Dataset Information

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.

SUBMITTER: Schneider BP

PROVIDER: S-EPMC4717479 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Schneider Bryan P BP Li Lang L Radovich Milan M Shen Fei F Miller Kathy D KD Flockhart David A DA Jiang Guanglong G Vance Gail G Gardner Laura L Vatta Matteo M Bai Shaochun S Lai Dongbing D Koller Daniel D Zhao Fengmin F O'Neill Anne A Smith Mary Lou ML Railey Elda E White Carol C Partridge Ann A Sparano Joseph J Davidson Nancy E NE Foroud Tatiana T Sledge George W GW

Clinical cancer research : an official journal of the American Association for Cancer Research 20150702 22

<h4>Purpose</h4>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.<h4>Experimental design</h4>We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare ...[more]

PMID: 26138065

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Project description:Major advances in early detection and therapy have significantly increased the survival of breast cancer patients. Unfortunately, most cancer therapies are known to carry a substantial risk of adverse long-term treatment-related effects. Little is known about patient susceptibility to severe side effects after chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxanes. Recent advances in genome-wide genotyping and sequencing technologies have supported the discoveries of a number of pharmacogenetic markers that predict response to chemotherapy. However, effectively implementing these pharmacogenetic markers in the clinic remains a major challenge. On the other hand, recent advances in proteomic technologies incorporating mass spectrometry (MS) for biomarker discovery show great promise to provide clinically relevant protein biomarkers. In this study, we evaluated the association between protein content in serum exosomes and severity of CIPN. Women with early stage breast cancer receiving adjuvant taxane chemotherapy were assessed with the FACT-Ntx score and serum was collected before and after the taxane treatment. Based on the change in FACT-Ntx score from baseline to 12 month follow-up, we separated patients into two groups: those who had no change (Group 1, N = 9) and those who had a ≥20% worsening (Group 1, N = 8). MS-based proteomics technology was used to identify proteins present in serum exosomes to determine potential biomarkers. Mann-Whitney-Wilcoxon analysis was applied and maximum FDR was controlled at 20%. From the serum exosomes derived from this cohort, we identified over 700 proteins known to be in different subcellular locations and have different functions. Statistical analysis revealed a 12-protein signature that resulted in a distinct separation between baseline serum samples of both groups (q<0.2) suggesting that the baseline samples can predict subsequent neurotoxicity. These toxicity-associated biomarkers can be further validated in larger retrospective cohorts for their utility in identifying patients at high risk for CIPN.

Dataset Information

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

Publications

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

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