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1. Impact of Next Generation Sequencing on Clinical Practice in Oncology in France: Better Genetic Profiles for Patients Improve Access to Experimental Treatments

Author: Patricia Marino, Morgane Michel, Meryl Darlington, Lionel Perrier, Isabelle Borget, S. Coquerelle, Isabelle Durand-Zaleski, Manon Durand, Sandrine Baffert, Unité de recherche clinique en économie de la santé d'Ile-de-France (URC Eco), Hôtel-Dieu-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Etudes et Recherche en économie de la santé, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR)-Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'analyse et de théorie économique (GATE Lyon Saint-Étienne), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), 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), NGSEco Group, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), CHU Rothschild [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe d'Analyse et de Théorie Economique Lyon - Saint-Etienne (GATE Lyon Saint-Étienne), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), HESAM Université (HESAM)-HESAM Université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), and CCSD, Accord Elsevier
Subjects: Oncology, Male, Lung Neoplasms, Time Factors, Survival, Colorectal cancer, medicine.medical_treatment, Health Services Accessibility, Targeted therapy, 0302 clinical medicine, Genotype, 030212 general & internal medicine, Molecular Targeted Therapy, [SHS.ECO] Humanities and Social Sciences/Economics and Finance, Melanoma, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 030503 health policy & services, Health Policy, High-Throughput Nucleotide Sequencing, Genomics, Middle Aged, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, 3. Good health, clinical practice, NGS, oncology, Female, France, 0305 other medical science, Colorectal Neoplasms, Adult, medicine.medical_specialty, Adolescent, DNA sequencing, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, Lung cancer, Aged, Retrospective Studies, business.industry, Public Health, Environmental and Occupational Health, Cancer, medicine.disease, somatic alterations, Clinical trial, Observational study, business
Abstract: International audience; Objectives: We evaluated how next generation sequencing (NGS) can modify care pathways in an observational impact study in France.Methods: All patients with lung cancer, colorectal cancer, or melanoma who had NGS analyses of somatic genomic alterations done in 1 of 7 biomolecular platforms certified by the French National Cancer Institute (INCa) between 2013 and 2016 were eligible. We compared patients' pathways before and after their NGS results. Endpoints consisted of the turnaround time in obtaining results, the number of patients with at least 1 genomic alteration identified, the number of actionable alterations, the impact of the genomic multidisciplinary tumor board on care pathways, the number of changes in the treatment plan, and the survival outcome up to 1 year after NGS analyses.Results: 1213 patients with a request for NGS analysis were included. NGS was performed for 1155 patients, identified at least 1 genomic alteration for 867 (75%), and provided an actionable alteration for 614 (53%). Turnaround time between analyses and results was on average 8 days (Min: 0; Max: 95) for all cancer types. Before NGS analysis, 33 of 614 patients (5%) were prescribed a targeted therapy compared with 54 of 614 patients (8%) after NGS analysis. Proposition of inclusion in clinical trials with experimental treatments increased from 5% (n = 31 of 614) before to 28% (n = 178 of 614) after NGS analysis. Patients who benefited from a genotype matched treatment after NGS analysis tended to have a better survival outcome at 1 year than patients with nonmatched treatment: 258 days (±107) compared with 234 days (±106), (P = .41).Conclusions: NGS analyses resulted in a change in patients' care pathways for 20% of patients (n = 232 of 1155).
Published: 2020
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2. Cost of cancer diagnosis using next-generation sequencing targeted gene panels in routine practice: a nationwide French study

Author: Patricia, Marino, Rajae, Touzani, Lionel, Perrier, Etienne, Rouleau, Dede Sika, Kossi, Zou, Zhaomin, Nathanaël, Charrier, Nicolas, Goardon, Claude, Preudhomme, Isabelle, Durand-Zaleski, Isabelle, Borget, Sandrine, Baffert, Dominique, Vaur, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'analyse et de théorie économique (GATE Lyon Saint-Étienne), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Etudes et Recherche en économie de la santé, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR)-Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Unité de recherche clinique en économie de la santé d'Ile-de-France (URC Eco), Hôtel-Dieu-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Laboratoire d'Hématologie [CHRU Lille] (Centre de Biologie et de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), This study was supported by a grant from the French National Cancer Institute, dedicated to economic analyses of innovative techniques (reference number 2013-1-NGS-02). This research was funded by the National Cancer Institute in France (INCa) and the Canceropôle Ile de France., NGSEco Group : Baffert S, Barillot E, Bezieau S, Borget I, Coppin L, Descapentries C, Durand-Zaleski I, Forget S, Frebourd T, Guardiola P, Goardon N, Houdayer C, Hupe P, Lacroix L, Leclerc J, Lespagnol A, Longuemare S, Marino P, Mosser J, Odou MF, Perrier L, Preudhomme C, Revillion F, Rouleau E, Sevenet N, Soubeyran I, Vaur D., Dao, Taï, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe d'Analyse et de Théorie Economique Lyon - Saint-Etienne (GATE Lyon Saint-Étienne), and École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: 0301 basic medicine, medicine.medical_specialty, Consumables, Total cost, Computer science, Context (language use), Routine practice, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Gene panel, Genetics, medicine, Humans, Medical physics, Genetic Testing, [SHS.ECO] Humanities and Social Sciences/Economics and Finance, Early Detection of Cancer, Genetics (clinical), health care economics and organizations, Correction, Cancer, Sequence Analysis, DNA, medicine.disease, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, 3. Good health, 030104 developmental biology, Cost driver, 030220 oncology & carcinogenesis, France
Abstract: International audience; It is currently unclear if next-generation sequencing (NGS) technologies can be implemented in the diagnosis setting at an affordable cost. The aim of this study was to measure the total cost of performing NGS in clinical practice in France, in both germline and somatic cancer genetics.The study was performed on 15 French representative cancer molecular genetics laboratories performing NGS panels' tests. The production cost was estimated using a micro-costing method with resources consumed collected in situ in each laboratory from a healthcare provider perspective. In addition, we used a top-down methodology for specific post-sequencing steps including bioinformatics, technical validation, and biological validation. Additional non-specific costs were also included. Costs were detailed per step of the process (from the pre-analytical phase to delivery of results), and per cost driver (consumables, staff, equipment, maintenance, overheads). Sensitivity analyses were performed.The mean total cost of NGS for targeted gene panels was estimated to 607€ (±207) in somatic genetics and 550€ (±140) in germline oncogenetic analysis. Consumables were the highest cost driver of the sequencing process. The sensitivity analysis showed that a 25% reduction of consumables resulted in a 15% decrease in total NGS cost in somatic genetics, and 13% in germline analysis. Additional costs accounted for 30-32% of the total NGS costs.Beyond cost assessment considerations, the diffusion of NGS technologies will raise questions about their efficiency when compared to more targeted approaches, and their added value in a context of routine diagnosis.
Published: 2018
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3. Dynamics of Long-Term Patient-Reported Quality of Life and Health Behaviors After Adjuvant Breast Cancer Chemotherapy

Author: Antonio Di Meglio, Julie Havas, Arnauld S. Gbenou, Elise Martin, Mayssam El-Mouhebb, Barbara Pistilli, Gwenn Menvielle, Agnes Dumas, Sibille Everhard, Anne-Laure Martin, Paul H. Cottu, Florence Lerebours, Charles Coutant, Anne Lesur, Olivier Tredan, Patrick Soulie, Laurence Vanlemmens, Florence Joly, Suzette Delaloge, Patricia A. Ganz, Fabrice André, Ann H. Partridge, Lee W. Jones, Stefan Michiels, Ines Vaz-Luis, Institut Gustave Roussy (IGR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), UNICANCER, Institut Curie [Paris], Institut Curie - Saint Cloud (ICSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Centre Léon Bérard [Lyon], CRLCC Paul Papin, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Département de médecine oncologique [Gustave Roussy], University of California [Los Angeles] (UCLA), University of California (UC), Dana-Farber Cancer Institute [Boston], Memorial Sloane Kettering Cancer Center [New York], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and ANR-18-IBHU-0002,PRISM,PRecISion Medicine Institute in oncology(2018)
Subjects: Cancer Research, Prevention, [SDV]Life Sciences [q-bio], Health Behavior, Clinical Sciences, Oncology and Carcinogenesis, Breast Neoplasms, Oncology, Chemotherapy, Adjuvant, Clinical Research, Breast Cancer, Behavioral and Social Science, Quality of Life, Humans, Chemotherapy, Female, Patient Reported Outcome Measures, Oncology & Carcinogenesis, Adjuvant, Cancer
Abstract: PURPOSE We aimed to characterize long-term quality of life (QOL) trajectories among patients with breast cancer treated with adjuvant chemotherapy and to identify related patterns of health behaviors. METHODS Female stage I-III breast cancer patients receiving chemotherapy in CANTO (CANcer TOxicity; ClinicalTrials.gov identifier: NCT01993498 ) were included. Trajectories of QOL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–C30 Summary Score) and associations with trajectory group membership were identified by iterative estimations of group-based trajectory models and multivariable multinomial logistic regression, respectively. RESULTS Four trajectory groups were identified (N = 4,131): excellent (51.7%), very good (31.7%), deteriorating (10.0%), and poor (6.6%) QOL. The deteriorating trajectory group reported fairly good baseline QOL (mean [95% CI], 78.3/100 [76.2 to 80.5]), which significantly worsened at year-1 (58.1/100 [56.4 to 59.9]) and never recovered to pretreatment values through year-4 (61.1/100 [59.0 to 63.3]) postdiagnosis. Healthy behaviors were associated with better performing trajectory groups. Obesity (adjusted odds ratio [aOR] v lean, 1.51 [95% CI, 1.28 to 1.79]; P < .0001) and current smoking (aOR v never, 1.52 [95% CI, 1.27 to 1.82]; P < .0001) at diagnosis were associated with membership to the deteriorating group, which was also characterized by a higher prevalence of patients with excess body weight and insufficient physical activity through year-4 and by frequent exposure to tobacco smoking during chemotherapy. Additional factors associated with membership to the deteriorating group included younger age (aOR, 1-year decrement 1.01 [95% CI, 1.01 to 1.02]; P = .043), comorbidities (aOR v no, 1.22 [95% CI, 1.06 to 1.40]; P = .005), lower income (aOR v wealthier households, 1.21 [95% CI, 1.07 to 1.37]; P = .002), and endocrine therapy (aOR v no, 1.14 [95% CI, 1.01 to 1.30]; P = .047). CONCLUSION This latent-class analysis identified some patients with upfront poor QOL and a high-risk cluster with severe, persistent postchemotherapy QOL deterioration. Screening relevant patient-level characteristics may inform tailored interventions to mitigate the detrimental impact of chemotherapy and preserve QOL, including early addressal of behavioral concerns and provision of healthy lifestyle support programs.
Published: 2022
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4. Molecular profiling of non-small-cell lung cancer patients with or without brain metastases included in the randomized SAFIR02-LUNG trial and association with intracranial outcome

Author: Alice Mogenet, Fabrice Barlesi, Benjamin Besse, Stefan Michiels, Maryam Karimi, Alicia Tran-Dien, Nicolas Girard, Julien Mazieres, Clarisse Audigier-Valette, Myriam Locatelli-Sanchez, Maud Kamal, Pierre Gestraud, Abderaouf Hamza, Alexandra Jacquet, Marta Jimenez, Sabrina Yara, Laurent Greillier, François Bertucci, David Planchard, Jean-Charles Soria, Ivan Bieche, Pascale Tomasini, Aix-Marseille Université - École de médecine (AMU SMPM MED), Aix-Marseille Université - Faculté des sciences médicales et paramédicales (AMU SMPM), Aix Marseille Université (AMU)-Aix Marseille Université (AMU), 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), Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Tarbiat Modares University [Tehran], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, ENGIE GREEN, parent, Service de pneumologie [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut Curie [Paris], Centre de Bioinformatique (CBIO), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, 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), 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, Multidisciplinary Oncology and Therapeutic Innovations Unit, and Hôpital Nord [CHU - APHM]
Subjects: Pulmonary and Respiratory Medicine, Cancer Research, Lung Neoplasms, MESH: Mutation, DNA Copy Number Variations, Molecular biology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Targeted therapy, Carcinoma, Non-Small-Cell Lung, MESH: Tumor Microenvironment, Tumor Microenvironment, Humans, MESH: Lung, Lung, Randomized Controlled Trials as Topic, Comparative Genomic Hybridization, MESH: Humans, Brain Neoplasms, Brain metastases, MESH: Lung Neoplasms, MESH: Comparative Genomic Hybridization, MESH: Randomized Controlled Trials as Topic, Oncology, Mutation, MESH: Brain Neoplasms, MESH: DNA Copy Number Variations, Immunotherapy, Lung cancer, MESH: Carcinoma, Non-Small-Cell Lung
Abstract: Lung cancer remains the most frequent cause of brain metastases (BMs) and is responsible for high morbidity and mortality. Intracranial response to systemic treatments is inconsistent due to several mechanisms: genomic heterogeneity, blood-tumor barrier, and the brain-specific microenvironment. We conducted a study using data from the SAFIR02-LUNG trial. The primary objective was to compare the molecular profiles of non-small-cell lung cancer (NSCLC) with or without BMs. The secondary objective was to explore central nervous system (CNS) outcomes with various maintenance treatment regimens.In total, 365 patients harboring interpretable molecular data were included in this analysis. Clinical and biological data were collected. Genomic analyses were based on array-comparative genomic hybridization and next-generation sequencing (NGS) following the trial recommendations.Baseline genomic analyses of copy number variations identified a 24-gene signature specific to lung cancer BM occurrence, all previously known to take part in oncogenesis. NGS analysis identified a higher proportion of KRAS mutations in the BM-positive group (44.3% versus 32.3%), especially G12C mutations (63% versus 47%). Protein interaction analyses highlighted several functional interactions centered on EGFR. Furthermore, the risk of CNS progression was decreased with standard pemetrexed maintenance therapy. The highest rate of CNS progression was observed with durvalumab, probably because of the specific intracranial immune microenvironment.This work identified a 24-gene signature specific to lung cancer with BM. Further studies are needed to precisely determine the functional implications of these genes to identify new therapeutic targets for the treatment of lung cancer with BM.
Published: 2022
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5. Dosimetric Effects of the Interfraction Variations during Whole Breast Radiotherapy: A Prospective Study

Author: Julian eJacob, Steve eHeymann, Isabelle eBorget, Isabelle eDumas, Elyes eRiahi, Pierre eMaroun, Patrick eEzra, Elena eRoberti, Sofia eRivera, Eric eDeutsch, Céline eBourgier, Département de radiothérapie [Gustave Roussy], Institut Gustave Roussy (IGR), Etudes et Recherche en économie de la santé, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR)-Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Radiothérapie moléculaire (UMR 1030), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and KARLI, Mélanie
Subjects: Cancer Research, dosimetry, interfraction variations, business.industry, Planning target volume, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast radiotherapy, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, inferior central margin, central lung distance, Whole breast radiotherapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Whole Breast Irradiation, Organ at risk, Dosimetry, Medicine, breast radiotherapy, Nuclear medicine, business, Prospective cohort study, Radiation treatment planning, Original Research
Abstract: International audience; Introduction: The aim of this work was to assess the dosimetric impact of the interfraction variations during breast radiotherapy.Materials and methods: Daily portal imaging measurements were prospectively performed in 10 patients treated with adjuvant whole breast irradiation (50 Gy/25 fractions). Margins between the clinical target volume and the planning target volume (PTV) were 5 mm in the three dimensions. Parameters of interest were the central lung distance (CLD) and the inferior central margin (ICM). Daily movements were applied to the baseline treatment planning (TP1) to design a further TP (TP2). The PTV coverage and organ at risk exposure were measured on both TP1 and TP2, before being compared.Results: A total of 241 portal images were analyzed. The random and systematic errors were 2.6 and 3.7 mm for the CLD, 4.3 and 6.9 mm for the ICM, respectively. No significant consequence on the PTV treatments was observed (mean variations: +0.1%, p = 0.56 and −1.8%, p = 0.08 for the breast and the tumor bed, respectively). The ipsilateral lung and heart exposure was not significantly modified.Conclusion: In our series, the daily interfraction variations had no significant effect on the PTV coverage or healthy tissue exposure during breast radiotherapy.
Published: 2015
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6. Efficacy of Vaccination against HPV infections to prevent cervical cancer in France

Author: Ribassin-Majed, Laureen, Hill, Catherine, Lounes, Rachid, Mathématiques Appliquées à Paris 5 ( MAP5 - UMR 8145 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National des Sciences Mathématiques et de leurs Interactions-Centre National de la Recherche Scientifique ( CNRS ), Service d'Épidémiologie et de Biostatistiques, Service d'Épidémiologie et de Biostatistiques-Service d'Épidémiologie et de Biostatistiques, Lounes, Rachid, Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), and Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR)-Direction de la recherche clinique [Gustave Roussy]
Subjects: modelling, [STAT.AP]Statistics [stat]/Applications [stat.AP], Human papillomavirus, [STAT.AP] Statistics [stat]/Applications [stat.AP], [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, cervical cancer, vaccine, [ STAT.AP ] Statistics [stat]/Applications [stat.AP], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: International audience; Human papillomavirus (HPV) types 16 and 18 cause 70% of cervical cancers, and currently two vaccines protecting against these types are available. In a previous paper, we estimated the long-term effect of HPV vaccination on the risk of cervical cancer in the French population using mathematical modeling. Several vaccination scenarios were tested, including different vaccination coverage rates of females alone or in conjunction with males. In the first scenario, which is based on the vaccination campaign initiated in France in 2007, 30% of females aged 14 to 19 years were vaccinated annually, resulting in a 60% cumulative vaccination coverage rate among 14 to 19 year old females 6 years after the beginning of the vaccination campaign. A catch-up program was also included with an annual vaccination rate of 10% among females aged 20 to 24 years. Using this scenario, the model predicted an 83% reduction in cervical cancer incidence 50 years after vaccination initiation. The following scenarios were also considered: extending vaccination: (1) to males, (2) to females under 14; and scenarios with (3) vaccination among 14 to 24 year-old females (annual rate of 80%), (4) vaccination among 14 to 24 year-old females and males (annual rate of 80%). Greater reductions in cervical cancer incidence of 92% to 98% were predicted.
Published: 2015

7. Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life—experience of the French Network

Author: Schenone, Laurence, Houillier, Caroline, Tanguy, Marie Laure, Choquet, Sylvain, Agbetiafa, Kossi, Ghesquières, Hervé, Damaj, Gandhi, Schmitt, Anna, Bouabdallah, Krimo, Ahle, Guido, Gressin, Remy, Cornillon, Jérôme, Houot, Roch, Marolleau, Jean-Pierre, Fornecker, Luc-Matthieu, Chinot, Olivier, Peyrade, Frédéric, Bouabdallah, Reda, Moluçon-Chabrot, Cécile, Gyan, Emmanuel, Chauchet, Adrien, Casasnovas, Olivier, Oberic, Lucie, Delwail, Vincent, Abraham, Julie, Roland, Virginie, Waultier-Rascalou, Agathe, Willems, Lise, Morschhauser, Franck, Fabbro, Michel, Ursu, Renata, Thieblemont, Catherine, Jardin, Fabrice, Tempescul, Adrian, Malaise, Denis, Touitou, Valérie, Nichelli, Lucia, Le Garff-Tavernier, Magali, Plessier, Aurélie, Bourget, Philippe, Bonmati, Caroline, Wantz-Mézières, Sophie, Giordan, Quentin, Dorvaux, Véronique, Charron, Cyril, Jabeur, Waliyde, Hoang-Xuan, Khê, Taillandier, Luc, Soussain, Carole, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département d'hématologie, Institut Curie, Site Saint-Cloud, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Bergonié [Bordeaux], UNICANCER, CHU Bordeaux [Bordeaux], Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-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 ), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, 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), CHU Strasbourg, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Dupuytren [CHU Limoges], Centre Hospitalier Saint Jean de Perpignan, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut du Cancer de Montpellier (ICM), Hopital Saint-Louis [AP-HP] (AP-HP), NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), 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), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département d'Oncologie Chirurgicale [Institut Curie], Institut Curie [Paris], Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon [AP-HP], CHU Necker - Enfants Malades [AP-HP], Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Hôpital de Mercy, Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Hôpital Ambroise Paré [AP-HP], Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Automatique de Nancy (CRAN), Institut Curie - Saint Cloud (ICSC), Immunité et cancer (U932), and We thank the clinicians involved in the French National 'Lymphome Oculo-Cérébral' LOC network, part of the network for rare cancers of the central nervous system, 'RENOCLIP-LOC Network', approved by the French National Institute of Cancer (INCa).
Subjects: Transplantation, Hematology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n\,=\,147) or at relapse (n\,=\,119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n\,=\,64), thiotepa-busulfan (n\,=\,24), BCNU-etoposide-cytarabine-melphalan (BEAM, n\,=\,36) and thiotepa-busulfan-cyclophosphamide (n\,=\,142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.
Published: 2022
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8. The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

