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1. Lynch syndrome: influence of additional susceptibility variants on cancer risk

Author

Roseline Vibert, Jasmine Hasnaoui, Alexandre Perrier, Alexandra Lefebvre, Chrystelle Colas, Marion Dhooge, Noémie Basset, Albain Chansavang, Camille Desseignes, Alex Duval, Solenne Farelly, Nadim Hamzaoui, Pierre Laurent-Puig, Julie Metras, Diane Moliere, Martine Muleris, Jeanne Netter, Mehdi Touat, Franck Bielle, Karim Labreche, Romain Nicolle, Géraldine Perkins, Mathilde Warcoin, Florence Coulet, and Patrick R. Benusiglio

Subjects
Genetics, Genetics (clinical)
Published
2023

2. Table S3 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

PFS6 and PFS12 depending of the in intention-to-treat or per protocole analyses as investigator or central review analyses.

Published
2023

3. Table S1 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Table S1: Patient characteristics T : Tumor ; IK : Karnofski index; NA : Not available, SST2 : SST2 receptor expression (IRS Immunoreactivity score ) ; Conv: Convexity; RT: Radiotherapy; RS: Radiosurgery; CT chemotherapy * : for the NF2 genomic alterations, deletion and mutation of the gene were researched according to the quality of the available tumoral fragment(cf Table S4)

Published
2023

4. Figure S4 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Study of correlation between SSTR2A receptor expression and growth rate (GR) before and under treatment as with progression. No significant correlation was observed. Immunohistochemical detection of SSTR2A protein was performed on 5 µm thick formalin fixed paraffin embedded (FFPE) tissue sections with Ventana Benchmark XT. The monoclonal SSTR2A antibody (clone UMB1, Abcam) was used at 1/4000 dilution.

Published
2023

5. Data from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Purpose:Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas.Patients and Methods:Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety.Results:A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003).Conclusions:The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Published
2023

6. Table S4 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Meningioma genes analyses The coding exons and exon-intron boundaries of 13 genes (NF2, AKT1, SMO, KLF4, TRAF7, PIK3CA, SUFU, SMARCB1, SMARCE1, CDKN2A, CDKN2B, PTEN and TERT was sequenced using the Custom QIAseq targeted DNA Panel (Qiagen, Germany) following the manufacturer's instructions. These genes were chosen according the most recent publication on whole genome sequencing or exome sequencing of meningiomas5. TheQIAseq targeted DNA panel utilizes Unique Molecular Indices (UMI)

Published
2023

7. Table S2 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Genes tested in molecular analysis and references

Published
2023

8. Figure S1 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Study flow chart

Published
2023

9. Figure S2 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Surface (2D area) growth rate before inclusion expressed in %/3months. Patients with a very high growth rate related to an initial very small tumor were not included in the pretreatement growth rate analysis.

Published
2023

10. Figure S3 from Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Louis Chinot, Henry Dufour, Anne Barlier, Dominique Figarella-Branger, Karine Baumstarck, Mohamed Boucekine, Stéphane Honoré, Anita Cohen, Maryline Barrie, Emeline Tabouret, Stéphane Fuentes, Pierre-Hugues Roche, Michel Kalamarides, Catherine Roche, Didier Autran, Noémie Basset, Hadrien Peyrière, Matthieu Peyre, Ahmed Idbaih, Chantal Campello, Marc Sanson, and Thomas Graillon

Abstract

Volume curves for all patients integrating pre and under treatment 3D volume data by central review. *patients with drugs intake < 2 months ** pre/post operative MRI non-available

Published
2023

11. Detection of a pathogenic Alu element insertion in PALB2 gene from targeted NGS diagnostic data

Author

Mélanie Eyries, Olivier Ariste, Gaelle Legrand, Noémie Basset, Erell Guillerm, Alexandre Perrier, Caroline Duros, Odile Cohen-Haguenauer, Pierre de la Grange, and Florence Coulet

Subjects
Ovarian Neoplasms, Alu Elements, Genetics, High-Throughput Nucleotide Sequencing, Humans, Breast Neoplasms, Female, Fanconi Anemia Complementation Group N Protein, Genetics (clinical), Retrospective Studies
Abstract

