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1. Phase I study of [131I] ICF01012, a targeted radionuclide therapy, in metastatic melanoma: MELRIV-1 protocol

Author

Emilie Thivat, Jacques Rouanet, Philippe Auzeloux, Nicolas Sas, Elodie Jouberton, Sophie Levesque, Tommy Billoux, Sandrine Mansard, Ioana Molnar, Marion Chanchou, Giovanna Fois, Lydia Maigne, Jean-Michel Chezal, Elisabeth Miot-Noirault, Michel D’Incan, Xavier Durando, and Florent Cachin

Subjects
[131I]ICF01012, Targeted radionuclide therapy, Metastatic melanoma, Dosimetry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Benzamide-based radioligands targeting melanin were first developed for imaging melanoma and then for therapeutic purpose with targeted radionuclide therapy (TRT). [131I]ICF01012 presents a highly favorable pharmacokinetics profile in vivo for therapy. Tumour growth reduction and increase survival have been established in preclinical models of melanoma. According the these preclinical results, we initiate a first-in-human study aimed to determine the recommended dose of [131I]ICF01012 to administer for the treatment of patients with pigmented metastatic melanoma. Methods The MELRIV-1 trial is an open-label, multicentric, dose-escalation phase I trial. The study is divided in 2 steps, a selection part with an IV injection of low activity of [131I]ICF01012 (185 MBq at D0) to select patients who might benefit from [131I]ICF01012 TRT in therapeutic part, i.e. patient presenting at least one tumour lesion with [131I]ICF01012 uptake and an acceptable personalized dosimetry to critical organs (liver, kidney, lung and retina). According to dose escalation scheme driven by a Continual Reassessment Method (CRM) design, a single therapeutic injection of 800 MBq/m2, or 1600 MBq/m2, or 2700 MBq/m2 or 4000 MBq/m2 of [131I]ICF01012 will be administered at D11 (± 4 days). The primary endpoint is the recommended therapeutic dose of [131I]ICF01012, with DLT defined as any grade 3-4 NCI-CT toxicity during the 6 weeks following therapeutic dose. Safety, pharmacokinetic, biodistribution (using planar whole body and SPECT-CT acquisitions), sensitivity / specificity of [131I]ICF01012, and therapeutic efficacy will be assessed as secondary objectives. Patients who received therapeutic injection will be followed until 3 months after TRT. Since 6 to 18 patients are needed for the therapeutic part, up to 36 patients will be enrolled in the selection part. Discussion This study is a first-in-human trial evaluating the [131I]ICF01012 TRT in metastatic malignant melanomas with a diagnostic dose of the [131I]ICF01012 to select the patients who may benefit from a therapeutic dose of [131I]ICF01012, with at least one tumor lesion with [131I]ICF01012 uptake and an acceptable AD to healthy organ. Trial registration Clinicaltrials.gov : NCT03784625 . Registered on December 24, 2018. Identifier in French National Agency for the Safety of Medicines and Health Products (ANSM): N°EudraCT 2016-002444-17.

Published
2022
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2. Retrospective analysis of real-world data to evaluate actionability of a comprehensive molecular profiling panel in solid tumor tissue samples (REALM study)

Author

Karen Leroy, Clarisse Audigier Valette, Jérôme Alexandre, Lise Boussemart, Jean Chiesa, Clotilde Deldycke, Carlos Gomez-Rocca, Antoine Hollebecque, Jacqueline Lehmann-Che, Antoinette Lemoine, Sandrine Mansard, Jacques Medioni, Isabelle Monnet, Samia Mourah, Thomas Pierret, Dominique Spaëth, Alexandre Civet, Sandrine Galoin, and Antoine Italiano

Subjects
Medicine, Science
Published
2023

3. Tetraspanin8 expression predicts an increased metastatic risk and is associated with cancer-related death in human cutaneous melanoma

Author

Odile Berthier-Vergnes, Laetitia Barbollat-Boutrand, Roxane M. Pommier, Arnaud de la Fouchardière, Patrick Combemale, Maxime Grimont, Noémie Lopez-Ramirez, Julie Caramel, Stéphane Dalle, Jean-Luc Perrot, Caroline Gaudy-Marqueste, Nicolas Macagno, Sandrine Mansard, Fanny Bouquet, and Ingrid Masse

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2021
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4. Effectiveness and safety of nivolumab in patients with advanced melanoma: A multicenter, observational study