Author: Pablo Berlanga, Gaelle Pierron, Ludovic Lacroix, Mathieu Chicard, Tiphaine Adam de Beaumais, Antonin Marchais, Anne C. Harttrampf, Yasmine Iddir, Alicia Larive, Aroa Soriano Fernandez, Imene Hezam, Cecile Chevassus, Virginie Bernard, Sophie Cotteret, Jean-Yves Scoazec, Arnaud Gauthier, Samuel Abbou, Nadege Corradini, Nicolas André, Isabelle Aerts, Estelle Thebaud, Michela Casanova, Cormac Owens, Raquel Hladun-Alvaro, Stefan Michiels, Olivier Delattre, Gilles Vassal, Gudrun Schleiermacher, Birgit Geoerger, Institut Català de la Salut, [Berlanga P] Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Pierron G] Unité de Génétique Somatique, Service de Génétique, Hospital Group, Institut Curie, Paris, France. [Lacroix L] Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Chicard M] INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center, PSL Research University, Institut Curie, Paris, France. [Adam de Beaumais T] Clinical Research Direction, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Marchais A] INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. [Soriano Fernandez A] Grup de Recerca Translacional en Càncer en la Infància i l’Adolescència, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Hladun-Alvaro R] Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Institut Gustave Roussy (IGR), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Curie [Paris], Department of Medical Oncology, Département de médecine oncologique [Gustave Roussy], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherche et de Documentation sur l'Océanie (CREDO), École des hautes études en sciences sociales (EHESS)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique [Châtenay-Malabry] (LabEx LERMIT), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biologie et pathologie médicales [Gustave Roussy], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Centre Léon Bérard [Lyon], Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)
Subjects: neoplasias::procesos neoplásicos::recurrencia neoplásica local [ENFERMEDADES], Pediatria, Adolescent, [SDV]Life Sciences [q-bio], Carcinoma, High-Throughput Nucleotide Sequencing, Neoplasms [DISEASES], neoplasias [ENFERMEDADES], Càncer - Recaiguda, terapéutica::medicina de precisión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Oncology, Mutation, Biomarkers, Tumor, Neoplasms::Neoplastic Processes::Neoplasm Recurrence, Local [DISEASES], Humans, Prospective Studies, Medicina personalitzada, Neoplasm Recurrence, Local, Precision Medicine, Child, Therapeutics::Precision Medicine [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Cell-Free Nucleic Acids
Abstract: Abstract MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA). Significance: MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity. This article is highlighted in the In This Issue feature, p. 1171
Published: 2022
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9. A Longitudinal Study of Individual Radiation Responses in Pediatric Patients Treated with Proton and Photon Radiotherapy, and Interventional Cardiology: Rationale and Research Protocol of the HARMONIC Project

Author: Maria Grazia Andreassi, Nadia Haddy, Mats Harms-Ringdahl, Jonica Campolo, Andrea Borghini, François Chevalier, Jochen M. Schwenk, Brice Fresneau, Stephanie Bolle, Manuel Fuentes, Siamak Haghdoost, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR), The Wenner-Gren Institute, Stockholm University, Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), ARCHADE (Advanced Resource Centre for HADrontherapy in Europe), Royal Institute of Technology [Stockholm] (KTH ), Université Paris-Saclay, Département de radiothérapie [Gustave Roussy], and Universidad de Salamanca
Subjects: cardiac catheterization, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Organic Chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, pediatric oncology, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, congenital heart disease, Catalysis, Computer Science Applications, Inorganic Chemistry, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, proton radiotherapy, HARMONIC project, radiation biomarkers, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Physical and Theoretical Chemistry, ionizing radiation, Molecular Biology, Spectroscopy, radiotherapy
Abstract: International audience; The Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy (photon and proton) in Pediatrics (HARMONIC) is a five-year project funded by the European Commission that aimed to improve the understanding of the long-term ionizing radiation (IR) risks for pediatric patients. In this paper, we provide a detailed overview of the rationale, design, and methods for the biological aspect of the project with objectives to provide a mechanistic understanding of the molecular pathways involved in the IR response and to identify potential predictive biomarkers of individual response involved in long-term health risks. Biological samples will be collected at three time points: before the first exposure, at the end of the exposure, and one year after the exposure. The average whole-body dose, the dose to the target organ, and the dose to some important out-of-field organs will be estimated. State-of-the-art analytical methods will be used to assess the levels of a set of known biomarkers and also explore high-resolution approaches of proteomics and miRNA transcriptomes to provide an integrated assessment. By using bioinformatics and systems biology, biological pathways and novel pathways involved in the response to IR exposure will be deciphered.
Published: 2023
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10. Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study

Author: Balazs Acs, Samuel C.Y. Leung, Kelley M. Kidwell, Indu Arun, Renaldas Augulis, Sunil S. Badve, Yalai Bai, Anita L. Bane, John M.S. Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Henk Buikema, Martin C. Chang, Robin L. Dietz, Andrew Dodson, Susan Fineberg, Cornelia M. Focke, Dongxia Gao, Allen M. Gown, Carolina Gutierrez, Johan Hartman, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M. Levenson, Rustin Mahboubi-Ardakani, Mauro G. Mastropasqua, Sharon Nofech-Mozes, C. Kent Osborne, Frédérique M. Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T. Rau, Stefan Reinhard, Stephanie Robertson, Roberto Salgado, Tomoharu Sugie, Bert van der Vegt, Giuseppe Viale, Lila A. Zabaglo, Daniel F. Hayes, Mitch Dowsett, Torsten O. Nielsen, David L. Rimm, Lisa M. McShane, Torsten Nielsen, Samuel Leung, Signe Borgquist, Angela Chan, Carsten Denkert, Anna Ehinger, Matthew Ellis, Margaret Flowers, Chad Galderisi, Abhi Gholap, Douglas J. Hartman, Judith C. Hugh, Anagha Jadhav, Elizabeth N. Kornaga, Hans Kreipe, Richard Levenson, Mauro Mastropasqua, Takuya Moriya, Hongchao Pan, Liron Pantanowitz, Ernesta Paola Neri, Mei-Yin Polley, Jason Ruan, Takashi Sakatani, Lois Shepherd, Ian Smith, Joseph Sparano, Melanie Spears, Malini Srinivasan, Jane Starczynski, Austin Todd, Shakeel Virk, Yihong Wang, Hua Yang, Zhiwei Zhang, Inti Zlobec, Rigshospitalet [Copenhagen], Copenhagen University Hospital, CHUV, Lausanne (Departement d'Oncologie), St Jude Children's Research Hospital, Laboratorio de Dianas Terapeuticas, Centro Integral Oncologico Clara Campal, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Washington [Seattle], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut Gustave Roussy (IGR), Direction de la recherche clinique [Gustave Roussy], Memorial Sloan Kettering Cancer Center (MSKCC), Weill Medical College of Cornell University [New York], Sylvester Comprehensive Cancer Center [Miami, FL, USA] (S3C), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)
Subjects: [SDV]Life Sciences [q-bio], Biopsy, Image Processing, DIGITAL-IMAGE-ANALYSIS, MULTICENTER, Medical and Health Sciences, MESH: Biopsy, Computer-Assisted, REPRODUCIBILITY, NEEDLE BIOPSIES, Receptors, Image Processing, Computer-Assisted, Pathology, MESH: Protein Kinase Inhibitors, 610 Medicine & health, Cancer, Tumor, PROLIFERATION, MESH: Receptor, trkA, KI-67 LABELING INDEX, MESH: Image Processing, Computer-Assisted, Immunohistochemistry, INTERNATIONAL KI67, Receptors, Estrogen, TRK fusion, RELIABILITY, MESH: Receptors, Estrogen, Female, MESH: Biomarkers, Tumor, NTRK gene fusions, MESH: Ki-67 Antigen, International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Settore MED/08 - Anatomia Patologica, Non-interventional study, Pathology and Forensic Medicine, Clinical Research, Biomarkers, Tumor, Humans, Ki-67 Antigen, Breast Cancer, BIOMARKER ASSESSMENT, Larotrectinib, MESH: Humans, MESH: Immunohistochemistry, Estrogen, MESH: Pyrimidines, 570 Life sciences, biology, MESH: Female, MESH: Pyrazoles, MESH: Breast Neoplasms, Biomarkers
Abstract: International audience; Abstract Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error ( p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections ( p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.; v2.5, 25 March 2021.
Published: 2022
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11. Lack of Prognostic Value of CTNNB1 Mutation Profile in Desmoid-Type Fibromatosis

Author: Nicolas Penel, Sylvie Bonvalot, André-Michel Bimbai, Alexandra Meurgey, François Le Loarer, Sébastien Salas, Sophie Piperno-Neumann, Christine Chevreau, Pascaline Boudou-Rouquette, Pascale Dubray-Longeras, Jean-Emmanuel Kurtz, Cécile Guillemet, Emmanuelle Bompas, Antoine Italiano, Axel Le Cesne, Daniel Orbach, Julien Thery, Marie-Cécile Le Deley, Jean-Yves Blay, Olivier Mir, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut Curie [Paris], Université de Bordeaux (UB), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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)-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), Département d'Oncologie Médicale [Institut Curie, Paris], Institut Claudius Regaud, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Les Hôpitaux Universitaires de Strasbourg (HUS), Service d'Oncologie Médicale, CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Laboratory of Solid Tumors Genetics, Nice University Hospital, Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 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), Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Centre d'Etudes Médiévales de Montpellier (CEMM), Université Paul-Valéry - Montpellier 3 (UPVM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), and Université Paris Descartes - Paris 5 (UPD5)
Subjects: Cancer Research, MESH: Humans, Oncology, MESH: beta Catenin, MESH: Fibromatosis, Aggressive, MESH: Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Female, MESH: Cohort Studies, MESH: Neoplasm Recurrence, Local, MESH: Male, MESH: Prognosis, MESH: Prospective Studies
Abstract: Purpose: This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations. Experimental Design: ALTITUDES (NCT02867033) was a nationwide prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS; progression, relapse, or death). We enrolled 628 patients managed by active surveillance, surgical resection, or systemic treatment as first-line therapy. Results: Overall, 516 (82.2%) patients [368 females (71.3%), median age 40.3 years (range, 1–89)] were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The first-line management was active surveillance in 352 (68.2%), surgical resection in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4–59.7) months. The estimated 3-year EFS rate was 66.2% [95% confidence interval (CI), 60.5%–71.2%]. DF harboring p.S45F was significantly associated with male sex (P = 0.03), non-abdominal wall sites (P = 0.05), pain (P = 0.007), and large tumor size (P = 0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (HR, 1.06; 95% CI, 0.65–1.73; P = 0.81) or in multivariate analysis (HR, 0.91; 95% CI, 0.55–1.49; P = 0.71). Conclusions: We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS. See related commentary by Greene and Van Tine, p. 3911
Published: 2022
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12. Characterization of Depressive Symptoms Trajectories After Breast Cancer Diagnosis in Women in France

Author: Cécile Charles, Aurélie Bardet, Alicia Larive, Philip Gorwood, Nicolas Ramoz, Emilie Thomas, Alain Viari, Marina Rousseau-Tsangaris, Agnès Dumas, Gwenn Menvielle, Sibille Everhard, Anne-Laure Martin, Seyive-yvon-arnauld Gbenou, Julie Havas, Mayssam El-Mouhebb, Antonio Di Meglio, Fabrice André, Barbara Pistilli, Charles Coutant, Paul Cottu, Asma Mérimèche, Florence Lerebours, Olivier Tredan, Laurence Vanlemmens, Christelle Jouannaud, Christelle Levy, Ines Vaz-Luis, Stefan Michiels, Sarah Dauchy, Institut Bergonié [Bordeaux], UNICANCER, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Synergie Lyon Cancer-Platform of Bioinformatics-Gilles Thomas, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut Curie [Paris], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Institut Curie - Saint Cloud (ICSC), Centre Léon Bérard [Lyon], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Institut Jean Godinot [Reims], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and Martinez Rico, Clara
Subjects: Male, Depression, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Middle Aged, Cohort Studies, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Prevalence, Quality of Life, Humans, Female, Child
Abstract: International audience; Importance: Breast cancer (BC) diagnosis and treatment expose patients to a 5-fold higher risk of depression compared with the general population, with an estimated prevalence of 10% to 25%. A depressive episode in patients with BC has implications for the tolerance of and adherence to treatment, impairing quality of life and reducing life expectancy.Objective: To identify and characterize distinct longitudinal patterns of depressive symptoms in patients with BC from diagnosis to 3 years after treatment.Design, settings, and participants: The CANTO-DEePRESS (Deeper in the Understanding and Prevention of Depression in Breast Cancer Patients) cohort study included women in the French multicenter CANTO (CANcer TOxicities) cohort study (conducted between March 20, 2012 and December 11, 2018), who were 18 years or older with invasive stage I to III BC and no previous BC treatment. The study aimed to characterize toxicities over a 5-year period following stage I to III primary BC treatment. Assessments of depressive symptoms were performed on a subset of patients with available data at diagnosis and at least 2 other time points. All data were extracted from the CANTO database on October 1, 2020.Main outcomes and measures: The primary outcome was the level of depressive symptoms at each assessment time point measured with the Hospital Anxiety and Depression Scale and depression subscale at BC diagnosis and at 3 to 6, 12, and 36 months after the end of treatment. The group-based trajectory modeling was used to identify trajectory groups, and multinomial logistic regression models were used to characterize the following factors associated with trajectory group affiliation: demographic, socioeconomic, clinical, lifestyle, and quality-of-life data.Results: A total of 4803 women (mean [SD] age, 56.2 [11.2] years; 2441 patients [50.8%] with stage I BC) were included in the study. Six trajectory groups that described the heterogeneity in the expression of depressive symptoms were identified: noncases with no expression of symptoms (n = 2634 [54.8%]), intermediate worsening (1076 [22.4%]), intermediate improvement (480 [10.0%]), remission (261 [5.4%]), delayed occurrence (200 [4.2%]), and stable depression (152 [3.2%]). HADS-D scores at diagnosis were consistently associated with the 5 depressive trajectory group affiliations, with an estimated higher probability per point increase of experiencing subthreshold or clinically significant depressive symptoms between diagnosis and the 3 years after the end of BC treatment. The higher probabilities ranged from 1.49 (95% CI, 1.43-1.54) for the intermediate worsening group to 10.53 (95% CI, 8.84-12.55) for the stable depression group. Trajectory groups with depressive symptoms differed from the noncases group without symptoms by demographic and clinical factors, such as having dependent children, lower household income, cancer stage, family history of BC, previous psychiatric hospitalizations, obesity, smoking status, higher levels of fatigue, and depression at diagnosis.Conclusions and relevance: In this cohort study, nearly a third of patients with BC experienced temporary or lasting significant depressive symptoms during and after treatment. Improving early identification of women at risk of developing long-term or delayed depression is therefore critical to increase quality of life and overall survival. Subjected to validation, this study is an important first step toward personalized care of patients with BC at risk of depression.
Published: 2022
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13. Concurrent cisplatin and dose escalation with intensity-modulated radiotherapy (IMRT) versus conventional radiotherapy for locally advanced head and neck squamous cell carcinomas (HNSCC): GORTEC 2004-01 randomized phase III trial

Author: Stéphanie Wong Hee Kam, Michel Rives, P. Boisselier, Yungan Tao, Yoann Pointreau, S. Heymann, Marc Alfonsi, Julian Biau, Ovidiu Veresezan, X. Sun, Cedrik Lafond, Pierre Blanchard, A. Cornely, Sophie Renard-Oldrini, Anne Auperin, Juliette Thariat, Odile Casiraghi, Pierre Graff, Jean Bourhis, Joël Castelli, Michel Lapeyre, Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de radiothérapie [Gustave Roussy], Institut Sainte Catherine [Avignon], Hôpital Nord Franche-Comté [Hôpital de Trévenans] (HNFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut Claudius Regaud, Centre Jean Bernard [Institut Inter-régional de Cancérologie - Le Mans], Centre Eugène Marquis (CRLCC), Centre Alexis Vautrin (CAV), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de physique corpusculaire de Caen (LPCC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre Jean Bernard [Le Mans], service de radiothérapie, UNICANCER-UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Radiation Oncology Service, Normandie Université (NU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), and COLO, Mouniati
Subjects: medicine.medical_specialty, Intensity-modulated radiotherapy, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Cell, Locally advanced, [SDV.CAN]Life Sciences [q-bio]/Cancer, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, otorhinolaryngologic diseases, medicine, Clinical endpoint, Humans, Radiology, Nuclear Medicine and imaging, IMRT, Stage (cooking), Head and neck cancer, Cisplatin, Dose escalation, Squamous Cell Carcinoma of Head and Neck, business.industry, Radiotherapy Dosage, Chemoradiotherapy, Hematology, medicine.disease, Concurrent chemoradiotherapy, 3. Good health, [SDV] Life Sciences [q-bio], Radiation therapy, stomatognathic diseases, medicine.anatomical_structure, Oncology, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Concomitant, Radiotherapy, Intensity-Modulated, Radiology, business, medicine.drug
Abstract: International audience; Background: Concurrent chemoradiotherapy (CRT) is the standard of care (SoC) in locally advanced (LA) head and neck squamous cell carcinomas (HNSCC). This trial was designed to test whether dose-escalated IMRT and cisplatin could improve locoregional control without increasing complications over 3D-radiotherapy.Methods: Patients were randomized between 70 Gy/35F in 7 weeks with 3D-RT (Arm A) versus 75 Gy/35F with IMRT (Arm B). Both arms received 50 Gy in 25 fractions followed by a sequential boost of 20 Gy/10F in Arm A and 25 Gy/10F to gross tumor volume in Arm B, as well as 3 cycles of cisplatin at 100 mg/m2 during RT. The primary endpoint was locoregional progression (LRP).Results: 188 patients were randomized: 85% oropharynx and 73% stage IVa. P16 status was documented for 137 oropharyngeal tumors with P16+ in 53 (39%) patients; and 90% were smokers. Median follow-up was 60.5 months. Xerostomia was markedly decreased in arm B (p < 0.0001). The 1-year grade ≥2 xerostomia (RTOG criteria) was 63% vs 23% and 3-year 45% vs 11% in arms A and B, respectively. Xerostomia LENT-SOMA scale was also reduced in arm B. Dose-escalated IMRT did not reduce LRP with an adjusted HR of 1.13 [95%CI = 0.64-1.98] (p = 0.68). Survival was not different (adjusted HR: 1.19 [95%CI = 0.78-1.81], p = 0.42). No interaction between p16 and treatment effect was found.Conclusion: Dose-escalated IMRT did not improve LRC in LA-HNSCC patients treated with concomitant CRT over standard 3D-RT. This trial reinforces the evidence showing IMRT reduces xerostomia in LA-HNSCC treated with radiotherapy. Clinicaltrial.gov: NCT00158678.
Published: 2020
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14. Individual-specific networks for prediction modelling – A scoping review of methods

