Pharmacogenetic analysis of the UK MRC MAGIC trial: association of polymorphisms with toxicity and survival in patients treated with perioperative ECF chemotherapy.

Abstract

PURPOSE Germline polymorphisms may affect chemotherapy efficacy and toxicity. We examined the effect of polymorphisms in drug metabolism and DNA repair genes on pathological response rates, survival, and toxicity for patients randomised to surgery alone or perioperative ECF chemotherapy in the MRC MAGIC trial. EXPERIMENTAL DESIGN DNA was extracted from non-tumor resection 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 was available for 289/456 (63.4%) operated patients. No polymorphism was statistically significantly associated with pathological 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.

DOI: 10.1158/1078-0432.CCR-16-3142

Cite this paper

@article{Smyth2017PharmacogeneticAO, title={Pharmacogenetic analysis of the UK MRC MAGIC trial: association of polymorphisms with toxicity and survival in patients treated with perioperative ECF chemotherapy.}, author={Elizabeth C. Smyth and Shenli Zhang and David C. Cunningham and Andrew Charles Wotherspoon and Richie Soong and Clare Peckitt and Nicola Valeri and Matteo Fassan and Massimo Rugge and Alicia F C Okines and William H. Allum and Sally Patricia Stenning and Matthew Nankivell and Ruth Elizabeth Langley and Patrick Tan}, journal={Clinical cancer research : an official journal of the American Association for Cancer Research}, year={2017} }