Despite routine analysis of a large panel of genes, pathogenic variants are only detected in approximately 20% of families with hereditary breast and/or ovarian cancer. Mobile element insertions (MEI) are known to cause genetic diseases in humans, but remain challenging to detect. Retrospective analysis of targeted next-generation sequencing (NGS) data from 359 patients was performed using a dedicated MEI detection pipeline. We detected one MEI in exon 9 of the PALB2 gene in a woman with a family history of breast cancer. The pathogenic variant, c.2872_2888delins114AluL2, disrupts the PALB2 coding sequence and leads to the production of a truncated protein, p.(Gln958Valfs*38). This is the first report of a pathogenic MEI in PALB2. This study illustrates that MEI analysis may help to improve molecular diagnostic yield and can be performed from targeted NGS data used for routine diagnosis.

Published
2022

12. Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach

Author

Marie-Noëlle Bonnet-Dupeyron, Helene Dreyfus, Nadia Boutry-Kryza, Cornel Popovici, Laurent Castera, Nancy Uhrhammer, Anthony Laugé, Yves-Jean Bignon, Hélène Delhomelle, Alice Fiévet, Christophe Guy, Noémie Bronnec, Bruno Buecher, Fabienne Prieur, Sophie Demontety, Vincent Goussot, Emmanuelle Mouret-Fourme, Claire Saule, Helene Zattara, Sarah Malsa, Paul Gesta, Cindy Meira, Erell Guillerm, Isabelle Turbiez, Agathe Ricou, Mélanie Léoné, Pierre Vande Perre, Sarab Lizard, Pascaline Berthet, Norbert Lignon, Adrien Buisson, Anne-Marie Birot, Philippe Denizeau, Etienne Rouleau, Odile Cohen-Haguenauer, Veronica Goldbarg, Virginie Moncoutier, Charlotte Benigni, Emmanuelle Barouk-Simonet, Flavie Boulouard, Caroline Jacquot-Sawka, Alice Yvard, Hakima Lallaoui, Veronica Cusin, Angélina Legros, Muriel Belotti, Christine Maugard, Marine Guillaud-Bataille, Jean-Marc Limacher, Marion Gauthier-Villars, Louise Crivelli, Afane Brahimi, Odile Cabaret, Ophelie Bertrand, Michel Longy, Gabrielle Le Guyadec, Doriane Livon, Amelie Bloucard, Dominique Stoppa-Lyonnet, Capucine Delnatte, Caroline Lecerf, Jennifer Carriere, Virginie Guibert, Véronique Mari, Anne-Sophie Allary, Florence Coulet, Françoise Bonnet, Paul Vilquin, Noémie Basset, Khadija Abidallah, Pierre Macquere, Nicolas Derive, Manon Boulaire, Stephanie Chieze-Valéro, Marine Le Mentec, Mathilde Gay-Bellile, Anne-Laure Conoy, Henri Margot, Pierre Devulder, Mathias Schwartz, Isabelle Tennevet, Stéphane Bézieau, Francesca Damiola, Violaine Bourdon, Audrey Mailliez, Zoe Nevière, Nicolas Viellard, Laurence Venat, Antoine De Pauw, Brigitte Bressac-de Paillerets, Agnès Hardouin, Sofiane Lacoste, Sandra Fert-Ferrer, Maud Privat, Helene Larbre, Dominique Vaur, Etienne Muller, Françoise Revillion, Clémentine Legrand, Rosette Lidereau, Laurence Gladieff, Sabine Raad, Jean Chiesa, Diane Molière, Ahmed Bouras, Nicolas Sevenet, Patrick R. Benusiglio, Sophie Giraud, Christine Toulas, Voreak Suybeng, Florine Oca, Tetsuro Noguchi, Catherine Dehainault, Sophie Lejeune, Céline Heude, Catherine Dubois d’Enghein, Thien-vu Nguyen Minh Tuan, Olivier Caron, Mathilde Warcoin, Christine Lasset, Claude Houdayer, Jessica Moretta-Serra, Julie Tinat, Hagay Sobol, Natalie Jones, Fanny Brayotel, Anne Fajac, Virginie Bubien, Maud Blanluet, Jean-Marc Rey, Anne Durlach, Sandrine M. Caputo, Isabelle Coupier, Fatoumata Simaga, Sophie Krieger, Catherine Noguès, Fabrice Airaud, Robin Fouillet, Celine Garrec, Valérie Bonadona, Julie Menjard, Bérengère Legendre, Chrystelle Colas, Christelle Berthemin, Camille Cohen, Caroline Abadie, Olivier Ingster, Audrey Remenieras, Anaïs Dupré, Jessica Le Gall, Lisa Golmard, Marie Bidart, Henrique Tenreiro, J Bombled, Marie-Charlotte Villy, Marie-Agnès Collonge-Rame, Sophie Dussart, Alain Lortholary, Lucie Salle, Samira Fekairi, Service de Génétique Oncologique, Institut Curie [Paris], Université Paris sciences et lettres (PSL), Département de Biologie des Tumeurs, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], CHU Pitié-Salpêtrière [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), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), 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 (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Références Cancers Rares (PREDIR), INCA, Institut national du cancer [Boulogne] (INCA), 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 de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Centre Hospitalier Universitaire de Reims (CHU Reims), dormoy, valerian, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, 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 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]

