR, 2.6; P = 1.1 × 10-11) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2?4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10-7). Conclusions: rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.

Original languageEnglish (US)
Pages (from-to)5082-5091
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number22
DOIs
StatePublished - Nov 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schneider, B. P., Li, L., Radovich, M., Shen, F., Miller, K. D., Flockhart, D. A., Jiang, G., Vance, G., Gardner, L., Vatta, M., Bai, S., Lai, D., Koller, D., Zhao, F., O'Neill, A., Smith, M. L., Railey, E., White, C., Partridge, A., ... Sledge, G. W. (2015). Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199. Clinical Cancer Research, 21(22), 5082-5091. https://doi.org/10.1158/1078-0432.CCR-15-0586