Author

Stéphane Dalle, Patrick Combemale, Yannick Le Corre, Caroline Dutriaux, E. Varey, Nathalie Beneton, Thomas Jouary, Caroline Robert, Henri Montaudié, Jean Philippe Arnault, Sandrine Monestier, Marie Thérèse Leccia, Sandrine Mansard, Laurent Mortier, Amir Khammari, Anne-Bénédicte Duval Modeste, François Skowron, Nicolas Meyer, Brigitte Dréno, Nabahet Ameur, Bernard Guillot, Philippe Saiag, E. Hainaut, Sophie Dalac-Rat, Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), 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), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, CHU Bordeaux [Bordeaux], Service de Dermatologie (CHU de Dijon), 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 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 Universitaire [Grenoble] (CHU), CHU Clermont-Ferrand, Hôpital Archet 2 [Nice] (CHU), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Centre Léon Bérard [Lyon], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Charles Nicolle [Rouen], Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Service de dermatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier de Pau, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Amgen Bristol-Myers Squibb, BMS Pfizer Novartis Roche AbbVie Les Laboratories Pierre Fabre LEO Pharma Research Foundation, Sandrine Monestier has received consultant fees from BMS and Roche, support for travel/congress from BMS, Roche, GSK and MSD, and has participated as an investigator on clinical trials for BMS, Roche‐ Genentech, GSK, Amgen, Novartis, MSD, Merck‐Serono and Astra Zeneca. Stéphane Dalle has received congress invitation and fees coverage from BMS, Pierre Fabre and MSD, translational study grant to institution from BMS and MSD. Laurent Mortier received support to travel to medical congresses from BMS, MSD, Roche and Novartis. Caroline Dutriaux has been a member of advisory boards and received consultancy fees from BMS, MSD, Pierre Fabre and Novartis. Sophie Dalac‐Rat has received honoraria, provided consultancy and been on advisory committees for BMS, MSD, Novartis and Sun pharma. Nicolas Meyer has received honoraria from Sun Pharma, Roche, Novartis and Pierre Fabre, research funding from BMS, MSD, provided consultancy to BMS, MSD, Roche, Novartis and Pierre Fabre, been on advisory committees for Amgen, Incyte, BMS, MSD, Roche, Novartis and Pierre Fabre. Sandrine Mansard has worked on advisory boards for BMS and Novartis, has received congress and travel fees from BMS and Pierre Fabre. Henri Montaudié has worked on advisory boards for BMS, MSD, Pierre Fabre and Novartis, provided consultancy to MSD and Pierre Fabre, received honoraria from BMS, MSD, Pierre Fabre and Novartis, received research funding from BMS and Leo Pharma. Philippe Saiag has received personal fees from Amgen, Bristol‐Myers Squibb, MSD, Merck‐Serono, Pfizer, Roche‐Genentech, Pierre Fabre and Novartis, received nonfinancial support from Bristol‐Myers Squibb, MSD, Roche‐Genentech and Novartis, received a funding grant from Roche‐Genentech. Patrick Combemale has worked on advisory committees for Roche, Pierre Fabre and AstraZenecca. Ewa Hainaut has been a speaker for BMS, Novartis and Sanofi, worked on advisory boards for Novartis and Sanofi, received research funding from Abbvie. Caroline Robert has received consultancy fees from BMS, MSD, Roche, Novartis, Sanofi, Pierre Fabre and Amgen. Yannick Le Corre has provided consultancy to BMS, MSD and Novartis, worked on advisory boards for BMS, MSD, Novartis and Pierre Fabre, received congress invitation from BMS, MSD and Novartis, has received honoraria from BMS. Nabahet Ameur is employee of Bristol‐Myers‐Squibb. Brigitte Dréno has received research funding from Amgen, BMS, Novartis and Roche, provided consultancy to BMS and Roche, worked on advisory boards for BMS, Roche and Pierre Fabre. Jean Philippe Arnault has been a speaker for BMS. Marie Thérèse Leccia, Bernard Guillot, François Skowron, Anne‐Bénédicte Duval Modeste, Nathalie Bénéton, Thomas Jouary, Emilie Varey, and Amir Khammari have no conflicts of interest to declare., Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), HAL UVSQ, Équipe, and 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)

Subjects
Male, advanced melanoma, safety, Cancer Research, medicine.medical_specialty, real-world, Databases, Factual, effectiveness, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, In patient, Adverse effect, Melanoma, Advanced melanoma, Aged, Retrospective Studies, Aged, 80 and over, nivolumab, business.industry, Incidence (epidemiology), Retrospective cohort study, Middle Aged, Survival Analysis, 3. Good health, Clinical trial, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Observational study, France, Nivolumab, business
Abstract

International audience; This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real-world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric-Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second- or subsequent-line therapy. The median durations of progression-free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0-34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3-5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real-world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.

