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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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,andOPRTSNPs were evaluated using Sequenom,GSTP1, GSTT1deletion, andTYMS(TS)5' 2R/3R using multiplex PCR. Post PCR amplification,TS2R/3R andGSTT1samples 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 anyTSgenotype was not different (1.76 years 2R/2R, 1.68 years 2R/3R, 2.09 years 3R/3R). Median OS for patients with aTS2R/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 rankPvalue = 0.0053). ThePvalue 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 aTS2R/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.
The Institute of Cancer Research (Grant ID: Unspecified)
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Medicine (RMH Smith Cunningham)
Gastrointestinal Cancer Biology and Genomics
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Clin Cancer Res, 2017, 23 (24), pp. 7543 - 7549