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1. A new role of glutathione peroxidase 4 during human erythroblast enucleation

Author

Yohann Demont, Delphine Lebon, Roggiero Lopes Dos Santos, Pascal Vong, Hakim Ouled-Haddou, Nicolas Jankovsky, Julien Demagny, Candice Carola, Jessica Platon, Alexis Caulier, Jacques Rochette, Nicolas Guillaume, Jean-Pierre Marolleau, Kahia Messaoudi, Loïc Garçon, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, CHU Amiens-Picardie, Hôpital Claude Huriez [Lille], CHU Lille, Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'Hématologie [CHU Amiens], and DESSAIVRE, Louise

Subjects
0301 basic medicine, Erythroblasts, [SDV]Life Sciences [q-bio], Membrane lipids, Immunology, Cell, Enucleation, GPX4, medicine.disease_cause, Biochemistry, Filipin, Cell membrane, Mice, 03 medical and health sciences, chemistry.chemical_compound, Red Cells, Iron, and Erythropoiesis, 0302 clinical medicine, Reticulocyte, Erythroblast, medicine, Animals, Ferroptosis, Humans, Erythropoiesis, Lipid raft, chemistry.chemical_classification, Chemistry, Glutathione peroxidase, Cholera toxin, Cell Biology, Hematology, Phospholipid Hydroperoxide Glutathione Peroxidase, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030104 developmental biology, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), Selenoprotein, 030215 immunology
Abstract

The Gluthation peroxidase (GPX) enzymes are part of the protective system against lipid peroxydation that includes prevention of oxydation and reduction of already oxidized lipid through enzymatic reactions catalyzed by GSH. GPX4 is one of the five GPX able to incorporate selenium. It is also the only GPX able to directly reduce in the membrane the oxidized fatty acids and cholesterol. Recent reports identified GPX4 as the central inhibitor of ferroptosis, a process during which iron-induced peroxydation of membrane lipids causes a specific cell death that can be reverted by lipophilic antioxydants or by iron chelators. GPX4 has recently been involved during mice erythropoiesis: GPX4-/-mice present a hemolytic anemia and a high apoptotic rate in spleen erythroid progenitors. Although transcriptomics and proteomics found it expressed in human erythroid precursors, its role during human erythropoiesis has not been described. Using an in-vitroerythroid differentiation protocol from CD34+cells obtained from apheresis, we confirmed that GPX4 expression was induced at RNA and protein level during differentiation. RSL3, a specific GPX4 inhibitor, didn't affect early steps of erythropoiesis (i.eclonogenic potential and progenitor amplification) nor the early maturation of erythroid precursors (assessed by sequential CD49d/CD235/CD71 staining) but led to a significant decrease in the enucleation rate as assessed by Hoechst staining using flow cytometry (74%±9 DMSO versus 35%±6 RSL3, p Using Western Blot, we observed that RSL3 exposure induced a strong GPX4 depletion in erythroid progenitors while it didn't affect GPX1, another member of the GPX family expressed in erythroid cells. In order to confirm that enucleation defect was related to GPX4 knockdown, we used an Sh-RNA strategy that allowed a 62%±6 GPX4 decrease at RNA level and a 46%±5 at protein level. We observed a significant defect in terminal enucleation in the cells transduced with shGPX4-lentiviruses in comparison with sh-Scramble (59%±5 Sh-Scr versus 39%±6 Sh-Gpx4, p We investigated then whether GPX4-knock-down affected quantitatively or qualitatively the membrane lipid content, which was shown to be involved in the enucleation process. Addition of Cholesterol to RSL3 in the medium partially restored the enucleation rate. However, lipidomics failed to show any significant difference in the total membrane lipid content (and particularly in the cholesterol content) after RSL3 exposure in comparison to DMSO. Since cholesterol is particularly abundant in the lipid rafts, we investigated whether the lipid distribution was qualitatively altered within the cell membrane. We observed a disruption of membrane lipid rafts when cells were exposed to RSL3, as shown by a 60%±12 decrease in the mean cholera toxin fluorescence intensity. GPX4 presence in lipid rafts was confirmed using immunofluorescence showing their co-localization at cell surface in human primary erythroblasts. Since lipid rafts play a role in the contractile ring that separates pyrenocyte from reticulocyte, we evaluated the myosin-light chain phosphorylation using flow cytometry and Western Blot and found it drastically decreased in GPX4-knockdown conditions. In summary, we identified GPX4 as a new actor of human terminal erythroid differentiation, independently to its function in ferroptosis control. We described its interaction at cell surface with lipid rafts that are required for the assembly of the contractile ring and cytokinesis leading to the nucleus extrusion. Disclosures No relevant conflicts of interest to declare.