Published
2021
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5. Positive Association Between Location of Melanoma, Ultraviolet Signature, Tumor Mutational Burden, and Response to Anti–PD-1 Therapy

Author

Léa Dousset, Florence Poizeau, Caroline Robert, Sandrine Mansard, Laurent Mortier, Charline Caumont, Émilie Routier, Alain Dupuy, Jacques Rouanet, Maxime Battistella, Anna Greliak, David Cappellen, Marie-Dominique Galibert, Clara Allayous, Alexandra Lespagnol, Émilie Gerard, Inès Kerneuzet, Séverine Roy, Caroline Dutriaux, Jean-Philippe Merlio, Beatrice Vergier, Alexa B. Schrock, Jessica Lee, Siraj M. Ali, Solène-Florence Kammerer-Jacquet, Céleste Lebbé, Marie Beylot-Barry, Lise Boussemart, CHU Bordeaux [Bordeaux], Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], Institut Gustave Roussy (IGR), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, CHU Lille, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Foundation Medicine Inc, 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), Dupuis, Christine, Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université Paris-Saclay, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de pathologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Bordeaux (UB), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-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)-Université Paris Cité (UPCité), Foundation Medicine, Inc. [Cambridge, MA, USA], EQRX Inc [Cambridge, MA, USA], 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 ), Service de Pathologie [Rennes] = Pathology [Rennes], Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-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, and Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)

Subjects
Cancer Research, [SDV]Life Sciences [q-bio], Infant, Newborn, ORIGINAL REPORTS, Cumulative sun exposure, B7-H1 Antigen, [SDV] Life Sciences [q-bio], Tumor mutational burden (TMB), Oncology, Child, Preschool, Mutation, Biomarkers, Tumor, Humans, Prospective Studies, Location of the primary melanoma, Precision Medicine, Melanoma
Abstract

PURPOSE Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti–PD-1 monotherapy. METHODS The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay. RESULTS One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, –1.05; chronic sun-exposed area, 1.12; P value for the location, < 10–5; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB (P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression. CONCLUSION Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice., The location of the primary melanoma in a sun-exposed area can help choosing first-line advanced melanoma treatment.

Published
2021
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6. Tetraspanin8 expression predicts an increased metastatic risk and is associated with cancer-related death in human cutaneous melanoma

Author

Sandrine Mansard, Nicolas Macagno, Laetitia Barbollat-Boutrand, Fanny Bouquet, Maxime Grimont, Arnaud de la Fouchardière, Stéphane Dalle, Roxane M. Pommier, Patrick Combemale, Noémie Lopez-Ramirez, Jean-Luc Perrot, Julie Caramel, Odile Berthier-Vergnes, Ingrid Masse, Caroline Gaudy-Marqueste, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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 Jean Monnet - Saint-Étienne (UJM), Aix Marseille Université (AMU), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, and Institut Roche [Boulogne-Billancourt, France]

Subjects
Oncology, Proto-Oncogene Proteins B-raf, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Tetraspanins, MEDLINE, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Internal medicine, medicine, Biomarkers, Tumor, Humans, RNA, Messenger, Neoplasm Metastasis, Letter to the Editor, Melanoma, RC254-282, Neoplasm Staging, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Prognosis, Immunohistochemistry, Cutaneous melanoma, Mutation, Molecular Medicine, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience

Published
2021
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7. Cemiplimab for locally advanced and metastatic cutaneous squamous-cell carcinomas: Real-life experience from the French CAREPI study group