Author: Mariella Gregorich, Federico Melograna, Martina Sunqvist, Stefan Michiels, Kristel Van Steen, Georg Heinze, Medizinische Universität Wien = Medical University of Vienna, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université de Liège, and Malbec, Odile
Subjects: EFFICIENCY, Epidemiology, [SDV]Life Sciences [q-bio], HEALTHY CONTROLS, TIME-SERIES, CONNECTIVITY NETWORKS, Health Informatics, FUNCTIONAL BRAIN NETWORKS, DISEASE, VISIBILITY GRAPH ANALYSIS, Science & Technology, IDENTIFICATION, Individual-specific network, Methodological review, MULTIPLE-SCLEROSIS, Genomics, Biomarker, METRICS, Personalized medicine, Graph theory, [SDV] Life Sciences [q-bio], Pathopsychology, Health Care Sciences & Services, Neurology, Network analysis, Prediction, Life Sciences & Biomedicine
Abstract: Background Recent advances in biotechnology enable the acquisition of high-dimensional data on individuals, posing challenges for prediction models which traditionally use covariates such as clinical patient characteristics. Alternative forms of covariate representations for the features derived from these modern data modalities should be considered that can utilize their intrinsic interconnection. The connectivity information between these features can be represented as an individual-specific network defined by a set of nodes and edges, the strength of which can vary from individual to individual. Global or local graph-theoretical features describing the network may constitute potential prognostic biomarkers instead of or in addition to traditional covariates and may replace the often unsuccessful search for individual biomarkers in a high-dimensional predictor space. Methods We conducted a scoping review to identify, collate and critically appraise the state-of-art in the use of individual-specific networks for prediction modelling in medicine and applied health research, published during 2000–2020 in the electronic databases PubMed, Scopus and Embase. Results Our scoping review revealed the main application areas namely neurology and pathopsychology, followed by cancer research, cardiology and pathology (N = 148). Network construction was mainly based on Pearson correlation coefficients of repeated measurements, but also alternative approaches (e.g. partial correlation, visibility graphs) were found. For covariates measured only once per individual, network construction was mostly based on quantifying an individual’s contribution to the overall group-level structure. Despite the multitude of identified methodological approaches for individual-specific network inference, the number of studies that were intended to enable the prediction of clinical outcomes for future individuals was quite limited, and most of the models served as proof of concept that network characteristics can in principle be useful for prediction. Conclusion The current body of research clearly demonstrates the value of individual-specific network analysis for prediction modelling, but it has not yet been considered as a general tool outside the current areas of application. More methodological research is still needed on well-founded strategies for network inference, especially on adequate network sparsification and outcome-guided graph-theoretical feature extraction and selection, and on how networks can be exploited efficiently for prediction modelling.
Published: 2022
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15. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer

Author: Anne-Gaëlle Goubet, Leonardo Lordello, Carolina Alves Costa Silva, Isabelle Peguillet, Marianne Gazzano, Maxime Descartes Mbogning-Fonkou, Cassandra Thelemaque, Cédric Lebacle, Constance Thibault, François Audenet, Géraldine Pignot, Gwenaelle Gravis, Carole Helissey, Luca Campedel, Morgan Roupret, Evanguelos Xylinas, Idir Ouzaid, Agathe Dubuisson, Marine Mazzenga, Caroline Flament, Pierre Ly, Virginie Marty, Nicolas Signolle, Allan Sauvat, Thomas Sbarrato, Mounia Filahi, Caroline Davin, Gabriel Haddad, Jacques Bou Khalil, Camille Bleriot, François-Xavier Danlos, Garett Dunsmore, Kevin Mulder, Aymeric Silvin, Thibault Raoult, Baptiste Archambaud, Shaima Belhechmi, Ivo Gomperts Boneca, Nadège Cayet, Maryse Moya-Nilges, Adeline Mallet, Romain Daillere, Etienne Rouleau, Camelia Radulescu, Yves Allory, Jacques Fieschi, Mathieu Rouanne, Florent Ginhoux, Gwénaël Le Teuff, Lisa Derosa, Aurélien Marabelle, Jeroen Van Dorp, Nick Van Dijk, Michiel S. Van Der Heijden, Benjamin Besse, Fabrice Andre, Miriam Merad, Guido Kroemer, Jean-Yves Scoazec, Laurence Zitvogel, Yohann Loriot, Université Paris-Saclay, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Curie [Paris], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Direction de la recherche clinique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Département de médecine oncologique [Gustave Roussy], Département de biologie et pathologie médicales [Gustave Roussy], Oncologie gynécologique, ANR-16-RHUS-0008, ANR-21-RHUS-0017, Bristol-Myers Squibb, BMS, Pfizer, Astellas Pharma US, APUS, AstraZeneca, Genentech, Merck, Roche, Gilead Sciences, Meso Scale Diagnostics, MSD, Janssen Pharmaceuticals, Merck Sharp and Dohme, MSD, Horizon 2020 Framework Programme, H2020: 19-CE15-0029-01, 825410, Clovis Oncology, Seerave Foundation, Fondation Philanthropia, Advanced Accelerator Applications, AAA, Agence Nationale de la Recherche, ANR: ANR-10-LABX-62-IBEID, Fondation pour la Recherche Médicale, FRM, Daiichi-Sankyo, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Institut Universitaire de France, IUF, Institut National Du Cancer, INCa, Cancéropôle Ile de France, Association Française d'Urologie, AFU, Labex Immuno-Oncology, The trial was conducted by the French Genitourinary Group (GETUG) and funded by MSD, which provided the drug. This study was approved by the ethics committee CPP Est-III in December 2017 and the French National Agency for the Safety of Medicines and Health Products (ANSM) in November 2017, and was conducted in accordance with the protocols and Good Clinical Practice Guidelines defined by the International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the principles of the Declaration of Helsinki., C. Alves Costa Silva reports grants from MSD Avenir Foundation during the conduct of the study. C. Thibault reports personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, We thank pathologists, nurses, and clinical research associates from Hôpital Européenn George Pompidou, Hôpital Begin, Institut Paoli-Calmettes, Hôpital Bichat, and Hôpital Pitié-Salpétrière for their participation in the PANDORE clinical trial. We are thankful to the flow and mass cytometry facility team of Gustave Roussy (Philippe Rameau and Cyril Catelain). We thank Fluidigm for their support. We are grateful for support for equipment from the French Government Programme Investissements d’Avenir France BioImag-ing (FBI, No. ANR-10-INSB-04-01) and the French Government (Agence Nationale de la Recherche) Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). A.-G. Goubet was supported by Fondation pour la Recherche Médicale. C. Alves Costa Silva was supported by MSD Avenir. F.-X. Danlos was supported by Fondation Philantropia. M. Roupret was supported by Fondation Foch and the Association Française d’Urologie (AFU). L. Zitvogel was funded by the RHU Torino Lumière (ANR-16-RHUS-0008). L. Zitvogel and L. Derosa were supported by RHU5 'ANR-21-RHUS-0017' IMMUNOLIFE, SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), as well as the SIGN’IT ARC foundation. L. Zitvogel was supported by European Union’s Horizon 2020 research and innovation programme under grant agreement number 825410 [project acronym: ONCOBIOME, project title: Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis, and prediction of treatment response]. L. Zitvogel also received an ANR grant–French-German Ileobiome 19-CE15-0029-01. L. Zitvogel and G. Kroemer received a donation from the Seerave Foundation. L. Zitvogel and G. Kroemer were supported by the Ligue contre le Cancer (équipe labelisée), ANR projets blancs, Cancéropôle Ile-de-France, Fondation pour la Recherche Médicale (FRM), a donation by Elior, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, the LabEx Immuno-Oncology, and FHU CARE, Dassault, and Badinter Philantropia. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact., Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA during the conduct of the study, as well as personal fees and nonfinancial support from Pfizer, Merck, MSD, Janssen, and Ipsen, grants, personal fees, and nonfinancial support from AstraZeneca, Bristol Myers Squibb, and Sanofi, and personal fees from Astellas and AAA outside the submitted work. F. Audenet reports personal fees from Astellas, Urodiag, Vitadx, and Bristol Myers Squibb, and nonfinancial support from Ipsen outside the submitted work. G. Gravis reports grants from Bristol Myers Squibb, and other support from MSD, Bristol Myers Squibb, and Merck–Pfizer alliance outside the submitted work. C. Helissey reports personal fees from Janssen-Cilag, Roche, Bayer, AstraZeneca, and Astellas outside the submitted work. L. Cam-pedel reports personal fees from MSD, Pfizer, Bristol Myers Squibb, and Bayer outside the submitted work. T. Sbarrato reports personal fees from Veracyte during the conduct of the study. T. Raoult reports grants, personal fees, and nonfinancial support from Merck Sharp & Dohme during the conduct of the study. E. Rouleau reports grants from AstraZeneca, Roche, Clovis, Bristol Myers Squibb, and MSD outside the submitted work. Y. Allory reports other support from Astra-Zeneca, MSD, and Bristol Myers Squibb outside the submitted work. J. Fieschi reports personal fees from Veracyte during the conduct of the study. A. Marabelle reports grants, personal fees, nonfinancial support, and other support from MSD, Bristol Myers Squibb, and AstraZeneca, and personal fees, nonfinancial support, and other support from Roche/Genentech and Pfizer outside the submitted work. J. Van Dorp reports other support from Bristol Myers Squibb during the conduct of the study. M.S. van der Heijden reports grants from Bristol Myers Squibb during the conduct of the study, as well as grants and personal fees from Bristol Myers Squibb, Roche, and AstraZeneca, grants from 4SC, and personal fees from MSD/Merck, Janssen, Pfizer, and Seagen outside the submitted work. B. Besse reports grants from 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Chu-gai Pharmaceutical, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, Eisai, Genzyme Corporation, GSK, Inivata, Ipsen, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche/Genentech, Sanofi, Takeda, Tolero Pharmaceuticals, and Turning Point Therapeutics during the conduct of the study. F. Andre reports grants and other support from AstraZeneca and Daiichi Sankyo, grants from Lilly and Sanofi, and other support from Novartis and Relay outside the submitted work. M. Merad reports grants and personal fees from Regeneron, personal fees from Compugen, Morphic Therapeutics, Myeloid Therapeutics, Nirogy, DrenBio, Oncoresponse, Asherbio, Pionyr, Owkin, and Larkspur, other support from Innate Pharma, Genenta, DBV, and OSE Immunotherapeutics, and grants from Boehringer outside the submitted work. G. Kroemer reports grants from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sotio, Tollys, Vascage, and Vasculox/Tioma, and personal fees from Reithera outside the submitted work, is on the Board of Directors for Bristol Myers Squibb Foundation France, and is a scientific cofounder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. L. Zitvogel reports grants and personal fees from EverImmune, and grants from 9 Meters and Pileje during the conduct of the study, grants from Daiichi Sankyo outside the submitted work, and a patent for B220028EPA pending. Y. Loriot reports grants from MSD and personal fees from MSD during the conduct of the study, personal fees from Bristol Myers Squibb, Pfizer, Merck Serono, AstraZeneca, Seattle Genetics, Gilead, Taiho, and Astel-las, grants and personal fees from Janssen, and grants from Roche and Celsius outside the submitted work, and a patent for EP2305181.4 pending. No disclosures were reported by the other authors., and FHU CARE, Dassault, and Badinter Philantropia., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), and ANR-21-RHUS-0017,IMMUNOLIFE,Microbiota-centered interventions to solve antibiotics-induced primary resistance to immune checkpoint inhibitors(2021)
Subjects: [SDV]Life Sciences [q-bio], Muscles, Programmed Cell Death 1 Receptor, T-Lymphocytes, Helper-Inducer, Chemokine CXCL13, B7-H1 Antigen, Neoadjuvant Therapy, Treatment Outcome, Oncology, Urinary Bladder Neoplasms, Immunoglobulin G, Escherichia coli, Humans, Immune Checkpoint Inhibitors
Abstract: Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale. Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli–specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221
Published: 2022
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16. Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration

Author: Aymeric Silvin, Stefan Uderhardt, Cecile Piot, Sandro Da Mesquita, Katharine Yang, Laufey Geirsdottir, Kevin Mulder, David Eyal, Zhaoyuan Liu, Cecile Bridlance, Morgane Sonia Thion, Xiao Meng Zhang, Wan Ting Kong, Marc Deloger, Vasco Fontes, Assaf Weiner, Rachel Ee, Regine Dress, Jing Wen Hang, Akhila Balachander, Svetoslav Chakarov, Benoit Malleret, Garett Dunsmore, Olivier Cexus, Jinmiao Chen, Sonia Garel, Charles Antoine Dutertre, Ido Amit, Jonathan Kipnis, Florent Ginhoux, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Weizmann Institute of Science [Rehovot, Israël], Shanghai Jiao Tong University School of Medicine, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Agency for science, technology and research [Singapore] (A*STAR), Collège de France - Chaire Neurobiologie et immunité, and Collège de France (CdF (institution))
Subjects: Aging, Membrane Glycoproteins, [SDV]Life Sciences [q-bio], Macrophages, Immunology, Brain, Mice, Infectious Diseases, Alzheimer Disease, Immunology and Allergy, Animals, Humans, Microglia, Receptors, Immunologic
Abstract: Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer's disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.
Published: 2022
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17. Development and Validation of a Predictive Model of Severe Fatigue After Breast Cancer Diagnosis: Toward a Personalized Framework in Survivorship Care

Author: Antonio Di Meglio, Julie Havas, Davide Soldato, Daniele Presti, Elise Martin, Barbara Pistilli, Gwenn Menvielle, Agnes Dumas, Cecile Charles, Sibille Everhard, Anne-Laure Martin, Charles Coutant, Carole Tarpin, Laurence Vanlemmens, Christelle Levy, Olivier Rigal, Suzette Delaloge, Nancy U. Lin, Patricia A. Ganz, Ann H. Partridge, Fabrice André, Stefan Michiels, Ines Vaz-Luis, Institut Gustave Roussy (IGR), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli studi di Genova = University of Genoa (UniGe), Università degli Studi di Pavia = University of Pavia (UNIPV), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), UNICANCER, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Dana-Farber Cancer Institute [Boston], University of California [Los Angeles] (UCLA), University of California (UC), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and ANR-18-IBHU-0002,PRISM,PRecISion Medicine Institute in oncology(2018)
Subjects: Cancer Research, Prevention, [SDV]Life Sciences [q-bio], Clinical Sciences, Oncology and Carcinogenesis, Breast Neoplasms, Survivorship, Good Health and Well Being, Cancer Survivors, Oncology, Clinical Research, Behavioral and Social Science, Breast Cancer, Quality of Life, Humans, Female, Survivors, Oncology & Carcinogenesis, Cancer
Abstract: PURPOSE Fatigue is common and troublesome among breast cancer survivors; however, limited tools exist to predict its risk. PATIENTS AND METHODS Participants with stage I-III breast cancer were prospectively included from CANTO (ClinicalTrials.gov identifier: NCT01993498 ), collecting longitudinal data at diagnosis (before the initiation of any cancer treatment) and 1 (T1), 2 (T2), and 4 (T3) years after diagnosis. The main outcome was severe global fatigue at T2 (score ≥ 40/100, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30). Analyses at T3 were exploratory. Secondary outcomes included physical, emotional, and cognitive fatigue (EORTC Quality of Life Questionnaire-FA12). Multivariable logistic regression models retained associations with severe fatigue by bootstrapped Augmented Backward Elimination. Validation methods included 10-fold internal cross-validation, overoptimism-corrected area under the receiver operating characteristic curves, and external validation. RESULTS Among 5,640, 5,000, and 3,400 patients at T1, T2, and T3, respectively, the prevalence of post-treatment severe global fatigue was 35.6%, 34.0%, and 31.5% in the development cohort. Retained risk factors for severe global fatigue at T2 were severe pretreatment fatigue (adjusted odds ratio v no 3.191 [95% CI, 2.704 to 3.767]); younger age (for 1-year decrement 1.015 [1.009 to 1.022]), higher body mass index (for unit increment 1.025 [1.012 to 1.038]), current smoking behavior ( v never 1.552 [1.291 to 1.866]), worse anxiety ( v noncase 1.265 [1.073 to 1.492]), insomnia (for unit increment 1.005 [1.003 to 1.007]), and pain at diagnosis (for unit increment 1.014 [1.010 to 1.017]), with an area under the receiver operating characteristic curve of 0.73 (95% CI, 0.72 to 0.75). Receipt of hormonal therapy was a risk factor for severe fatigue at T3 ( v no 1.448 [1.165 to 1.799]). Dimension-specific risk factors included body mass index for physical fatigue and emotional distress for emotional and cognitive fatigue. CONCLUSION We propose a predictive model to assess fatigue among breast cancer survivors, within a personalized survivorship care framework. This may help clinicians to provide early management interventions or to correct modifiable risk factors and offer more tailored monitoring and education to patients at risk of severe post-treatment fatigue.
Published: 2022
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18. Rationale and design of ON-TRK:a novel prospective non-interventional study in patients with TRK fusion cancer treated with larotrectinib

Author: James C. H. Yang, Marcia S. Brose, Gilberto Castro, Edward S. Kim, Ulrik N. Lassen, Serge Leyvraz, Alberto Pappo, Fernando López-Ríos, John A. Reeves, Marc Fellous, Frédérique Penault-Llorca, Erin R. Rudzinski, Ghazaleh Tabatabai, Gilles Vassal, Alexander Drilon, Jonathan Trent, National Taiwan University Cancer Center [Taipei], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Instituto do Câncer do Estado = Cancer Institute of the State of São Paulo (ICESP), Levine Cancer Institute, Atrium Health [Charlotte, NC, USA] (LCIAH), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], St Jude Children's Research Hospital, Hospital Universitario HM Sanchinarro [Madrid, Spain], Bayer HealthCare Pharmaceuticals Inc [Whippany], Bayer HealthCare Pharmaceuticals, Inc. [Basel, Switzerland] (BHCP), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Washington [Seattle], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut Gustave Roussy (IGR), Direction de la recherche [Gustave Roussy], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Sylvester Comprehensive Cancer Center [Miami, FL, USA] (S3C), Malbec, Odile, The Levine Cancer Institute, Direction de la recherche clinique [Gustave Roussy], and Memorial Sloan Kettering Cancer Center (MSKCC)
Subjects: Adult, Cancer Research, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], Fibrosarcoma, Neoplasms, Second Primary, Non-interventional study, [SDV] Life Sciences [q-bio], Pyrimidines, Oncology, TRK fusion, Neoplasms, Genetics, Humans, Pyrazoles, Prospective Studies, Gene Fusion, Receptor, trkA, Child, Protein Kinase Inhibitors, NTRK gene fusions, Larotrectinib
Abstract: Background Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods. Methods ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients Discussion The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA. Study registration This study is registered at ClinicalTrials.gov (NCT04142437). Protocol version v2.5, 25 March 2021.
Published: 2022
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19. Cost-Effectiveness Analysis of Sequential Treatment Strategies for Advanced Melanoma in Real Life in France

