Publications by authors named "Jean-Christophe Boyer"

40 Publications

Model-Based Quantification of Impact of Genetic Polymorphisms and Co-Medications on Pharmacokinetics of Tamoxifen and Six Metabolites in Breast Cancer.

Clin Pharmacol Ther 2020 Oct 12. Epub 2020 Oct 12.

Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.

Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7-compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient's CYP2D6 phenotype for TAM dose adaptation.
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http://dx.doi.org/10.1002/cpt.2077DOI Listing
October 2020

Looking for Root Hairs to Overcome Poor Soils.

Trends Plant Sci 2021 01 23;26(1):83-94. Epub 2020 Sep 23.

Biochimie et Physiologie Moléculaire des Plantes, UMR BPMP, Univ Montpellier, CNRS, INRAE, Montpellier SupAgro, Montpellier 34060, France. Electronic address:

Breeding new cultivars allowing reduced fertilization and irrigation is a major challenge. International efforts towards this goal focus on noninvasive methodologies, platforms for high-throughput phenotyping of large plant populations, and quantitative description of root traits as predictors of crop performance in environments with limited water and nutrient availability. However, these high-throughput analyses ignore one crucial component of the root system: root hairs (RHs). Here, we review current knowledge on RH functions, mainly in the context of plant hydromineral nutrition, and take stock of quantitative genetics data pointing at correlations between RH traits and plant biomass production and yield components.
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http://dx.doi.org/10.1016/j.tplants.2020.09.001DOI Listing
January 2021

[Pharmacogenetics for patient care in France: A discipline that evolves!]

Therapie 2020 Sep - Oct;75(5):459-470. Epub 2019 Oct 30.

Inserm U1144, service de biochimie, hôpital européen Georges-Pompidou, université Paris Descartes, 75015 Paris, France.

Pharmacogenetics, which concepts are known for a long time, is entering a new period at least as far as its practical applications for patients are concerned. In recent years there have been more and more initiatives to promote widespread dissemination, and health authorities are increasingly incorporating these concepts into drug labels. In France, the national network of pharmacogenetics (RNPGx) works to promote these activities, both with health actors (biologists, clinicians) and health authorities. This article reviews the current situation in France and the milestones of the year 2018. It highlights recent advances in this field, in terms of currently recommended analyses, sharing of information or technological developments, and the prospects for future developments in the near future from targeted pharmacogenetics to eventually preemptive approaches.
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http://dx.doi.org/10.1016/j.therap.2019.09.006DOI Listing
October 2019

[Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists].

Bull Cancer 2019 Sep 25;106(9):759-775. Epub 2019 Jun 25.

Laboratoire d'oncopharmacologie, centre Antoine-Lacassagne, 33, avenue de Valombrose, 06189 Nice cedex 2, France. Electronic address:

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of early severe toxicities induced by fluoropyrimidines (FP). The French Group of Clinical Oncopharmacology (GPCO)-Unicancer and the French Pharmacogenetics Network (RNPGx) initiated two surveys, one addressed to oncologists, the other to biologists, in order to evaluate routine practices regarding DPD deficiency screening at national level, as well as compliance, motivations and obstacles for implementation of these tests. These anonymized online surveys were performed with the logistic assistance of the Francophone Federation of Digestive Oncology (FFCD) and the support of numerous medical and biological societies. The surveys were conducted in 2016-2017 before the creation of the French INCa/HAS expert panel, which contributed to the drafting of rules and recommendations for DPD deficiency screening published in December 2018. In all, 554 questionnaires from clinicians were analyzed (23% participation) and 35 from biologists. The main arguments raised by clinicians for justifying the limited practice of DPD deficiency screening were: the lack of recommendations from medical societies or Health Authorities, delays in obtaining results, and the lack of adequate reimbursement by the health insurance system. The goal of these surveys was to provide the French Health Authorities with an overview on nationwide DPD-deficiency screening practices and thus help to design recommendations for the standardization and improvement of the management and safety of cancer patients receiving FP-based chemotherapy.
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http://dx.doi.org/10.1016/j.bulcan.2019.04.013DOI Listing
September 2019

Factors Affecting Tamoxifen Metabolism in Patients With Breast Cancer: Preliminary Results of the French PHACS Study.

Clin Pharmacol Ther 2019 09 10;106(3):585-595. Epub 2019 Apr 10.

Cancer Research Center of Toulouse (CRCT), Inserm U1037, Université Paul Sabatier, Toulouse, France.