Author

Pierre-Emmanuel Stoebner, Christophe Bedane, A. Jannic, Marc Dumas, Marie Moncourier, Sandrine Mansard, Anne-Bénédicte Duval-Modeste, David Solub, Sophie Darras, Suzanne Devaux, Julia Sanchez, Nicolas Meyer, Laurent Misery, Valentine Heidelberger, Raoul Triller, Ingrid Kupfer-Bessaguet, Nathalie Beneton, Florence Brunet-Possenti, Gaëlle Quéreux, E. Maubec, Sophie Dalac, François Skowron, Safia Abed, Caroline Gaudy-Marqueste, Laurent Mortier, Monica Dinulescu, F. Herms, Lucie Peuvrel, Marouane Boubaya, Candice Hober, Pierre Guillet, Mahtab Samimi, Yves Reguerre, Nicolas Poulalhon, Anne Pham-Ledard, Stéphanie Catala, Eve-Marie Neidhardt, Romain Lesbazeilles, Jean-Philippe Arnault, Brigitte Dréno, Olivier Collard, Philippe Celerier, Julie De Quatrebarbes, Youssef Tazi, Pierre Combe, Caroline Jacobzone, Élodie Archier, F. Aubin, Dominique Spaeth, Clémence Berthin, Nora Kramkimel, Florent Grange, Candice Lesage, Lisa Fredeau, A. Schoeffler, Marc Pracht, Bertille Bonniaud, Laure Cesaire, Maxime Etienne, Olivier Lauche, CHU Lille, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Hopital Saint-Louis [AP-HP] (AP-HP), Hôpital Saint-Louis de La Rochelle (CH La Rochelle), Université de Bourgogne (UB), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Le Mans (CH Le Mans), Hôpital Pontchaillou, Hôpital Henri Mondor, 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 Toulouse (CHU Toulouse), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Léon Bérard [Lyon], Hôpital Saint-Joseph [Marseille], Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Cochin [AP-HP], Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier de Valence (CH DE VALENCE), Centre hospitalier de Valence, CH Annecy Genevois, CHU de Nîmes, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), CH Boulogne sur Mer, Hôpital Robert Ballanger [Aulnay-sous-Bois], Centre Hospitalier de la Côte Basque (CHCB), Centre Hospitalier Universitaire [Grenoble] (CHU), Université de Bretagne Occidentale, CHU Clermont-Ferrand, Centre Hospitalier Intercommunal de Cornouaille (CHIC), Centre Hospitalier Intercommunal de Cornouaille [Quimper] (CHI Cornouaille [Quimper]), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Clinique Saint Pierre, Perpignan, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Clinique Sainte Anne [Strasbourg], Centre d'Oncologie de Gentilly, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut hospitalier Franco-Britannique [Levallois-Perret], CH René Dubos, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Pôle Santé Léonard de Vinci, Partenaires INRAE, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), CHU Limoges, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Sorbonne Paris Nord, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Centre hospitalier universitaire de Toulouse - CHU Toulouse, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Le CHCB, Centre Hospitalier de la Côte Basque, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Cancer Research, medicine.medical_specialty, cutaneous squamous cell carcinoma, Locally advanced, Best Overall Response, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, Article, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Overall survival, Medicine, Adverse effect, Group performance, RC254-282, Immune status, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Mean age, medicine.disease, chronic dermatosis, Toxic epidermal necrolysis, 3. Good health, immunocompromised, real-life setting, Oncology, 030220 oncology & carcinogenesis, PD-1–blocking antibody, cemiplimab, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%, partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS &lt, 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.

Published
2021
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8. Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib

Author

Sandrine Mansard, Philippe Saiag, Hervé Maillard, Amine Denden, Caroline Robert, Laurent Mortier, S. Dalac-Rat, Charlée Nardin, Olivier Dereure, Thierry Lesimple, Laurent Machet, Eve-Marie Neidhardt, Florent Grange, Alexandra Szenik, Caroline Dutriaux, Christophe Bedane, Céleste Lebbé, Jean-Jacques Grob, HAL UVSQ, Équipe, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), 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 de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Université de Lille, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Léon Bérard [Lyon], Centre Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Francois Rabelais [Tours], Service de Dermatologie [CHU Limoges], CHU Limoges, Service de dermatologie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Novartis Pharma S.A.S., CHU Bordeaux [Bordeaux], Amgen, Bristol-Myers Squibb, BMS, Pfizer, Merck, Novartis, Roche, Sanofi, Meso Scale Diagnostics, MSD, Novartis Pharma, Les Laboratories Pierre Fabre, This work was supported by Novartis Pharma S.A.S. , France., Philippe Saiag has received personal fees from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, Sanofi and Novartis, he has received non-financial support from Bristol-Myers Squibb, MSD, Roche-Genentech and Novartis, and has received a funding grant from Roche-Genentech., Céléste Lebbe has received honoraria from BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte, has acted as a consultant or has served as a member of an advisory board for BMS, and has received travel grant support from BMS and MSD., Jean-Jacques Grob has received honoraria from BMS, MSD, Merck, Pfizer, Incyte, Novartis, Roche, Amgen and Pierre Fabre, has received travel grant support from BMS, MSD and Roche, and has acted as a consultant and advisor for BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Adult, Male, Proto-Oncogene Proteins B-raf, Oncology, Cancer Research, medicine.medical_specialty, Pyridones, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pyrimidinones, 030204 cardiovascular system & hematology, Regression tree, 03 medical and health sciences, BRAF V600-mutation, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Trametinib, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Oximes, medicine, Humans, Prospective Studies, Stage (cooking), Prospective cohort study, education, neoplasms, Melanoma, Aged, Neoplasm Staging, education.field_of_study, Proportional hazards model, business.industry, Dabrafenib, Imidazoles, Middle Aged, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Mutation, Disease Progression, Female, business, Brain metastasis, medicine.drug
Abstract

