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2. Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis

Author

Le Teuff, Gwénaël, Cozic, Nathalie, Boyer, Jean-Christophe, Boige, Valérie, Diasio, Robert B., Taieb, Julien, Meulendijks, Didier, Palles, Claire, Schwab, Matthias, Deenen, Maarten, Largiadèr, Carlo R., Marinaki, Anthony, Jennings, Barbara A., Wettergren, Yvonne, Di Paolo, Antonello, Gross, Eva, Budai, Barna, Ackland, Stephen P., van Kuilenburg, André B. P., McLeod, Howard L., Milano, Gérard, Thomas, Fabienne, Loriot, Marie-Anne, Kerr, David, Schellens, Jan H. M., Laurent-Puig, Pierre, Shi, Qian, Pignon, Jean-Pierre, and Etienne-Grimaldi, Marie-Christine

Published
2024
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4. Can we identify patients carrying targeted deleterious DPYD variants with plasma uracil and dihydrouracil? A GPCO-RNPGx retrospective analysis.

Author

Launay, Manon, Raymond, Laure, Guitton, Jérôme, Loriot, Marie-Anne, Chatelut, Etienne, Haufroid, Vincent, Thomas, Fabienne, and Etienne-Grimaldi, Marie-Christine

Subjects
DIHYDROPYRIMIDINE dehydrogenase, URACIL, PHENOTYPES, GENOTYPES, RETROSPECTIVE studies
Abstract

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main cause of severe fluoropyrimidine-related toxicities. The best strategy for identifying DPD-deficient patients is still not defined. The EMA recommends targeted DPYD genotyping or uracilemia (U) testing. We analyzed the concordance between both approaches. This study included 19,376 consecutive French patients with pre-treatment plasma U, UH2 and targeted DPYD genotyping (*2A, *13, D949V, *7) analyzed at Eurofins Biomnis (2015–2022). Mean U was 9.9 ± 10.1 ng/mL (median 8.7, range 1.6–856). According to French recommendations, 7.3 % of patients were partially deficient (U 16–150 ng/mL) and 0.02 % completely deficient (U≥150 ng/mL). DPYD variant frequencies were *2A: 0.83 %, *13: 0.17 %, D949V: 1.16 %, *7: 0.05 % (2 homozygous patients with U at 22 and 856 ng/mL). Variant carriers exhibited higher U (median 13.8 vs. 8.6 ng/mL), and lower UH2/U (median 7.2 vs. 11.8) and UH2/U2 (median 0.54 vs. 1.37) relative to wild-type patients (p<0.00001). Sixty-six% of variant carriers exhibited uracilemia <16 ng/mL, challenging correct identification of DPD deficiency based on U. The sensitivity (% patients with a deficient phenotype among variant carriers) of U threshold at 16 ng/mL was 34 %. The best discriminant marker for identifying variant carriers was UH2/U2. UH2/U2<0.942 (29.7 % of patients) showed enhanced sensitivity (81 %) in identifying deleterious genotypes across different variants compared to 16 ng/mL U. These results reaffirm the poor concordance between DPD phenotyping and genotyping, suggesting that both approaches may be complementary and that targeted DPYD genotyping is not sufficiently reliable to identify all patients with complete deficiency. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Reply to: "Is uracil enough for effective pre-emptive DPD testing?".

Author

Thomas, Fabienne, Launay, Manon, Raymond, Laure, Guitton, Jérôme, Loriot, Marie-Anne, Chatelut, Etienne, Haufroid, Vincent, and Etienne-Grimaldi, Marie-Christine

Subjects
GENETIC variation, HAPLOTYPES, GENE frequency, DNA sequencing, FUNCTIONAL analysis
Abstract

This document is a reply to a letter discussing the effectiveness of uracil for pre-emptive DPD testing. The authors acknowledge the limitations of their study, including the omission of testing for haplotype B3 and the lack of information on renal and liver functions. They disagree with the assumption that a non-detectable UH2 is necessary for a true DPD deficient status. The authors suggest that a combination of indirect phenotyping and extended genotyping may improve the identification of patients at risk for severe fluoropyrimidine toxicity. [Extracted from the article]