In addition to the effect of cytochrome P450 (CYP) 2D6 genetic polymorphisms, the metabolism of tamoxifen may be impacted by other factors with possible consequences on therapeutic outcome (efficacy and toxicity). This analysis focused on the pharmacokinetic (PK)-pharmacogenetic evaluation of tamoxifen in 730 patients with adjuvant breast cancer included in a prospective multicenter study. Plasma concentrations of tamoxifen and six major metabolites, the genotype for 63 single-nucleotide polymorphisms, and comedications were obtained 6 months after treatment initiation. Plasma concentrations of endoxifen were significantly associated with CYP2D6 diplotype (P < 0.0001), CYP3A4*22 genotype (P = 0.0003), and concomitant intake of potent CYP2D6 inhibitors (P < 0.001). Comparison of endoxifen levels showed that the CYP2D6 phenotype classification could be improved by grouping intermediate metabolizer (IM)/IM and IM/poor metabolizer diplotype into IM phenotype for future use in tamoxifen therapy optimization. Finally, the multivariable regression analysis showed that formation of tamoxifen metabolites was independently impacted by CYP2D6 diplotype and CYP3A4*22, CYP2C19*2, and CYP2B6*6 genetic polymorphisms.
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http://dx.doi.org/10.1002/cpt.1404DOI Listing
September 2019

How can we best monitor 5-FU administration to maximize benefit to risk ratio?

Expert Opin Drug Metab Toxicol 2018 Dec 23;14(12):1303-1313. Epub 2018 Nov 23.

g Service Pharmacie , Centre Georges-François Leclerc , Dijon , France.

Introduction: 5-Fluorouracil (5-FU) is currently used as a chemotherapy in several cancers such as head-and-neck (H&N) and colorectal cancers. 5-FU dosing is traditionally based on body surface area (BSA), but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM). Areas covered: 5-FU pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed. Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under- or overexposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers.
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http://dx.doi.org/10.1080/17425255.2018.1550484DOI Listing
December 2018

[5-fluorouracil therapeutic drug monitoring: Update and recommendations of the STP-PT group of the SFPT and the GPCO-Unicancer].

Bull Cancer 2018 Sep 10;105(9):790-803. Epub 2018 Aug 10.

Centre Georges-François-Leclerc, service pharmacie, 1, rue Pr.-Marion, 21000 Dijon, France. Electronic address:

Despite being 60-years old now, 5-FU remains the backbone of numerous regimen to treat a variety of solid tumors such as breast, head-and-neck and digestive cancers either in neo-adjuvant, adjuvant or metastatic settings. Standard 5-FU usually claims 15-40% of severe toxicities and up to 1% of toxic-death. Numerous studies show a stiff relationship between 5-FU exposure and toxicity or efficacy. In addition, 5-FU pharmacokinetics is highly variable between patients. Indeed, 80% of the 5-FU dose is catabolized in the liver by dihydropyrimidine dehydrogenase (DPD) into inactive compounds. It is now well established that DPD deficiency could lead to severe toxicities and, thus, require dose reduction in deficient patients. However, despite dosage adaptation based on DPD status, some patients may still experience under- or over-exposure, leading to inefficacy or major toxicity. The "Suivi thérapeutique pharmacologique et personnalisation des traitements" (STP-PT) group of the "Société française de pharmacologie et de thérapeutique" (SFPT) and the "Groupe de pharmacologie clinique oncologique" (GPCO)-Unicancer, based on the latest and most up-to-date literature data, recommend the implementation of 5-FU Therapeutic Drug Monitoring in order to ensure an adequate 5-FU exposure.
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http://dx.doi.org/10.1016/j.bulcan.2018.06.008DOI Listing
September 2018

[Dihydropyrimidine déhydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks].

Bull Cancer 2018 Apr 24;105(4):397-407. Epub 2018 Feb 24.

Laboratoire d'oncopharmacologie, centre Antoine-Lacassagne, 33, avenue de Valombrose, 06189 Nice cedex 2, France. Electronic address:

Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme of 5-FU catabolism. DPD deficiency may be identified through pharmacogenetics testing including phenotyping (direct or indirect measurement of enzyme activity) or genotyping (detection of inactivating polymorphisms on the DPYD gene). Approximately 3 to 15% of patients exhibit a partial deficiency and 0.1 to 0.5% a complete DPD deficiency. Currently, there is no regulatory obligation for DPD deficiency screening in patients scheduled to receive a fluoropyrimidine-based chemotherapy. Based on the levels of evidence from the literature data and considering current French practices, the Group of Clinical Pharmacology in Oncology (GPCO)-UNICANCER and the French Network of Pharmacogenetics (RNPGx) recommend the following: (1) to screen DPD deficiency before initiating any chemotherapy containing 5-FU or capecitabine; (2) to perform DPD phenotyping by measuring plasma uracil (U) concentrations (possibly associated with dihydrouracil/U ratio), and DPYD genotyping (variants *2A, *13, p.D949V, HapB3); (3) to reduce the initial FU dose (first cycle) according to DPD status, if needed, and further, to consider increasing the dose at subsequent cycles according to treatment tolerance. In France, 17 public laboratories currently undertake routine screening of DPD deficiency.
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http://dx.doi.org/10.1016/j.bulcan.2018.02.001DOI Listing
April 2018

New advances in DPYD genotype and risk of severe toxicity under capecitabine.