International audience; Background: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. Methods: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan–Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. Results: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33–8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with

Published
2021
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9. Association of Anti–Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma

Author

Mona Amini-Adle, Yannick Le Corre, Alexis Guyot, Boris Campillo-Gimenez, D. Legoupil, Angélique Brunot, Nicolas Meyer, Géraldine Jeudy, Florent Grange, Thierry Lesimple, F. Aubin, Bernard Guillot, Florence Granel-Brocard, Julien Edeline, Laurent Mortier, Jean-Jacques Grob, Céleste Lebbé, Damien Giacchero, Nora Kramkimel, Monica Dinulescu, Henri Montaudié, Sandrine Mansard, Astrid Blom, and Sorilla Prey

Subjects
Oncology, Male, medicine.medical_specialty, Skin Neoplasms, Drug-Related Side Effects and Adverse Reactions, Programmed Cell Death 1 Receptor, Ipilimumab, Dermatology, Pembrolizumab, Kaplan-Meier Estimate, Antibodies, Monoclonal, Humanized, Severity of Illness Index, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Recurrence, Internal medicine, Medicine, Humans, CTLA-4 Antigen, Adverse effect, Immune Checkpoint Inhibitors, Melanoma, Response Evaluation Criteria in Solid Tumors, Original Investigation, Aged, Retrospective Studies, business.industry, Brain Neoplasms, Middle Aged, medicine.disease, Discontinuation, Nivolumab, 030220 oncology & carcinogenesis, Female, business, medicine.drug, Follow-Up Studies
Abstract

Importance Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies. Objectives To evaluate the risk of a recurrence of immune toxic effects associated with anti–programmed cell death 1 antibody (anti–PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs. Design, Settings, and Participants This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti–PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017. Exposures Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti–PD-1 (nivolumab or pembrolizumab) therapy. Main Outcomes and Measures The primary outcome was the rate of immune-related AEs associated with anti–PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti–PD-1 immune–related AEs and overall response rate and overall survival associated with anti–PD-1 therapy. Results Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti–tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti–PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing). Conclusions and Relevance The findings suggest that anti–PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.

Published
2020

10. Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas

Author

Coralie Bloch-Queyrat, Florent Grange, Lydia Deschamps, Sandrine Mansard, Nicole Basset-Seguin, Annick Tibi, Vincent Levy, Sarah Guégan, D. Legoupil, Jean-Philippe Arnault, Henri Montaudié, Marouane Boubaya, Olivier Dereure, Yannick Le Corre, A. Stefan, François Aubin, Céline Alloux, Jean-Jacques Grob, Peter Petrow, Soufian Cherbal, Groupe de cancérologie cutanée, Philippe Saiag, Nicolas Meyer, Isabelle Lopez, Marie Beylot-Barry, Eve Maubec, Marie-Thérèse Leccia, Brigitte Dréno, Ouidad Zehou, Laurent Machet, Julie De Quatrebarbes, Sophie Dalac, Monica Dinulescu, E. Wierzbicka-Hainaut, Isabelle Scheer-Senyarich, Herrada, Anthony, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13), Polyclinique Saint Côme, Institut Curie [Paris], CHU Bordeaux [Bordeaux], Hopital Saint-Louis [AP-HP] (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Grenoble, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Ambroise Paré [AP-HP], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), 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 Toulouse (CHU Toulouse), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Clermont-Ferrand, Hôpital Cochin [AP-HP], CHU Amiens-Picardie, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Agence Générale des Equipements et Produits de Santé [Paris] (AGEPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Skin Neoplasms, Time Factors, MESH: Immune Checkpoint Inhibitors, Cell, Phases of clinical research, Pembrolizumab, B7-H1 Antigen, Antineoplastic Agents, Immunological, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Progression-Free Survival, MESH: B7-H1 Antigen, Medicine, Immune Checkpoint Inhibitors, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, MESH: Carcinoma, Squamous Cell, Middle Aged, Progression-Free Survival, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Monoclonal, Carcinoma, Squamous Cell, Disease Progression, Female, MESH: Disease Progression, France, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Pharmacotherapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Carcinoma, Humans, Progression-free survival, Aged, MESH: Humans, business.industry, MESH: Skin Neoplasms, MESH: Time Factors, MESH: Quality of Life, MESH: Adult, medicine.disease, MESH: Antineoplastic Agents, Immunological, MESH: Male, Clinical trial, MESH: France, 030104 developmental biology, MESH: Antibodies, Monoclonal, Humanized, Quality of Life, business, MESH: Female
Abstract