Subjects
Cosegregation, Genotype, [SDV]Life Sciences [q-bio], Breast Neoplasms, Biology, Article, 03 medical and health sciences, Likely benign, Genetics, medicine, Humans, Clinical significance, Genetic Predisposition to Disease, Genetic Testing, Uncertain significance, Gene, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, 0303 health sciences, Cancer predisposition, BRCA1 Protein, 030305 genetics & heredity, Cancer, Genetic Variation, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Classification methods, Female
Abstract

Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.

Published
2021

13. Molecular tumor testing in patients with Lynch-like syndrome reveals a de novo mosaic variant of a mismatch repair gene transmitted to offspring

Author

Florence Coulet, Erell Guillerm, Armelle Bardier-Dupas, Noémie Basset, Chrystelle Colas, and Magali Svrcek

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, Somatic cell, Offspring, Colon, Genetic counseling, Biology, MLH1, Brief Communication, Germline, 03 medical and health sciences, Genetics, medicine, Humans, Genetics (clinical), 0303 health sciences, Mosaicism, 030305 genetics & heredity, Microsatellite instability, nutritional and metabolic diseases, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, Pedigree, MSH2, Mutation, DNA mismatch repair, Female, MutL Protein Homolog 1
Abstract

In Lynch-like syndrome, patients have tumors with microsatellite instability but no germline pathogenic variant in mismatch repair genes or somatic methylation of the MLH1 promoter. Identification of the mechanism that causes these tumors is crucial for guiding screening of the patients and their relatives. Double somatic hits are the usual explanation for these cases; however, we have previously reported a de novo mosaic pathogenic variant in a patient with Lynch-like syndrome. Using tumoral NGS analysis of a series of 16 patients with Lynch-like syndrome, we found six patients with double somatic hits, including one patient with mosaicism of a de novo pathogenic variant in MSH2. This variant was transmitted to the patient's offspring, which has significant implications for genetic counseling.

Published
2020

14. Brief CommunicationCirculating tumor DNA is present in the most aggressive meningiomas

Author

Sébastien Boissonneau, Pauline Romanet, Emeline Tabouret, Olivier Chinot, Grégory Mougel, Noémie Basset, Dominique Figarella-Branger, Chantal Campello, Stéphane Fuentes, Anne Barlier, Kaissar Farah, Mikael Meyer, Catherine Roche, Romain Appay, Thomas Graillon, Henry Dufour, 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), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Département de Neurochirurgie [CHU Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut de neurophysiopathologie (INP), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Neoplasm DNA, business.industry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Brief Communication, medicine.disease, nervous system diseases, Meningioma, chemistry.chemical_compound, Text mining, chemistry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Mutation (genetic algorithm), otorhinolaryngologic diseases, Cancer research, medicine, business, neoplasms, DNA
Abstract