PLoS One 2017 8;12(5):e0175998. Epub 2017 May 8.

Centre Antoine Lacassagne, Nice, France.

Background: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine.

Methods: Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement.

Results: Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3-4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3-4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR.

Conclusions: Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3-4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175998PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421769PMC
September 2017

Cancer genomics guide clinical practice in personalized medicine.

Therapie 2017 Sep 30;72(4):439-451. Epub 2017 Jan 30.

Laboratoire de biochimie, CHU de Nîmes Carémeau, 30029 Nîmes, France; Unité Inserm U1194, Institut de recherche en cancérologie de Montpellier (IRCM), 34298 Montpellier, France.

Targeted therapies have revolutionized the treatment of many cancers. Widely developed over the last decade, this new concept of precision medicine relies on the use of genomic technologies to analyze tumor samples in order to identify actionable targets and biomarkers of resistance. The goal is to optimize treatment by identifying which therapeutic approach is best for each patient, i.e. the treatment that is effective, has minimal adverse effects, and avoids unnecessary intervention and cost. The purpose of this review is to highlight, using a few seminal examples of therapeutic targets, the important contribution of appropriate analysis of key oncogenes or driver genes in making clinical decisions. Cancer genomics is now an indispensable part of clinical management. Furthermore, the development of next generation sequencing (NGS) will enable exploration of more and more genes of interest, leading to new treatment options for personalized medicine.
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http://dx.doi.org/10.1016/j.therap.2016.09.015DOI Listing
September 2017

Pharmacogenetics-based personalized therapy: Levels of evidence and recommendations from the French Network of Pharmacogenetics (RNPGx).

Therapie 2017 Apr 30;72(2):185-192. Epub 2017 Jan 30.

Laboratoire de biochimie, pharmacogénétique et oncologie moléculaire, hôpital européen Georges-Pompidou, 75908 Paris, France.

More than 50 laboratories offer pharmacogenetic testing in France. These tests are restricted to a limited number of indications: prevention of serious adverse drug reactions; choice of most appropriate therapeutic option; dose adjustment for a specific drug. A very small proportion of these tests are mentioned in drug information labeling and the data provided (if any) are generally insufficient to ascertain whether a test is required and if it is useful. This article discusses the rationale for evaluating the performance and clinical usefulness of pharmacogenetics and provides, on behalf of the French national network of pharmacogenetics (RNPGx), three levels of recommendation for testing: essential, advisable, and possibly helpful.
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http://dx.doi.org/10.1016/j.therap.2016.09.014DOI Listing
April 2017

La génétique somatique des tumeurs solides, un incontournable à l’ère de la médecine de précision.

Therapie 2017 Apr 3;72(2):217-230. Epub 2017 Jan 3.

Laboratoire de ciochimie, CHU de Nîmes-Carémeau, 30029 Nîmes, France; Unité Inserm U1194, IRCM (institut de recherche en cancérologie de Montpellier), 34298 Montpellier cedex 5, France.

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http://dx.doi.org/10.1016/j.therap.2016.09.009DOI Listing
April 2017

Traitements personnalisés grâce à la pharmacogénétique : niveaux de preuve et de recommandations du Réseau national de pharmacogénétique (RNPGx).

Therapie 2017 Apr 3;72(2):175-183. Epub 2017 Jan 3.

Laboratoire de biochimie, pharmacogénétique et oncologie moléculaire, hôpital européen Georges-Pompidou, 75908 Paris, France.

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http://dx.doi.org/10.1016/j.therap.2016.09.007DOI Listing
April 2017

Circulating tumour cells from patients with colorectal cancer have cancer stem cell hallmarks in culture.

Gut 2017 10 25;66(10):1802-1810. Epub 2016 Jul 25.

Centre National de la Recherche Scientifique, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.

Objective: Although counting of circulating tumour cells (CTC) has attracted a broad interest as potential markers of tumour progression and treatment response, the lack of functional characterisation of these cells had become a bottleneck in taking these observations to the clinic. Our objective was to culture these cells in order to understand them and exploit their therapeutic potential to the full.

Design: Here, hypothesising that some CTC potentially have cancer stem cell (CSC) phenotype, we generated several CTC lines from the blood of patients with advanced metastatic colorectal cancer (CRC) based on their self-renewal abilities. Multiple standard tests were then employed to characterise these cells.

Results: Our CTC lines self-renew, express CSC markers and have multilineage differentiation ability, both and . Patient-derived CTC lines are tumorigenic in subcutaneous xenografts and are also able to colonise the liver after intrasplenic injection. RNA sequencing analyses strikingly demonstrate that drug metabolising pathways represent the most upregulated feature among CTC lines in comparison with primary CRC cells grown under similar conditions. This result is corroborated by the high resistance of the CTC lines to conventional cytotoxic compounds.

