ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 OC5.1 | DOI: 10.1530/endoabs.63.OC5.1

Positive impact of genetic test on the management and outcome of patients with paraganglioma and/or pheochromocytoma

Alexandre Buffet1, Laurène Ben Aim2, Sophie Leboulleux3, Delphine Drui4, Delphine Vezzosi5, Rossella Libé6, Christiane Ajzenberg7, Daniele Bernardeschi8, Bertrand Cariou4, Frédéric Chabolle9, Olivier Chabre10, Vincent Darrouzet11, Brigitte Delemer12, Rachel Desailloud13, Bernard Goichot14, Annabelle Esvant15, Lucile Offredo1, Philippe Herman16, Sandrine Laboureau17, Hervé Lefebvre18, Peggy Pierre19, Isabelle Raingeard20, Yves Reznik21, Jean-Louis Sadoul22, Julien Hadoux3, Antoine Tabarin23, Igor Tauveron24, Delphine Zenaty25, Judith Favier1, Jerôme Bertherat6, Eric Baudin3, Laurence Amar26 & Anne-Paule Gimenez-Roqueplo2

1INSERM, UMR970, Paris-Centre de Recherche Cardiovasculaire, Paris, France; 2Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France; 3Gustave Roussy, Université Paris-Saclay, Service de médecine nucléaire et cancérologie endocrinienne, Villejuif, France; 4Service d’Endocrinologie, Diabétologie et Maladies Métaboliques, L’institut du thorax, Centre Hospitalier Universitaire de Nantes, Hôpital Nord Laënnec, Nantes, France; 5Service d’Endocrinologie, Hôpital Larrey, CHU de Toulouse, Toulouse, France; 6Assistance Publique, Hôpitaux de Paris, Hôpital Cochin, Service d’Endocrinologie ‘Centre de référence maladies rares de la surrénale’, Paris, France; 7Assistance Publique, Hôpitaux de Paris, Service de Médecine Interne et Endocrinologie, Hôpital Henri Mondor, Créteil, France; 8Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Pitié-Salpêtrière, Service d’ORL, unité d’otologie, implantologie auditive et chirurgie de la base du crâne, Paris, France; 9Service d’ORL et de Chirurgie Cervico-faciale, Hôpital Foch, Suresnes, France; 10Service d’Endocrinologie, CHU de Grenoble-Alpes, La Tronche, Grenoble, France; 11Service d’ORL et de Chirurgie Cervico-faciale, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France; 12Service d’Endocrinologie, Hôpital Robert Debré, CHU de Reims, Reims, France; 13Service d’Endocrinologie, Hôpital Nord, CHU d’Amiens-Picardie, Amiens, France; 14Service de Médecine Interne, Endocrinologie et Nutrition, Hôpitaux Universitaires de Strasbourg, Faculté de Médecine, Université de Strasbourg, Strasbourg, France; 15Service d’Endocrinologie, CHU de RennesService d’Endocrinologie, CHU de Rennes, Rennes, France; 16Assistance Publique, Hôpitaux de Paris, Service ORL-CCF, hôpital Lariboisière, université Paris VII, AP-HP, Paris, France; 17Service d’Endocrinologie, Centre Hospitalier Universitaire d’Angers, Angers, France; 18Centre Hospitalier Universitaire de Rouen, Service d’Endocrinologie, Diabète et Maladies Métaboliques, Rouen, France; 19Service d’Endocrinologie, Hôpital Bretonneau, CHU de Tours, Tours, France; 20Service d’Endocrinologie, CHU Montpellier, Hôpital Lapeyronie, Montpellier, France; 21Service d’Endocrinologie, CHU de Caen, Caen, France; 22Service d’Endocrinologie, Hôpital de L’Archet, CHU de Nice, Nice, France; 23Service d’Endocrinologie, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France; 24Service d’Endocrinologie, Hôpital Gabriel Montpied, CHU de Clermont-Ferrand, Clermont-Ferrand, France; 25Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Service d’Endocrinologie Diabétologie Pédiatrique, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du développement, Paris, France; 26Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’hypertension artérielle et médecine vasculaire, Paris, France.

Context: Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumors, characterized by a strong genetic component. Indeed, up to 40% of patients carry a germline mutation in a PPGL susceptibility gene. In accordance with the international recommendations, genotyping of PPGL susceptibility genes is therefore proposed to all patients with PPGL, but it has actually never been shown whether the identification of a germline mutation in one PPGL susceptibility gene changes the outcome of mutation-carriers.

Objective: Our objective was to evaluate how a positive genetic test impacts the management and outcome of propositus patients with PPGL carrying a germline mutation in one of the four major PPGL susceptibility genes (SDHB, SDHD, SDHC and VHL).

Design: We performed a multicentric retrospective study on 221 propositus carrying a SDHB, SDHD, SDHC or VHL germline mutation and followed in 24 French clinical centers of the Group of Endocrine Tumors and/or the COMETE network. Patients were divided into two groups: Genetic patients, who were informed of their genetic status within the year following the first PPGL diagnosis, and Historic patients who only benefited from the genetic test several years after initial PPGL diagnosis.

Results: Compared to Historic patients, Genetic patients had a better follow-up, with a higher number of examinations and a reduced number of patients lost to follow-up (9.6% versus 72%). During follow-up, smaller (18.7 mm versus 27.6, P=0.0128) new PPGL and metastases as well as lower metastatic spread were observed in Genetic patients. Importantly, these differences were reversed in the Historic cohort after genetic testing. Genetic patients who developed metachronous metastases had a better 5-year survival than Historic ones (P=0.0127).

Conclusion: Altogether our study clearly shows the positive impact of the identification of an SDHx or VHL mutation in the management, clinical outcome and survival of patients with PPGL. It reveals, for the first time, the clinical benefits of the practice of oncogenetics for patients with a rare cancer and strongly strengthens the recommendations of the Endocrine Society to consider PPGL genetic testing in all patients affected by PPGL.

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