Pharmacogenetics of Oxaliplatin as Adjuvant Treatment in Colon Carcinoma
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Pharmacogenetics of Oxaliplatin as Adjuvant Treatment in Colon Carcinoma Are Single Nucleotide Polymorphisms in GSTP1, ERCC1, and ERCC2 Good Predictive Markers? Arantza Farin˜a Sarasqueta,1,2 Gesina van Lijnschoten,1 Valery E.P.P. Lemmens,3 Harm J.T. Rutten4 and Adriaan J.C. van den Brule1 1 2 3 4
PAMM Laboratory for Pathology, Eindhoven, the Netherlands Fontys University of Applied Science, Eindhoven, the Netherlands Comprehensive Cancer Centre South, Eindhoven, the Netherlands Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands
Abstract
Purpose: Adjuvant chemotherapy improves survival in stage III colon cancer patients. However, a subgroup of patients still develops recurrent disease at some point in time, partly because of the ineffectiveness of the chemotherapy. Predictive markers of response are therefore crucial. Our aim was to study the predictive value of functional polymorphisms in genes involved in the metabolism of oxaliplatin and in DNA repair in stage III colon cancer patients. Materials and Methods: Normal DNA was isolated from 98 patients diagnosed with stage III colon carcinoma. Single nucleotide polymorphisms (SNPs) in three genes (the excision repair cross-complementing genes ERCC1 [19007T>C] and ERCC2 [2251A>C], and the glutathione S-transferase pi 1 gene [GSTP1 313A>G]) were tested by PCR followed by digestion with restriction enzymes or by direct sequencing. These genes and SNPs were selected on the basis of their reported associations with oxaliplatin response in colorectal cancer. Results: The genotype frequencies were in Hardy-Weinberg equilibrium. GSTP1 and ERCC2 polymorphisms were significantly associated with sex. The AA genotype of GSTP1 313A>G was more frequent in men than in women (59% vs 30%, p = 0.02), and the CC genotype of ERCC2 2251A>C was significantly more frequent in women than in men (24% vs 6%, p = 0.02). In univariate and multivariate survival analysis, none of the tested polymorphisms seemed to influence disease-free survival. The GSTP1 AA genotype had different effects on survival between men and women; homozygous A men had significantly worse cancerspecific survival and overall survival than women with the same genotype (log rank p = 0.029 and p = 0.015, respectively). Conclusion: None of the tested polymorphisms is likely to be a reliable marker of response to oxaliplatin therapy. The GSTP1 313A>G homozygous A genotype may have a prognostic value in male patients.
Introduction Oxaliplatin was approved for adjuvant treatment of stage III colon carcinoma patients in the Netherlands in 2004. When administered in combination with fluorouracil, this platinum compound has been proven to decrease the recurrence risk by 23% in the first 3 years after surgery and to increase overall
survival by 4.2% after 6 years of follow-up.[1-3] Age and the presence of comorbidity are known factors limiting the use of chemotherapy, even when chemotherapy is advised according to guidelines.[4,5] I
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