Conclusions: Taken together, our results directly demonstrate the existence of patient-derived colorectal CTCs that bear all the functional attributes of CSCs. The CTC culture model described here is simple and takes <1 month from blood collection to drug testing, therefore, routine clinical application could facilitate access to personalised medicine.

Clinical Trial Registration: ClinicalTrial.gov NCT01577511.
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http://dx.doi.org/10.1136/gutjnl-2016-311447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595103PMC
October 2017

Nod Factor Effects on Root Hair-Specific Transcriptome of Medicago truncatula: Focus on Plasma Membrane Transport Systems and Reactive Oxygen Species Networks.

Front Plant Sci 2016 7;7:794. Epub 2016 Jun 7.

Biochimie and Physiologie Moléculaire des Plantes, UMR 5004 Centre National de la Recherche Scientifique/386 Institut National de la Recherche Agronomique/SupAgro Montpellier/Université de Montpellier, Campus SupAgro-Institut National de la Recherche Agronomique Montpellier, France.

Root hairs are involved in water and nutrient uptake, and thereby in plant autotrophy. In legumes, they also play a crucial role in establishment of rhizobial symbiosis. To obtain a holistic view of Medicago truncatula genes expressed in root hairs and of their regulation during the first hours of the engagement in rhizobial symbiotic interaction, a high throughput RNA sequencing on isolated root hairs from roots challenged or not with lipochitooligosaccharides Nod factors (NF) for 4 or 20 h was carried out. This provided a repertoire of genes displaying expression in root hairs, responding or not to NF, and specific or not to legumes. In analyzing the transcriptome dataset, special attention was paid to pumps, transporters, or channels active at the plasma membrane, to other proteins likely to play a role in nutrient ion uptake, NF electrical and calcium signaling, control of the redox status or the dynamic reprogramming of root hair transcriptome induced by NF treatment, and to the identification of papilionoid legume-specific genes expressed in root hairs. About 10% of the root hair expressed genes were significantly up- or down-regulated by NF treatment, suggesting their involvement in remodeling plant functions to allow establishment of the symbiotic relationship. For instance, NF-induced changes in expression of genes encoding plasma membrane transport systems or disease response proteins indicate that root hairs reduce their involvement in nutrient ion absorption and adapt their immune system in order to engage in the symbiotic interaction. It also appears that the redox status of root hair cells is tuned in response to NF perception. In addition, 1176 genes that could be considered as "papilionoid legume-specific" were identified in the M. truncatula root hair transcriptome, from which 141 were found to possess an ortholog in every of the six legume genomes that we considered, suggesting their involvement in essential functions specific to legumes. This transcriptome provides a valuable resource to investigate root hair biology in legumes and the roles that these cells play in rhizobial symbiosis establishment. These results could also contribute to the long-term objective of transferring this symbiotic capacity to non-legume plants.
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http://dx.doi.org/10.3389/fpls.2016.00794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894911PMC
July 2016

Effect of Single Nucleotide Polymorphisms in the Xenobiotic-sensing Receptors NR1I2 and NR1I3 on the Pharmacokinetics and Toxicity of Irinotecan in Colorectal Cancer Patients.

Clin Pharmacokinet 2016 09;55(9):1145-57

Laboratoire de biochimie, Centre Hospitalier Universitaire de Nîmes, Hôpital Carémeau, Place du Professeur Robert Debré, 30029, Nîmes Cedex 9, France.

Background And Objectives: Nuclear receptors PXR (pregnane X receptor, NR1I2) and CAR (constitutive androstane receptor, NR1I3) are key regulators of irinotecan metabolism, and ligand-dependent modulation of their activity leads to significant drug-drug interactions. Because genetic polymorphisms can also affect the activity of these xenobiotic-sensing receptors, we hypothesized that they could contribute to the interpatient variability of irinotecan pharmacokinetics and to the toxicity of irinotecan-based regimens.

Patients And Methods: In a cohort of 109 metastatic colorectal cancer patients treated with irinotecan (180 mg/m(2)) in combination with other drugs, associations were assessed between 21 selected single nucleotide polymorphisms of NR1I2 or NR1I3 and pharmacokinetic parameters or toxicity of irinotecan and its metabolites.

Results: After adjustment of the tests by the UGT1A1*28 genotype and correction for multiple testing, the A allele of NR1I2-rs10934498 was associated with a decreased exposition and an increased degradation of SN-38, the active metabolite (p = 0.009 and p = 0.017, respectively). The risk of hematological toxicity was associated with NR1I2-rs10934498 and NR1I2-rs2472677 (p = 0.009 and p = 0.003, respectively).