PURPOSE To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). PATIENTS AND METHODS Patients, predominantly men, with their CSSCs’ immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort’s objective response rate at week 15 (ORRW15). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy–General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORRW15 difference between PD-L1+ and PD-L1– patients, was assessed for ORR, disease control rate, and safety, but not survival. RESULTS Median age of all patients was 79 years. The primary cohort’s ORRW15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORRW15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1– patients (17%; P = .02). Responders’ W15 total FACT-G score had improved ( P = .025) compared with nonresponders. CONCLUSION First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.

Published
2020
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11. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Preexisting Autoimmune Disease: A Nationwide Multicenter Cohort Study

Author

François-Xavier Danlos, Club Rhumatismes et Inflammations, Catherine Dubos, Thierry Lesimple, Gilles Gonzales, Julie De Quatrebarbes, Laurent Misery, Florence Brunet-Possenti, Marie Kostine, Emmanuel Nowak, Mickaël Lambert, Elisa Funck-Brentano, Laurent Chiche, Stéphanie Martinez, Sandrine Mansard, Hélène Doubre, Marie Marcq, Camille Scalbert, Yohann Loriot, Olivier Lambotte, Sarah Maanaoui, Gwenaelle Le Garff, Marie Beylot-Barry, Christos Chouaid, Jean-Bernard Auliac, Anne Pham-Ledard, Emilie Routier, Damien Giacchero, Bertille Bonniaud, Hervé Vallerand, Gilles Quere, C. Stavris, Florian Guisier, François Aubin, Chantal Decroisette, Nathalie Beneton, Ouidad Zehou, Alice Tison, Caroline Robert, Christophe Roge, R. Veillon, Groupe de cancérologie cutanée, François Skowron, Catherine Michel, Divi Cornec, Ioana Carpiuc, Nora Kramkimel, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Ambroise Paré , Assistance Publique - Hôpitaux de Paris (AP - HP), Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncologie génito-urinaire, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Eugène Marquis (CRLCC), Hopital d'Aix en Provence, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), CHI Créteil, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen [Fondation Ambroise Paré - Marseille], Centre Hospitalier Le Mans (CH Le Mans), CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-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)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Hôpital Foch [Suresnes], Centre Hospitalier de Valence (CH DE VALENCE), Centre hospitalier de Valence, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Henri Mondor, CH Morlaix, CHU Bordeaux [Bordeaux], Hôpital Cochin [AP-HP], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), CH, Mantes-La-Jolie, Centre hospitalier Les Chanaux [Mâcon], Hôpital de St Brieuc, Clinique des Cèdres, Service de Médecine Respiratoire [CHU Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), CHD Vendee (La Roche Sur Yon), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Lymphocyte B et Auto-immunité (LBAI), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, autoimmune disease, Inflammatory bowel disease, Autoimmune Diseases, immune checkpoint inhibitors, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Rheumatology, Internal medicine, Psoriasis, Neoplasms, medicine, Immunology and Allergy, Humans, cancer, Progression-free survival, Survival rate, Aged, Retrospective Studies, Autoimmune disease, Aged, 80 and over, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Symptom Flare Up, Progression-Free Survival, 3. Good health, Discontinuation, Survival Rate, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Rheumatoid arthritis, immune-related adverse events, Female, immunotherapy, business, Immunosuppressive Agents
Abstract

Objective Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. Methods A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. Results The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. Conclusion Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

