Endocrine Abstracts

Introduction: Streptozotocin (SZ) is an active drug for the treatment of advanced adrenocortical carcinoma (ACC) in a minority of patients with an objective response rate of <10%. It has been reported that expression of glucose transporter-2 (GLUT-2) is essential for SZ to enter tumor cells and that high activity of O-6-methylguanine-DNA methyltransferase (MGMT) counteracts the alkylating effect of SZ. Therefore, we aimed to clarify the role of GLUT-2 and MGMT in the response of ACC to SZ.

Methods: GLUT-2 membrane protein expression was analyzed by immunohistochemistry in paraffin embedded tissue sections from 78 ACC patients (28 SZ responders and 50 with progressive disease). Methylation status of the promoter regions of MGMT and DNA mismatch repair (MMR) genes MLH1, 3, MSH2, 3, 6; PMS2 was assessed by multiplex ligation–dependent probe amplification (MLPA) using corresponding tumor and germ line DNA and compared with methylation of the same promoter in 6 normal adrenal glands.

Results: Membrane-located GLUT-2 protein was detected in all patients with objective response after SZ treatment and in 46/50 (92%) of the non-responders, without significant difference in average expression levels. Analysis of the samples with GLUT-2 membrane expression for promoter hypermethylation revealed significantly higher MGMT promoter methylation in responders than in non-responders (P=0.02) while other MMR gene promoters showed higher methylation in non-responders (P=0.03). MGMT hypermethylation was strongly associated with improved progression free survival during SZ (unmethylated: 3.9±1.7 months; hypermethylated: 5.1±0.8 months, P=0.06) while hypermethylation of MMR gene promoters was strongly associated with progression-free survival independent of treatment (unmethylated: 8.79±2.3 months; hypermethylated: 19.23±8.2 months, P=0.05).

Conclusion: These data demonstrate that GLUT-2 expression is necessary but not sufficient for therapeutic response to SZ in ACC. MGMT promoter hypermethylation is strongly associated with clinical efficacy of SZ, while hypermethylation of 6 other MMR gene promoters is associated with less aggressive tumors. This may be related with their role in creating neo-antigens similar to other solid cancers.