Conclusion: Our results reveal for the first time the involvement of NR1I2 in the pharmacogenetics of irinotecan and suggest that it may help to predict the toxicity of low-dose irinotecan.
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http://dx.doi.org/10.1007/s40262-016-0392-5DOI Listing
September 2016

Polymorphisms in SLCO1B3 and NR1I2 as genetic determinants of hematotoxicity of carboplatin and paclitaxel combination.

Pharmacogenomics 2015 12;16(13):1439-50. Epub 2015 Aug 12.

Laboratoire de biochimie, Centre Hospitalier Universitaire (CHU) of Nîmes, Hôpital Carémeau, Nîmes, France.

Aim: The goal of our study was to assess the impact of patients' genetic background on their sensitivity to carboplatin/paclitaxel hematotoxicity.

Patients & Methods: Parameters describing sensitivity to neutropenia and to thrombocytopenia of 201 patients were extracted from a previous pharmacokinetic/pharmacodynamics analysis, in order to assess their association with 52 candidates SNPs in 18 genes.

Results: Carriers of a T allele of SLCO1B3-rs4149117 were 19% less sensitive to thrombocytopenia than the homozygotes for the G allele (p = 0.00279). Carriers of two copies of the ATG haplotypes of NR1I2-rs1523130, rs3814055 and rs1523127 were 19% less sensitive to thrombocytopenia than those harboring other haplotypes (p = 0.025).

Conclusion: Our results revealed the importance of SLCO1B3 and NR1I2 in the sensitivity to carboplatin/paclitaxel thrombocytopenia.
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http://dx.doi.org/10.2217/pgs.15.84DOI Listing
June 2016

The Arabidopsis root stele transporter NPF2.3 contributes to nitrate translocation to shoots under salt stress.

Plant J 2015 Aug 2;83(3):466-79. Epub 2015 Jul 2.

Biochimie et Physiologie Moléculaire des Plantes, Institut de Biologie Intégrative des Plantes, UMR 5004 CNRS, UMR 0386 INRA/Montpellier SupAgro/Université de Montpellier, F-34060, Montpellier, France.

In most plants, NO(3)(-) constitutes the major source of nitrogen, and its assimilation into amino acids is mainly achieved in shoots. Furthermore, recent reports have revealed that reduction of NO(3)(-) translocation from roots to shoots is involved in plant acclimation to abiotic stress. NPF2.3, a member of the NAXT (nitrate excretion transporter) sub-group of the NRT1/PTR family (NPF) from Arabidopsis, is expressed in root pericycle cells, where it is targeted to the plasma membrane. Transport assays using NPF2.3-enriched Lactococcus lactis membranes showed that this protein is endowed with NO(3)(-) transport activity, displaying a strong selectivity for NO(3)(-) against Cl(-). In response to salt stress, NO(3)(-) translocation to shoots is reduced, at least partly because expression of the root stele NO(3)(-) transporter gene NPF7.3 is decreased. In contrast, NPF2.3 expression was maintained under these conditions. A loss-of-function mutation in NPF2.3 resulted in decreased root-to-shoot NO(3)(-) translocation and reduced shoot NO(3)(-) content in plants grown under salt stress. Also, the mutant displayed impaired shoot biomass production when plants were grown under mild salt stress. These mutant phenotypes were dependent on the presence of Na(+) in the external medium. Our data indicate that NPF2.3 is a constitutively expressed transporter whose contribution to NO(3)(-) translocation to the shoots is quantitatively and physiologically significant under salinity.
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http://dx.doi.org/10.1111/tpj.12901DOI Listing
August 2015

UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice.

Fundam Clin Pharmacol 2015 Jun 4;29(3):219-37. Epub 2015 May 4.

Unité de pharmacogénétique, Laboratoire de biochimie et biologie moléculaire, CHU Bretonneau, 2 bis boulevard Tonnellé, 37044, Tours, France.

Irinotecan is a major drug in the treatment of advanced colorectal cancer. Its active form is the SN38 metabolite, which is cleared by the biliary route after glucuronidation by uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). UGT1A1 activity exhibits a wide intersubject variability, in part related to UGT1A1 gene polymorphisms. The present review on the impact of the deficient UGT1A1*28 variant on irinotecan efficacy and toxicity was produced by a French joint workgroup comprising the Group of Clinical Onco-pharmacology (GPCO-Unicancer) and the National Pharmacogenetics Network (RNPGx). It clearly emerges that for irinotecan doses at least equal to 180 mg/m(2) , patients homozygous for the UGT1A1*28 allele are at increased risk of developing hematological and/or digestive toxicities. Irinotecan dose reduction is thus recommended in homozygous *28/*28 patients. In addition, this personalized medicine strategy aims to secure high-dose irinotecan administration (≥240 mg/m(2) ) that have proven to be safe in homozygous *1/*1 patients only. The clinical relevance of this test is discussed in terms of treatment efficacy improvement, as increasing the irinotecan dose appears to be safe in patients not bearing a deficient allele. Best execution practices, cost-effectiveness, and result interpretation are discussed with the aim of facilitating the implementation of this analysis in clinical practice. The existence of networks of laboratories performing this test in routine hospital treatment, as in France, offers the prospect of widespread screening, thus guaranteeing equal access to safe treatment and optimized therapy for patients receiving irinotecan-based therapy in advanced colorectal cancer.
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http://dx.doi.org/10.1111/fcp.12117DOI Listing
June 2015