International audience; Recent discoveries of multiple driver mutations open promising perspectives for targeted therapies in meningioma. Nevertheless, iterative recurrences of most aggressive meningiomas as extended skull base meningiomas are not systematically operated and histologically documented. This suggests the interest and the relevance of liquid biopsy in meningiomas. In a proof-of-concept study, we detected the NF2 mutation in 2 of 6 cell-free plasma DNAs and 1 of 1 cerebrospinal fluid (CSF) from high-grade recurrent cases, suggesting that identification of the driver mutation in blood and CSF is today feasible. Liquid biopsy could be an interesting tool to adapt the targeted therapy in meningiomas in the near future.

Published
2020

15. Les trois temps de la prise en charge oncogénétique : la consultation, l’analyse en laboratoire et le suivi personnalisé

Author

Noémie Basset, Florence Coulet, Christilla Boucher, Patrick R. Benusiglio, Camille Desseignés, Service de Génétique Cytogénétique et Embryologie [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), Instabilité des microsatellites et cancers [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Gestionnaire, HAL Sorbonne Université 5, Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], conseil génétique, EGFR T790M, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, immunohistochimie, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, fumarate hydratase, anatomopathologie, medicine, oncogénétique, Gynecology, next generation sequencing, genetic susceptibility to cancer, genetic counseling, Philosophy, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, 030104 developmental biology, séquençage haut débit, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, prédisposition génétique au cancer, immunohistochemistry, pathology
Abstract

It is paramount to identify patients whose cancer is associated with genetic susceptibility to the disease, since their long-term management depends on it. Anatomical and molecular pathologists play a key role in the process. Indeed, their diagnosis supports or even sometimes warrants germline genetic testing. For example, a colorectal cancer with mismatch repair protein expression loss suggests Lynch syndrome, while a rare type of renal cell carcinoma with fumarate hydratase expression loss is highly evocative of hereditary leiomyomatosis and renal cell carcinoma syndrome. Similarly, the presence of the T790M EGFR variant before treatment in a non-small cell lung carcinoma warrants further testing as the variant is likely of germline origin. Patients with suspected genetic susceptibility to cancer are referred to the nearest clinical cancer genetics clinic. The cancer geneticist, assisted by a genetic counselor, then collects detailed personal and familial information, sometimes feeds them into bioinformatics tools or clinico-pathological scores, decides whether germline genetic analysis is justified, determines which genes should be analysed, and prescribes testing. Germline testing is carried out on a blood sample by expert laboratories using next generation sequencing on panels of cancer susceptibility genes. The cancer geneticists then returns the result to the patient. When a pathogenic variant is identified, the patient’s management ismodified, with recommendations ranging from intensified surveillance to risk-reducing surgery. Treatment is sometimes adapted to the pathogenic variant. In addition, relatives can undergo genetic testing, should they wish to know whether they carry the familial variant. In the near future, we expect clinical cancer genetics to move towards strengthened partnerships with molecular pathologists and medical oncologists. Somatic genetic analyses are now routine, at least in metastatic cancer, and a proportion of the tumoral variants identified are actually of germline origin. As for the oncologists, the development of mainstreaming programs where they are allowed to prescribe germline testing under the supervision of a cancer genetics team is unavoidable., Les patients dont le cancer est associé à une prédisposition génétique doivent être identifiés, puisque leur prise en charge à long terme en dépend. Les anatomopathologistes jouent un rôle clé dans l’initiation de cette démarche. En effet, un diagnostic précis oriente les investigations oncogénétiques, voire les justifie s’il s’agit par exemple d’un cancer colorectal avec perte d’expression de protéines codées par les gènes de mésappariements de l’ADN ou d’un type rare de cancer du rein perdant l’expression de la fumarate hydratase. Les analyses génétiques tumorales représentent aussi une porte d’entrée pour l’Oncogénétique, par exemple cancer bronchopulmonaire avec variant tumoral EGFR T790M pré-traitement. En cas de suspicion de prédisposition génétique, le patient est adressé en consultation d’Oncogénétique. Le médecin accompagné d’un conseiller en génétique y collecte les informations personnelles et familiales, les intègre à un processus décisionnel impliquant des outils bioinformatiques et des scores clinico- pathologiques, et prescrit les analyses constitutionnelles. Le laboratoire d’Oncogénétique réalise ensuite l’analyse sous forme de panel de gènes avec des machines de séquençage haut débit. Le résultat est rendu quelques semaines plus tard par l’Oncogénéticien. L’observation d’un variant pathogène résulte en des recommandations de prise en charge à long terme, dépistage et chirurgie de réduction de risque. Les avancées de la médecine permettent aussi dorénavant d’adapter parfois les traitements au résultat. En outre, l’identification d’un variant pathogène permet ensuite aux apparentés de bénéficier de tests génétiques. L’évolution à court terme de l’Oncogénétique se caractérisera par un partenariat renforcé avec les anatomopathologistes et pathologistes moléculaires, puisque la généralisation des analyses génétiques tumorales à visée thérapeutique révèlera de manière incidentale des variants pathogènes constitutionnels. Par ailleurs la mise en place de circuits de « mainstreaming » avec les oncologues, dans lesquels ces derniers prescrivent des analyses constitutionnelles dans un cadre précis et sous la supervision d’un Oncogénéticien, est inéluctable.