Published
2020
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2. Microsatellite instability in stage III colon cancer patients receiving fluoropyrimidine ± oxaliplatin: an

Author

Cohen, Romain, Taieb, Julien, Fiskum, Jack, Yothers, Greg, Goldberg, Richard, Yoshino, Takayuki, Alberts, Steven, Allegra, Carmen, De Gramont, Aimery, Seitz, Jean-Francois, O'Connell, Michael, Haller, Daniel, Wolmark, Norman, Erlichman, Charles, Zaniboni, Alberto, Lonardi, Sara, Kerr, Rachel, Grothey, Axel, Sinicrope, Franck, André, Thierry, Shi, Qian, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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), Mayo Clinic [Rochester], University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Center for Climate Systems Research [New York] (CCSR), Columbia University [New York], University of Tokyo [Kashiwa Campus], The University of Florida College of Medicine, Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, 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), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Fondazione Poliambulanza, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Oxford [Oxford], and West German Cancer Center [Essen, Germany]

Subjects
deficient mismatch repair, oxaliplatin, microsatellite instability, [SDV.CAN]Life Sciences [q-bio]/Cancer, prognosis, neoplasms, digestive system diseases, Colon cancer
Abstract

International audience; PURPOSE:In patients with stage III colon cancer (CC) whose tumors demonstrate microsatellite instability (MSI), the efficacy of adjuvant fluoropyrimidine (FP) with or without oxaliplatin has not been clearly demonstrated and the prognostic value of MSI remains uncertain.MATERIALS AND METHODS:Individual patient data from the ACCENT database were used to evaluate the effect of FP with or without oxaliplatin on disease-free survival (DFS) and overall survival (OS) among patients with MSI stage III CC and the prognostic value of MSI in patients treated with FP plus oxaliplatin, by stratified Cox models adjusted for demographic and clinicopathological factors.RESULTS:MSI status was available for 5,457 patients (609 MSI, 11.2%; 4848 microsatellite stable [MSS], 88.8%) from 12 randomized clinical trials (RCTs). Oxaliplatin significantly improved OS of MSI patients from the two RCTs testing FP with or without oxaliplatin (n = 185; adjusted hazard ratio [aHR] = 0.52, 95% CI, 0.28 to 0.93). Among the 4,250 patients treated with FP plus oxaliplatin (461 MSI and 3789 MSS), MSI was associated with better OS in the N1 group compared with MSS (aHR = 0.66; 95% CI, 0.46 to 0.95) but similar survival in the N2 population (aHR = 1.13; 95% CI, 0.86 to 1.48; P interaction = .029). The main independent prognosticators of MSI patients treated with FP plus oxaliplatin were T stage (aHR = 2.09; 95% CI, 1.29 to 3.38) and N stage (aHR = 3.57; 95% CI, 2.32 to 5.48). Similar results were observed for DFS in all analyses.CONCLUSION:Adding oxaliplatin to FP improves OS and DFS in patients with MSI stage III CC. Compared with MSS, MSI patients experienced better outcomes in the N1 group but similar survival in the N2 group.

Published
2021
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3. Combinations of Bevacizumab and Erlotinib Show Activity in Colorectal Cancer Independent of RAS Status

Author

Christophe Tournigand, Ariel Savina, Aimery de Gramont, Anaïs Bouygues, Benoist Chibaudel, Nathalie Ferrand, Michèle Sabbah, Paul Mésange, Alexandre E. Escargueil, Annette K. Larsen, Thierry André, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Cancer Research, Bevacizumab, medicine.drug_class, Colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Monoclonal antibody, 03 medical and health sciences, 0302 clinical medicine, medicine, neoplasms, Cetuximab, business.industry, Cancer, medicine.disease, respiratory tract diseases, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cancer research, Immunohistochemistry, Erlotinib, business, Tyrosine kinase, medicine.drug
Abstract

Purpose: There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant RAS. Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib. Experimental Design: The antitumor activity of bevacizumab, erlotinib, and their combination was determined in colorectal cancer models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot, and ELISA assays. The influence of cetuximab and erlotinib on EGF-mediated migration and the EGFR–EGF ligand feedback loop was established in colorectal cancer cell lines with different RAS status. Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGF-mediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wild-type cells. Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab–erlotinib combination, compared with bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types. Clin Cancer Res; 24(11); 2548–58. ©2018 AACR.

