Long-Term Outcome and MGMT as a Predictive Marker in 24 Patients With Atypical Pituitary Adenomas and Pituitary Carcinomas Given Treatment With Temozolomide

TY - JOUR

T1 - Long-Term Outcome and MGMT as a Predictive Marker in 24 Patients With Atypical Pituitary Adenomas and Pituitary Carcinomas Given Treatment With Temozolomide

AU - Bengtsson, Daniel

AU - Schrøder, Henrik Daa

AU - Andersen, Marianne

AU - Maiter, Dominique

AU - Berinder, Katarina

AU - Feldt Rasmussen, Ulla

AU - Rasmussen, Åse Krogh

AU - Johannsson, Gudmundur

AU - Hoybye, Charlotte

AU - van der Lely, Aart Jan

AU - Petersson, Maria

AU - Ragnarsson, Oskar

AU - Burman, Pia

PY - 2015/4/1

Y1 - 2015/4/1

N2 - CONTEXT/OBJECTIVE: Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited.DESIGN AND SETTING: We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas.MAIN OUTCOME: Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry.RESULTS: Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ.CONCLUSIONS: This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.

AB - CONTEXT/OBJECTIVE: Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited.DESIGN AND SETTING: We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas.MAIN OUTCOME: Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry.RESULTS: Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ.CONCLUSIONS: This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.

KW - Adenoma

KW - Adolescent

KW - Adult

KW - Aged

KW - Antineoplastic Agents, Alkylating

KW - Biomarkers, Pharmacological

KW - Biomarkers, Tumor

KW - Carcinoma

KW - DNA Modification Methylases

KW - DNA Repair Enzymes

KW - Dacarbazine

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Male

KW - Middle Aged

KW - Pituitary Neoplasms

KW - Prognosis

KW - Treatment Outcome

KW - Tumor Suppressor Proteins

KW - Young Adult

U2 - 10.1210/jc.2014-4350

DO - 10.1210/jc.2014-4350

M3 - Journal article

C2 - 25646794

SN - 0021-972X

VL - 100

SP - 1689

EP - 1698

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -