Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 26, No 15S (May 20 Supplement), 2008: 4501
© 2008 American Society of Clinical Oncology

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Abstract

Polymorphisms of genes involved in gemcitabine metabolism correlate with prognosis in patients receiving neoadjuvant therapy for pancreatic cancer

University of Texas M. D. Anderson Cancer Center, Houston, TX

4501

Background: Genetic variations in gemcitabine transport and metabolism may affect the clinical response, toxicity, and prognosis of pancreatic cancer patients treated with gemcitabine. Methods: We evaluated 17 single nucleotide polymorphisms (SNPs) of 8 genes (CDA, dCK, RRM1, DCTD, hCNT1, hCNT2, hCNT3, and hENT1) involved in gemcitabine metabolism in a homogeneous population of 126 patients with resectable pancreatic cancer treated with neoadjuvant gemcitabine- based chemotherapy plus radiation therapy. Whole blood was collected from patients at the time of enrollment, and DNA was extracted from peripheral lymphocytes using a DNA isolation kit (Qiagen Valencia, CA). Polymorphisms were detected using the TaqMan genotyping assays provided by Applied Biosystems (Foster City, CA). Survival was determined from pathologic diagnosis to death or last follow-up. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare survival of patients according to genotype. Results: Six of the 17 SNPs had a borderline-significant effect on OS (p <0.1, log-rank test). A significant combined genotype effect on OS was observed for the metabolic or target gene SNPs CDA 111CC, CDA -76AA, RRM1 42GG, and DCTD -47CT (p <0.001) and for the transporter gene SNPs hCNT1 -16AA/AG, hCNT2 -17CC, and hENT1 913CC (p = 0.006). The CDA C111T and dCK C-1205T genotypes were also significantly associated with toxicity (p = 0.05 and 0.03, respectively). The CDA 111CC and dCK -1205TT alleles that were associated with poorer survival actually conferred less toxicity. Conclusion. These observations suggest that polymorphic variants of gemcitabine metabolic genes play an important role in affecting the efficacy of gemcitabine treatment for patients with pancreatic cancer.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Genentech, Merck, sanofi-aventis

Abstract presentation from the 2008 ASCO Annual Meeting