Thymidylate synthase (TYMS) enhancer region genotype-directed phase II trial of oral capecitabine for 2nd line treatment of advanced pancreatic cancer
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Purpose The primary aim of this study was to characterize the 6-month overall survival and toxicity associated with second-line capecitabine treatment of advanced pancreatic cancer patients harboring the TYMS *2/*2 allele. The secondary aim was to analyze the response rate and pharmacokinetics of capecitabine-based therapy in this patient population. Lastly, TYMS, ATM and RecQ1 single nucleotide polymorphism were analyzed relative to overall survival in patients screened for study participation. Methods Eighty patients with stage IV pancreatic cancer were screened for the *2/*2 TYMS allele. Patients with the *2/*2 TYMS polymorphism were treated with capecitabine, 1,000 mg/m2 twice daily for 14 consecutive days of a 21 day cycle. Screened patients not possessing TYMS *2/*2 were monitored for survival. Pharmacokinetic analysis was done during Cycle 1 of the therapy. Results Sixteen of the 80 screened patients tested positive for *2/*2 TYMS variant. Four out of the 16 eligible patients were treated on study. The study was terminated early due to poor accrual and increased toxicity. Three patients experienced grade 3 non-hematologic toxicities of palmer-plantar erythrodysesthesia, diarrhea, nausea and vomiting. Grade 2 toxicities were similar and occurred in all patients. Only one patient was evaluable for response after completion of three cycles of therapy. The presence of the *2/*2 TYMS genotype in all of the screened patients trended toward a decreased overall survival. Conclusion To our knowledge, this study represents the first genotype-directed clinical trial for patients with pancreatic adenocarcinoma. Although the study was closed early, it appears capecitabine therapy in pancreatic cancer patients harboring the TYMS *2/*2 variant may be associated with increased non-hematologic toxicity. This study also demonstrates the challenges performing a genotype-directed study in the second-line setting for patients with advanced pancreatic cancer.
KeywordsPancreatic cancer Thymidine synthase enhancer region (TYMS) Capecitabine Gemcitabine RecQ1 ATM
This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Roche Laboratories, Inc. This research was supported by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH P30 CA069773). Colin Weekes was supported by a United Negro College Fund UNCF-Merck Science Initiative Postdoctoral Research Fellowship.
We would like to thank Ming Zhao and Ping He for their technical support and Susan Davidson for her quality assurance of the data.
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