Published
2018
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4. Prognostic Value of Tumor Deposits for Disease-Free Survival in Patients With Stage III Colon Cancer: A Post Hoc Analysis of the IDEA France Phase III Trial (PRODIGE-GERCOR)

Author

Jérôme Dauba, S. Fratte, Olivier Dupuis, Julien Taieb, Jean-François Emile, Frédéric Bibeau, Jean François Delattre, Yves Becouarn, Magali Svrcek, Romain Cohen, Dewi Vernerey, Benoist Chibaudel, Julie Henriques, Antoine Falcoz, Christophe Louvet, Thierry André, Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Hôpital Nord Franche-Comté [Hôpital de Trévenans] (HNFC), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, CHU Mont de Marsan, Service d'Oncologie médicale [Clinique Victor Hugo], Clinique Victor Hugo, Institut Bergonié [Bordeaux], UNICANCER, Département de Pathologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), 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), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), and Service de Pathologie [CHU Saint-Antoine]

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Disease free survival, Colorectal cancer, [SDV]Life Sciences [q-bio], TNM staging system, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Post-hoc analysis, medicine, Humans, In patient, 030212 general & internal medicine, Aged, Neoplasm Staging, business.industry, Cancer, Middle Aged, medicine.disease, Prognosis, 3. Good health, Stage III Colon Cancer, 030220 oncology & carcinogenesis, Colonic Neoplasms, Female, business
Abstract

PURPOSE Tumor deposits (TDs) seem to affect the prognosis of patients with colon cancer (CC). In the seventh edition of the American Joint Committee on Cancer TNM staging system for CC, the presence of TDs is only considered in the absence of lymph node metastases (LNMs). In the era of personalized duration of histopathologic criteria-based adjuvant therapy, this could potentially lead to a decrease in the prognostic prediction accuracy. PATIENTS AND METHODS A post hoc analysis of all pathologic reports from patients with stage III CC included in the IDEA France phase III study (ClinicalTrials.gov identifier: NCT00958737 ) investigating the duration of adjuvant fluorouracil, leucovorin, and oxaliplatin or capecitabine and oxaliplatin therapy (3 v 6 months) was performed. The primary objective was to determine the prognostic impact of TD on disease-free survival (DFS). The effect of the addition of TD to LNM count on pN restaging was also evaluated. A multivariable analysis was performed to establish the association between TD and DFS. RESULTS Of 1,942 patients, 184 (9.5%) had TDs. The pN1a/b and pN1c populations showed similar DFS. TD-positive patients had worse prognosis compared with TD-negative patients, with 3-year DFS rates of 65.6% (95% CI, 58.0% to 72.1%) and 74.7% (95% CI, 72.6% to 76.7%; P = .0079), respectively. On multivariable analysis, TDs were associated with a higher risk of recurrence or death (hazard ratio [HR], 1.36; P = .0201). Other adverse factors included pT4 and/or pN2 disease (HR, 2.21; P < .001), the 3 months of adjuvant treatment (HR, 1.29; P = .0029), tumor obstruction (HR, 1.28; P = .0233), and male sex (HR, 1.24; P = .0151). Patients restaged as having pN2 disease (n = 35, 2.3%) had similar DFS as patients initially classified as pN2. CONCLUSION The presence of TDs is an independent prognostic factor for DFS in patients with stage III CC. The addition of TD to LNM may help to better define the duration of adjuvant therapy.

Published
2020
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5. RECIST and CHOI criteria in the evaluation of tumor response in patients with metastatic colorectal cancer treated with regorafenib, a prospective multicenter study

