Effect of Genetic Polymorphisms on Therapeutic Response and Clinical Outcomes in Pancreatic Cancer Patients Treated with Gemcitabine

Abstract

Aim: Gemcitabine is the first chemotherapeutic agent to show clinical benefits in pancreatic cancer patients. While interindividual variability in chemoresponse is observed, genetic factors that affect drug metabolism have not been clearly defined. The purpose of this study is to evaluate the relationships between genetic polymorphisms and therapeutic efficacy in pancreatic cancer patients treated with gemcitabine. Patients & methods: The study population consisted of 102 pancreatic cancer patients who had been treated with a gemcitabine-based chemotherapeutic regimen. 102 genetic polymorphisms were selected from 23 genes involved in the metabolism and action sites of gemcitabine and screened for polymorphisms using the MassARRAY^® system. The polymorphisms and haplotypes were analyzed in relation to overall survival (OS), time-to-progression (TTP) and disease progression. Results:CMPK1 360C>T was significantly associated with OS, TTP and disease progression (p = 0.042, 0.007 and 0.040, respectively, in a dominant genetic model). Additionally, CMPK1 240G>T was correlated with OS and TTP. The frequencies of the haplotypes for the CMPK1, SLC28A1, DCTD and TLE4 genes differed according to disease progression. Conclusion: Genetic polymorphisms in genes related to metabolism and action sites of gemcitabine showed associations with the therapeutic efficacy, in terms of OS, TTP and disease progression in pancreatic cancer patients treated with gemcitabine-based chemotherapy. In particular, polymorphisms of the CMPK1 gene seem to provide important prognostic information.

Original submitted 21 February 2012; Revised submitted 7 May 2012

KEYWORDS::

• CMPK1
• gemcitabine
• pancreatic cancer
• pharmacogenetics
• single nucleotide polymorphism
• SNP

Financial & competing interests disclosure

This study was supported by a grant from the Korean Ministry of Education, Science and Technology, FPR08A2-130 of the 21C Frontier Functional Proteomics Program and a grant from the Korea Healthcare technology R&D Project, Ministry of Health, Welfare & Family Affairs, Republic of Korea (A070001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This study was supported by a grant from the Korean Ministry of Education, Science and Technology, FPR08A2-130 of the 21C Frontier Functional Proteomics Program and a grant from the Korea Healthcare technology R&D Project, Ministry of Health, Welfare & Family Affairs, Republic of Korea (A070001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.