FFCD-1004 Clinical Trial: Impact of Cytidine Deaminase Activity on Clinical Outcome in Gemcitabine-Monotherapy Treated Patients.

Cindy Serdjebi,Abakar Abakar-Mahamat,Joseph Ciccolini,Carole Montérymard,Francine Fein,Rosine Guimbaud,Johan Gagnière,Gaël Deplanque,Pierre Guillet,Côme Lepage,Jean-Louis Legoux,Thierry Lecomte,Thierry André,Jérôme Desramé,Julien Volet,Dominique Arsène ,Jean‐François Seitz ,Véronique Guerin‐Meyer ,Ετιεννε François ,Laëtitia Dahan

doi:10.1371/journal.pone.0135907

Abstract

PurposeBecause cytidine deaminase (CDA) is the key enzyme in gemcitabine metabolism, numerous studies have attempted to investigate impact of CDA status (i.e. genotype or phenotype) on clinical outcome. To date, data are still controversial because none of these studies has fully investigated genotype-phenotype CDA status, pharmacokinetics and clinical outcome relationships in gemcitabine-treated patients. Besides, most patients were treated with gemcitabine associated with other drugs, thus adding a confounding factor. We performed a multicenter prospective clinical trial in gemcitabine-treated patients which aimed at investigating the link between CDA deficiency on the occurrence of severe toxicities and on pharmacokinetics, and studying CDA genotype-phenotype relationships.Experimental designOne hundred twenty patients with resected pancreatic adenocarcinoma eligible for adjuvant gemcitabine monotherapy were enrolled in this study promoted and managed by the Fédération Francophone de Cancérologie Digestive. Toxicities were graded according to National Cancer Institute’s Common Terminology Criteria for Adverse Events Version 4. They were considered severe for grade ≥ 3, and early when occurring during the first eight weeks of treatment. CDA status was evaluated using a double approach: genotyping for 79A>C and functional testing. Therapeutic drug monitoring of gemcitabine and its metabolite were performed on the first course of gemcitabine.ResultsFive patients out of 120 (i.e., 4.6%) were found to be CDA deficient (i.e., CDA activity <1.3 U/mg), and only one among them experienced early severe hematological toxicity. There was no statistically significant difference in CDA activity between patients experiencing hematological severe toxicities (28.44%) and patients who tolerated the treatment (71.56%). CDA genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity. Regarding pharmacokinetics, a wide inter-individual variability has been observed in patients.ConclusionThis study, which included only 4.6% of CDA-deficient patients, failed in identifying CDA status as a predictive marker of toxicities with gemcitabine. A lack of statistical power because of smoothing effect of CDA variability as compared with real life conditions could explain this absence of impact.Trial RegistrationClinicalTrials.gov NCT01416662

Highlights

Gemcitabine is an antimetabolite drug widely prescribed to treat various types of cancer, from solid tumors to hematological disorders such as pancreatic adenocarcinoma, non-small cell lung cancer, sarcoma or lymphoma, alone or in combination with others cytotoxics such as capecitabine, nab-paclitaxel or oxaliplatin [1,2,3,4,5]]
cytidine deaminase (CDA) genetic analysis failed in evidencing an impact in terms of toxicities or in CDA activity
This meta-analysis suggested that the A/A genotype seems to be a protective factor with respect to incidence of severe anemia, whereas the C/C genotype did not show a significant impact on the response rate in nonsmall cell lung cancer (NSCLC) patients treated with gemcitabine

Summary

Introduction

Gemcitabine is an antimetabolite drug widely prescribed to treat various types of cancer, from solid tumors to hematological disorders such as pancreatic adenocarcinoma, non-small cell lung cancer, sarcoma or lymphoma, alone or in combination with others cytotoxics such as capecitabine, nab-paclitaxel or oxaliplatin [1,2,3,4,5]]. Since identification of cytidine deaminase (CDA) as the key enzyme involved in the metabolic pathway of gemcitabine in the early 90’s [6], many studies have been conducted to try to better understand whether changes in CDA activity could impact on efficacy and toxicity of gemcitabine-based regimen [7] The existing wide inter-individual variability in CDA activity allows patients to be sorted into 3 categories: poor metabolizers (PM), defined with a reduced CDA activity (CDA6 U/mg) and patients with a normal CDA phenotype (extensive metabolizers, EM) showing a median activity of 3.2 in adults and 3.4 U/mg in children [8] This marked variability among activities is partly linked to genetic and epigenetic polymorphisms [9]. This meta-analysis suggested that the A/A genotype seems to be a protective factor with respect to incidence of severe anemia, whereas the C/C genotype did not show a significant impact on the response rate in nonsmall cell lung cancer (NSCLC) patients treated with gemcitabine

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Results

Conclusion