Author

Olivier Lucidarme, Benoist Chibaudel, Stefano Kim, Benoit Rousseau, Julie Henriques, Mathilde Wagner, Thierry André, Aurélien Gobert, Jean-Baptiste Bachet, Romain Cohen, Marie-Line Garcia-Larnicol, Paul Gillard, Christophe Louvet, Thibault Mazard, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CIC Pitié BT, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cooperator Multidisciplinary Oncology Group (GERCOR), CHU Henri Mondor, Institut du Cancer de Montpellier (ICM), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, CHU Saint-Antoine [AP-HP], 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 [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Male, Oncology, Pyridines, Colorectal cancer, Tumor response, 030218 nuclear medicine & medical imaging, chemistry.chemical_compound, 0302 clinical medicine, Choi Criteria, Clinical endpoint, Prospective Studies, Neoplasm Metastasis, Computed tomography, education.field_of_study, Radiological and Ultrasound Technology, General Medicine, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, Research Article, Adult, lcsh:Medical physics. Medical radiology. Nuclear medicine, medicine.medical_specialty, lcsh:R895-920, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, Regorafenib, medicine, Humans, Radiology, Nuclear Medicine and imaging, In patient, education, Response Evaluation Criteria in Solid Tumors, Aged, business.industry, Phenylurea Compounds, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Multicenter study, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Tomography, X-Ray Computed, business
Abstract

Background To evaluate the objective response rate (ORR) at 2 months of treatment with regorafenib according to RECIST 1.1, Choi, and modified Choi (mChoi) criteria in patients with metastatic colorectal cancer (mCRC). Methods Baseline and 2-month contrast-enhanced computed-tomography (CECT) scans of 55 patients with mCRC, prospectively enrolled in phase II TEXCAN trial, were centrally assessed. The primary endpoint was 2-month ORR by RECIST 1.1, Choi, and mChoi criteria. Final outcome was overall survival (OS). Results Of 55 patients included in this study (Intention-to-treat [ITT1] population), 35 had CECT at 2 months (ITT2 population). According to RECIST 1.1 criteria, 20 (57%) patients were SD and 15 were PD (43%) in the ITT2 population. According to Choi criteria, 18 (51%) patients were responders and 17 (48%) were non-responders. Median OS was 5.3 months (95% CI 3.7–8.6) in the ITT1 population and 8.9 months (95% CI 5.1–12.6) in the ITT2 population. In the ITT2 population, median OS was 16 months (95% CI 6.6–17.5) in SD patients (n = 20) and 4.6 months (95% CI 3.3–5.8) in PD patients (n = 15), according to RECIST 1.1 criteria (HR = 6.48). Median OS was 7.9 months (95% CI 4.2–17.5) in responders (n = 18) and 9.9 months (95% CI 3.7-NA) in non-responders (n = 17) according to Choi criteria (HR = 1.06). All patients except one were classified as non-responders with mChoi criteria. Conclusion At 2 months, unlike RECIST 1.1, Choi and mChoi criteria could not identify mCRC patients with regorafenib survival benefit. Trial registration ClinicalTrials.gov Identifier: NCT02699073.Registered March 4, 2016, Retrospectively registered.

Published
2019
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6. FOLFIRI3-aflibercept in previously treated patients with metastatic colorectal cancer

Author

Annette K. Larsen, Stefano Kim, Hélène Marijon, Christophe Borg, Magdalena Benetkiewicz, Marie-Line Garcia-Larnicol, Benoist Chibaudel, Aimery de Gramont, Leila Bengrine-Lefevre, Nils Steuer, Thierry André, François Ghiringhelli, Hubert Richa, Linda Dainese, Candice Carola, Juliette Barlet, Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de pathologie de Paris (IPP), Chirurgie viscérale endocrinienne et Cancérologique (Institut Hospitalier Franco-Britannique), Institut hospitalier Franco-Britannique [Levallois-Perret], Fondation Aide et Recherche en Cancérologie Digestive (Levallois-Perret) (ARCAD), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, medicine.medical_specialty, Colorectal cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, Second-line, Neutropenia, Irinotecan, Gastroenterology, 03 medical and health sciences, Folinic acid, 0302 clinical medicine, Internal medicine, parasitic diseases, medicine, Clinical endpoint, Chemotherapy, Aflibercept, business.industry, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, FOLFIRI, Liver function, business, medicine.drug
Abstract

Aim To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer. Methods This is a retrospective multicenter cohort, evaluating the efficacy and safety of the association of aflibercept with FOLFIRI3 (day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m2, irinotecan 90 mg/m2, 5-fluorouracil infusion 2400 mg/m2 per 46 h; day 3: irinotecan 90 mg/m2) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept (n = 3), more than one prior treatment line in irinotecan-naive patients (n = 3), and inadequate liver function (n = 3). In the "irinotecan-naive" patients (n = 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo (95%CI: 6.1-29.0) and 17.0 mo (95%CI: 13.0-17.3), respectively. The most common (> 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), and hypertension (6.7%). In the "pre-exposed irinotecan" patients (n = 35), 20 (57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo (95%CI: 3.9-10.4) and 14.3 mo (95%CI: 12.8-19.5), respectively. Conclusion Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.