Published
2019
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12. Incidence and Clinical Impact of Anti-TNFα Treatment of Severe Immune Checkpoint Inhibitor-induced Colitis in Advanced Melanoma: The Mecolit Survey

Author

Christine Longvert, C. Lesage, François-Xavier Lesage, Sarah Maanaoui, Olivier Dereure, Bernard Guillot, François Skowron, Ouidad Zehou, Géraldine Jeudy, Sorilla Prey, L. Visseaux, Nora Kramkimel, Brigitte Dréno, François Aubin, Laurent Machet, Sandrine Mansard, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Clermont-Ferrand, Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Dynamique des capacités humaines et des conduites de santé (EPSYLON), Université de Montpellier (UM)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université Montpellier 1 (UM1), Université de Montpellier (UM), Université Montpellier 1 (UM1)-Université Paul-Valéry - Montpellier 3 (UPVM)-Université de Montpellier (UM), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Necrosis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Colonoscopy, Ipilimumab, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Internal medicine, Biomarkers, Tumor, medicine, Humans, Immunology and Allergy, Colitis, Melanoma, Aged, Neoplasm Staging, Aged, 80 and over, Pharmacology, medicine.diagnostic_test, Tumor Necrosis Factor-alpha, business.industry, Incidence, Incidence (epidemiology), Immunotherapy, Middle Aged, Prognosis, medicine.disease, Infliximab, 3. Good health, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Tumor necrosis factor alpha, Neoplasm Grading, medicine.symptom, business, medicine.drug
Abstract

International audience; Immune checkpoint inhibitors (ICI) significantly improve overall survival (OS) in patients with advanced melanoma, but immune-related colitis may occur and warrant anti-tumor necrosis factor α (TNFα) treatment in severe forms. A nationwide, multicenter retrospective survey was conducted to assess both, the real-life incidence of grade 3/4 ICI-induced colitis treated with anti-TNFα, in patients with advanced melanoma, and the consequence of this therapeutic strategy on disease outcome. All patients with advanced melanoma treated with anti-TNFα agents for severe ICI-related colitis in the participating centers were included. Relative incidence was calculated according to the total number of patients treated with ICI in network centers during the period of inclusion. The possible impact of anti-TNFα treatment on disease outcome was evaluated through comparison of objective response rate, progression-free survival, and OS with pivotal literature data. Twenty-seven patients from 13 tertiary referral centers were included. Overall, severe ICI-related colitis treated with anti-TNFα occurred in 1% of patients with advanced melanoma, mostly with ipilimumab. Infliximab was successfully used in all patients but 1, mostly after 1 infusion. OS and progression-free survival of 12 and 3 months, respectively, were observed in these patients, along with an objective response rate of 41% at 12 months. This survey shows a low real-life incidence of severe colitis requiring anti-TNFα. Response rates to immunotherapy and survival data do not appear to significantly differ from those observed in pivotal studies. Severe ICI-induced colitis requiring anti-TNFα treatment appears to be a rare event in advanced melanoma, and infliximab does not seem to adversely affect disease outcome.

Published
2019
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13. Familial melanoma: Clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family

Author

Christophe Blondel, Jean-Luc Perrot, Florence Demenais, Marie-Thérèse Leccia, Eve Maubec, F. Boitier, Hamida Mohamdi, Pierre Vabres, Eve Corda, Valérie Chaudru, Sandrine Mansard, Lynda Vincent-Fetita, Béatrice Crickx, Stéphane Dalle, Brigitte Bressac-de Paillerets, Sébastien Forget, Florent Grange, Hélène Zattara, Dominique Stoppa Lyonnet, Luc Thomas, Ludovic Martin, Marie-Françoise Avril, Patricia Margaritte-Jeannin, Pascal Joly, Groupe de Recherche en Economie Théorique et Appliquée (GREThA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel - EA 3886), Université d'Évry-Val-d'Essonne (UEVE), Surgery, Informatics and Robotics (CHIR), 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), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-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), Laboratoire de Physique des Lasers (LPL), Université Sorbonne Paris Cité (USPC)-Institut Galilée-Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Valorisation Recherche et Innovations Alimentaire (Valorial), Département de Génétique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Reims (CHU Reims), Département Pluridisciplinaire de Médecine, Dermatologie, CHU Grenoble-Hôpital Michallon, Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Méthodologie statistique et épidémiologie génétique des maladies multifactorielles, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Variabilité Génétique et Maladies Humaines, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-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), Université Paris 13 (UP13)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie [Paris], AP-HP - Hôpital Bichat - Claude Bernard [Paris], and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)

