Background Temozolomide (TMZ) and other alkylating agents (ALK) yield high response rates when used in metastatic neuroendocrine tumors (NETs). Several series reported higher response rates when used in tumors with low expression of O6-Methylguanine DNA Methyltransferase (MGMT) with immunohistochemistry or promoter methylation. However, evidence is most consistent in pancreatic neuroendocrine tumors. Variations in MGMT assessment further complicate direct comparisons and clinical application. Thus, the predictive role of MGMT in patients with NETs treated with ALK is still debated. Methods A systematic review of the literature based on PRISMA methodology was performed searching in public medical database. Peer-reviewed full-text English language articles published until April 14th, 2025 were screened. Results 23 studies out of 649 published articles screened were deemed eligible for the analysis. Overall, these studies enrolled 1826 all-grade NET patients, 1462 of whom treated with TMZ or other ALK-based chemotherapy. The status of MGMT had been tested in 1092 (76.6%) of them with various techniques. The overall response rate (ORR) and progression free survival (PFS) were higher in MGMT-deficient compared with MGMT-proficient NETs. Conclusions Our work suggested that MGMT status may be predictive of ALK efficacy, especially TMZ-based. The high heterogeneity of the studies and of techniques employed should be considered for potential interpretation biases. On this basis the MGMT testing before ALK therapy is not currently recommended as a routine in daily clinical practice.
Maratta et al. (Fri,) studied this question.
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