Author: Marguerite Kandel, Aurélie Bardet, Stéphane Dalle, Clara Allayous, Laurent Mortier, Bernard Guillot, Caroline Dutriaux, Marie-Thérèse Leccia, Sophie Dalac, Henri Montaudie, Philippe Saiag, Delphine Legoupil, Florence Brunet-Possenti, Jean-Philippe Arnault, Julie De Quatrebarbes, Marie Beylot-Barry, Eve Maubec, Thierry Lesimple, François Aubin, Jean-Jacques Grob, Florence Granel-Brocard, Pierre-Emmanuel Stoebner, Alain Dupuy, Brigitte Dreno, Stefan Michiels, Céleste Lebbe, Isabelle Borget, Institut Gustave Roussy [IGR], Oncostat [U1018 (Équipe 2)], Centre Léon Bérard [Lyon], Immunologie humaine, physiopathologie & immunothérapie [HIPI (UMR_S_976 / U976)], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Centre Hospitalier Universitaire de Bordeaux [CHU de Bordeaux], Centre Hospitalier Universitaire [Grenoble] [CHU], Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Nice [CHU Nice], Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Régional Universitaire de Brest [CHRU Brest], AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Amiens-Picardie, Hôpital Avicenne [AP-HP], Centre Eugène Marquis [CRLCC], Centre Hospitalier Régional Universitaire de Besançon [CHRU Besançon], Hôpital de la Timone [CHU - APHM] [TIMONE], Service de Dermatologie et Allergologie [CHRU Nancy], Hôpital Universitaire Carémeau [Nîmes] [CHU Nîmes], Institut de Recherche en Cancérologie de Montpellier [IRCM - U1194 Inserm - UM], CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Nantes [CHU Nantes], Groupe de Recherche et d'Accueil en Droit et Economie de la Santé [GRADES], Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Centre Hospitalier Universitaire de Bordeaux (CHU de Bordeaux), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre hospitalier universitaire de Nantes (CHU Nantes), Groupe de Recherche et d'Accueil en Droit et Economie de la Santé (GRADES), Université Paris-Saclay, and This research was funded by the French Institute National of Cancer (DOC 16-009).
Subjects: Proto-Oncogene Proteins B-raf, MESH: Melanoma, Cost-Benefit Analysis, Cost-Effectiveness Analysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, JEL: I - Health, Education, and Welfare/I.I1 - Health/I.I1.I18 - Government Policy • Regulation • Public Health, Targeted therapy, Advanced melanoma, Cost-effectiveness analysis, Immunotherapy, Real-life clinical practice, Humans, Prospective Studies, Melanoma, MESH: Proto-Oncogene Proteins B-raf, MESH: Humans, MESH: Cost-Effectiveness Analysis, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, MESH: Prospective Studies, MESH: France, cost-effectiveness analysis, advanced melanoma, real-life clinical practice, immunotherapy, targeted therapy, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, MESH: Cost-Benefit Analysis
Abstract: International audience; Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients’ characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.
Published: 2022
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20. Comprehensive Genome Profiling in Patients With Metastatic Non-Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Author: Boyault, Sandrine, Attignon, Valery, Soubeyran, Isabelle, Morel, Alain, Tran-Dien, Alicia, Jacquet, Alexandra, Dall'Olio, Filippo Gustavo, Jimenez, Marta, Soria, Jean-Charles, Besse, Benjamin, Barlesi, Fabrice, Tomasini, Pascale, Karimi, Maryam, Michiels, Stefan, Raimbourg, Judith, Daniel, Catherine, Janicot, Henri, Madroszyk, Anne, Audigier-Valette, Clarisse, Quoix, Elisabeth, Mazieres, Julien, Moro-Sibilot, Denis, Dansin, Eric, Molinier, Olivier, Morel, Hugues, Pichon, Eric, Cortot, Alexis, Otto, Josiane, Chomy, Francois, Souquet, Pierre-Jean, Cloarec, Nicolas, Giroux-Leprieur, Etienne, Bieche, Ivan, Lacroix, Ludovic, Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Institut Bergonié [Bordeaux], UNICANCER, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Multidisciplinary Oncology and Therapeutic Innovations Unit, Hôpital Nord [CHU - APHM], Tarbiat Modares University [Tehran], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Curie [Paris], Service de Pneumologie [CHU Clermont-Ferrand], Pôle RHEUNNIRS [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, CHU Strasbourg, Service de pneumologie [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU de Grenoble-Alpes, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre Hospitalier Le Mans (CH Le Mans), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Henri Duffaut (Avignon), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, and Département de biologie et pathologie médicales [Gustave Roussy]
Subjects: ErbB Receptors, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, [SDV]Life Sciences [q-bio], Antineoplastic Combined Chemotherapy Protocols, Mutation, Humans, Receptor Protein-Tyrosine Kinases, Precision Medicine, B7-H1 Antigen
Abstract: International audience; Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods: SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6-2.9] with TT versus 2.7 months (1.6-4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7-1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62-1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) >= 1%, (n = 29; HR, 0.29; 95% CI, 0.11-0.75) as compared with PD-L1 < 1% (n = 31; HR, 0.71; 95% CI, 0.31-1.60; P-interaction = 0.036). Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 >= 1 patients.
Published: 2022
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21. Machine Learning and Mechanistic Modeling for the prediction of Overall Survival on the basis of 1st line Tumor Dynamics in Head and Neck Squamous Cell Carcinoma

Author: Atsou, Kevin, Auperin, Anne, Guigay, Joêl, Salas, Sébastien, Benzekry, Sébastien, 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), 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 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), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), 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)-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), and ATSOU, Kokou
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], [SDV.CAN] Life Sciences [q-bio]/Cancer, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], [SDV.CAN]Life Sciences [q-bio]/Cancer, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [STAT.ML] Statistics [stat]/Machine Learning [stat.ML], [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI]
Abstract: The prediction of Overall Survival and Response to 2nd line treatment is a major challenge in treatment of Head and Neck Squamous Cell Carcinoma (HNSCC). Here we used tumor kinetics measured by the Sum of the Largest Diameters (SLD) of the lesions in the patients during the first line to provide interesting predictive metrics for Overall Survival. Using a mechanistic mathematical model, we were able to fit the clinical data of SLD measurements in a HNSCC clinical trial. The data we used consist of 528 patients with 22 baseline clinical feaures. After benchmarking different machine learning algorithms, the Random Survival Forest Algorithm combined with the mechanistic model was able to predict the Overall Survival with a C-index of 0.7 in cross-validation on the train set and 0.67 on the test set. Likewise, the most impacting parameters for the prediction of OS are the parameters resulting from the mathematical model describing the kinetics of tumors (the tumor growth rate and Time to Growth after shrinkage)., La prédiction de la survie globale et de la réponse au traitement de 2e ligne est un défi majeur dans le traitement du carcinome épidermoïde de la tête et du cou (HNSCC pour Head and Neck Squamous Cell Carcinoma). Ici, nous avons utilisé la cinétique tumorale mesurée par la somme des plus grands diamètres (SLD) des lésions chez les patients au cours de la première ligne pour fournir des métriques prédictives intéressantes pour la survie globale. À l'aide d'un modèle mathématique mécaniste, nous avons pu ajuster les données cliniques des mesures SLD dans un essai clinique HNSCC. Les données que nous avons utilisées se composent de 528 patients avec 22 variables cliniques de base. Après avoir comparé différents algorithmes d'apprentissage automatique, l'algorithme de Forêts Aléatoires de Survie (RSF pour Random Survival Forest) combiné au modèle mécaniste a pu prédire la survie globale avec un indice C de 0.7 en validation croisée sur l'ensemble d'entrainement et de 0.67 sur l'ensemble de test. De même, les paramètres les plus impactants pour la prédiction de la Survie Globale sont les paramètres résultant du modèle mathématique décrivant la cinétique des tumeurs (le taux de croissance tumorale et le temps de croissance après rétrécissement).
Published: 2021

22. Smoking and cannabis use among childhood cancer survivors: Results of the french childhood cancer survivor study

Author: Neige Journy, Imene Mansouri, Carole Rubino, Vincent Souchard, Rodrigue S. Allodji, Nadia Haddy, Joffrey Marchi, Florent de Vathaire, Odile Oberlin, Sandrine Pinto, François Pein, Nicolas Bougas, Brice Fresneau, Giao Vu-Bezin, Angela Jackson, Agnès Dumas, Charlotte Demoor-Goldschmidt, A. Mayet, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'épidémiologie et de santé publique des armées [Marseille] (CESPA), Service de Santé des Armées, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université Paris-Saclay, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Institut National Du Cancer, INCa, HAL UVSQ, Équipe, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), and Direction de la recherche clinique [Gustave Roussy]
Subjects: Adult, Male, Epidemiology, Population, Childhood cancer, Marijuana Smoking, Childhood Cancer Survivor Study, Logistic regression, Cigarette Smoking, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Cancer Survivors, Quality of life, Surveys and Questionnaires, Environmental health, Humans, Medicine, 030212 general & internal medicine, education, Adverse effect, education.field_of_study, business.industry, Smoking, Mental health, humanities, 3. Good health, Oncology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, 030220 oncology & carcinogenesis, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, business
Abstract: Background: Unhealthy behaviors among childhood cancer survivors increase the risks for cancer treatment adverse effects. We aimed to assess tobacco and cannabis use prevalence in this population and to identify factors associated with these consumptions. Methods: This study involved 2,887 5-year survivors from the French childhood cancer survivor study (FCCSS) cohort. Data on health behaviors were compared with those of controls from the general population. Associations of current smoking and cannabis use with clinical features, sociodemographic characteristics, and health-related quality of life (QOL) were investigated using multivariable logistic regressions. Results: Prevalence for tobacco use was lower in survivors (26%) than in controls (41%, P < 0.001). Among current smokers, survivors smoked more cigarettes per day and started at a younger age than controls. Women, college graduates, older, married, and CNS tumor survivors, as well as those who received chemotherapy and thoracic radiation therapy, were less likely to be smokers and/or cannabis consumers than others. Participants with a poor mental QOL were more likely to smoke. Conclusions: Preventive interventions and cessation programs must be carried out as early as possible in survivors' life, especially among young males with low educational level and poor mental health. Impact: This study brings new insights to health behaviors among childhood cancer survivors from a population with high rates of smoking and cannabis use.
Published: 2021
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23. Shall patients’ anxiety influence surgical decisions for atypical breast lesions? A substudy of the prospective NOMAT trial

Author: Catherine Uzan, Cécile Charles, Flore Salviat, Institut Gustave Roussy (IGR), Sexualité et soins (Genre, Sexualité, Santé) (CESP - INSERM U1018 - Equipe 7), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Unité de psycho-oncologie (UPO), Département Interdisciplinaire de Soins de Support aux Patients en Onco-hématologie [Gustave Roussy] (DISSPO), Service de Chirurgie et Cancérologie Gynécologique et Mammaire [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), Pathologies biliaires, fibrose et cancer du foie [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), HAL-SU, Gestionnaire, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Service de chirurgie gynécologique et mammaire [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), 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)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]
Subjects: Cancer Research, medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, MEDLINE, [SHS.PSY]Humanities and Social Sciences/Psychology, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Anxiety, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SHS.PSY] Humanities and Social Sciences/Psychology, 03 medical and health sciences, 0302 clinical medicine, Text mining, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Breast, Prospective Studies, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, medicine.disease, Anxiety Disorders, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Oncology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business
Abstract: International audience
Published: 2021
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24. Molecular genotyping in refractory thyroid cancers in 2021: When, how and why? A review from the TUTHYREF network

Author: Slimane Zerdoud, Camille Buffet, Stéphane Bardet, Abir Al Ghuzlan, Myriam Decaussin-Petrucci, Johanna Wassermann, Sophie Leboulleux, Isabelle Borget, Yann Godbert, Fabien Calcagno, Christelle De La Fouchardiere, Christine Do Cao, Françoise Borson Chazot, Centre Léon Bérard [Lyon], Service d'Oncologie médicale [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), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Hospices Civils de Lyon (HCL), CHU Lille, Institut E3M [CHU Pitié-Salpêtrière], Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Bergonié [Bordeaux], UNICANCER, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], and HAL-SU, Gestionnaire
Subjects: Oncology, Cancer Research, medicine.medical_specialty, TUTHYREF, medicine.medical_treatment, Locally advanced, BRAF, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, 030304 developmental biology, International level, 0303 health sciences, Refractory thyroid cancer, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Thyroid, Cancers thyroïdiens réfractaires, Inhibiteurs de kinase, Treatment options, Hematology, General Medicine, Molecular genotyping, 3. Good health, Radiation therapy, medicine.anatomical_structure, ALK, Kinase inhibitors, 030220 oncology & carcinogenesis, business, RET, NTRK, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Refractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting., Les cancers thyroïdiens réfractaires regroupent les cancers de souche folliculaire réfractaires à l’iode, les cancers médullaires métastatiques ou localement avancés non résécables et les cancers anaplasiques. Leur prise en charge est basée depuis quelques années sur l’utilisation d’inhibiteurs de kinase multicibles, à action principalement anti-angiogénique, exception faite des cancers anaplasiques habituellement traités par chimio- et radiothérapie. La situation a récemment évolué en raison de la mise à disposition de techniques de génotypage moléculaire permettant la découverte d’anomalies moléculaires rares mais ciblables, et de nouveaux traitements, possiblement plus efficaces et moins toxiques que les inhibiteurs de kinase multicibles préalablement disponibles. La prise en charge de ces cancers se complexifie donc à la fois au niveau diagnostique avec la nécessité de savoir quand, comment et pourquoi rechercher ces anomalies moléculaires mais également au niveau thérapeutique, avec la question de la disponibilité des traitements innovants et de l’accès aux essais cliniques. Le coût des analyses moléculaires et l’accès aux médicaments sont à harmoniser car des disparités pourraient conduire à une inégalité des soins au niveau national ou international. Enfin, la stratégie d’identification des altérations moléculaires et de traitement pour ces tumeurs rares renforce l’importance d’une discussion en réunion de concertation pluridisciplinaire.
Published: 2021
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25. Génotypage moléculaire dans les cancers réfractaires de la thyroïde en 2021 : quand, comment, et pourquoi ? Un travail du réseau TUTHYREF

Author: De La Fouchardière, Christelle, Wassermann, Johanna, Calcagno, Fabien, Bardet, Stéphane, Al Ghuzlan, Abir, Borget, Isabelle, Borson Chazot, Françoise, Do Cao, Christine, Buffet, Camille, Zerdoud, Slimane, Decaussin-Petrucci, Myriam, Godbert, Yann, Leboulleux, Sophie, Centre Léon Bérard [Lyon], Service d'Oncologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [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 Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut Gustave Roussy (IGR), Pathologie morphologique, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Hospices Civils de Lyon (HCL), CHU Lille, Institut E3M [CHU Pitié-Salpêtrière], Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Refractory thyroid cancer, ALK, Kinase inhibitors, TUTHYREF, Cancers thyroïdiens réfractaires, Inhibiteurs de kinase, RET, NTRK, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, BRAF
Abstract: International audience; Refractory thyroid cancers include radio-iodine-refractory cancers, metastatic or locally advanced unresectable medullary and anaplastic thyroid cancers. Their management has been based for several years on the use of multi-target kinase inhibitors, with anti-angiogenic action, with the exception of anaplastic cancers usually treated with chemo- and radiotherapy. The situation has recently evolved due to the availability of molecular genotyping techniques allowing the discovery of rare but targetable molecular abnormalities. New treatment options have become available, more effective and less toxic than the previously available multi-target kinase inhibitors. The management of refractory thyroid cancers is therefore becoming more complex both at a diagnosis level with the need to know when, how and why to look for these molecular abnormalities but also at a therapeutic level, innovative treatments being hardly accessible. The cost of molecular analyzes and the access to treatments need also to be homogenized because disparities could lead to inequality of care at a national or international level. Finally, the strategy of identifying molecular alterations and treating these rare tumors reinforces the importance of a discussion in a multidisciplinary consultation meeting.; Les cancers thyroïdiens réfractaires regroupent les cancers de souche folliculaire réfractaires à l’iode, les cancers médullaires métastatiques ou localement avancés non résécables et les cancers anaplasiques. Leur prise en charge est basée depuis quelques années sur l’utilisation d’inhibiteurs de kinase multicibles, à action principalement anti-angiogénique, exception faite des cancers anaplasiques habituellement traités par chimio- et radiothérapie. La situation a récemment évolué en raison de la mise à disposition de techniques de génotypage moléculaire permettant la découverte d’anomalies moléculaires rares mais ciblables, et de nouveaux traitements, possiblement plus efficaces et moins toxiques que les inhibiteurs de kinase multicibles préalablement disponibles. La prise en charge de ces cancers se complexifie donc à la fois au niveau diagnostique avec la nécessité de savoir quand, comment et pourquoi rechercher ces anomalies moléculaires mais également au niveau thérapeutique, avec la question de la disponibilité des traitements innovants et de l’accès aux essais cliniques. Le coût des analyses moléculaires et l’accès aux médicaments sont à harmoniser car des disparités pourraient conduire à une inégalité des soins au niveau national ou international. Enfin, la stratégie d’identification des altérations moléculaires et de traitement pour ces tumeurs rares renforce l’importance d’une discussion en réunion de concertation pluridisciplinaire.
Published: 2021
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26. A single-arm multicentre phase II trial of doxorubicin in combination with trabectedin in the first-line treatment for leiomyosarcoma with long-term follow-up and impact of cytoreductive surgery

Author: Anne Floquet, Frédéric Selle, Esma Saada-Bouzid, Benjamin Lacas, Olivier Collard, Christine Chevreau, François Bertucci, Patricia Pautier, C. Delcambre, Maud Toulmonde, P Soulier, Didier Cupissol, Valerie Lebrun-Ly, Florence Duffaud, Emmanuelle Bompas, C. Guillemet, Jérôme Alexandre, N. Isambert, A. Le Cesne, Nicolas Penel, Sophie Piperno-Neumann, Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Institut Bergonié [Bordeaux], UNICANCER, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CRLC Val d'Aurelle-Paul Lamarque, CRLCC Val d'Aurelle - Paul Lamarque, Groupe Hospitalier Diaconesses Croix Saint-Simon, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut Curie [Paris], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Hôpital Dupuytren [CHU Limoges], CRLCC Paul Papin, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital de la Timone [CHU - APHM] (TIMONE), Bertucci, François, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Leiomyosarcoma, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, doxorubicin plus trabectedin, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Doxorubicin, education, Trabectedin, Original Research, Chemotherapy, education.field_of_study, business.industry, Soft tissue, Cytoreduction Surgical Procedures, leiomyosarcoma, medicine.disease, Confidence interval, Surgery, first-line chemotherapy, Oncology, Female, business, Pegfilgrastim, Follow-Up Studies, medicine.drug
Abstract: Background Uterine leiomyosarcomas (U-LMSs) and soft tissue leiomyosarcomas (ST-LMSs) are rare tumours with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with manageable toxicity. Herein, we report the updated and long-term results of progression-free survival (PFS) and overall survival (OS). Patients and methods Patients received 60 mg/m2 intravenous doxorubicin followed by trabectedin 1.1 mg/m2 as a 3-h infusion on day 1 and pegfilgrastim on day 2, every 3 weeks, up to six cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. Results One-hundred and eight patients were enrolled, mainly with metastatic disease (85%), and 20 patients (18.5%) had surgical resection of metastases after chemotherapy. With a median follow-up of 7.2 years [95% confidence interval (CI) 6.9-8.2 years], the median PFS was 10.1 months (95% CI 8.5-12.6 months) in the whole population, and 8.3 months (95% CI 7.4-10.3 months) and 12.9 months (95% CI 9.2-14.1 months) for U-LMSs and ST-LMSs, respectively. The median OS was 34.4 months (95% CI 26.9-42.7 months), 27.5 months (95% CI 17.9-38.2 months), and 38.7 months (95% CI 31.0-52.9 months) for the whole population, U-LMSs, and ST-LMSs, respectively. The median OS of the patients with resected metastases was not reached versus 31.6 months in the overall population without surgery (95% CI 23.9-35.4 months). Conclusions These updated results confirm the impressive efficiency of the doxorubicin plus trabectedin combination given in first-line therapy for patients with locally advanced/metastatic LMS in terms of PFS and OS. Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing the doxorubicin plus trabectedin combination versus doxorubicin alone in first-line therapy in metastatic LMSs, are pending., Highlights • Long-term results on PFS and OS of doxorubicin and trabectedin in first-line treatment for advanced leiomyosarcoma. • The update confirms the impressive efficiency of the doxo+trab in terms of PFS and OS. • Results of a randomized phase-III study comparing dox+trab combination versus doxo alone in first-line therapy in metastatic LMS are pending.
Published: 2021
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27. Therapy-related myeloid neoplasms following treatment with PARP inhibitors: new molecular insights

Author: Sylvain Garciaz, Olivier Caron, Amine Belhabri, Norbert Vey, Jacques Vargaftig, Veronique Verge, Sophie Cotteret, S. de Botton, Flore Salviat, Suzette Delaloge, Iléana Antony-Debré, Patricia Pautier, Christophe Marzac, Sarah Bertoli, Florence Pasquier, Jean-Baptiste Micol, Sabine Khalife-Hachem, Alexandra Leary, Etienne Rouleau, A Renneville, M Kfoury, Filippo Rosselli, Thomas Grinda, Christian Recher, Madalina Uzunov, Jean-Edouard Martin, Gabriel Etienne, Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Curie [Paris], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Intégrité du génome et cancers (IGC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Oncologie gynécologique, Institut Bergonié [Bordeaux], UNICANCER, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), and NUNES, Jacques A
Subjects: Myeloid, DNA Repair, Poly ADP ribose polymerase, [SDV]Life Sciences [q-bio], MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Therapy related, business.industry, Hematology, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Poly(ADP-ribose) Polymerases, business
Abstract: International audience; No abstract available
Published: 2021
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28. Quality‐of‐life assessment in French patients with metastatic melanoma in real life

