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.Key words: malignant pheochromocytoma, paraganglioma, O(6)-methylguanine-DNA methyltransferase (MGMT), succinate dehydrogenase B (SDHB), temozolomide Additional Supporting Information may be found in the online version of this article. Malignant pheochromocytoma and paraganglioma (PP) are frequently associated with mutations in succinate dehydrogenase B (SDHB). We found a correlation between mutations in SDHB and hypermethylation of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) in tumour samples from a French cohort of 190 patients with PP. Temozolomide yielded a clinical benefit in 67% of 15 patients treated for progressive malignant PP. The expression of MGMT was deficient in tumour samples from four of the five patients who responded to treatment. These results suggest that a personalized therapeutic approach may be applicable to this rare cancer.

In Vivo Detection of Succinate by Magnetic Resonance Spectroscopy as a Hallmark of SDHx Mutations in Paraganglioma

“…Knowledge of the SDHx-mutated status is critical for the follow-up and clinical management of patients and of their relatives. On the basis of an early knowledge of the SDHx mutational status, surgeons may decide to (36). Although these results will need to be evaluated in larger, prospective, and comparative studies, they nevertheless pave the way toward personalized medicine for inherited PPGL.…”

THERAPY OF ENDOCRINE DISEASE: Treatment of malignant pheochromocytoma and paraganglioma

“…Temozolomide is expected to have less toxicity than the CVD regimen. Recently, a team from the Gustave Roussy Institute has reported that the response rates of MPP patients on temozolomide therapy are similar to those of MPP patients on the CVD regimen (48).…”

“…MGMT plays a role in the cell detoxification process by relieving O 6 -methylguanine adducts. The recently published findings of researchers from the Gustave Roussy Institute and Hospital Georges Pompidou indicate that tumors associated with SDHB mutations are MGMT deficient and thus might respond better to CVD or temozolomide therapy than apparently sporadic tumors that are not associated with somatic mutations in the SDHB gene (48). Nevertheless, some carriers of SDHB mutations do not respond to CVD therapy (19).…”

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…Detection of a PPGL-related somatic mutation in the tumour of a germ line 'negative PPGL' suggests sporadic disease, and, consequently, averts the need for screening the patient's relatives. Moreover, identification of a somatic mutation provides insights into tumour biology, and might guide targeted therapies, especially in patients with metastatic disease (when treatment options are limited) [56][57][58][59] . The Study Group recommends that the analysis of somatic mutations in PPGLs be carried out whenever possible.…”