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 Sparano; Nancy E. Davidson; Tatiana Foroud; George W. Sledge

doi:10.1158/1078-0432.CCR-15-0586

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

Medicine

Research output: Contribution to journal › Article › peer-review

104 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 language	English (US)
Pages (from-to)	5082-5091
Number of pages	10
Journal	Clinical Cancer Research
Volume	21
Issue number	22
DOIs	https://doi.org/10.1158/1078-0432.CCR-15-0586
State	Published - Nov 15 2015

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General Medicine

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10.1158/1078-0432.CCR-15-0586

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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

Schneider, BP, Li, L, Radovich, M, Shen, F, Miller, KD, Flockhart, DA, Jiang, G, Vance, G, Gardner, L, Vatta, M, Bai, S, Lai, D, Koller, D, Zhao, F, O'Neill, A, Smith, ML, Railey, E, White, C, Partridge, A, Sparano, J, Davidson, NE, Foroud, T & Sledge, GW 2015, 'Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199', Clinical Cancer Research, vol. 21, no. 22, pp. 5082-5091. https://doi.org/10.1158/1078-0432.CCR-15-0586

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title = "Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2015 American Association for Cancer Research.",

year = "2015",

month = nov,

day = "15",

doi = "10.1158/1078-0432.CCR-15-0586",

language = "English (US)",

volume = "21",

pages = "5082--5091",

journal = "Clinical Cancer Research",

issn = "1078-0432",

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TY - JOUR

T1 - Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199

AU - Schneider, Bryan P.

AU - Li, Lang

AU - Radovich, Milan

AU - Shen, Fei

AU - Miller, Kathy D.

AU - Flockhart, David A.

AU - Jiang, Guanglong

AU - Vance, Gail

AU - Gardner, Laura

AU - Vatta, Matteo

AU - Bai, Shaochun

AU - Lai, Dongbing

AU - Koller, Daniel

AU - Zhao, Fengmin

AU - O'Neill, Anne

AU - Smith, Mary Lou

AU - Railey, Elda

AU - White, Carol

AU - Partridge, Ann

AU - Sparano, Joseph

AU - Davidson, Nancy E.

AU - Foroud, Tatiana

AU - Sledge, George W.

PY - 2015/11/15

Y1 - 2015/11/15

N2 - 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.

AB - 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.

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

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