Author: Florence Granel-Brocard, Alain Dupuy, D. Legoupil, Jean-Jacques Grob, Marie Beylot-Barry, Marie-Thérèse Leccia, Jean-Philippe Arnault, Florence Brunet-Possenti, A. Bardet, Pierre-Emmanuel Stoebner, Céleste Lebbe, Stéphane Dalle, Eve Maubec, Clara Allayous, Isabelle Borget, Bernard Guillot, Brigitte Dréno, Julie DeQuatrebarbes, Philippe Saiag, Laurent Mortier, Marguerite Kandel, Sophie Dalac, Caroline Dutriaux, Thierry Lesimple, Stefan Michiels, Henri Montaudié, François Aubin, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Gustave Roussy (IGR), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe hospitalier Saint-André, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Universitaire de Nice (CHU Nice), Service de dermatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Avicennes University Hospital, Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Dermatologie [Rennes] = Dermatology [Rennes], CHU Pontchaillou [Rennes], Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Léon Bérard [Lyon], AP-HP. Université Paris Saclay, Amgen Pfizer Merck Novartis Roche Janssen Biotech Meso Scale Diagnostics, MSD Array BioPharma Takeda Pharmaceutical Company Sanofi Pasteur British Microcirculation Society, BMS Institut National Du Cancer, INCa: DOC 16‐009, This work was supported by the French National Cancer Institute (DOC 16‐009)., Stéphane Dalle reports institutional research funding Roche, institutional research funding and nonfinancial support from Bristol‐Myers Squibb (BMS), and an immediate family member who is employed by Sanofi and owns stock or other ownership interest in the company. Aurélie Bardet was employed by Roche and held stock and other ownership interest in the company until March of 2018. Clara Allayous reports nonfinancial support from BMS, Amgen, and Roche outside the submitted work. Laurent Mortier reports personal fees and nonfinancial support from Roche, Novartis, BMS, and Merck Sharp & Dohme (MSD) outside the submitted work. Caroline Dutriaux reports personal fees from Roche, BMS, Novartis, MSD, and Pierre Fabre Laboratories outside the submitted work. Philippe Saiag reports research funding and personal fees from Roche, grants, personal fees, and nonfinancial support from BMS, MSD, Novartis, and Pierre Fabre Laboratories, and personal fees from Array, Sanofi, and Merck, all outside the submitted work. Henri Montaudié reports institutional research funding from LeoPharma, institutional research funding, personal fees, and nonfinancial support from BMS, personal fees from Pierre Fabre Laboratories and MSD, and nonfinancial support from Novartis, all outside the submitted work. Jean‐Phillipe Arnault reports institutional research funding and personal fees from BMS and institutional research funding from Novartis outside the submitted work. Jean‐Jacques Grob reports personal fees and nonfinancial support from BMS, Roche, MSD, Novartis, Merck, Amgen, Pierre Fabre Laboratories, Sanofi, and Pfizer and nonfinancial support from Amgen, all outside the submitted work. Julie De Quatrebarbes reports nonfinancial support from BMS, MSD, and Janssen outside the submitted work. Thierry Lesimple reports research funding and personal fees from Roche and personal fees from BMS, MSD, Novartis, Pierre Fabre Laboratories, and Incyte, all outside the submitted work. François Aubin reports personal fees and nonfinancial support from Novartis, MSD, and Roche outside the submitted work. Eve Maubec reports grants, personal fees, and nonfinancial support from MSD, personal fees from Sanofi and Novartis, personal fees and nonfinancial support from BMS, and nonfinancial support from Pierre Fabre Laboratories, all outside the submitted work. Stefan Michiels reports personal fees from IDDI Belgium, Janssen Cilag France, Hexal, Johnson & Johnson, Ipsen, Genticel, Mabxience, Steba, IQVIA, Roche, Sensorion, Biophytis, and Servier, all outside the submitted work. Céleste Lebbe reports institutional research funding, personal fees, and nonfinancial support from BMS, institutional funding and personal fees from Roche, personal fees and nonfinancial support from MSD, and personal fees from Aventis, Novartis, Amgen, Pierre Fabre Laboratories, Pfizer, and Incyte, all outside the submitted work. Isabelle Borget reports research funding from the BMS Foundation during the course of the study and personal fees from Roche, Janssen, CSC Behring, Novartis, and Takeda outside the submitted work. The remaining authors made no disclosures., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)
Subjects: Male, Cancer Research, MESH: Adolescent, Adult, Aged, 80 and over, Cohort Studies, Disease Progression, Female, France / epidemiology, Humans, Disease, Clinical practice, Targeted therapy, 0302 clinical medicine, Second line, Quality of life, Advanced disease, Medicine, Molecular Targeted Therapy, Prospective Studies, 030212 general & internal medicine, Neoplasm Metastasis, Melanoma, MESH: Immunotherapy, Melanoma / epidemiology, Melanoma / immunology, Melanoma / pathology, Melanoma / therapy, MESH: Middle Aged, Neoplasms, Second Primary / epidemiology, Young Adult, Real-life, Neoplasms, Second Primary, Middle Aged, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Cohort, France, Immunotherapy, medicine.medical_specialty, Adolescent, Metastatic melanoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, In real life, Survival rate, Aged, business.industry, MESH: Neoplasms, Second Primary / immunology, Neoplasms, Second Primary / pathology, Quality of Life, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Background: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life. Methods: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates. Results: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of −0.027 (95% CI, −0.03, −0.02) in the utility score, −1.82 (95% CI, −1.88, −1.76) in the FACT-General score, and −2.98 (95% CI, −3.05, −2.91) in the FACT-Melanoma score compared with first-line treatment. Conclusions: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed.
Published: 2019
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29. Fatigue and physical activity in cancer survivors: A cross‐sectional population‐based study

Author: Mohamed Neji, Ines Vaz-Luis, Stefan Michiels, Margarida Matias, Karim Fizazi, Ann H. Partridge, Fabrice Andre, Antonio Di Meglio, Marc-Karim Bendiane, Giulia Baciarello, Michel Ducreux, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Département de médecine oncologique [CHI Créteil], Centre Hospitalier Intercommunal de Créteil (CHIC), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Department of Medical Oncology [Boston, MA, USA], Harvard Medical School [Boston] (HMS)-Dana-Farber Cancer Institute [Boston], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Data were provided from the Reseau Quetelet, from the inquire La vie deux ans après un diagnostic de cancer. Susan Komen for the Cure Career Catalyst Research Grant (CCR 17483507). ESMO‐ European Society of Medical Oncology fellowship grant to Antonio Di Meglio to Ines Vaz‐Luis., and Dupuis, Christine
Subjects: Male, 0301 basic medicine, Cancer Research, physical activity, Comorbidity, 0302 clinical medicine, Cancer Survivors, Quality of life, Risk Factors, Prostate, Neoplasms, Surveys and Questionnaires, Odds Ratio, Prevalence, Medicine, Original Research, education.field_of_study, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, medicine.anatomical_structure, Oncology, Population Surveillance, 030220 oncology & carcinogenesis, Female, France, Cancer Prevention, medicine.medical_specialty, Population, Physical activity, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Survivorship curve, Internal medicine, cancer, Humans, Radiology, Nuclear Medicine and imaging, education, Exercise, Aged, business.industry, Cancer, Odds ratio, medicine.disease, Confidence interval, Cross-Sectional Studies, 030104 developmental biology, quality of life, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, fatigue, business, survivorship
Abstract: International audience; PURPOSE:A substantial proportion of cancer survivors experience fatigue after diagnosis. Physical activity (PA) can impact fatigue after cancer. In this study, we evaluated the prevalence and association of fatigue and the practice of PA in a population with early cancer.METHODS:Using the national population-based French cross-sectional study Vie après le cancer 2, we included 1984 patients with early breast (61.1%), prostate (21.5%), and colorectal (17.4%) cancer. Severe fatigue at 2 years postdiagnosis was defined by a score ≥40 in the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ C30) fatigue subscale. PA was defined as (a) self-reported PA before diagnosis (active/inactive) and (b) change in PA since diagnosis (increased/maintained exposure vs decreased exposure/remaining inactive). Multivariate regression examined associations of severe fatigue with PA, adjusting for baseline clinical and treatment variables.RESULTS:Median age was 52 years. 51.5% of patients experienced severe fatigue 2 years post-diagnosis. 87.7% reported to be physically active before cancer diagnosis; 53.3% of patients either decreased PA or remained inactive at 2 years postdiagnosis. At 2 years postdiagnosis, severe fatigue was associated with a change in PA since diagnosis: patients with decreasing PA/remaining inactive from pre- to postdiagnosis had a higher risk of severe fatigue vs those with increasing/maintaining PA (adjusted odds ratio [95% confidence interval] 2.32 [1.85-2.90]).CONCLUSION:Fatigue continues to be a substantial problem for cancer survivors 2 years after cancer diagnosis and is associated with PA decreasing/remaining inactive since diagnosis. Interventions to maintain or increase PA for cancer survivors should be tested to mitigate long-term fatigue after cancer.
Published: 2019
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30. Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer

Author: Flora Nguyen Van Long, Audrey Lardy-Cleaud, Dimitri Carène, Caroline Rossoni, Frédéric Catez, Paul Rollet, Nathalie Pion, Déborah Monchiet, Agathe Dolbeau, Marjorie Martin, Valentin Simioni, Susan Bray, Doris Le Beherec, Fernanda Mosele, Ibrahim Bouakka, Amélie Colombe-Vermorel, Laetitia Odeyer, Alexandra Diot, Lee B. Jordan, Alastair M. Thompson, Françoise Jamen, Thierry Dubois, Sylvie Chabaud, Stefan Michiels, Isabelle Treilleux, Jean-Christophe Bourdon, David Pérol, Alain Puisieux, Fabrice André, Jean-Jacques Diaz, Virginie Marcel, Malbec, Odile, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Ninewells Hospital and Medical School [Dundee], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), University of Dundee, Baylor College of Medicine (BCM), Baylor University, Complexité, Innovation, Activités Motrices et Sportives (CIAMS), Université d'Orléans (UO)-Université Paris-Saclay, Département de Recherche Translationnelle, Institut Curie [Paris], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Direction de la recherche [Gustave Roussy], Département de médecine oncologique, and CRLCC Paul Strauss
Subjects: Cancer Research, rRNA 2’O-ribose methylation complex, Chromosomal Proteins, Non-Histone, [SDV]Life Sciences [q-bio], Breast Neoplasms, AgNOR, [SDV] Life Sciences [q-bio], Breast cancer, Fibrillarin, Oncology, Ribosome biogenesis, Genetics, Humans, Female, RNA, Messenger, Ribosomes, Biomarkers
Abstract: Background A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated. Methods Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours. Results We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct. Conclusion Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.
Published: 2021
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31. Atrophie musculaire dans les carcinomes ORL: étude de la reprogrammation transcriptionnelle sous-jacente

Author: Héla, Hachicha, Aurore, Gelin, François, Bidault, Thierry, Ragot, Pierre, Busson, Hachicha, Héla, Pirozhkova, Iryna, Rouffiac, Valérie, Dayris, Thibault, Ragot, Thierry, Breuskin, Ingrid, Even, Caroline, Gorphe, Philippe, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Université Paris-Saclay, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques (METSY), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), and Département de cancérologie cervico-faciale [Gustave Roussy] (CCF)
Subjects: Sarcopenia, Cachexia, IL-32 gene, Head and Neck carcinomas, [SDV]Life Sciences [q-bio], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], BIRC3 gene, [SDV.CAN]Life Sciences [q-bio]/Cancer, RNAseq
Abstract: International audience; Introduction:Cancer cachexia is a multifactorial syndrome associated with a skeletal muscle atrophy that affects at least 55% of patients bearing Head and Neck Squamous Cell Carcinomas (HNSCCs). To our knowledge, molecular mechanisms of muscle alterations have never been investigated on clinical muscle specimens from HNSCC patients. The aim of this study was to perform transcriptome profiling by bulk RNAseq on muscle fragments from HNSCC patients with and without cachexia and from nude mice bearing human HNSCC xenografts.Methods:Our study was made in three parts: 1) In Vitro investigations on human myoblasts co-cultivated with HNSCC cells. 2) In Situ investigations on muscles collected from nude mice xenografted with HNSSCs cells (FADU). 3) Exploration of clinical muscle samples collected from HNSCC patients. RNA sequencing was used to assess gene expression changes and gene function enrichment related to cachexia, in myoblasts co-cultivated with malignant cells as well as skeletal muscle samples collected from mice xenografted with HNSCC cells (FADU) or HNSCC patients.Results:In vitro experimentations showed significant impact of malignant cells on myoblast proliferation and differentiation. In nude mice, FADU xenografts resulted in distant loss of muscle mass at various anatomic locations. RNA sequencing of muscle samples from cachectic patients showed significant differences in gene expression compared with control muscles samples from tumor-free donors. Commonly modified pathways included immune and inflammatory response, mitochondrial metabolism and striated muscle differentiation. The most remarkable finding was the up-regulation of the BIRC3 transcript which encodes the anti-apoptotic protein c-IAP2. This alteration was observed both in human cachectic muscles and murine muscle fragments from tumor-bearing mice.Conclusions:Although the mechanism of BIRC3 up-regulation in cachectic muscle cells is not well understood, this finding is likely to be important for patient management in a context of promising therapeutic results obtained using Smac mimetics. Because these compounds are inhibitors of the c-IAP protein family, it will be important in the future to monitor their positive or negative effects on muscle alterations in cachectic HNSCC patients.
Published: 2021
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32. The Activity of Crizotinib in Chemo-Refractory MET-Amplified Esophageal and Gastric Adenocarcinomas: Results from the AcSé-Crizotinib Program

Author: Rosine Guimbaud, Carlos Gomez-Roca, Laurent Mineur, Thomas Aparicio, Emmanuelle Samalin, Gilles Vassal, Jannick Selves, Christelle De La Fouchardiere, Paul Arthur Haineaux, Yves Menu, Florence Mary, Alain Gratet, Nathalie Cozic, N. Colignon, Jérôme Edouard Plaza, Laetitia Johnson, Frédéric Legrand, Emeline Meriaux, Thierry Lecomte, Gestionnaire, Hal Sorbonne Université, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, CRLCC René Gauducheau, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut du Cancer de Montpellier (ICM), Hôpital Avicenne [AP-HP], Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Clinique Pasteur [Toulouse], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut national du cancer [Boulogne] (INCA), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Adult, Cancer Research, medicine.medical_specialty, Esophageal Neoplasms, [SDV]Life Sciences [q-bio], Met amplification, Adenocarcinoma, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Refractory, Crizotinib, Stomach Neoplasms, Internal medicine, medicine, Humans, Pharmacology (medical), In patient, Prospective Studies, Original Research Article, Protein Kinase Inhibitors, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Oncology, Tolerability, 030220 oncology & carcinogenesis, Immunohistochemistry, business, Fluorescence in situ hybridization, medicine.drug
Abstract: Background The AcSé-crizotinib program provides extensive screening of crizotinib-targeted genomic alteration in several malignancies. We here report the results in patients with esogastric MET-amplified adenocarcinomas. Objective The objective of the study was to evaluate the efficacy and tolerability of crizotinib in patients with pretreated esogastric MET-amplified adenocarcinoma who have no alternative treatment options. Patients and Methods MET expression was evaluated by fluorescence in situ hybridization in tumor samples with immunohistochemistry scores ≥ 2+. Patients with chemo-refractory tumors showing ≥ 6 MET copies were eligible for crizotinib 250 mg twice daily. The primary efficacy outcome was the objective response rate after two cycles of crizotinib. Results MET was prospectively analyzed in 570 esogastric adenocarcinomas. Amplifications were found in 35/570 adenocarcinomas (29/523 gastric and 6/47 esophageal). Nine patients were treated with crizotinib. The objective response rate after two cycles was 33.3% (95% CI 7.5–70), the best overall response rate was 55.6% (95% CI 21.2–86.3), with median progression-free survival of 3.2 months (95% CI 1.0–5.4), and overall survival of 8.1 months (95% CI 1.7–24.6). Safety was consistent with that previously reported for crizotinib. Conclusions Large-scale screening for MET-amplified esogastric adenocarcinomas is feasible. MET amplification was observed in 5.5% of gastric and 12.8% of esophageal adenocarcinomas. Crizotinib shows encouraging results in selected patients. Thus, c-MET inhibition for MET-amplified tumors deserves further evaluation. Trial Registration Number NCT02034981. Date of Registration 14 January 2014.
Published: 2021
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33. Qual Life Res

Author: Foulon, S, CONY-MAKHOUL, P, GUERCI-BRESLER, A, DABAN, M, KAPSO, R, Tubert-Bitter, P, BONASTRE, J, Institut Gustave Roussy (IGR), Méthodologie et épidémiologie clinique en oncologie moléculaire (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Institut Bergonié [Bordeaux], UNICANCER, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and ANR-10-IBHU-0001,MMO (IHU-CANCER),Institut de Médecine Personnalisée du Cancer(2010)
Subjects: Quality of life, Health utility score, Chronic myeloid leukemia, Tyrosine kinase inhibitor, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, humanities
Abstract: International audience; PURPOSE: Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of chronic myeloid leukemia (CML). We aimed to assess health state utility and quality of life (QoL) in French patients with CML in real-life setting, to study the determinants of utility score and to compare health-related QoL values to general population norms. METHODS: We conducted a cross-sectional study in 412 patients with CML. Data were collected by electronic survey. Three patient-reported outcomes questionnaires were used: EORTC QLQ-C30, EORTC QLQ-CML24 and EuroQol EQ-5D-3L. Health state utility values were computed using the French value set. We computed deviations from reference norms from the general population. We studied the determinants of health utility score using multiple regression models. RESULTS: The mean utility score (SD) was 0.72 (0.25) in the chronic phase and 0.84 (0.21) in treatment-free remission, with marked variations by gender. Patients with CML had a deviation from the reference norm of -0.15 on average (SD: 0.25). In terms of QoL, social functioning, role functioning and cognitive functioning were notably impacted with a mean difference of -16.0, -13.1 and -11.7 respectively. Fatigue, dyspnea and pain were the symptoms with the highest deviation from general population norms (mean difference of 20.6, 14.0 and 8.3 respectively). In the multiple regression analysis, fatigue was the most important independent predictor of the utility score. CONCLUSION: Although TKIs prevent the disease from progressing and even allow remission without treatment, QoL in patients with CML is notably altered. The utility scores deteriorate with CML symptoms.
Published: 2021
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34. RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer

Author: Marie Terroir, Laurence Leenhardt, Désirée Deandreis, Martin Schlumberger, Sophie Leboulleux, Lavinia Vija, Aline Maillard, Slimane Zerdoud, Claire Bournaud, Christophe Sajous, Isabelle Borget, Institut Gustave Roussy (IGR), Université Paris-Saclay, University of Turin, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CIC Pitié BT, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [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 - Faculté de Médecine (SU FM), Sorbonne Université (SU), Università degli studi di Torino = University of Turin (UNITO), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique Biothérapie [CHU Pitié-Salpêtrière] (CIC-BTi), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), 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 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), and Gestionnaire, Hal Sorbonne Université
Subjects: Radium-223, Alpha emitters, Bone metastases, Leukemia, Refractory thyroid cancer, Aged, Humans, Iodine Radioisotopes, Positron Emission Tomography Computed Tomography, Prospective Studies, Tomography, X-Ray Computed, Bone Neoplasms, Radium, Thyroid Neoplasms, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine, Radiology, Nuclear Medicine and imaging, Adverse effect, Prospective cohort study, Tomography, Thyroid cancer, business.industry, Cryoablation, General Medicine, medicine.disease, Interim analysis, X-Ray Computed, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Original Article, Thyroglobulin, business, Nuclear medicine, Progressive disease, medicine.drug
Abstract: PurposeThis is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer.MethodsRADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by18F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by18F-FDG PET/CT,99mTc-HMDP bone scan and18FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety.ResultsTen patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4–35.6), external radiation therapy (n = 9), bone surgery (n = 8), cimentoplasty (n = 5), and cryoablation (n = 2).18F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections,99mTc-HMDP bone scan showed SD in 9 cases and was NE in 1 case;18FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3–4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related.ConclusionThe trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation.Trial registration numberNCT02390934. Registration date 18.03.2015.
Published: 2021
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35. Screening for SARS-CoV-2 by RT-PCR: Saliva or nasopharyngeal swab? Rapid review and meta-analysis