Published
2024
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10. Intérêts et limites de la recherche du déficit en dihydropyrimidine déshydrogénase dans le suivi des patients traités par fluoropyrimidines : résultats de deux enquêtes nationales de pratiques réalisées auprès des médecins et des biologistes

Author

Loriot, Marie-Anne, Masskouri, Fadil, Carni, Paolo, Le Malicot, Karine, Seitz, Jean-François, Michel, Pierre, Legoux, Jean-Louis, Bouché, Olivier, André, Thierry, Faroux, Roger, Delaloge, Suzette, Malka, David, Guigay, Joel, Thariat, Juliette, Thomas, Fabienne, Barin-Le-Guellec, Chantal, Ciccolini, Joseph, Boyer, Jean-Christophe, and Étienne-Grimaldi, Marie-Christine

Published
2019
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11. Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

Author

Chamorey, Emmanuel, Pujalte-Martin, Marc, Ferrero, Jean-Marc, Mahammedi, Hakim, Gravis, Gwenaelle, Roubaud, Guilhem, Beuzeboc, Philippe, Largillier, Remy, Borchiellini, Delphine, Linassier, Claude, Bouges, Hélène, Etienne-Grimaldi, Marie-Christine, Schiappa, Renaud, Gal, Jocelyn, and Milano, Gérard

Subjects
CASTRATION-resistant prostate cancer, ABIRATERONE acetate, PROSTATE cancer patients, CANCER patients, OLDER patients, DOCETAXEL, ACETATES
Abstract

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx

Author

Loriot, Marie-Anne, Ciccolini, Joseph, Thomas, Fabienne, Barin-Le-Guellec, Chantal, Royer, Bernard, Milano, Gérard, Picard, Nicolas, Becquemont, Laurent, Verstuyft, Céline, Narjoz, Céline, Schmitt, Antonin, Bobin-Dubigeon, Christine, Harle, Alexandre, Paci, Angelo, Poinsignon, Vianney, Quaranta, Sylvie, Evrard, Alexandre, Hennart, Benjamin, Broly, Franck, Fonrose, Xavier, Lafay-Chebassier, Claire, Wozny, Anne-Sophie, Masskouri, Fadil, Boyer, Jean-Christophe, and Etienne-Grimaldi, Marie-Christine

Published
2018
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16. Figure S1 from Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial

Author

Mauge, Laetitia, primary, Mejean, Arnaud, primary, Fournier, Laure, primary, Pereira, Helena, primary, Etienne-Grimaldi, Marie-Christine, primary, Levionnois, Emeline, primary, Caty, Armelle, primary, Abadie-Lacourtoisie, Sophie, primary, Culine, Stéphane, primary, Le Moulec, Sylvestre, primary, Linassier, Claude, primary, Théodore, Christine, primary, Ravaud, Alain, primary, Albiges, Laurence, primary, Grine, Abel, primary, Tartour, Eric, primary, Milano, Gérard, primary, Gille, Anne-Sophie, primary, Verkarre, Virginie, primary, Helley, Dominique, primary, and Oudard, Stéphane, primary

Published
2023
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17. Table S4 from Sunitinib Prior to Planned Nephrectomy in Metastatic Renal Cell Carcinoma: Angiogenesis Biomarkers Predict Clinical Outcome in the Prospective Phase II PREINSUT Trial

Author

Mauge, Laetitia, primary, Mejean, Arnaud, primary, Fournier, Laure, primary, Pereira, Helena, primary, Etienne-Grimaldi, Marie-Christine, primary, Levionnois, Emeline, primary, Caty, Armelle, primary, Abadie-Lacourtoisie, Sophie, primary, Culine, Stéphane, primary, Le Moulec, Sylvestre, primary, Linassier, Claude, primary, Théodore, Christine, primary, Ravaud, Alain, primary, Albiges, Laurence, primary, Grine, Abel, primary, Tartour, Eric, primary, Milano, Gérard, primary, Gille, Anne-Sophie, primary, Verkarre, Virginie, primary, Helley, Dominique, primary, and Oudard, Stéphane, primary

Published
2023
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18. Supplementary Table 1 from Contrasted Outcomes to Gefitinib on Tumoral IGF1R Expression in Head and Neck Cancer Patients Receiving Postoperative Chemoradiation (GORTEC Trial 2004-02)