[Interest of UGT1A1 genotyping within digestive cancers treatment by irinotecan].

Bull Cancer 2014 Jun;101(6):533-53

CHU Bretonneau, unité de pharmacogénétique, Laboratoire de biochimie biologie moléculaire, Tours, France.

Irinotecan is a cytotoxic agent administered by IV infusion in the treatment of advanced colorectal cancer. Its anticancer activity results from its bioactivation into SN-38 metabolite, which is cleared through glucuronidation by the hepatic enzyme uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). In the general population, there is wide inter-subject variability in UGT1A1 enzyme activity related to UGT1A1 gene polymorphisms. The French joint workgroup coming from the National Pharmacogenetic Network (RNPGx) and the Group of Clinical Oncologic Pharmacology (GPCO) herein presents an updated review dealing with efficacy and toxicity clinical studies related to UGT1A1 genetic variants. From a critical analysis of this review it clearly emerges that, for doses higher than 180 mg/m(2), hematologic and digestive irinotecan-induced toxicities could be prevented in daily clinical practice by generalizing the use of a simple pharmacogenetic test before starting treatment. The clinical relevance of this test is also discussed in terms of treatment efficacy improvement, with the possibility of increasing the irinotecan dose in patients not bearing the deleterious allele. This test involves using a blood sample to analyze the promoter region of the UGT1A1 gene (UGT1A1*28 allele). Best execution practices, laboratory costs, as well as results interpretation are described with the aim of facilitating the implementation of this analysis in clinical routine. The existence of a French laboratories network performing this test in clinical routine makes it possible to generalize UGT1A1 deficiency screening, so as to guarantee equal access to safe treatment and optimized irinorecan-based therapy for the many patients receiving irinotecan-based therapy in advanced colorectal cancer.
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http://dx.doi.org/10.1684/bdc.2014.1933DOI Listing
June 2014

Unilateral subarachnoid and intravitreous FLAIR hyperintensities after gadolinium-enhanced MRI.

Acta Neurol Belg 2015 Mar 13;115(1):89-90. Epub 2014 Jun 13.

Department of Neurology, CHU Nîmes, Hôpital Caremeau, Place du Pr Debré, 30029, Nîmes Cedex 4, France,

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http://dx.doi.org/10.1007/s13760-014-0321-zDOI Listing
March 2015

A unified nomenclature of NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER family members in plants.

Trends Plant Sci 2014 Jan 18;19(1):5-9. Epub 2013 Sep 18.

Biochimie et Physiologie Moléculaire des Plantes, UMR CNRS/INRA/UM2/SupAgro, Institut de Biologie Intégrative des Plantes 'Claude Grignon', Place Viala, 34060 Montpellier, France. Electronic address:

Members of the plant NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NRT1/PTR) family display protein sequence homology with the SLC15/PepT/PTR/POT family of peptide transporters in animals. In comparison to their animal and bacterial counterparts, these plant proteins transport a wide variety of substrates: nitrate, peptides, amino acids, dicarboxylates, glucosinolates, IAA, and ABA. The phylogenetic relationship of the members of the NRT1/PTR family in 31 fully sequenced plant genomes allowed the identification of unambiguous clades, defining eight subfamilies. The phylogenetic tree was used to determine a unified nomenclature of this family named NPF, for NRT1/PTR FAMILY. We propose that the members should be named accordingly: NPFX.Y, where X denotes the subfamily and Y the individual member within the species.
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http://dx.doi.org/10.1016/j.tplants.2013.08.008DOI Listing
January 2014

Performance and cost efficiency of KRAS mutation testing for metastatic colorectal cancer in routine diagnosis: the MOKAECM study, a nationwide experience.

PLoS One 2013 25;8(7):e68945. Epub 2013 Jul 25.

UMR-S775, INSERM, Paris, France.

Purpose: Rapid advances in the understanding of cancer biology have transformed drug development thus leading to the approval of targeted therapies and to the development of molecular tests to select patients that will respond to treatments. KRAS status has emerged as a negative predictor of clinical benefit from anti-EGFR antibodies in colorectal cancer, and anti-EGFR antibodies use was limited to KRAS wild type tumors. In order to ensure wide access to tumor molecular profiling, the French National Cancer Institute (INCa) has set up a national network of 28 regional molecular genetics centers. Concurrently, a nationwide external quality assessment for KRAS testing (MOKAECM) was granted to analyze reproducibility and costs.