Published
2018
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7. Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC)

Author

Neuzillet, Cindy, Gaujoux, Sebastien, Williet, Nicolas, Bachet, Jean-Baptiste, Bauguion, Lucile, Durand, Laurianne Colson, Conroy, Thierry, Dahan, Laetitia, Gilabert, Marine, Huguet, Florence, Marthey, Lysiane, Meilleroux, Julie, Mestier, Louis, Napoleon, Bertrand, Portales, Fabienne, Cunha, Antonio Sa, Schwarz, Lilian, Taieb, Julien, Chibaudel, Benoist, Bouche, Olivier, Hammel, Pascal, Dig, Thesaurus Natl Cancerologie, Gastroenterol, Soc Natl Francaise, Cancerolo, Federation Francophone, Multidisciplinair, Grp Cooperateur, Contre, Federation Natl Ctr Lutte, Digestive, Soc Francaise Chirurg, Diges, Soc Francaise, Oncolo, Soc Francaise Radiotherapie, Hepato-Bilio-Pancrea, Assoc Chirurg, Afc, Assoc Francaise Chirurg, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chirurgie digestive, hépato-biliaire et endocrinienne [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hépato-gastroentérologie [CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, 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), 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 Tenon [AP-HP], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, CHU Toulouse [Toulouse], hopital jean mermoz, Departement de Gastroenterologie, UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Hôpital Paul Brousse, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse, Hôpital Charles Nicolle [Rouen], Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hépato-Gastro Entérologie et Oncologie Digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
medicine.medical_specialty, Hepatology, business.industry, FOLFIRINOX, medicine.medical_treatment, General surgery, [SDV]Life Sciences [q-bio], Gastroenterology, Evidence-based medicine, medicine.disease, Gemcitabine, 3. Good health, Oxaliplatin, Radiation therapy, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Pancreatic cancer, medicine, 030211 gastroenterology & hepatology, business, Chemoradiotherapy, medicine.drug
Abstract

Background: This document is a summary of the French intergroup guidelines regarding the management of pancreatic adenocarcinoma (PA), updated in July 2018. Design: This collaborative work was produced under the auspices of all French medical and surgical societies involved in the management of PA. It is based on the previous guidelines, recent literature review and expert opinions. Recommendations were graded in three categories, according to the level of evidence. Results: Over the last seven years, significant changes in PA management have been implemented in clinical practice. Imaging/staging: diffusion magnetic resonance imaging is useful before surgery to rule out small liver metastases. Surgery: centralization of pancreatic surgery in expert centers is associated with a decreased postoperative mortality. Adjuvant chemotherapy: modified FOLFIRINOX in fit patients, or gemcitabine, or 5-FU, or gemcitabine plus capecitabine, to be discussed on a case-by-case basis. Locally advanced PA: no survival benefit of chemoradiotherapy. Metastatic PA: FOLFIRINOX and gemcitabine plus nab-paclitaxel combination are first-line standards in fit patients; second-line with 5FU/nal-IRI or 5FU/oxaliplatin combination after first-line gemcitabine. Conclusion: Guidelines for management of PA are continuously evolving and need to be regularly updated. This constant progress is made possible through clinical and translational research. However, as each individual case is particular, they cannot substitute to multidisciplinary tumor board discussion. (C) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Published
2018
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8. PEPCOL: a GERCOR randomized phase II study of nanoliposomal irinotecan PEP02 (MM-398) or irinotecan with leucovorin/5-fluorouracil as second-line therapy in metastatic colorectal cancer

Author

Chibaudel, Benoist, Maindrault-Goebel, Frédérique, Bachet, Jean-Baptiste, Louvet, Christophe, Khalil, Ahmed, Dupuis, Olivier, Hammel, Pascal, Garcia, Marie-Line, Bennamoun, Mostefa, Brusquant, David, Tournigand, Christophe, André, Thierry, Arbaud, Claire, Larsen, Annette K, Wang, Yi-Wen, Yeh, C. Grace, Bonnetain, Franck, de Gramont, Aimery, Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AAREC Filia Research (AFR), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Oncologie Médicale [Montsouris], Institut Mutualiste de Montsouris (IMM), Service d'Oncologie médicale [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Oncologie médicale [Clinique Victor Hugo], Clinique Victor Hugo, Service de Gastroentérologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Oncologie médicale [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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), PharmaEngine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor [Créteil], Service d'Oncologie Médicale [CHU Saint-Antoine], and HAL UPMC, Gestionnaire