Author

Thariat, Juliette, primary, Bensadoun, René-Jean, primary, Etienne-Grimaldi, Marie-Christine, primary, Grall, Dominique, primary, Penault-Llorca, Frédérique, primary, Dassonville, Olivier, primary, Bertucci, Francois, primary, Cayre, Anne, primary, De Raucourt, Dominique, primary, Geoffrois, Lionnel, primary, Finetti, Pascal, primary, Giraud, Philippe, primary, Racadot, Séverine, primary, Morinière, Sylvain, primary, Sudaka, Anne, primary, Van Obberghen-Schilling, Ellen, primary, and Milano, Gérard, primary

Published
2023
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19. Abigene, a Prospective, Multicentric Study of Abiraterone Acetate Pharmacogenetics in Metastatic Castration-Resistant Prostate Cancer

Author

Ferrero, Jean-Marc, primary, Mahammedi, Hakim, additional, Gravis, Gwenaelle, additional, Roubaud, Guilhem, additional, Beuzeboc, Philippe, additional, Largillier, Remi, additional, Borchiellini, Delphine, additional, Linassier, Claude, additional, Ebran, Nathalie, additional, Pace-Loscos, Tanguy, additional, Etienne-Grimaldi, Marie-Christine, additional, Schiappa, Renaud, additional, Gal, Jocelyn, additional, and Milano, Gérard, additional

Published
2023
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22. Plasma Uracil as a DPD Phenotyping Test: Pre-Analytical Handling Matters!

Author

Thomas, Fabienne, Launay, Manon, Guitton, Jérôme, Loriot, Marie-Anne, Boyer, Jean-Christophe, Haufroid, Vincent, Etienne-Grimaldi, Marie-Christine, Royer, Bernard, GPCO-UNICANCER Group, UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de biochimie médicale

Subjects
Pharmacology, Dihydropyrimidine Dehydrogenase Deficiency, Humans, Pharmacology (medical), Fluorouracil, Uracil, Dihydrouracil Dehydrogenase (NADP)
Abstract

To the Editor: We read with interest the article by de With et al. reporting the results of a prospective multicenter study where pretreatment uracil blood samples were collected and handled in 17 Dutch hospitals but analyzed in the reference hospital. [...]

Published
2022

25. Quantitative impact of pre-analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency

Author

Maillard, Maud, Launay, Manon, Royer, Bernard, Guitton, Jérôme, Gautier-Veyret, Elodie, Broutin, Sophie, Tron, Camille, Le Louedec, Félicien, Ciccolini, Joseph, Richard, Damien, Alarcan, Hugo, Haufroid, Vincent, Tafzi, Naïma, Schmitt, Antonin, Etienne-Grimaldi, Marie-Christine, Narjoz, Céline, Thomas, Fabienne, Groupe de Pharmacologie Clinique Oncologique (GPCO), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut Gustave Roussy (IGR), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Louise Michel [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Catholique de Louvain = Catholic University of Louvain (UCL), Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, UCL - (SLuc) Service de biochimie médicale, Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes

Subjects
Pharmacology, Dihydropyrimidine Dehydrogenase Deficiency, [SDV]Life Sciences [q-bio], dihydropyrimidine dehydrogenase, [SDV.CAN]Life Sciences [q-bio]/Cancer, Plasma, Phenotype, intra-individual variability, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Humans, Pharmacology (medical), uracil, Fluorouracil, pre-analytical practices, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], dihydrouracil, Dihydrouracil Dehydrogenase (NADP)
Abstract