Methods: 96 cell-line DNAs and 24 DNA samples from paraffin embedded tumor tissues were sent to 40 French laboratories. A total of 5448 KRAS results were collected and analyzed and a micro-costing study was performed on sites for 5 common methods by an independent team of health economists.

Results: This work provided a baseline picture of the accuracy and reliability of KRAS analysis in routine testing conditions at a nationwide level. Inter-laboratory Kappa values were >0.8 for KRAS results despite differences detection methods and the use of in-house technologies. Specificity was excellent with only one false positive in 1128 FFPE data, and sensitivity was higher for targeted techniques as compared to Sanger sequencing based methods that were dependent upon local expertise. Estimated reagent costs per patient ranged from €5.5 to €19.0.

Conclusion: The INCa has set-up a network of public laboratories dedicated to molecular oncology tests. Our results showed almost perfect agreements in KRAS testing at a nationwide level despite different testing methods ensuring a cost-effective equal access to personalized colorectal cancer treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0068945PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723748PMC
March 2014

Lexical fields of predictive and personalized medicine.

Drug Metabol Drug Interact 2013 ;28(2):125-32

Institut de Biologie Clinique Schaffner, Lens, LABCO, Paris, France.

With human genome mapping, the omics revolution and the empowering sequencing technologies developed at the turn of the century, the new goals in medicine are to switch from population medicine to individualized therapies, not only to cure diseases but also to prevent them. The purpose of this review by the pharmacogenetics and predictive medicine working group of the French clinical biology society (SFBC) is to situate in their correct context the notions of personalized medicine, pharmacogenetics, genetics and genomics, emphasizing their interactions and discussing their significance for researchers and clinicians.
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http://dx.doi.org/10.1515/dmdi-2013-0024DOI Listing
September 2013

[Lexical fields of predictive and personalized medicine].

Ann Biol Clin (Paris) 2012 Nov-Dec;70(6):651-8

Institut de biologie clinique Schaffner, Lens, France.

After human genome mapping, omics revolution and empowering sequencing technologies developed at the turn of the century, new deals are to switch from population medicine to individual therapies, from curing the disease to preventing it. This review by the pharmacogenetics and predictive medicine working group of the French clinical biology society (SFBC) aims at placing into perspective the notions of tailored medicine, pharmacogenetics, genetics and genomics, emphasizing their interactions and discussing their signifiance according to researchers and to clinicians.
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http://dx.doi.org/10.1684/abc.2012.0767DOI Listing
July 2013

Cross-validation study for epidermal growth factor receptor and KRAS mutation detection in 74 blinded non-small cell lung carcinoma samples: a total of 5550 exons sequenced by 15 molecular French laboratories (evaluation of the EGFR mutation status for the administration of EGFR-TKIs in non-small cell lung carcinoma [ERMETIC] project--part 1).

J Thorac Oncol 2011 Jun;6(6):1006-15

Laboratoire de Biologie Moléculaire, Hôpital de Hautepierre, Strasbourg, France.

Introduction: The Evaluation of the epidermal growth factor receptor (EGFR) Mutation status for the administration of EGFR-Tyrosine Kinase Inhibitors in non-small cell lung Carcinoma (NSCLC) (ERMETIC) project part 1 assessed the accuracy of EGFR and KRAS mutations detection in NSCLC among 15 French centers.

Methods: The 15 ERMETIC centers selected 74 NSCLC surgical specimens from previously untreated patients. Paraffin and paired frozen DNA were sequenced for EGFR exons 18 to 21 and KRAS exon 2 by an external molecular laboratory, yielding a gold standard. The 74 blinded paraffin DNAs were redistributed to the 15 ERMETIC laboratories for sequencing of a total of 5550 exons. Results were compared with the gold standard and between centers by discordance rates and kappa statistics.

Results: The gold standard included 39 mutated samples with 22 EGFR and 17 KRAS mutated samples. Kappa statistics showed that 10, 6, and 6 of the 15 ERMETIC centers had a moderate to good kappa score, when compared with external laboratory for EGFR exon 19, EGFR exon 21, and KRAS exon 2, respectively. Kappa statistics showed moderate score between centers which increased to good for EGFR exon 19 mutation when removing 16 poor-quality samples with high nonamplificable rates.

Conclusions: Paraffin-embedded specimens may represent a suitable source of DNA for sequencing analyses in ERMETIC centers. EGFR exon 19 deletions were most accurately detected by ERMETIC centers. Ease and accuracy of results, depended more on the quality of sample than on the difference in molecular sequencing procedures between centers, emphasize the need of preanalytical quality control programs.
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http://dx.doi.org/10.1097/JTO.0b013e318211dceeDOI Listing
June 2011

[Interprofessional cooperation, a new mode of regulation?].