Author: Dan Chaltiel, Catherine Hill, Gwénaël Le Teuff, Nusaïbah Ibrahimi, Jean-François Rupprecht, Marie-Claude Potier, Jean Yves Thuret, Agnès Delaunay-Moisan, Institut Gustave Roussy (IGR), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Physique Théorique - UMR 7332 (CPT), Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), CPT - E5 Physique statistique et systèmes complexes, Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Toulon (UTLN)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), HAL-SU, Gestionnaire, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: RNA viruses, Viral Diseases, Saliva, Physiology, Coronaviruses, Artificial Gene Amplification and Extension, Polymerase Chain Reaction, Mathematical and Statistical Techniques, Medical Conditions, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Nasopharynx, Medicine and Health Sciences, Screening method, Viral load, 030212 general & internal medicine, Pathology and laboratory medicine, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, 0303 health sciences, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, Approximation Methods, Statistics, Medical microbiology, Research Assessment, Metaanalysis, Body Fluids, 3. Good health, Infectious Diseases, Real-time polymerase chain reaction, COVID-19 Nucleic Acid Testing, Meta-analysis, Viruses, Physical Sciences, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA, Viral, Medicine, Anatomy, Pathogens, SARS CoV 2, COVID 19, Research Article, medicine.medical_specialty, SARS coronavirus, Coronavirus disease 2019 (COVID-19), Concordance, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Science, Virus testing, Research and Analysis Methods, Sensitivity and Specificity, Microbiology, Specimen Handling, 03 medical and health sciences, Diagnostic Medicine, Internal medicine, medicine, Humans, Statistical Methods, Molecular Biology Techniques, Molecular Biology, Reverse transcriptase-polymerase chain reaction, SARS-CoV-2, 030306 microbiology, business.industry, Organisms, Viral pathogens, COVID-19, Biology and Life Sciences, Microbial pathogens, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Mathematics
Abstract: Background Diagnosis of COVID-19 in symptomatic patients and screening of populations for SARS-CoV-2 infection require access to straightforward, low-cost and high-throughput testing. The recommended nasopharyngeal swab tests are limited by the need of trained professionals and specific consumables and this procedure is poorly accepted as a screening method In contrast, saliva sampling can be self-administered. Methods In order to compare saliva and nasopharyngeal/oropharyngeal samples for the detection of SARS-CoV-2, we designed a meta-analysis searching in PubMed up to December 29th, 2020 with the key words “(SARS-CoV-2 OR COVID-19 OR COVID19) AND (salivary OR saliva OR oral fluid)) NOT (review[Publication Type]) NOT (PrePrint[Publication Type])” applying the following criteria: records published in peer reviewed scientific journals, in English, with at least 15 nasopharyngeal/orapharyngeal swabs and saliva paired samples tested by RT-PCR, studies with available raw data including numbers of positive and negative tests with the two sampling methods. For all studies, concordance and sensitivity were calculated and then pooled in a random-effects model. Findings A total of 377 studies were retrieved, of which 50 were eligible, reporting on 16,473 pairs of nasopharyngeal/oropharyngeal and saliva samples. Meta-analysis showed high concordance, 92.5% (95%CI: 89.5–94.7), across studies and pooled sensitivities of 86.5% (95%CI: 83.4–89.1) and 92.0% (95%CI: 89.1–94.2) from saliva and nasopharyngeal/oropharyngeal swabs respectively. Heterogeneity across studies was 72.0% for saliva and 85.0% for nasopharyngeal/oropharyngeal swabs. Interpretation Our meta-analysis strongly suggests that saliva could be used for frequent testing of COVID-19 patients and “en masse” screening of populations.
Published: 2021
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36. Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium

Author: Pierre Laurent-Puig, Yan Ren, Frédérique Rachédi, Pascal Guénel, Sandya Liyanarachchi, Asta Försti, Albert de la Chapelle, Om Kulkarni, Claire Mulot, Huiling He, Federica Gemignani, Julie Guibon, Anne-Valérie Guizard, Fabienne Lesueur, Rossella Elisei, Ausrele Kesminiene, Anthony F. Herzig, Mojgan Karimi, Pierre-Emmanuel Sugier, Thérèse Truong, Delphine Bacq-Daian, Anne-Louise Leutenegger, Constance Xhaard, Daniel F. Comiskey, Celia M Pereda, Evgenia Ostroumova, Florent de Vathaire, Elisabeth Adjadj, Françoise Borson-Chazot, Jean-François Deleuze, Carole Rubino, Anne Boland-Auge, Hauke Thomsen, Elise A. Lucotte, Marie-Christine Boutron-Ruault, Juan J Lence-Anta, Rosa Ortiz, Claire Schvartz, Institut Gustave Roussy (IGR), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université Paris-Saclay, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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 de Paris (UP), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Institut Jean Godinot [Reims], UNICANCER, Registre Général des Tumeurs du Calvados, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), 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)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de Taaone, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institute of Oncology and Radiobiology, Ohio State University [Columbus] (OSU), University of Pisa - Università di Pisa, Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Consortium [Heidelberg] (DKTK), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, MESRI: 2102 918823 National Institute of Ecology, NIE Agence Nationale de la Recherche, ANR: ANR‐10‐COHO‐0006 Fondation ARC pour la Recherche sur le Cancer, ARC: PGA120150202302 Ligue Contre le Cancer Fondation de France Institut National Du Cancer, INCa: 9533 Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, ANSES Mutuelle Générale de l'Education Nationale, MGEN Electricité de France, EDF: EP 2019‐01, We thank Dr Yannick Rougier and Dr Dominique Baron-Dubourdieu for providing pathological reports for the NC study, as well as Dr Sylvie Laumond, Dr Jean-Paul Grangeon (Direction des affaires sanitaires et sociales de Nouvelle-Cal?donie) and the country's provincial health authorities (DPASS Sud, DPASS Nord, DPASS Iles Loyaut?) for support during data collection in the NC study. We thank Milagros Velasco, Mae Chappe and Idalmis Infante (Institute of Oncology and Radiobiology, La Havana, Cuba) and Silvia Turcios (National Institute of Endocrinology, La Havana, Cuba) for helping in the collection of the data in the Cuban Study. We thank John Paoaafaite and Joseph Teuri who contacted and interviewed cases and controls for the study. Finally, we also thank P. Morales, J. Iltis, P. Giraud, P. Didiergeorge, M. Brisard, G. Soubiran, B. Caillou, P. Dupire, J. Ienfa, G. de Clermont, N. Cerf, B. Oddo, M. Bambridge, C. Baron, A. Mouchard-Rachet, O. Simonet, D. Lamarque, J. Vabret, J. Delacre, M.P. Darquier and J. Leninger, for their help in the collection of the cases or in the organization of study in French Polynesia. We would like to thank the Association Centre de Regroupement Informatique et Statistique en Anatomie Pathologique en Provence-Alpes-C?te d'Azur (CRISAP PACA), as well as Dr Arlette Danzon, Dr Genevi?ve Sasolas, Dr Marc Christophe Sattonnet, Dr Marc Colonna, Dr Brigitte Lacour, Dr Michel Velten, Dr Enora Clero, Dr St?phane Maillard, Dr Laurent Bailly, Dr Eug?nia Marin? Barjoan, Dr Jean-Luc Lassalle, Dr Z Hafdi-Nejjari, Dr P Delafosse, Dr Elisabeth Adjadj, Kami-Marie Moreau, Cyrielle Orenes, Laurianne Sarrazin, St?phanie Bonnay, Fr?d?rique Chatelain, Maryse Barouh, Evelyne Rapp, Julie Festra?ts, Julie Valbousquet, Yusuf Atilgan, Jean Chappellet, Lallia Bedhouche, Florent Dayet and Ziyan Fami, for their help in the collection of cases, the organization and the management of the Young-Thyr study. We acknowledge Stefano Landi for the Italian GWAS data and Subhayan Chattopadhyay and Yasmeen Niazi (Division of Molecular Genetic Epidemiology, German Cancer Research Center?DKFZ) for technical assistance in these data analysis. We are grateful to Dr Herv? Perdry for his help in using the GASTON package. The EPITHYR GWAS was supported by Institut National du Cancer (grant number 9533) and Fondation ARC (grant number PGA120150202302). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its setup and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR) (grant number ANR-10-COHO-0006) within the Investissement d'Avenir program and from the French Ministry of Higher Education, Research and Innovation (MESRI, grant number 2102 918823). The other participating studies were funded by Ligue Nationale Contre le Cancer, ANR, the Direction G?n?rale de la Sante, the Agence Fran?aise de S?curit? Sanitaire de l'alimentation, de l'environnement et du travail (ANSES), CHILDTHYR EEC program, and the Fondation de France. JG was the recipient of a PhD fellowship from R?gion Ile-de-France, part of OK was the recipient of a post-doc fellowship from Electricit? de France (conseil scientifique de Radioprotection d'EDF, grant EP 2019-01)., The EPITHYR GWAS was supported by Institut National du Cancer (grant number 9533) and Fondation ARC (grant number PGA120150202302). The E3N cohort received support from the MGEN, Gustave Roussy and Ligue contre le cancer for its setup and maintenance. The E3N cohort was also supported by a state grant from the Agence Nationale pour la Recherche (ANR) (grant number ANR‐10‐COHO‐0006) within the Investissement d'Avenir program and from the French Ministry of Higher Education, Research and Innovation (MESRI, grant number 2102 918823). The other participating studies were funded by Ligue Nationale Contre le Cancer, the Direction Générale de la Sante, the Agence Française de Sécurité Sanitaire de l'alimentation, and the Fondation de France. JG was the recipient of a PhD fellowship from Région Ile‐de‐France, part of OK was the recipient of a post‐doc fellowship from Electricité de France (conseil scientifique de Radioprotection d'EDF, grant EP 2019‐01)., Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, Cancer Research, Native Hawaiian or Other Pacific Islander, [SDV]Life Sciences [q-bio], Ethnic group, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Informed consent, Epidemiology, thyroid cancer, Chromosomes, Human, Medicine, Prospective cohort study, Thyroid cancer, Genetics, 0303 health sciences, education.field_of_study, Incidence (epidemiology), Middle Aged, Checklist, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Pacific islanders, Female, Adult, medicine.medical_specialty, case-control study, education, Population, Biology, Pacific Islands, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Thyroid Neoplasms, Aged, 030304 developmental biology, genome-wide association study, business.industry, Case-control study, medicine.disease, Clinical trial, Case-Control Studies, Family medicine, business
Abstract: Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. Here, we conducted a genome-wide association study (GWAS) involving 1,554 cases/1,973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from the EPITHYR consortium. Our results confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 (rs334729) and 16q23.2 (rs16950982), which were associated with TSH levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. The frequency of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans and may explain part of the highest DTC incidence observed in Oceanians.Competing Interest StatementThe authors have declared no competing interest.Funding StatementINCA (grant number 9533) and ARC (grant number PGA120150202302), Ligue Nationale Contre le Cancer, Agence Nationale pour la Recherche (ANR), the Direction Generale de la Sante, the Agence Francaise de Securite Sanitaire de l alimentation, de lenvironnement et du travail (ANSES), CHILDTHYR EEC program, and the Fondation de France. JG and CX were the recipient of a PhD fellowship from Region Ile-de-France.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:All participants provided informed consent and each study was approved by their governing ethics committee.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. (Less)
Published: 2021
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37. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade

Author: Carolina Alves Costa Silva, Deborah Lefevre, Lisa Derosa, Claudia Grajeda-Iglesias, Gladys Ferrere, Maryam Tidjani Alou, Anne-Gaëlle Goubet, Fanny Aprahamian, Conrad Rauber, Didier Raoult, Aurélie Fluckiger, Monica Arnedos, Damien Drubay, Romain Daillère, Cassandra Thelemaque, Tim D. Spector, Sylvère Durand, Liwei Zhao, Guido Kroemer, Emeline Colomba, Oliver Kepp, Valerio Iebba, Laurence Zitvogel, Nicola Segata, Francesco Asnicar, Marine Fidelle, Peng Liu, Bernhard Ryffel, Immunologie intégrative des tumeurs et immunothérapie des cancers (INTIM), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, 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), Università degli studi di Trieste = University of Trieste, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Oncologie gynécologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pathologie mammaire, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], King‘s College London, Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, Ferrere, G., Alou, M. T., Liu, P., Goubet, A. -G., Fidelle, M., Kepp, O., Durand, S., Iebba, V., Fluckiger, A., Daillere, R., Thelemaque, C., Grajeda-Iglesias, C., Silva, C. A. C., Aprahamian, F., Lefevre, D., Zhao, L., Ryffel, B., Colomba, E., Arnedos, M., Drubay, D., Rauber, C., Raoult, D., Asnicar, F., Spector, T., Segata, N., Derosa, L., Kroemer, G., Zitvogel, L., Gestionnaire, Hal Sorbonne Université, LUMIERE - - LUMIERE2016 - ANR-16-RHUS-0008 - RHUS - VALID, European Union’s Horizon 2020 research and innovation programme under grant agreement. - ONCOBIOME - 825410 - INCOMING, 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 de Paris (UP), University of Trieste, Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Ketogenic, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Programmed Cell Death 1 Receptor, Cancer, Immunotherapy, Metabolism, Mouse models, Oncology, 3-Hydroxybutyric Acid, Animals, CTLA-4 Antigen, Cell Line, Tumor, Combined Modality Therapy, Female, Gastrointestinal Microbiome, Humans, Immune Checkpoint Inhibitors, Ketone Bodies, Kidney Neoplasms, Melanoma, Experimental, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Receptors, G-Protein-Coupled, Diet, Ketogenic, Pharmacology, CXCR3, Inbred C57BL, 0302 clinical medicine, Neoplasms, Ketogenesis, Receptors, Ketone Bodie, Melanoma, Inbred BALB C, Tumor, Chemistry, Kidney Neoplasm, General Medicine, 3. Good health, [SDV] Life Sciences [q-bio], Immunosurveillance, 030220 oncology & carcinogenesis, Ketone bodies, Medicine, Human, Research Article, Immune Checkpoint Inhibitor, Mouse model, Cell Line, 03 medical and health sciences, Experimental, G-Protein-Coupled, Downregulation and upregulation, medicine, Animal, Immune checkpoint, Diet, 030104 developmental biology, Ketogenic diet
Abstract: International audience; Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
Published: 2021
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38. Trend of antibiotic consumption and its association with influenza-like illnesses in France between 2004 and 2018

Author: Sally Yaacoub, Emilie Lanoy, Nadine Saleh, Patrick Maison, Karima Hider-Mlynarz, Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis] (ANSM), Institut National de Santé Publique, Epidémiologie Clinique et Toxicologie [Beyrouth, Liban] (INSPECT-LB), Faculty of Public Health [Lebanese University] (FSP III), Lebanese University [Beirut] (LU), CHI Créteil, and HAL UVSQ, Équipe
Subjects: medicine.drug_class, Antibiotics, Environmental health, Influenza, Human, medicine, lincosamide, media_common.cataloged_instance, Humans, European union, media_common, Consumption (economics), Lincosamides, Respiratory tract infections, business.industry, macrolides, Incidence (epidemiology), beta-lactam antibiotics, Topic antibiotics, Public Health, Environmental and Occupational Health, streptogramins, Antimicrobial, Drug Utilization, Anti-Bacterial Agents, penicillin, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, community, Observational study, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, business, influenza
Abstract: Background Antibiotic consumption has been reported to be driven by the treatment of respiratory tract infections. Our objectives were to describe the trend of antibiotic consumption in France compared with that of other European countries; to describe the evolution of each antibiotic class in France; and to explore the relationship between antibiotic consumption and incidence of influenza-like illnesses. Methods In this observational study, antibiotic consumption was reported as defined daily doses per 1000 inhabitants per day in the community and hospital sectors in descriptive and graphical formats, using data from the European Surveillance of Antimicrobial Consumption Network database. The total consumption and the consumption of different classes of antibiotics in France according to time and influenza-like illnesses were studied using multiple linear regression models. Results The total consumption of antibiotics in France was constant over the 15 years. It was driven by the community sector (92.8%) and was higher than the consumption of other European Union countries (P-value Conclusion Our results suggest that antibiotics used in the management of respiratory tract infections might be involved in the irrational use of antibiotics.
Published: 2021
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39. Infectious complications in patients treated with immune checkpoint inhibitors

Author: Jean-Marie Michot, Emilie Lanoy, Nicolas Noel, Anne-Laure Voisin, Jean-Denis Karam, Olivier Lambotte, Hôpital Bicêtre, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Infectious Diseases Models for Innovative Therapies (IDMIT), Institut Gustave Roussy (IGR), Direction de la recherche clinique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and CCSD, Accord Elsevier
Subjects: 0301 basic medicine, Male, Cancer Research, medicine.medical_specialty, Opportunistic infection, [SDV]Life Sciences [q-bio], Cancer immunotherapy, Pembrolizumab, Immune checkpoint inhibitor, Skin infection, Infections, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Interquartile range, Internal medicine, Neoplasms, Immune-related adverse event, medicine, Humans, Adverse effect, Immune Checkpoint Inhibitors, Aged, Retrospective Studies, Infectious disease, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Infliximab, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Nivolumab, Oncology, 030220 oncology & carcinogenesis, Female, business, Immunosuppressive Agents, medicine.drug
Abstract: International audience; Objective: Immune checkpoint inhibitor (ICI) antibodies constitute a new generation of cancer treatments, associated with immune-related adverse events (irAEs). A previous retrospective study of patients with metastatic melanoma (treated mostly with anti-CTLA4 antibodies) reported a serious infection rate of 7.3%. The main risk factors were corticoids and infliximab use. We sought to describe infections and risk factors among patients receiving anti-PD-1/PD-L1 ICIs.Patients and methods: We reviewed 200 medical records sampled randomly from a French prospective registry, which collates patients treated with anti-PD-1/PD-L1 ICIs. We recorded demographic data, the occurrence of irAEs, immunosuppressant use, and the outcome.Results: Thirty-six patients (18%) experienced an infection by a median (interquartile range) of 47 (19.2-132) days after initiation of the ICI. Twenty-one patients (58.3%) had a lung infection, seven (19.4%) had a skin infection, seven (19.4%) had a urinary tract infection, and all of them received antibiotics. The infection was generally mild, and the patients were treated as outpatient. There were no infection-related deaths and no opportunistic infection. Sixty percent of the patients were being treated for metastatic melanoma and 35.5% for non-small cell lung cancer, and 106 irAEs (mostly grade II) were reported. Forty-seven patients received steroids for cancer symptoms or irAEs, and five received immunosuppressants during the immunotherapy. We did not observe any association between corticosteroid or immunosuppressant use and the occurrence of an infection.Conclusion: The infection rate in patients treated with an anti-PD-1/PD-L1 ICI was 18%, without any severe or opportunistic infection. The occurrence of an infection was not associated with corticosteroid or immunosuppressant use.
Published: 2020
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40. Impact of follow-up on generalized pairwise comparisons for estimating the irinotecan benefit in advanced/metastatic gastric cancer

