Critical appraisal of MGMT in digestive NET treated with alkylating agents

Abstract

The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT, and targets for potential antitumor synergy such as PARP.

FOLFOX‐bevacizumab chemotherapy in patients with metastatic neuroendocrine tumors

“…There is currently no validated biomarker to select the best candidates for either alkylating‐ or platinum‐based chemotherapy. However, low tumor expression of O6‐methylguanine‐methyltransferase (MGMT) has been repeatedly reported to predict efficacy of alkylating‐based chemotherapy in pancreatic NETs, with ORR of approximately 55%–60%, as compared to 10%–20% in patients with high tumor expression of MGMT 32–34 . In contrast, MGMT expression does not appear to influence the efficacy of platinum‐based chemotherapy 34 .…”

Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

“…However, although somatostatin analogs proved to be effective treatments in aggressive pulmonary carcinoids [98], somatostatin receptor expression has no role in predicting the response to somatostatin analogs in thoracic well-differentiated neuroendocrine neoplasms. Alkylating agents are the mainstay for chemotherapy, and deficiency of O6-methylguaninemethyltransferase (MGMT) enzyme has been associated with a better response to these agents [99]. However, in lung welldifferentiated neuroendocrine tumors, despite MGMT being shown to be deficient in approximately 50% of cases [100], no data are available on a predictive role of MGMT status in chemotherapy-treated patients.…”

Chemotherapy in NEN: still has a role?

“…Small cell NECs (SC-NECs) are molecularly more homogeneous and often characterized by bi-allelic inactivation of TP53 and RB1. Large cell NECs (LC-NECs) have a better prognosis than SC-NECs, and within LC-NECs, those of GI origin have a better prognosis than lung LC-NECs [122]. LC-NECs are molecularly more complex and heterogeneous, and up to 40% have a non-neuroendocrine component.…”