Published
2020

16. Everolimus and Octreotide for Patients with Recurrent Meningioma: Results from the Phase II CEVOREM Trial

Author

Olivier Chinot, Marc Sanson, Hadrien Peyrière, Emeline Tabouret, Thomas Graillon, Ahmed Idbaih, Stéphane Honoré, Anita Cohen, Matthieu Peyre, Dominique Figarella-Branger, Pierre-Hugues Roche, Noémie Basset, Mohamed Boucekine, Maryline Barrie, Henry Dufour, Michel Kalamarides, Chantal Campello, Didier Autran, Anne Barlier, Catherine Roche, Karine Baumstarck, Stéphane Fuentes, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de Neurochirurgie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Beaujon-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Département de neurochirurgie, Hôpital Nord [CHU - APHM], Département de Neurochirurgie [CHU Timone], SERVICE DE NEUROONCOLOGIE MARSEILLE, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Assistance Publique-Hôpitaux de Marseille (AP-HM), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix-Marseille Université - Faculté de médecine (AMU MED), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Hôpital Beaujon [AP-HP]-Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)

Subjects
Male, Cancer Research, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Octreotide, Gastroenterology, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Meningeal Neoplasms, Prospective Studies, Receptors, Somatostatin, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, TOR Serine-Threonine Kinases, Middle Aged, 3. Good health, Tumor Burden, Survival Rate, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Patient Safety, Meningioma, medicine.drug, Recurrent Meningioma, Adult, medicine.medical_specialty, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, otorhinolaryngologic diseases, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Everolimus, neoplasms, Survival rate, Aged, business.industry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, nervous system diseases, Clinical trial, Radiation therapy, Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery
Abstract

Purpose: Aggressive meningiomas that progress after surgery/radiotherapy represent an unmet medical need. Strong and constant expression of SSTR2A receptors and activation of the Pi3K/Akt/mTOR pathway have been demonstrated in meningiomas. The combination of everolimus, an mTOR inhibitor, and octreotide, a somatostatin agonist, has shown additive antitumor effect in vitro. The phase II CEVOREM trial investigated the efficacy of this combination on recurrent meningiomas. Patients and Methods: Patients with documented recurrent tumor progression ineligible for further surgery/radiotherapy were eligible to receive octreotide (30 mg/d, day 1) and everolimus (10 mg/d, days 1–28). The primary endpoint was the 6-month progression-free survival rate (PFS6). The secondary endpoints were overall survival, response rate, tumor growth rate according to central review, and safety. Results: A total of 20 patients were enrolled, including 2 with World Health Organization (WHO) grade I tumors, 10 with WHO grade II tumors, and 8 with WHO grade III tumors; furthermore, 4 patients harbored NF2 germline mutation. The overall PFS6 was 55% [95% confidence interval (CI), 31.3%–73.5%], and overall 6- and 12-month survival rates were 90% (95% CI, 65.6%–97.4%) and 75% (95% CI, 50.0%–88.7%), respectively. A major decrease (>50%) was observed in the growth rate at 3 months in 78% of tumors. The median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (P < 0.0002) and 0.48%/3 months at 6 months after treatment (P < 0.0003). Conclusions: The combination of everolimus and octreotide was associated with clinical and radiological activity in aggressive meningiomas and warrants further studies. Decrease in the tumor volume growth rate should be considered a complementary and sensitive endpoint to select potentially effective drugs for recurrent meningiomas.