Author: Xavier Paoletti, Koji Oba, Olivier Bouché, Ali N. Chamseddine, Narikazu Boku, A. Auperin, Tuvana Satar, Marc Buyse, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was partially funded by a French governmental grant from the Programme Hospitalier pour la Recherche Clinique (PHRC) . The funder had no involvement neither in the data collection, design, analysis nor interpretation of the data., Chamseddine, AN, Oba, K, BUYSE, Marc, Boku, N, Bouche, O, Satar, T, Auperin, A, and PAOLETTI, Xavier
Subjects: Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Generalized pairwise comparisons, Irinotecan, law.invention, Metastatic gastric cancer, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Stomach Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Randomized Controlled Trials as Topic, Net treatment effect, 030505 public health, business.industry, Follow-up, Hazard ratio, General Medicine, 3. Good health, Regimen, Advanced metastatic gastric cancer, Censoring (clinical trials), Toxicity, Pairwise comparison, 0305 other medical science, business, medicine.drug, Follow-Up Studies
Abstract: Background and objectives: The net treatment effect ( increment ) is a new method to assess the treatment benefit that combines multiple time-to-event, binary and continuous endpoints according to a pre-specified sequence. It represents the net probability for a random patient treated in the experimental arm to have a better overall outcome than a random patient from the control arm does. We aimed at characterizing the impact of follow-up on increment estimated from both time-to-event and binary toxicity endpoints, in randomized controlled trials (RCTs) of irinotecan-based regimen in advanced/metastatic gastric cancer (AGC).Study design: Three RCTs are reanalysed. The net treatment effect using from one to three outcomes (i.e. overall survival, time to progression and toxicity in this order) and the hazard ratio (HR) were estimated after various cut-off dates and compared to the values obtained after complete follow-up were reported. Results: In all three RCTs (897 patients), the irinotecan-based regimen was superior to the non-irinotecan containing regimen in terms of HR and increment . This superiority was lower when the net treatment effect also accounted for toxicity. The HR was slightly less influenced by an incomplete follow-up than increment was, but correction proposed by Pe & acute;ron to account for censored observations showed quite robust results.Conclusions: The net treatment effect using Pe & acute;ron's correction can be used in case of interim analyses or high censoring rates. In addition to relative measures such as the hazard ratio, it provides a simple mean to evaluate the net treatment effect with and without toxicity outcomes. This work was partially funded by a French governmental grant from the Programme Hospitalier pour la Recherche Clinique (PHRC). The funder had no involvement neither in the data collection, design, analysis nor interpretation of the data. We are strongly indebted to the F ́ed ́eration Francophone de Canc ́erologie Digestive (FFCD) Group, the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group and Sanofi for providing individual patients data to the GASTRIC collaboration. The trials’ sponsors were not involved in the design, the analysis and interpretation of this contribution. We thank the GASTRIC collaboration for giving access to their data collection
Published: 2020
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41. Immunodynamics of explanted human tumors for immuno‐oncology

Author: Dubuisson, Agathe, Fahrner, Jean Eudes, Goubet, Anne Gaëlle, Terrisse, Safae A., Voisin, Nicolas, Bayard, Charles, Lofek, Sébastien, Drubay, Damien, Bredel, Delphine, Mouraud, Séverine, Susini, Sandrine, Cogdill, Alexandria P., Rebuffet, Lucas, Ballot, Elise, Jacquelot, Nicolas, Thomas de Montpreville, Vincent, Casiraghi, Odile, Radulescu, Camélia, Ferlicot, Sophie, Figueroa, David J., Yadavilli, Sapna, Waight, Jeremy D., Ballas, Marc S., Hoos, Axel X., Condamine, Thomas, Parier, Bastien, Gaudillat, Christophe, Routy, Bertrand, Ghiringhelli, François, Derosa, Lisa, Breuskin, Ingrid, Rouanne, Mathieu, André, Fabrice, Lebacle, Cédric, Baumert, Hervé, Wislez, Marie, Fadel, Élie, Cremer, Isabelle, Albiges, Laurence, Geoerger, Birgit, Scoazec, Jean Yves, Loriot, Yohann, Kroemer, Guido, Marabelle, Aurélien, Bonvalet, Mélodie, Zitvogel, Laurence, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), The University of Texas M.D. Anderson Cancer Center [Houston], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, The Walter and Eliza Hall Institute of Medical Research (WEHI), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Département de médecine oncologique [Gustave Roussy], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Foch [Suresnes], Direction de la recherche [Gustave Roussy], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 de Paris (UP), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), 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), Karolinska University Hospital [Stockholm], Chancellerie des Universités de Paris Agence Nationale de la Recherche, ANR Seerave Foundation Association pour la Recherche sur le Cancer, ARC ANR‐16‐RHUS‐0008 Ligue Contre le Cancer European Commission, EC Fondation pour la Recherche Médicale, FRM Institut National Du Cancer, INCa Institut Universitaire de France, IUF European Research Council, ERC Fondation Leducq RP170067 Association pour la Recherche sur le Cancer, ARC, LZ and GK were supported by the Ligue contre le Cancer (équipe labelisée), Agence Nationale de la Recherche (ANR) francogermanique ANR‐19‐CE15‐0029, ANR Projects blancs, ANR under the frame of E‐Rare‐2, the ERA‐Net for Research on Rare Diseases, Association pour la recherche sur le cancer (ARC), Bristol‐Myers Squibb Company (International Immuno‐Oncology Network), Cancéropôle Ile‐de‐France, Chancellerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM), a donation by Elior, the European Commission (ArtForce), the European Research Council (ERC), Fondation Carrefour, Institut National du Cancer (INCa), Inserm (HTE), Institut Universitaire de France, LeDucq Foundation, the LabEx Immuno‐Oncology, the RHU Torino Lumière (ANR‐16‐RHUS‐0008), H2020 ONCOBIOME, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), FHU CARE, Dassault, and Badinter Philantropia, and the Paris Alliance of Cancer Research Institutes (PACRI). AC is supported by the CPRIT Research Training Program (RP170067). JEF was supported by Transgene and AGG was supported by FRM. AM has been or is currently an investigator in clinical trials sponsored by BMS, MSD, GSK/Tesaro, Janssen, Roche/Genentech, Pfizer, Astra Zeneca (AZ), Amgen. AM has been or is currently a member of Clinical Trial Scientific Steering Committee for AZ and GSK. AM has been or is currently a member of the scientific advisory board of the following companies: Merck Serono, Novartis, BMS, Symphogen, Amgen, Tesaro/GSK, Pfizer, Astra Zeneca/Medimmune, Servier, Sanofi. AM has provided Scientific & Medical Consulting to the following companies: Roche, Sanofi. AM is a member of the Data Safety and Monitoring Board for the following trial NCT02423863 (TLR3 agonist, Oncovir). AM has received research funding and or drug supply for pre‐Clinical and clinical research projects from: BMS, Boehringer Ingelheim, Idera, MSD, Fondation MSD Avenir, SIRIC (INCa‐DGOS‐Inserm_12551)., ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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 (UPC)
Subjects: Medicine (General), [SDV]Life Sciences [q-bio], Immunology, QH426-470, Medical Oncology, immune checkpoint inhibitors, R5-920, immunomonitoring, Report, precision oncology, Neoplasms, Genetics, “in sitro” assay, Tumor Microenvironment, cancer, Humans, Immunotherapy, Prospective Studies, Reports
Abstract: Decision making in immuno‐oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno‐assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti‐PD‐1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay., To predict cancer resistance to PD‐1 blockade and design suitable combinations of immunomodulators, a 60‐h functional in sitro assay was set up in 43 tumors that allowed calculation of the “Immune Reactivity Score (IRS)” based on 17 TCR‐dependent‐ cytokines/chemokines.
Published: 2020
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42. On the Use of Neural Networks with Censored Time-to-Event Data

Author: Paul-Henry Cournède, Stefan Michiels, Elvire Roblin, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), CentraleSupélec-Université Paris-Saclay, Oncostat team [Villejuif], and Institut Gustave Roussy (IGR)
Subjects: 0303 health sciences, Artificial neural network, Computer science, business.industry, [SDV]Life Sciences [q-bio], Machine learning, computer.software_genre, 01 natural sciences, 010104 statistics & probability, 03 medical and health sciences, Survival data, Work (electrical), Event data, Artificial intelligence, 0101 mathematics, [MATH]Mathematics [math], business, computer, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Motivation: The objective of this work is to confront artificial neural network models with time-to-event data, using specific ways to handle censored observations such as pseudo-observations and tailored loss functions.
Published: 2020
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43. Self-supervised Nuclei Segmentation in Histopathological Images Using Attention

Author: Roberto Salgado, Stefan Michiels, Stergios Christodoulidis, Fabrice Andre, Maria Vakalopoulou, Mihir Sahasrabudhe, Sherene Loi, Nikos Paragios, Mathématiques et Informatique pour la Complexité et les Systèmes (MICS), CentraleSupélec-Université Paris-Saclay, OPtimisation Imagerie et Santé (OPIS), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de vision numérique (CVN), Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Université Paris-Saclay-CentraleSupélec-Université Paris-Saclay, Institut Gustave Roussy (IGR), Peter MacCallum Cancer Center, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), TheraPanacea [Paris], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Subjects: FOS: Computer and information sciences, Attention Models, Computer science, Computer Vision and Pattern Recognition (cs.CV), Computer Science - Computer Vision and Pattern Recognition, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, 02 engineering and technology, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], 03 medical and health sciences, 0302 clinical medicine, Deep Learning, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, 0202 electrical engineering, electronic engineering, information engineering, Code (cryptography), FOS: Electrical engineering, electronic engineering, information engineering, Pathology, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Segmentation, Nuclei segmentation, business.industry, Self-Supervision, Deep learning, Nuclei Segmentation, Image and Video Processing (eess.IV), [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, Electrical Engineering and Systems Science - Image and Video Processing, 3. Good health, Identification (information), Task (computing), 030220 oncology & carcinogenesis, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Whole Slide Images, 020201 artificial intelligence & image processing, Artificial intelligence, business
Abstract: Segmentation and accurate localization of nuclei in histopathological images is a very challenging problem, with most existing approaches adopting a supervised strategy. These methods usually rely on manual annotations that require a lot of time and effort from medical experts. In this study, we present a self-supervised approach for segmentation of nuclei for whole slide histopathology images. Our method works on the assumption that the size and texture of nuclei can determine the magnification at which a patch is extracted. We show that the identification of the magnification level for tiles can generate a preliminary self-supervision signal to locate nuclei. We further show that by appropriately constraining our model it is possible to retrieve meaningful segmentation maps as an auxiliary output to the primary magnification identification task. Our experiments show that with standard post-processing, our method can outperform other unsupervised nuclei segmentation approaches and report similar performance with supervised ones on the publicly available MoNuSeg dataset. Our code and models are available online to facilitate further research., Comment: 10 pages. Code available online at https://github.com/msahasrabudhe/miccai2020_self_sup_nuclei_seg
Published: 2020
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44. Mechanistic Learning for Combinatorial Strategies With Immuno-oncology Drugs: Can Model-Informed Designs Help Investigators?

Author: Joseph Ciccolini, Fabrice Barlesi, Sebastien Benzekry, Dominique Barbolosi, Nicolas André, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), 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)-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), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Gustave Roussy (IGR), Direction de la recherche clinique [Gustave Roussy], Modélisation Mathématique pour l'Oncologie (MONC), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Benzekry, Sebastien, Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cancer Research, Computer science, Big data, [SDV.CAN]Life Sciences [q-bio]/Cancer, Machine learning, computer.software_genre, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [STAT.AP] Statistics [stat]/Applications [stat.AP], Set (psychology), 030304 developmental biology, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], business.industry, Statistical model, Predictive analytics, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Pharmacometrics, 3. Good health, Oncology, Drug development, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Artificial intelligence, [INFO.INFO-MO] Computer Science [cs]/Modeling and Simulation, business, Oncology drugs, computer, [PHYS.PHYS.PHYS-DATA-AN] Physics [physics]/Physics [physics]/Data Analysis, Statistics and Probability [physics.data-an], [PHYS.PHYS.PHYS-DATA-AN]Physics [physics]/Physics [physics]/Data Analysis, Statistics and Probability [physics.data-an], Systems pharmacology
Abstract: International audience; The amount of 'big' data generated in clinical oncology, whether from molecular, imaging, pharmacological or biological origin, brings novel challenges. To mine efficiently this source of information, mathematical models able to produce predictive algorithms and simulations are required, with applications for diagnosis, prognosis, drug development or prediction of the response to therapy. Such mathematical and computational constructs can be subdivided into two broad classes: biologically agnostic, statistical models using artificial intelligence techniques, and physiologically-based, mechanistic models. In this review, recent advances in the applications of such methods in clinical oncology are outlined. These include machine learning applied to big data (omics, imaging or electronic health records), pharmacometrics, quantitative systems pharmacology, tumor size kinetics, and metastasis modeling. Focus is set on studies with high potential of clinical translation, as well as applied to cancer immunotherapy. Perspectives are given in terms of combinations of the two approaches: 'mechanistic learning'.
Published: 2020
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45. Serum Detection of Nonadherence to Adjuvant Tamoxifen and Breast Cancer Recurrence Risk

Author: Léonor Fasse, Charles Coutant, Laurence Vanlemmens, A. Bardet, Arlindo R. Ferreira, Alexandra L. Dima, Angelo Paci, Agnès Dumas, Olivier Tredan, Florence Lerebours, Christelle Jouannaud, Fabrice Andre, Nan Lin, Patrick Soulié, Ann H. Partridge, Suzette Delaloge, Stefan Michiels, Ines Vaz-Luis, Gwenn Menvielle, Sandrine Pinto, Antonio Di Meglio, Barbara Pistilli, Sarah Dauchy, Anne Laure Martin, Paul Cottu, A. Lesur, Vianney Poinsignon, Sibille Everhard, Patrick Arveux, Christelle Levy, Institut Gustave Roussy (IGR), Pharmacologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Champalimaud Centre for the Unknown [Lisbon], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Roche France, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Interdisciplinaire de Soins de Support aux Patients en Onco-hématologie [Gustave Roussy] (DISSPO), Département de médecine oncologique [Gustave Roussy], Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], and Direction de la recherche [Gustave Roussy]
Subjects: Adult, Oncology, Cancer Research, medicine.medical_specialty, Antineoplastic Agents, Hormonal, medicine.medical_treatment, Breast Neoplasms, Medication Adherence, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Breast Cancer, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Medical prescription, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Chemotherapy, [SHS.SOCIO]Humanities and Social Sciences/Sociology, medicine.diagnostic_test, business.industry, Hazard ratio, ORIGINAL REPORTS, Middle Aged, medicine.disease, 3. Good health, Tamoxifen, Treatment Outcome, Chemotherapy, Adjuvant, Therapeutic drug monitoring, 030220 oncology & carcinogenesis, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, medicine.drug
Abstract: PURPOSE Nonadherence to long-term treatments is often under-recognized by physicians and there is no gold standard for its assessment. In breast cancer, nonadherence to tamoxifen therapy after surgery constitutes a major obstacle to optimal outcomes. We sought to evaluate the rate of biochemical nonadherence to adjuvant tamoxifen using serum assessment and to examine its effects on short-term, distant disease-free survival (DDFS). PATIENTS AND METHODS We studied 1,177 premenopausal women enrolled in a large prospective study (CANTO/NCT01993498). Definition of biochemical nonadherence was based on a tamoxifen serum level < 60 ng/mL, assessed 1 year after prescription. Self-reported nonadherence to tamoxifen therapy was collected at the same time through semistructured interviews. Survival analyses were conducted using an inverse probability weighted Cox proportional hazards model, using a propensity score based on age, staging, surgery, chemotherapy, and center size. RESULTS Serum assessment of tamoxifen identified 16.0% of patients (n = 188) below the set adherence threshold. Patient-reported rate of nonadherence was lower (12.3%). Of 188 patients who did not adhere to the tamoxifen prescription, 55% self-reported adherence to tamoxifen. After a median follow-up of 24.2 months since tamoxifen serum assessment, patients who were biochemically nonadherent had significantly shorter DDFS (for distant recurrence or death, adjusted hazard ratio, 2.31; 95% CI, 1.05 to 5.06; P = .036), with 89.5% of patients alive without distant recurrence at 3 years in the nonadherent cohort versus 95.4% in the adherent cohort. CONCLUSION Therapeutic drug monitoring may be a useful method to promptly identify patients who do not take adjuvant tamoxifen as prescribed and are at risk for poorer outcomes. Targeted interventions facilitating patient adherence are needed and have the potential to improve short-term breast cancer outcomes.
Published: 2020
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46. Deciphering the response and resistance to immunecheckpoint inhibitors in lung cancer with artificial intelligence-based analysis: the pioneer and quantic joint-projects

Author: Ciccolini, Joseph, Benzekry, Sébastien, Barlesi, Fabrice, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), 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)-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), Modélisation Mathématique pour l'Oncologie (MONC), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Direction de la recherche clinique [Gustave Roussy], PIONeeRis supported by French National Research Agency (grant# ANR-17-RHUS-0007) and is a partnership between AMU, APHM, AstraZeneca, Centre Léon Bérard, CNRS, HalioDx, ImCheck Therapeutics, Innate Pharma, Inserm, Institut Paoli Calmettes with an APHM sponsoring.QUANTIC is funded by ITMO Cancer AVIESAN and French Institut National du Cancer (grant #19CM148-00)., ANR-17-RHUS-0007,PIONEER,Precision Immuno-Oncology for advanced Non small cell lung cancer patients with PD-1 ICI Resistance(2017), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [STAT.AP]Statistics [stat]/Applications [stat.AP], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, [PHYS.PHYS.PHYS-DATA-AN]Physics [physics]/Physics [physics]/Data Analysis, Statistics and Probability [physics.data-an]
Abstract: International audience; Despite striking results, clinical outcome with immune checkpoint inhibitors remains too often uncertain. This joint-project aims at generating dense longitudinal data in lung cancer patients undergoing anti-PD1 or anti-PDL1 therapy, alone or in combination with other anticancer agents. Mathematical modelling with mechanistic learning algorithms will be used next to decipher the mechanisms underlying response or resistance to immunotherapy. Ultimately, this project should help to better understand the mechanisms underlying resistance to immune checkpoint inhibitors and identify a serial of actionable items to increase the efficacy of immunotherapy.
Published: 2020
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47. Occupational socioeconomic risk associations for head and neck cancer in Europe and South America: individual participant data analysis of pooled case-control studies within the INHANCE Consortium