Subjects
Male, Sucrose, [SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, MM398, Leucovorin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Irinotecan, nanoliposomal irinotecan, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Antineoplastic Combined Chemotherapy Protocols, Humans, Neoplasm Metastasis, Original Research, Cancer Biology, Aged, Aged, 80 and over, PEP02, Middle Aged, phase II, Combined Modality Therapy, Colorectal cancer, digestive system diseases, Drug Combinations, Treatment Outcome, Retreatment, Quality of Life, Camptothecin, Female, Fluorouracil, Colorectal Neoplasms
Abstract

International audience; A multicenter, open-label, noncomparative, randomized phase II study (PEPCOL) was conducted to evaluate the efficacy and safety of the irinotecan or PEP02 (MM-398, nanoliposomal irinotecan) with leucovorin (LV)/5-fluorouracil (5-FU) combination as second-line treatment in patients with metastatic colorectal cancer (mCRC). Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomized toirinotecan with LV/5-FU (FOLFIRI) or PEP02 with LV/5-FU (FUPEP; PEP02 80mg/m2 with LV 400mg/m2 on day 1 and 5-FU 2400mg/m2 on days 1–2). Bevacizumab (5mg/kg, biweekly) was allowed in both arms. The primary endpoint was 2-month response rate (RR). Fifty-five patients were randomized (FOLFIRI, n=27; FUPEP, n=28). In the intent-to-treat population (n=55), 2-month RR response rate was observed in two (7.4%) and three (10.7%) patients in the FOLFIRI and FUPEP arms, respectively. The most common grade 3–4 adverse events reported in the respective FOLFIRI and FUPEP arms were diarrhea (33% vs. 21%), neutropenia (30% vs. 11%), mucositis (11% vs. 11%), and grade 2 alopecia (26% vs. 25%). FUPEP has activity and acceptable safety profile in oxaliplatin-pretreated mCRC patients.

Published
2016
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9. New Therapeutic Opportunities Based on DNA Mismatch Repair and BRAF Status in Metastatic Colorectal Cancer

Author

Chantal Dreyer, Pascale Cervera, Marc Pocard, Alex Duval, Aimery de Gramont, Jean-François Fléjou, Thierry André, Romain Cohen, Magali Svrcek, HAL-UPMC, Gestionnaire, Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Cooperator Multidisciplinary Oncology Group (GERCOR), Service de Chirurgie d'Oncologie Digestive [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Oncologie Médicale [Institut Hospitalier Franco-Britannique], Division of Medical Oncology - Institut Hospitalier Franco-Britannique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'Oncologie Médicale [CHU Saint -Antoine]

Subjects
0301 basic medicine, MAPK/ERK pathway, Proto-Oncogene Proteins B-raf, Colorectal cancer, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, DNA Mismatch Repair, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, PD-L1, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Medicine, Humans, Molecular Targeted Therapy, Mutation, biology, business.industry, Microsatellite instability, medicine.disease, Prognosis, PD-1, PD-L1, Immune checkpoint, digestive system diseases, 3. Good health, 030104 developmental biology, BRAF mutation, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, DNA mismatch repair, business, Colorectal Neoplasms
Abstract

International audience; Recently, colorectal cancer (CRC) subtyping consortium identified four consensus molecular subtypes (CMS1–4). CMS1 is enriched for deficient mismatch repair (dMMR) and BRAF V600E tumors. Intriguingly, this subtype has better relapse-free survival but worse overall survival after relapse compared with the other subtypes. Growing evidence is accumulating on the benefit of specific therapeutic strategies such as immune checkpoint inhibition therapy in dMMR tumors and mitogen-activated protein kinase (MAPK) pathway targeted therapy in tumors harboring BRAF V600E mutation. After reviewing dMMR prognostic value, immune checkpoints as major targets for dMMR carcinomas will be highlighted. Following, BRAF V600E prognostic impact will be reviewed and therapeutic strategies with the combination of cytotoxic agents and especially the combinations of BRAF and MAPK inhibitors will be discussed.

Published
2016
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