O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET)

Lemelin, Annie; Barritault, Marc; Hervieu, Valérie; Payen, Léa; Péron, Julien; Couvelard, Anne; Cros, Jérôme; Scoazec, Jean‐Yves; Bin, Sylvie; Villeneuve, Laurent; Lombard‐Bohas, Catherine; Walter, Thomas; investigators, Mgmt-Net

doi:10.1016/j.dld.2019.02.001

Cited by 34 publications

(26 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…MGMT status might affect the treatment effect from the mechanism [7]; our work only researched the influence of alkylating agents in patients with NENs based on MGMT status. Whether or not-other types of drug treatment responses, such as everolimus related regimens, are significantly affected by MGMT status warrants further study [28]. MGMT may play a very important role in carcinogenesis and invasive risk.…”

Section: Discussionmentioning

confidence: 99%

Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis

Tan

2020

Bioscience Reports

View full text Add to dashboard Cite

Background: O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients with neuroendocrine neoplasms (NENs) is controversial. We conducted a meta-analysis to assess the influence of MGMT status on the therapeutic sensitivity of alkylating agents in patients with NENs. Methods: We searched PubMed, EmBase, and Cochrane library public databases through 3 July 2019. The objective response rate (ORR) was the outcome data of interest. Subgroup analysis was performed according based on MGMT methylation and expression of MGMT protein. Results: Eleven studies were included in the meta-analysis. The proportion of patients with NENs that achieved an ORR after alkylating agent treatment was higher in the MGMT-deficient group than the non-deficient group (OR: 5.00; 95% CI: 3.04–8.22; P < 0.001; I2: 3%). Similar results were noted in the MGMT methylation and MGMT protein expression subgroups. Conclusion: Patients with NENs and MGMT methylation or low protein expression had a higher ORR proportion than patients without MGMT methylation or high protein expression. The MGMT status can be used as a biological indicator of the response to alkylating agent treatment in patients with NENs.

show abstract

Section: Discussionmentioning

confidence: 99%

Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis

Tan

2020

Bioscience Reports

View full text Add to dashboard Cite

show abstract

“…Currently, the most advanced predictive factor for response to alkylating agents remains the O6-methylguanine-DNA methyltransferase (MGMT) status, but this was not explored herein. MGMT promoter methylation or loss of MGMT protein expression seems to be associated with increased OR and survival under alkylating agents in NET ( 3 , 18 , 19 ), but this has not yet been demonstrated in a prospective study, which is the aim of the ongoing MGMT-NET study ( 19 ). Moreover, this biomarker has been poorly explored in NEC patients: in the study reported by Welin et al ., only 1 out of 20 patients had MGMT methylation and a negative MGMT expression upon IHC; this patient had an OR for 15 months and an OS of 22 months, which is much longer than that of the whole population ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma

Couronne

Girot

Hadoux

et al. 2020

Endocrine Connections

Self Cite

View full text Add to dashboard Cite

Objective First-line chemotherapy in metastatic neuroendocrine carcinomas (NECs) is based on etoposide and platinum. However, there is no standard concerning second-line treatment. The objective of this study was to evaluate efficacy and tolerance of dacarbazine or temozolomide in metastatic digestive NEC as post first-line treatment. Material and methods This study included patients with a metastatic NEC of digestive or unknown primary site. All patients received platinum-etoposide as first-line chemotherapy. Primary endpoint was progression-free survival (PFS). Secondary endpoints were clinical/morphological responses, toxicity, and overall survival (OS). Results Twenty-seven patients were included: 17 received dacarbazine and 10 temozolomide as post-first line treatments. Median PFS was 3.0 (95%CI (2.2;3.7)) months. There was no significant difference between dacarbazine and temozolomide on PFS. Clinical and morphological responses were found in 12 and 9 patients, respectively. Median OS was 7.2 (95%CI (2.2;12.2)) months. The toxicity profile was that expected with such treatments. Conclusion LV5FU2-dacarbazine or temozolomide-capecitabine chemotherapies allow a temporary clinical response for almost half of patients and/or a morphological response for a third of patients.

show abstract

“…The use of a continuous scoring system, while more adaptative to the expected clinical benefit, would require the choice of the clone and methods of immunohistochemistry and scoring to be standardized. Current trials on the predictive value of MGMT promoter methylation and immunohistochemistry should help to clarify the best method to assess the MGMT status (Lemelin et al 2019).…”

Section: Methodology Of Evaluation Of the Mgmt Statusmentioning

confidence: 99%

“…Overall, despite aforementioned heterogeneity of the literature, the pooled analysis of available data advocate that MGMT may be a relevant biomarker predictive of sensitivity to alkylating agents in NETs. In order to further explore this hypothesis, the MGMT-NET randomized phase II study (NCT03217097) aims at evaluating the value of the MGMT status in the prediction of the objective response at 3 months in patients treated with alkylating agents (Lemelin et al 2019).…”

Section: Mgmt Status As a Predictive Biomarker Of Progression In Advamentioning

confidence: 99%

Critical appraisal of MGMT in digestive NET treated with alkylating agents

Mestier

Couvelard

Blažević

et al. 2020

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

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.

show abstract

O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET)

Cited by 34 publications

References 39 publications

Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis

Association between MGMT status and response to alkylating agents in patients with neuroendocrine neoplasms: a systematic review and meta-analysis

Post first-line dacarbazine or temozolomide in neuroendocrine carcinoma

Critical appraisal of MGMT in digestive NET treated with alkylating agents

Contact Info

Product

Resources

About