title: SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma.
abstract: Cyclophosphamide-dacarbazine-vincristine regimen is recommended for the treatment of malignant pheochromocytoma and paraganglioma (MPP); however, dacarbazine is the only recognized active drug in neuroendocrine tumours. We investigated the therapeutic benefit of temozolomide (TMZ), an oral alternative to dacarbazine, in patients with MPP. This is a retrospective study of consecutive patients with documented progressive MPP. We examined the correlation between Succinate dehydrogenase B (SDHB) mutation and O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation and MGMT expression in the French nation-wide independent cohort of 190 pheochromocytomas or paragangliomas (PP). Progression-free survival (PFS) according to RECIST 1.1 and PERCIST 1.0 criteria was the primary end point. Fifteen consecutive patients with MPP were enrolled; ten (67%) carried a mutation in SDHB. The mean dose intensity of TMZ was 172 mg/m(2) /d for 5 days every 28 days. Median PFS was 13.3 months after a median follow-up of 35 months. There were five partial responses (33%), seven stable (47%) and three progressive diseases (20%). Grade 3 toxicities were lymphopenia in two patients and hypertension in one. Partial responses were observed only in patients with mutation in SDHB. MGMT immunohistochemistry was negative in tumour samples from four patients who responded to treatment. SDHB germline mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT in 190 samples of the French nation-wide independent cohort. This study demonstrates that TMZ is an effective antitumour agent in patients with SDHB-related MPP. The silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumours may explain this finding.
authors.affiliation: Department of Nuclear Medicine and Endocrine Tumors, Gustave Roussy, University Paris-Sud, F-94800, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Hadoux
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Sophie
authors.initials: S
authors.lastname: Leboulleux
authors.forename: Abir
authors.initials: A
authors.lastname: Al Ghuzlan
authors.forename: Caroline
authors.initials: C
authors.lastname: Caramella
authors.forename: Désirée
authors.initials: D
authors.lastname: Déandreis
authors.forename: Isabelle
authors.initials: I
authors.lastname: Borget
authors.forename: Céline
authors.initials: C
authors.lastname: Loriot
authors.forename: Cécile
authors.initials: C
authors.lastname: Chougnet
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Laurence
authors.initials: L
authors.lastname: Amar
authors.forename: Jérome
authors.initials: J
authors.lastname: Bertherat
authors.forename: Rosella
authors.initials: R
authors.lastname: Libé
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dumont
authors.forename: Frédéric
authors.initials: F
authors.lastname: Deschamps
authors.forename: Martin
authors.initials: M
authors.lastname: Schlumberger
authors.forename: Anne Paule
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.forename: Eric
authors.initials: E
authors.lastname: Baudin
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010235:Paraganglioma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D010673:Pheochromocytoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies; D013385:Succinate Dehydrogenase / Q000235:genetics*; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: O(6)-methylguanine-DNA methyltransferase (MGMT); malignant pheochromocytoma; paraganglioma; succinate dehydrogenase B (SDHB); temozolomide