International audience; AIMS: Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient’s uracil (U) plasma concentration is mandatory before fluoropyrimidines (FP) administration in France. In this study, we aimed to refine the pre-analytical recommendations for determining U and dihydrouracil (UH(2) ) concentrations, since they are essential in reliable DPD deficiency testing.METHODS: U and UH(2) concentrations were collected from 14 hospital laboratories. Stability in whole blood and plasma after centrifugation, the type of anticoagulant and long-term plasma storage were evaluated. The variation induced by time and temperature was calculated and compared to an acceptability range of ± 20%. Inter-occasion variability (IOV) of U and UH(2) was assessed in 573 patients double sampled for DPD-deficiency testing. RESULTS: Storage of blood samples before centrifugation at room temperature (RT) should not exceed 1 h, whereas cold (+4°C) storage maintains U stable after 5 hours. For patients correctly double sampled, IOV of U reached 22.4% for U (SD = 17.9%, range = [0-99%]). Notably, 17% of them were assigned with a different phenotype (normal or DPD deficient) based on the analysis of their two samples. For those having at least one non-compliant sample, this percentage increased up to 33.8%. The moment of blood collection did not affect the DPD phenotyping result.CONCLUSION: Caution should be taken when interpreting U concentrations if the time before centrifugation exceeds 1 h at RT, since it rises significantly afterwards. Not respecting the pre-analytical conditions for DPD phenotyping increases the risk of DPD status misclassification.

Published
2022
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29. Quantitative impact of pre‐analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency.

Author

Maillard, Maud, Launay, Manon, Royer, Bernard, Guitton, Jérôme, Gautier‐Veyret, Elodie, Broutin, Sophie, Tron, Camille, Le Louedec, Félicien, Ciccolini, Joseph, Richard, Damien, Alarcan, Hugo, Haufroid, Vincent, Tafzi, Naïma, Schmitt, Antonin, Etienne‐Grimaldi, Marie‐Christine, Narjoz, Céline, and Thomas, Fabienne

Subjects
DIHYDROPYRIMIDINE dehydrogenase, URACIL, PLASMA materials processing, BLOOD collection, HOSPITAL laboratories
Abstract

Aims: Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient's uracil (U) plasma concentration is mandatory before fluoropyrimidine (FP) administration in France. In this study, we aimed to refine the pre‐analytical recommendations for determining U and dihydrouracil (UH2) concentrations, as they are essential in reliable DPD‐deficiency testing. Methods: U and UH2 concentrations were collected from 14 hospital laboratories. Stability in whole blood and plasma after centrifugation, the type of anticoagulant and long‐term plasma storage were evaluated. The variation induced by time and temperature was calculated and compared to an acceptability range of ±20%. Inter‐occasion variability (IOV) of U and UH2 was assessed in 573 patients double sampled for DPD‐deficiency testing. Results: Storage of blood samples before centrifugation at room temperature (RT) should not exceed 1 h, whereas cold (+4°C) storage maintains the stability of uracil after 5 hours. For patients correctly double sampled, IOV of U reached 22.4% for U (SD = 17.9%, range = 0–99%). Notably, 17% of them were assigned with a different phenotype (normal or DPD‐deficient) based on the analysis of their two samples. For those having at least one non‐compliant sample, this percentage increased up to 33.8%. The moment of blood collection did not affect the DPD phenotyping result. Conclusion: Caution should be taken when interpreting U concentrations if the time before centrifugation exceeds 1 hour at RT, since it rises significantly afterwards. Not respecting the pre‐analytical conditions for DPD phenotyping increases the risk of DPD status misclassification. [ABSTRACT FROM AUTHOR]

Published
2023
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33. Artificial increase of uracilemia during fluoropyrimidine treatment can lead to DPD deficiency misinterpretation.

Author

UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Centre de toxicologie clinique, Thomas, Fabienne, Maillard, Maud, Launay, Manon, Tron, Camille, Etienne-Grimaldi, Marie-Christine, Gautier-Veyret, Elodie, Haufroid, Vincent, Pallet, Nicolas, Royer, Bernard, Narjoz, Céline, Schmitt, Antonin, Groupe de Pharmacologie Clinique Oncologique (GPCO-UNICANCER), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, UCL - (SLuc) Service de biochimie médicale, UCL - (SLuc) Centre de toxicologie clinique, Thomas, Fabienne, Maillard, Maud, Launay, Manon, Tron, Camille, Etienne-Grimaldi, Marie-Christine, Gautier-Veyret, Elodie, Haufroid, Vincent, Pallet, Nicolas, Royer, Bernard, Narjoz, Céline, Schmitt, Antonin, and Groupe de Pharmacologie Clinique Oncologique (GPCO-UNICANCER)

Abstract

Each year in France, >75 000 patients receive fluoropyrimidines, including 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Xeloda), to treat digestive, breast and head and neck cancers.1 Among them, ∼20% will experience severe hematological and digestive toxicities and <2% will have a fatal outcome in the first two cycles. A part of these toxicities may result from a deficiency in dihydropyrimidine dehydrogenase (DPD) which catabolizes the endogenous uracil (U) into dihydrouracil (UH2) as well as 5-FU. In 2018, French Health Authorities [Haute Autorité de Santé (HAS) and Institut National du Cancer, (INCa)] recommended the evaluation of the enzymatic activity of DPD by measuring the plasma U concentration before administration of fluoropyrimidines. [...]

