Pharmacogenetic Analysis of the UK MRC (Medical Research Council) MAGIC Trial: Association of Polymorphisms with Toxicity and Survival in Patients Treated with Perioperative Epirubicin, Cisplatin, and 5-fluorouracil (ECF) Chemotherapy.
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Date
2017-12Author
Smyth, E
Zhang, S
Cunningham, D
Wotherspoon, A
Soong, R
Peckitt, C
Valeri, N
Fassan, M
Rugge, M
Okines, A
Allum, W
Stenning, S
Nankivell, M
Langley, R
Tan, P
Type
Journal Article
Metadata
Show full item recordAbstract
Purpose: Germline polymorphisms may affect chemotherapy efficacy and toxicity. We examined the effect of polymorphisms in drug metabolism and DNA repair genes on pathologic response rates, survival, and toxicity for patients randomized to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. Experimental Design: DNA was extracted from nontumor resection formalin-fixed paraffin-embedded (FFPE) blocks. ERCC1, ERCC2, XRCC1, DYPD, and OPRT SNPs were evaluated using Sequenom, GSTP1, GSTT1 deletion, and TYMS ( TS) 5' 2R/3R using multiplex PCR. Post PCR amplification, TS 2R/3R and GSTT1 samples underwent gel electrophoresis. Results: Polymorphism data were available for 289 of 456 (63.4%) operated patients. No polymorphism was statistically significantly associated with pathologic response to chemotherapy. Median overall survival (OS) for patients treated with surgery alone with any TS genotype was not different (1.76 years 2R/2R, 1.68 years 2R/3R, 2.09 years 3R/3R). Median OS for patients with a TS 2R/2R genotype treated with chemotherapy was not reached, whereas median OS for 2R/3R and 3R/3R patients were 1.44 and 1.60 years, respectively (log rank P value = 0.0053). The P value for the interaction between treatment arm and genotype (3R/3R and 3R/2R vs. 2R/2R) was 0.029. No polymorphism was statistically significantly associated with chemotherapy toxicity. Conclusions: In MAGIC, patients with a TS 2R/2R genotype appeared to derive a larger benefit from perioperative ECF chemotherapy than patients with 3R containing genotypes. Further exploration of this potential predictive biomarker in this patient population is warranted. Clin Cancer Res; 23(24); 7543-9. ©2017 AACR .
Collections
Subject
Humans
Esophageal Neoplasms
Stomach Neoplasms
Cisplatin
Fluorouracil
Epirubicin
Thymidylate Synthase
Neoplasm Proteins
Disease-Free Survival
Genotype
Germ-Line Mutation
Polymorphism, Single Nucleotide
Adult
Aged
Middle Aged
Female
Male
Genetic Association Studies
Perioperative Period
Drug-Related Side Effects and Adverse Reactions
United Kingdom
Research team
Medicine (RMH Smith Cunningham)
Gastrointestinal Cancer Biology and Genomics
Language
eng
Date accepted
2017-09-26
License start date
2017-12
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (24), pp. 7543 - 7549