Subjects
Oncology, medicine.medical_specialty, Pathology, Skin Neoplasms, Dermatology, Germline, 03 medical and health sciences, cutaneous melanoma, 0302 clinical medicine, Germline mutation, CDKN2A, Pancreatic cancer, Internal medicine, family clustering, Humans, Medicine, Melanoma, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetic testing, 0303 health sciences, medicine.diagnostic_test, business.industry, Odds ratio, Middle Aged, medicine.disease, 3. Good health, multiple primary melanomas, 030220 oncology & carcinogenesis, Cutaneous melanoma, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

Background Features associated with an increased frequency of cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been identified in families with 3 or more patients with cutaneous melanoma (CM). However, in families with 2 patients with CM, which represent the majority of familial melanoma, these factors have been rarely studied. Objective We investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of CM family clustering (2 vs ≥3 patients with CM among first-degree relatives in a family). Methods We included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. Results The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. Limitations The study was not population based. Conclusions This study shows that factors associated with CDKN2A mutations differ by extent of CM family clustering. It indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma.

Published
2012
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14. The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma

Author

F, Lesueur, M, de Lichy, M, Barrois, G, Durand, J, Bombled, M-F, Avril, A, Chompret, F, Boitier, G M, Lenoir, B, Bressac-de Paillerets, Monique, Baccard, Bertrand, Bachollet, Pascaline, Berthet, Valérie, Bonadona, Jean-Marie, Bonnetblanc, Olivier, Caron, Jacqueline, Chevrant-Breton, Jean-François, Cuny, Stéphane, Dalle, Michèle, Delaunay, Liliane, Demange, Julie, De Quatrebarbes, Jean-François, Doré, Marc, Frénay, Jean-Pierre, Fricker, Marion, Gauthier-Villars, Paul, Gesta, Sophie, Giraud, Philippe, Gorry, Florent, Grange, Andrew, Green, Laetitia, Huiart, Nicolas, Janin, Pascal, Joly, Delphine, Kérob, Christine, Lasset, Dominique, Leroux, Jean-Marc, Limacher, Michel, Longy, Sandrine, Mansard, Karine, Marrou, Tanguy, Martin-Denavit, Christine, Mateus, Eve, Maubec, Laurence, Olivier-Faivre, Vincent, Orlandini, Pascal, Pujol, Bruno, Sassolas, Dominique, Stoppa-Lyonnet, Luc, Thomas, Pierre, Vabres, Laurence, Venat, Ewa, Wierzbicka, Hélène, Zattara, Groupe de Recherche en Economie Théorique et Appliquée (GREThA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Sect Mech Carcinogenesis, International Agency for Cancer Research (IACR), Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Vectorologie et transfert de gènes (VTG / UMR8121), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Génétique [Villejuif], Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital Michallon, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Equipe de Recherche Médicale Appliquée (ERMA), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service de Dermatologie [Rennes] = Dermatology [Rennes], CHU Pontchaillou [Rennes], Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Génomique Fonctionnelle (IGF), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Oncogénèse et progression tumorale, 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 Hospitalier Universitaire de Reims (CHU Reims), Luxembourg Institute of Health (LIH), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital pasteur [Colmar], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service de dermatologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Pathologie moléculaire des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), 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)-Arts et Métiers Sciences et Technologies, 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)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)

Subjects
Male, Cancer Research, p14ARF, Exon, 0302 clinical medicine, CDKN2A, Tumor Suppressor Protein p14ARF, Multiplec ligation-dependent probe amplification, multiplex ligation-dependent probe amplification, Melanoma, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetics, Aged, 80 and over, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Exons, Middle Aged, 3. Good health, Pedigree, Melanoma-prone families, Oncology, 030220 oncology & carcinogenesis, Female, Chromosomes, Human, Pair 9, Molecular Sequence Data, Locus (genetics), Biology, 03 medical and health sciences, Germline mutation, p16INK4a, Humans, Point Mutation, Genetic Predisposition to Disease, Multiplex ligation-dependent probe amplification, Gene, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, 030304 developmental biology, Aged, Base Sequence, Point mutation, Genes, p16, Genetics and Genomics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cancer research, KLHL9, Carrier Proteins, Gene Deletion, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.

Published
2008
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