Published
2021

35. Expression of a mutant HSP110 sensitizes colorectal cancer cells to chemotherapy and improves disease prognosis

Author

Dorard, Coralie, de Thonel, Aurelie, Collura, Ada, Marisa, Laetitia, Svrcek, Magali, Lagrange, Anais, Jego, Gaetan, Wanherdrick, Kristell, Joly, Anne Laure, Buhard, Olivier, Gobbo, Jessica, Penard-Lacronique, Virginie, Zouali, Habib, Tubacher, Emmanuel, Kirzin, Sylvain, Selves, Janick, Milano, Gerard, Etienne-Grimaldi, Marie-Christine, Bengrine-Lefevre, Leila, Louvet, Christophe, Tournigand, Christophe, Lefevre, Jeremie H., Parc, Yann, Tiret, Emmanuel, Flejou, Jean-Francis, Gaub, Marie-Pierre, Garrido, Carmen, and Duval, Alex

Subjects
Heat shock proteins -- Physiological aspects -- Genetic aspects -- Research, Colorectal cancer -- Genetic aspects -- Drug therapy -- Prognosis, Chemotherapy -- Physiological aspects -- Genetic aspects -- Research, Cancer -- Chemotherapy, Biological sciences, Health
Abstract

Heat shock proteins (HSPs) are necessary for cancer cell survival. We identified a mutant of HSP110 (HSP110δE9) in colorectal cancer showing microsatellite instability (MSI CRC), generated from an aberrantly spliced mRNA and lacking the HSP110 substrate-binding domain. This mutant was expressed at variable levels in almost all MSI CRC cell lines and primary tumors tested. HSP110ΔE9 impaired both the normal cellular localization of HSP110 and its interaction with other HSPs, thus abrogating the chaperone activity and antiapoptotic function of HSP110 in a dominant-negative manner. HSP110ΔE9 overexpression caused the sensitization of cells to anticancer agents such as oxaliplatin and 5-fluorouracil, which are routinely prescribed in the adjuvant treatment of people with CRC. The survival and response to chemotherapy of subjects with MSI CRCs was associated with the tumor expression level of HSP110ΔE9. HSP110 may thus constitute a major determinant for both prognosis and treatment response in CRC., The human tumor phenotype referred to as MSI arises because of defects in the DNA mismatch repair (MMR) system (1-3). MSI was first observed in inherited tumors associated with Lynch [...]

Published
2011
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37. Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity

Author

van Kuilenburg, André B. P., Meijer, Judith, Mul, Adri N. P. M., Meinsma, Rutger, Schmid, Veronika, Dobritzsch, Doreen, Hennekam, Raoul C. M., Mannens, Marcel M. A. M., Kiechle, Marion, Etienne-Grimaldi, Marie-Christine, Klümpen, Heinz-Josef, Maring, Jan Gerard, Derleyn, Veerle A., Maartense, Ed, Milano, Gérard, Vijzelaar, Raymon, and Gross, Eva

Published
2010
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42. VEGF-Related Germinal Polymorphisms May Identify a Subgroup of Breast Cancer Patients with Favorable Outcome under Bevacizumab-Based Therapy—A Message from COMET, a French Unicancer Multicentric Study

Author

Gal, Jocelyn, primary, Milano, Gérard, additional, Brest, Patrick, additional, Ebran, Nathalie, additional, Gilhodes, Julia, additional, Llorca, Laurence, additional, Dubot, Coraline, additional, Romieu, Gilles, additional, Desmoulins, Isabelle, additional, Brain, Etienne, additional, Goncalves, Anthony, additional, Ferrero, Jean-Marc, additional, Cottu, Paul-Henri, additional, Debled, Marc, additional, Tredan, Olivier, additional, Chamorey, Emmanuel, additional, Merlano, Marco Carlo, additional, Lemonnier, Jérôme, additional, Etienne-Grimaldi, Marie-Christine, additional, and Pierga, Jean-Yves, additional