Author: Alexander W. Daudt, Kristina Kjærheim, Paolo Boffetta, Antonio Agudo, Leticia Fernandez, Peter Thomson, Cristina Canova, Alastair Ross, Isabelle Stücker, Diego Serraino, David I. Conway, Marta Vilensky, Rosalina Jorge Koifman, Paul Brennan, Lorenzo Richiardi, Gary J. Macfarlane, Mia Hashibe, Thomas Behrens, Pagona Lagiou, Simone Benhamou, Claire M. Healy, Amy Lee Yuan-Chin, Maria Paula Curado, Victor Wünsch-Filho, Wolfgang Ahrens, Alex D. McMahon, Gwenn Menvielle, Ariana Znaor, Ivana Holcatova, Heribert Ramroth, Jan Hovanec, Danièle Luce, Ana M. B. Menezes, University of Glasgow, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Leibniz Institute for Prevention Research and Epidemiology - BIPS, Leibniz Association, First Faculty of Medicine Charles University [Prague], University of Athens Medical School [Athens], Universita degli Studi di Padova, University of Turin, Trinity College Dublin, Cancer Registry of Norway, University of Aberdeen, The University of Hong Kong (HKU), L’Hospitalet de Llobregat [Barcelona, Spain], Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), University of Heidelberg, Medical Faculty, Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Bologna, University of Buenos Aires [Argentina], Universidade Federal de Pelotas = Federal University of Pelotas (UFPel), Hospital de Clínicas de Porto Alegre (HCPA), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), University of São Paulo (USP), University of Utah School of Medicine [Salt Lake City], National Cancer Institute, NCI: R03CA113157, National Institute of Dental and Craniofacial Research, NIDCR: R03DE016611, European Commission, EC: IC18-CT97-0222, Agence Nationale de la Recherche, ANR, Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP: 01/01768-2, Bundesministerium für Bildung und Forschung, BMBF: 01GB9702/3, Fondation pour la Recherche Médicale, FRM, Fondation ARC pour la Recherche sur le Cancer, ARC, Fondation de France, Ministère des Affaires Sociales et de la Santé, Fifth Framework Programme, FP5: FOR381.88, KFS1069-09-2000, QLK1-CT-2001-00182, Institut National Du Cancer, INCa, Fondo para la Investigación Científica y Tecnológica, FonCyT, Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail, ANSES, Institut Gustave-Roussy: 88D28, Institut de Veille Sanitaire, InVS, Swiss Cancer Research Foundation: AKT 617, Conway D.I., Hovanec J., Ahrens W., Ross A., Holcatova I., Lagiou P., Serraino D., Canova C., Richiardi L., Healy C., Kjaerheim K., Macfarlane G.J., Thomson P., Agudo A., Znaor A., Brennan P., Luce D., Menvielle G., Stucker I., Benhamou S., Ramroth H., Boffetta P., Vilensky M., Fernandez L., Curado M.P., Menezes A., Daudt A., Koifman R., Wunsch-Filho V., Yuan-Chin A.L., Hashibe M., Behrens T., McMahon A.D., Università degli Studi di Padova = University of Padua (Unipd), Università degli studi di Torino = University of Turin (UNITO), 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 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University of Bologna/Università di Bologna, Universitad de Buenos Aires = University of Buenos Aires [Argentina], Universidade de São Paulo = University of São Paulo (USP), HAL UR1, Admin, and Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ)
Subjects: Data Analysis, medicine.medical_specialty, Epidemiology, Risk factors in diseases, Occupational prestige, [SDV]Life Sciences [q-bio], Socioeconomic Factor, Head cancer, socioeconomic, Cancer, Cancer Epidemiology, Occupational, Socioeconomic, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Epidemiology of cancer, medicine, Humans, 030212 general & internal medicine, Socioeconomic status, Càncer de cap, Original Research, business.industry, Factors de risc en les malalties, Prestige, Risk Factor, Head and neck cancer, Public Health, Environmental and Occupational Health, Case-control study, South America, medicine.disease, Neck cancer, Càncer de coll, [SDV] Life Sciences [q-bio], Europe, Data Analysi, Socioeconomic Factors, cancer: occupational, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Case-Control Studies, cancer epidemiology, business, Case-Control Studie, Psychosocial, Demography, Human
Abstract: BackgroundThe association between socioeconomic disadvantage (low education and/or income) and head and neck cancer is well established, with smoking and alcohol consumption explaining up to three-quarters of the risk. We aimed to investigate the nature of and explanations for head and neck cancer risk associated with occupational socioeconomic prestige (a perceptual measure of psychosocial status), occupational socioeconomic position and manual-work experience, and to assess the potential explanatory role of occupational exposures.MethodsPooled analysis included 5818 patients with head and neck cancer (and 7326 control participants) from five studies in Europe and South America. Lifetime job histories were coded to: (1) occupational social prestige—Treiman’s Standard International Occupational Prestige Scale (SIOPS); (2) occupational socioeconomic position—International Socio-Economic Index (ISEI); and (3) manual/non-manual jobs.ResultsFor the longest held job, adjusting for smoking, alcohol and nature of occupation, increased head and neck cancer risk estimates were observed for low SIOPS OR=1.88 (95% CI: 1.64 to 2.17), low ISEI OR=1.74 (95% CI: 1.51 to 1.99) and manual occupations OR=1.49 (95% CI: 1.35 to 1.64). Following mutual adjustment by socioeconomic exposures, risk associated with low SIOPS remained OR=1.59 (95% CI: 1.30 to 1.94).ConclusionsThese findings indicate that low occupational socioeconomic prestige, position and manual work are associated with head and neck cancer, and such risks are only partly explained by smoking, alcohol and occupational exposures. Perceptual occupational psychosocial status (SIOPS) appears to be the strongest socioeconomic factor, relative to socioeconomic position and manual/non-manual work.
Published: 2020
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48. Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Author: Kos, Z., Roblin, E., Kim, R. S., Michiels, S., Gallas, B. D., Chen, W., van de Vijver, K. K., Goel, S., Adams, S., Demaria, S., Viale, G., Nielsen, T. O., Badve, S. S., Symmans, W. F., Sotiriou, C., Rimm, D. L., Hewitt, S., Denkert, C., Loibl, S., Luen, S. J., Bartlett, J. M. S., Savas, P., Pruneri, G., Dillon, D. A., Cheang, M. C. U., Tutt, A., Hall, J. A., Kok, M., Horlings, H. M., Madabhushi, A., van der Laak, J., Ciompi, F., Laenkholm, A. -V., Bellolio, E., Gruosso, T., Fox, S. B., Araya, J. C., Floris, G., Hudecek, J., Voorwerk, L., Beck, A. H., Kerner, J., Larsimont, D., Declercq, S., Van den Eynden, G., Pusztai, L., Ehinger, A., Yang, W., Abduljabbar, K., Yuan, Y., Singh, R., Hiley, C., Bakir, M., Lazar, A. J., Naber, S., Wienert, S., Castillo, M., Curigliano, G., Dieci, M. -V., Andre, F., Swanton, C., Reis-Filho, J., Sparano, J., Balslev, E., Chen, I. -C., Stovgaard, E. I. S., Pogue-Geile, K., Blenman, K. R. M., Penault-Llorca, F., Schnitt, S., Lakhani, S. R., Vincent-Salomon, A., Rojo, F., Braybrooke, J. P., Hanna, M. G., Soler-Monso, M. T., Bethmann, D., Castaneda, C. A., Willard-Gallo, K., Sharma, A., Lien, H. -C., Fineberg, S., Thagaard, J., Comerma, L., Gonzalez-Ericsson, P., Brogi, E., Loi, S., Saltz, J., Klaushen, F., Cooper, L., Amgad, M., Moore, D. A., Salgado, R., Hyytiainen, A., Hida, A. I., Thompson, A., Lefevre, A., Gown, A., Lo, A., Sapino, A., Moreira, A. M., Richardson, A., Vingiani, A., Bellizzi, A. M., Guerrero, A., Grigoriadis, A., Garrido-Castro, A. C., Cimino-Mathews, A., Srinivasan, A., Acs, B., Singh, B., Calhoun, B., Haibe-Kans, B., Solomon, B., Thapa, B., Nelson, B. H., Ballesteroes-Merino, C., Criscitiello, C., Boeckx, C., Colpaert, C., Quinn, C., Chennubhotla, C. S., Solinas, C., Drubay, D., Sabanathan, D., Peeters, D., Zardavas, D., Hoflmayer, D., Johnson, D. B., Thompson, E. A., Perez, E., Elgabry, E. A., Blackley, E. F., Reisenbichler, E., Chmielik, E., Gaire, F., F. -I., Lu, Azmoudeh-Ardalan, F., Peale, F., Hirsch, F. R., Acosta-Haab, G., Farshid, G., Broeckx, G., Koeppen, H., Haynes, H. R., Mcarthur, H., Joensuu, H., Olofsson, H., Cree, I., Nederlof, I., Frahm, I., Brcic, I., Chan, J., Ziai, J., Brock, J., Weseling, J., Giltnane, J., Lemonnier, J., Zha, J., Ribeiro, J., Lennerz, J. K., Carter, J. M., Hartman, J., Hainfellner, J., Le Quesne, J., Juco, J. W., van den Berg, J., Sanchez, J., Cucherousset, J., Adam, J., Balko, J. M., Saeger, K., Siziopikou, K., Sikorska, K., Weber, K., Steele, K. E., Emancipator, K., El Bairi, K., Allison, K. H., Korski, K., Buisseret, L., Shi, L., Kooreman, L. F. S., Molinero, L., Estrada, M. V., Van Seijen, M., Lacroix-Triki, M., Sebastian, M. M., Balancin, M. L., Mathieu, M. -C., van de Vijver, M., Rebelatto, M. C., Piccart, M., Goetz, M. P., Preusser, M., Khojasteh, M., Sanders, M. E., Regan, M. M., Barnes, M., Christie, M., Misialek, M., Ignatiadis, M., de Maaker, M., Van Bockstal, M., Harbeck, N., Tung, N., Laudus, N., Sirtaine, N., Burchardi, N., Ternes, N., Radosevic-Robin, N., Gluz, O., Grimm, O., Nuciforo, P., Jank, P., Kirtani, P., Watson, P. H., Jelinic, P., Francis, P. A., Russell, P. A., Pierce, R. H., Hills, R., Leon-Ferre, R., de Wind, R., Shui, R., Leung, S., Tabbarah, S., Souza, S. C., O'Toole, S., Swain, S., Dudgeon, S., Willis, S., Ely, S., Bedri, S., Irshad, S., Liu, S., Hendry, S., Bianchi, S., Braganca, S., Paik, S., Luz, S., Gevaert, T., D'Alfons, T., John, T., Sugie, T., Kurkure, U., Bossuyt, V., Manem, V., Camaea, V. P., Tong, W., Tran, W. T., Wang, Y., Allory, Y., Husain, Z., Bago-Horvath, Z., Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Division of Pathology and Laboratory Medicine, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Charité, Institute of Pathology, Translational Tumorpathology Unit, German Breast Group, University of the Sunshine Coast (USC), European Institute of Oncology [Milan] (ESMO), Breakthrough Breast Cancer Centre, London Institute of Cancer, Department of Pathology, The Netherlands Cancer Institute, Division of Experimental Therapy, The Netherlands Cancer Institute NKI/AvL, Odense University Hospital, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Breast Medical Oncology [Houston], The University of Texas M.D. Anderson Cancer Center [Houston], Helsingborg Hospital, Division of Experimental Therapeutics [Milan, Italy], Département de médecine oncologique [Gustave Roussy], Cancer Research UK Lung Cancer Centre of Excellence [Londres, Royaume-Uni], University College of London [London] (UCL), Memorial Sloane Kettering Cancer Center [New York], Herlev and Gentofte Hospital, Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Southern Queensland (USQ), Pharmacogenomics Unit [Paris], Department of Genetics [Paris], Institut Curie [Paris]-Institut Curie [Paris], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Ctr Biomol Struct & Org, University of Maryland [College Park], University of Maryland System-University of Maryland System, The University of Sydney, Breast Cancer Translational Research Laboratory, Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Innovation North - Faculty of Information and Technology, Leeds Metropolitan University, Int Immuno-Oncology Biomarker, Graduate School, CCA - Cancer biology and immunology, Pathology, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), German Breast Group (GBG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Gallas, Brandon D [0000-0001-7332-1620], van de Vijver, Koen K [0000-0002-2026-9790], Demaria, Sandra [0000-0003-4426-0499], Badve, Sunil S [0000-0001-8861-9980], Symmans, W Fraser [0000-0002-1526-184X], Rimm, David L [0000-0001-5820-4397], Savas, Peter [0000-0001-5999-428X], Hall, Jacqueline A [0000-0003-0708-1360], Horlings, Hugo M [0000-0003-4782-8828], van der Laak, Jeroen [0000-0001-7982-0754], Bellolio, Enrique [0000-0003-0079-5264], Araya, Juan Carlos [0000-0003-3501-8203], Floris, Giuseppe [0000-0003-2391-5425], Hudeček, Jan [0000-0003-1071-5686], Ehinger, Anna [0000-0001-9225-7396], Lazar, Alexander J [0000-0002-6395-4499], Castillo, Miluska [0000-0002-0111-3176], Curigliano, Giuseppe [0000-0003-1781-2518], Sparano, Joseph [0000-0002-9031-2010], Braybrooke, Jeremy P [0000-0003-1943-7360], Hanna, Matthew G [0000-0002-7536-1746], Willard-Gallo, Karen [0000-0002-1150-1295], Sharma, Ashish [0000-0002-1011-6504], Comerma, Laura [0000-0002-0249-4636], Gonzalez-Ericsson, Paula [0000-0002-6292-6963], Loi, Sherene [0000-0001-6137-9171], Cooper, Lee [0000-0002-3504-4965], Apollo - University of Cambridge Repository, Research Programs Unit, Heikki Joensuu / Principal Investigator, HUS Comprehensive Cancer Center, Department of Oncology, Medicum, Gallas, Brandon D. [0000-0001-7332-1620], van de Vijver, Koen K. [0000-0002-2026-9790], Badve, Sunil S. [0000-0001-8861-9980], Symmans, W. Fraser [0000-0002-1526-184X], Rimm, David L. [0000-0001-5820-4397], Hall, Jacqueline A. [0000-0003-0708-1360], Horlings, Hugo M. [0000-0003-4782-8828], Lazar, Alexander J. [0000-0002-6395-4499], Braybrooke, Jeremy P. [0000-0003-1943-7360], and Hanna, Matthew G. [0000-0002-7536-1746]
Subjects: Oncology, [SDV]Life Sciences [q-bio], THERAPY, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], Prognostic markers, 0302 clinical medicine, Breast cancer, Medicine and Health Sciences, Pharmacology (medical), Lymphocytes, Stromal tumor, health care economics and organizations, 0303 health sciences, CHEMOTHERAPY, Sciences bio-médicales et agricoles, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], PROGNOSTIC VALUE, Clinical Practice, 030220 oncology & carcinogenesis, Educational resources, Immunosurveillance, medicine.medical_specialty, 3122 Cancers, [SDV.CAN]Life Sciences [q-bio]/Cancer, IMMUNITY, lcsh:RC254-282, Article, Limfòcits, Càncer de mama, 03 medical and health sciences, Gastrointestinal cancer, SDG 3 - Good Health and Well-being, Internal medicine, 692/53/2422, medicine, Radiology, Nuclear Medicine and imaging, Càncer gastrointestinal, 030304 developmental biology, Predictive biomarker, Tumor-infiltrating lymphocytes, business.industry, Médecine pathologie humaine, medicine.disease, Cancérologie, Human medicine, business, SYSTEM, 631/67/580/1884
Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls., info:eu-repo/semantics/published
Published: 2020
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49. A prospective multicentre REFCOR study of 470 cases of head and neck Adenoid cystic carcinoma: epidemiology and prognostic factors

Author: Esteban Brenet, Sylvain Morinière, Pierre Philouze, Jean Michel Goujon, Odile Casiraghi, Florent Espitalier, Laurence Digue, A. Auperin, Nicolas Fakhry, Christian Righini, Rabah Taouachi, Michel Wassef, Olivier Mauvais, Muriel Hourseau, Franck Jegoux, Bertrand Baujat, Marie Christine Kaminsky, Olivier Bouchain, Chloé Bertolus, Juliette Thariat, Jean Paul Marie, Valentin Calugaru, Emmanuelle Uro-Coste, Sarah Atallah, Anne Sudaka, Cécile Badoual, Nicolas Saroul, Philippe Schultz, Stéphanie Dakpé, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Institut Curie [Paris], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, CHU Amiens-Picardie, CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), Université de Picardie Jules Verne (UPJV), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service ORL et chirurgie cervico-faciale [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'Anatomopathologie [Bichat - Claude Bernard], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Pitié-Salpêtrière [AP-HP], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Strasbourg, Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Chirurgie Maxillo-Faciale et Chirurgie Plastique [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de Recherche sur le Handicap Ventilatoire (GRHV), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'ORL, chirurgie cervico-faciale [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], and Adenoid Cystic Carcinoma Research Foundation
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, Adolescent, Adenoid cystic carcinoma, [SDV]Life Sciences [q-bio], Prognostic factors, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Internal medicine, Epidemiology, medicine, Humans, Prospective Studies, Prospective cohort study, Survival analysis, Aged, Aged, 80 and over, Proportional hazards model, business.industry, Hazard ratio, Event-free survival, Middle Aged, medicine.disease, Prognosis, Salivary Gland Neoplasms, Carcinoma, Adenoid Cystic, Survival Analysis, REFCOR, Progression-Free Survival, 030104 developmental biology, Oncology, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Cohort, Disease Progression, Female, France, business, Body mass index
Abstract: International audience; Background: Adenoid cystic carcinoma (ACC) accounts for 1% of malignant head and neck tumours [1] and 10% of salivary glands malignant tumours. The main objective of our study is to investigate the prognostic factors influencing the event-free survival (EFS) of patients with ACC. Patients and methods: A multicentre prospective study was conducted from 2009 to 2018. All 470 patients with ACC whose survival data appear in the REFCOR database were included in the study. The main judgement criterion was EFS. Both a bivariate survival analysis using log-rank test and a multivariate using Cox model were performed using the R software. Results: Average age was 55 years. Females accounted for 59.4% of the cohort. The body mass index (BMI) was normal in 86% of cases. Tumours were located in minor salivary glands in 60% of cases. T3/T4 stages represented 58%; 89% of patients were cN0. histological grade III was observed on 21% of patients. The EFS and overall 5-year survival rates were 50% and 85%, respectively. After adjustment, the most significant pejorative prognostic factors were age >= 65 years (hazard ratio [HR] = 1.67), BMI
Published: 2020
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50. The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

Author: Gonzalez-Ericsson, Paula, Stovgaard, Elisabeth, Sua, Luz, Reisenbichler, Emily, Kos, Zuzana, Carter, Jodi, Michiels, Stefan, Le Quesne, John, Nielsen, Torsten, Laenkholm, Anne-Vibeke, Fox, Stephen, Adam, Julien, Bartlett, John MS, Rimm, David, Quinn, Cecily, Peeters, Dieter, Dieci, Maria, Vincent-Salomon, Anne, Cree, Ian, Hida, Akira, Balko, Justin, Haynes, Harry, Frahm, Isabel, Acosta-Haab, Gabriela, Balancin, Marcelo, Bellolio, Enrique, Yang, Wentao, Kirtani, Pawan, Sugie, Tomoharu, Ehinger, Anna, Castaneda, Carlos, Kok, Marleen, McArthur, Heather, Siziopikou, Kalliopi, Badve, Sunil, Fineberg, Susan, Gown, Allen, Viale, Giuseppe, Schnitt, Stuart, Pruneri, Giancarlo, Penault-Llorca, Frédérique, Hewitt, Stephen, Thompson, E Aubrey, Allison, Kimberly, Symmans, William, Bellizzi, Andrew, Brogi, Edi, Moore, David, Larsimont, Denis, Dillon, Deborah, Lazar, Alexander, Lien, Huangchun, Goetz, Matthew, Broeckx, Glenn, El Bairi, Khalid, Harbeck, Nadia, Cimino-Mathews, Ashley, Sotiriou, Christos, Adams, Sylvia, Liu, Shi-Wei, Loibl, Sibylle, Chen, I-Chun, Lakhani, Sunil, Juco, Jonathan, Denkert, Carsten, Blackley, Elizabeth, Demaria, Sandra, Leon-Ferre, Roberto, Gluz, Oleg, Zardavas, Dimitrios, Emancipator, Kenneth, Ely, Scott, Loi, Sherene, Salgado, Roberto, Sanders, Melinda, Gonzalez‐Ericsson, Paula, Lænkholm, Anne‐Vibeke, Vincent‐Salomon, Anne, Acosta‐Haab, Gabriela, Penault‐Llorca, Frederique, Cimino‐Mathews, Ashley, Liu, Shi‐wei, Chen, I‐Chun, Leon‐Ferre, Roberto, Int Immuno-Oncology Biomarker Work, Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University of Leicester, Department of Pathology, Odense University Hospital, Universita degli Studi di Padova, Pharmacogenomics Unit [Paris], Department of Genetics [Paris], Institut Curie [Paris]-Institut Curie [Paris], Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Helsingborg Hospital, Ctr Biomol Struct & Org, University of Maryland [College Park], University of Maryland System-University of Maryland System, The Netherlands Cancer Institute, Division of Pathology and Laboratory Medicine, Università degli Studi di Milano [Milano] (UNIMI)-European Institute of Oncology [Milan] (ESMO), European Institute of Oncology [Milan] (ESMO), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Innovation North - Faculty of Information and Technology, Leeds Metropolitan University, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), The University of Texas M.D. Anderson Cancer Center [Houston], Université Mohamed 1 Oujda MAROC, Frauenklinik, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), German Breast Group, University of Southern Queensland (USQ), Charité, Institute of Pathology, Translational Tumorpathology Unit, West German Study Group, Breast International Group [Brussels, Belgium] (BIG aisbl), Breast Cancer Translational Research Laboratory, Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Oncostat (U1018 (Équipe 2)), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli Studi di Padova = University of Padua (Unipd), Università degli Studi di Milano = University of Milan (UNIMI)-European Institute of Oncology [Milan] (ESMO), and German Breast Group (GBG)
Subjects: 0301 basic medicine, Oncology, PD-L1, medicine.medical_specialty, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Triple Negative Breast Neoplasms, Pembrolizumab, biomarker risk-management, B7-H1 Antigen, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Lymphocytes, Tumor-Infiltrating, Atezolizumab, Internal medicine, Biomarkers, Tumor, Medicine, Humans, TILs, Triple-negative breast cancer, Tumor marker, Cancer immunology, Risk Management, business.industry, Médecine pathologie humaine, Sciences bio-médicales et agricoles, immunotherapy, medicine.disease, 3. Good health, Clinical trial, Cancérologie, 030104 developmental biology, 030220 oncology & carcinogenesis, Human medicine, Nivolumab, business
Abstract: Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer. TILs can be easily assessed on hematoxylin and eosin stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Since TILs and PD-L1 are parts of an immunological spectrum in breast cancer, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immune-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with breast cancer. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in breast cancer. This article is protected by copyright. All rights reserved., info:eu-repo/semantics/published
Published: 2020
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