Inactivation of MGMT is Associated With the Efficacy of Streptozocin and High-grade Pancreatic Neuroendocrine Neoplasms

Abstract Purpose O6-methylguanine-DNA methyltransferase (MGMT) has been linked with alkylating agent resistance and tumor growth suppression. However, its role remains undetermined in pancreatic neuroendocrine neoplasms (Pan-NENs). This study examined the expression of MGMT in Pan-NENs and explored how MGMT affects the efficacy of the alkylating agent streptozocin (STZ). Methods The expression of MGMT was examined by immunohistochemistry (IHC) staining in 146 Pan-NEN patients at our institute; MGMT immunoreactivity and clinicopathological factors were evaluated. Results In 146 Pan-NEN, 99 cases (67.8%) were judged as MGMT-positive and 47 cases (32.2%) as negative. MGMT-negative cases were associated significantly with larger tumor size (p < 0.001), higher mitotic index (p < 0.001), and higher Ki-67 index (p < 0.001). Of the 19 cases treated with STZ, 6 cases were determined as SD and 4 cases as PD in MGMT-positive patients (N = 10), while 5 cases were determined as PR and 4 cases as SD in MGMT-negative patients (N = 9). Progression-free survival in MGMT-negative cases was significantly better than in MGMT-positive cases (p = 0.042). Conclusions MGMT expression was decreased with higher grade Pan-NENs, and STZ improved the therapeutic outcomes of MGMT-negative Pan-NENs. These findings indicate that higher grade Pan-NENs may represent a better therapeutic target for STZ treatment.