Published
2019

17. Utility of a mainstreamed genetic testing pathway in breast and ovarian cancer patients during the COVID-19 pandemic

Author

Charlotte Paul, Patrick R. Benusiglio, Jean Pierre Lotz, Erell Guillerm, Florence Coulet, Sophie Geoffron, Roseline Vibert, Sandrine Richard, Joël Ezenfis, Nathalie Chabbert-Buffet, Veronique Byrde, Noémie Basset, Joseph Gligorov, Manon Lejeune, Clément Korenbaum, CCSD, Accord Elsevier, 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), Service de Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], CHU Tenon [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), Site de recherche intégrée en cancérologie (SiRIC CURAMUS), 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)-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), Service d'Oncologie médicale [CHU Tenon], 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), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Sud Francilien, Grand Hôpital de l'Est Francilien (GHEF), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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], Gynécologie-obstétrique et médecine de la reproduction - Maternité [CHU Tenon], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Genetic testing, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Breast cancer, 0302 clinical medicine, Pandemic, Young adult, Mastectomy, Genetics (clinical), Neoadjuvant therapy, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, medicine.diagnostic_test, BRCA1 Protein, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, General Medicine, Middle Aged, Neoadjuvant Therapy, 3. Good health, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, 030220 oncology & carcinogenesis, Hereditary Breast and Ovarian Cancer Syndrome, Female, Fanconi Anemia Complementation Group N Protein, Adult, Paris, medicine.medical_specialty, Genetic counseling, Salpingo-oophorectomy, Breast Neoplasms, Genetic Counseling, Article, Young Adult, 03 medical and health sciences, Ovarian cancer, Internal medicine, Genetics, medicine, Humans, Genetic Predisposition to Disease, Pandemics, Aged, BRCA2 Protein, business.industry, COVID-19, medicine.disease, business
Abstract

International audience; Introduction: Mainstreamed genetic testing (MGT) obviates the need for a cancer genetics consultation, since trained oncologists (O) and gynaecologists (G) provide counseling, prescribe testing and deliver results. We report results from our MGT program and emphasize its utility during the COVID-19 lockdown, when cancer genetics clinics had suspended their activity.Methods: An MGT pathway for breast and ovarian cancer (BC/OC) patients was established in Jan-2018 between the Assistance Publique - Hôpitaux de Paris.Sorbonne Université Cancer Genetics team and the Oncology/Gynecology departments at one teaching and two regional hospitals. Trained O + G evaluated patients with the Manchester Scoring System. A 12-point threshold was recommended for testing. Next-generation sequencing of BRCA1, BRCA2, PALB2, RAD51C and RAD51D was performed. Results were delivered to the patient by O/G. Pathogenic variants (PV) carriers were referred to the genetics clinic. Results are reported for the 2nd-Jan-2018 to 1st-June-2020 period. That includes the eight-week COVID-19 lockdown and three-week de-confinement phase 1.Results: Results were available for 231/234 patients. Twenty-eight (12.1%) carried a PV. Of the 27 patients tested during the COVID-19 period, three carried a PV, two in BRCA1 and one in RAD51C. The clinical impact was immediate for the two BRCA1 BC cases undergoing neo-adjuvant chemotherapy, since double mastectomy and salpingo-oophorectomy will now be performed using two-step strategies.Conclusions: MGT guaranteed care continuity in BC/OC patients during the critical phases of the COVID-19 pandemic, with immediate implications for PV carriers. More broadly, we report for the first time the successful implementation of MGT in France.

Published
2020

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