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

Smyth, E; Zhang, S; Cunningham, D; Wotherspoon, A; Soong, R; Peckitt, C; Valeri, N; ... Tan, P; + view all (2017) Pharmacogenetic analysis of the UK MRC MAGIC trial: association of polymorphisms with toxicity and survival in patients treated with perioperative ECF chemotherapy. Clinical Cancer Research , 23 (24) pp. 7543-7549. 10.1158/1078-0432.CCR-16-3142. Green open access

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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.

Type: Article
Title: Pharmacogenetic analysis of the UK MRC MAGIC trial: association of polymorphisms with toxicity and survival in patients treated with perioperative ECF chemotherapy
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-16-3142
Publisher version: https://doi.org/10.1158/1078-0432.CCR-16-3142
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10024465
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