Rapid Deaminator Status is Associated With Poor Clinical Outcome in Pancreatic Cancer Patients Treated with a Gemcitabine-Based Regimen

Abstract

Background: Gemcitabine is a mainstay in the treatment of biliary and pancreatic cancers, with limited efficacy in most settings. The gemcitabine elimination pattern is primarily driven by deamination in the liver by CDA. CDA is affected by genetic polymorphisms, leading to marked variations in activity and, subsequently, to erratic drug plasma exposures in patients administered with standard dosage. CDA deficiency has been a rising concern with gemcitabine since several studies have proven that poor metabolizer patients experience life-threatening toxicities upon drug intake. In theory, ultrarapid metabolizer (UM) patients should be conversely at risk of treatment failure, although thus far few studies have addressed this issue in digestive oncology. Patients & methods: A pilot study was conducted on 40 pancreatic cancer patients, all treated with gemcitabine-based therapy. CDA status was primarily established on a phenotypic basis determined by measurement of residual CDA enzymatic activity in serum. Additionally, a search for c208G>A and c79A>C polymorphisms was carried out. Results: No patients carrying c208G>A polymorphisms were found, and only heterozygous c79A>C patients were observed. Eight out of the 40 patients (i.e., 20%) were identified as UM, with CDA activities over 6 U/mg. CDA activity was significantly different between progressive disease patients and patients with controlled disease (8.4 vs 3 U/mg; p < 0.001). Conversely, fewer gemcitabine-related severe toxicities were observed in UM patients. Conclusion: This pilot study strongly suggests that UM patients are nearly five-times more likely to have progressive disease than patients with normal or low CDA activities, and that beside molecular events at the tumor level, upstream deregulations affecting drug disposition should be taken into account.

Original submitted 12 March 2013; Revision submitted 3 May 2013

KEYWORDS::

• cytidine deaminase
• efficacy
• gemcitabine
• genetic polymorphism
• pancreatic cancer

Disclosure

This work was presented, in part, at the ASCO-GI Meeting, Orlando, FL, USA, 2010 (Abstract e14558).

Financial & competing interests disclosure

J Ciccolini, M Duluc, LH Ouafik and J-F Seitz (Aix Marseille University, APHM,) are listed as coinventors of the CDA functional test described in this study (patent US 20130011392 A1 published on 10 January 2013). C Serdjebi received a grant from the Fondation pour la Recherche Médicale (FRM), grant # FDM20120624035 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

J Ciccolini, M Duluc, LH Ouafik and J-F Seitz (Aix Marseille University, APHM,) are listed as coinventors of the CDA functional test described in this study (patent US 20130011392 A1 published on 10 January 2013). C Serdjebi received a grant from the Fondation pour la Recherche Médicale (FRM), grant # FDM20120624035 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.