Soins 2010 Dec(751):51-2

Avocat au Barreau de Paris, SCP Boyer-lambropoulo.

The "Hospital, patients, health and territories" law marks a paradigm shift in the establishing of the regulatory framework of healthcare professionals' practice in France. From the current situation of national homogeneity, an evolution towards the emergence of regional regulatory frameworks could take place.
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December 2010

Factors for hematopoietic toxicity of carboplatin: refining the targeting of carboplatin systemic exposure.

J Clin Oncol 2010 Oct 20;28(30):4568-74. Epub 2010 Sep 20.

Institut Claudius-Regaud and EA3035 University of Toulouse, Toulouse, France.

Purpose: Area under the curve (AUC) dosing is routinely carried out for carboplatin, but the chosen target AUC values remain largely empirical. This multicenter pharmacokinetic-pharmacodynamic (PK-PD) study was performed to determine the covariates involved in the interindividual variability of carboplatin hematotoxicity that should be considered when choosing individual target AUCs.

Patients And Methods: Three hundred eighty-three patients received carboplatin as part of established regimens. A semi-physiologic population PK-PD model was applied to describe separately the time course of absolute neutrophil and platelet counts using NONMEM software. The plasma ultrafiltrable carboplatin concentration (C(Carbo)) was assumed to inhibit the proliferation of blood cell precursors through a linear model: drug effect = slope × C(Carbo). The slope corresponds to the patients' sensitivity to carboplatin hematotoxicity. The relationships between the patients' sensitivity to the neutropenic or thrombopenic effects of carboplatin and various covariates, including associated chemotherapies, demographic, biologic, and pharmacogenetic data, were studied.

Results: The sensitivity of carboplatin-induced thrombocytopenia decreased in the case of concomitant paclitaxel chemotherapy (slope decreased by 24%), whereas it increased with coadministration of etoposide and gemcitabine (slope increased by 45% and 133%, respectively). For neutropenia, the sensitivity increased when carboplatin was combined with other cytotoxics (slope increased by 76%).

Conclusion: This study provides useful information to clinicians to better estimate the hematopoietic toxicity of carboplatin and thus choose more rationally carboplatin target AUCs as a function of pretreatment or concomitantly administered chemotherapies. For example, an AUC of 5 mg/mL · min is associated with a risk of grade 3 or 4 thrombocytopenia of 2% in combination with paclitaxel versus 38% with gemcitabine in a non-pretreated patient.
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http://dx.doi.org/10.1200/JCO.2010.29.3597DOI Listing
October 2010

Reversal of bupivacaine-induced cardiac electrophysiologic changes by two lipid emulsions in anesthetized and mechanically ventilated piglets.

Anesth Analg 2010 May;110(5):1473-9

Department of Anesthesiology, Critical Care, Emergency and Pain, University-Hospital of Nîmes, France.

Background: Accidental IV administration of bupivacaine can compromise cardiovascular function by inducing lethal arrhythmias whose hemodynamic consequences may be alleviated by lipid emulsions. However, little is known about the electrophysiologic effects of lipid emulsions. In this study, we assessed whether 2 different lipid emulsions can reverse cardiac electrophysiologic impairment induced by the IV administration of bupivacaine in anesthetized and mechanically ventilated piglets.

Methods: Bupivacaine (4 mg . kg(-1)) was injected over a 30-second period in 26 piglets. Thirty seconds after the end of bupivacaine injection, 1.5 mL . kg(-1) saline solution for the control group, and long-chain triglyceride emulsion (LCT group) or a mixture of long-chain and medium-chain triglyceride emulsion (LCT/MCT group) were infused over 1 minute. Cardiac conduction variables and hemodynamic variables were monitored for 30 minutes after injection.

Results: Bupivacaine induced similar electrophysiologic and hemodynamic changes. After 3 minutes, His ventricle intervals (median and interquartiles) were 100 (85-105), 45 (35-55), and 53 (48-73) milliseconds in the control, LCT, and LCT/MCT groups, respectively (P < 0.001 between control and both lipid emulsion groups). Lipid emulsions also reversed the effects on QRS duration, atrial-His, and PQ (the onset of the P wave to the Q wave of the QRS complex) intervals. LCT/MCT emulsion restored the decrease in maximal first derivative of left ventricular pressure (P < 0.01 after 3 minutes versus control group).

Conclusions: LCT and LCT/MCT emulsions reversed the lengthening of His ventricle, QRS, atrial-His, and PQ intervals induced by the IV injection of 4 mg . kg(-1) bupivacaine.
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http://dx.doi.org/10.1213/ANE.0b013e3181d53c8dDOI Listing
May 2010