Published
2020
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46. [Dihydropyrimidine dehydrogenase deficiency screening for management of patients receiving a fluoropyrimidine: Results of two national practice surveys addressed to clinicians and biologists]

Author

Loriot, Marie-Anne, Masskouri, Fadil, Carni, Paolo, Le Malicot, Karine, Seitz, Jean-François, Michel, Pierre, Legoux, Jean-Louis, Bouche, Olivier, André, Thierry, Faroux, Roger, Delaloge, Suzette, Malka, David, Guigay, Joël, Thariat, Juliette, Thomas, Fabienne, Barin-Le-Guellec, Chantal, Ciccolini, Joseph, Boyer, Jean-Christophe, Etienne-Grimaldi, Marie-Christine, Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Francophone de la Cancérologie Digestive, FFCD, Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), F2ME, PSA Peugeot - Citroën (PSA), PSA Peugeot Citroën (PSA)-PSA Peugeot Citroën (PSA)-Laboratoire Pluridisciplinaire de Recherche en Ingénierie des Systèmes, Mécanique et Energétique (PRISME), Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges)-Université d'Orléans (UO)-Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges)-Université d'Orléans (UO), Regional Hospital of Orleans, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHD Vendée - Hôpital Les Oudairies [La Roche sur Yon], Institut Gustave Roussy (IGR), Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Medical Oncology Department [Nice], COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Laboratoire de biochimie et biologie moléculaire, Université d'Orléans (UO)-Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges)-Université d'Orléans (UO)-Ecole Nationale Supérieure d'Ingénieurs de Bourges (ENSI Bourges), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Biomedical Research, Dihydropyrimidine Dehydrogenase Deficiency, MESH: Pharmacovigilance, [SDV]Life Sciences [q-bio], Surveys, MESH: Health Care Surveys, Digestive System Neoplasms, MESH: Genotype, Pharmacovigilance, MESH: Practice Guidelines as Topic, Antineoplastic Combined Chemotherapy Protocols, MESH: Otorhinolaryngologic Neoplasms, Oncologists, MESH: Antimetabolites, Antineoplastic, Enquête, DPD, MESH: Antineoplastic Combined Chemotherapy Protocols, Practice Guidelines as Topic, Screening, Female, Fluorouracil, France, Dihydropyrimidine dehydrogenase, Fluoropyrimidine, Antimetabolites, Antineoplastic, Genotype, Breast Neoplasms, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Dihydropyrimidine déshydrogénase, Reimbursement Mechanisms, Toxicité, MESH: Reimbursement Mechanisms, MESH: Biology, Humans, Biology, Capecitabine, MESH: Humans, Toxicity, MESH: Digestive System Neoplasms, MESH: Biomedical Research, MESH: Oncologists, MESH: Capecitabine, MESH: France, Otorhinolaryngologic Neoplasms, Pyrimidines, Dépistage, Health Care Surveys, MESH: Pyrimidines, MESH: Dihydropyrimidine Dehydrogenase Deficiency, MESH: Female, MESH: Fluorouracil, MESH: Breast Neoplasms
Abstract

International audience; 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.

Published
2019
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50. Pharmacogenetic profiling and cetuximab outcome in patients with advanced colorectal cancer

Author

Dahan Laetitia, Norguet Emmanuelle, Etienne-Grimaldi Marie-Christine, Formento Jean-Louis, Gasmi Mohamed, Nanni Isabelle, Gaudart Jean, Garcia Stéphane, Ouafik L'Houcine, Seitz Jean-François, and Milano Gérard

Subjects
EGFR inhibitors, cetuximab, clinical outcome, colorectal cancer, polymorphisms, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background We analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy. Methods Fifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients). Results Analysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival. Conclusions Present original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that CCND1 A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, FCGR3A F158V polymorphism was a significant independent predictor of overall survival.

Published
2011
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