O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents

Walter, Thomas; Brakel, B van; Vercherat, Cécile; Hervieu, Valérie; Forestier, Julien; Chayvialle, JA; Molin, Yann; Lombard‐Bohas, Catherine; Joly, M-O; Scoazec, J.Y.

doi:10.1038/bjc.2014.660

Cited by 114 publications

(105 citation statements)

References 42 publications

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“…Among the available techniques to assess MGMT promoter methylation, pyrosequencing appears to be the most robust (Karayan-Tapon et al 2010, Quillien et al 2012. Similar findings regarding the predictive value of MGMT promoter methylation were suggested in PNETs (Schmitt et al 2014, Walter et al 2015. In addition, methylation of the MGMT promoter appears to have a prognostic value in neuroendocrine tumor (NET) independently of TEM treatment.…”

Section: Introductionmentioning

confidence: 64%

“…In addition, methylation of the MGMT promoter appears to have a prognostic value in neuroendocrine tumor (NET) independently of TEM treatment. MGMT promoter methylation is associated with a wide methylation of the genome, which introduces a potential bias in the assessment of the predictive value of this biomarker (Schmitt et al 2014, Walter et al 2015.…”

Section: Introductionmentioning

confidence: 99%

“…Since then, various methylation-independent mechanisms of MGMT expression have been described, explaining this discrepancy (Lavon et al 2007, Kitange et al 2012, Kohsaka et al 2012, Kreth et al 2013. Finally, it was suggested that MGMT expression assessed by immunochemistry could be a good predictor of response to TEM-based treatment in patients with PNET, but the cohorts reported until yet were small and heterogeneous (Ekeblad et al 2007, Kulke et al 2009, Schmitt et al 2014, Walter et al 2015.…”

Section: Introductionmentioning

confidence: 99%

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MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Cros

Hentic

Rebours

et al. 2016

Endocrine-Related Cancer

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Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O 6 -methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58 years (27-84)) with grade 1 WDPNET (n = 6) or 2 (n = 36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P = 0.04) and better progression-free survival (PFS) (HR = 0.35 (0.15-0.81), P = 0.01). Disease control rate at 18 months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR = 0.37 (0.29-1.08), P = 0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

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Section: Introductionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Cros

Hentic

Rebours

et al. 2016

Endocrine-Related Cancer

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“…(Dejeux et al 2009). MGMT promoter methylation occurs in PanNET as well (Schmitt et al 2014, Walter et al 2015.…”

Section: Pancreatic Netmentioning

confidence: 99%

“…MGMT promoter methylation has a predicting power in glioma patients treated with temozolomide. Similarly to gliomas, MGMT promoter methylation seems to predict for better therapy response to the DNA alkylating agent temozolomide in PanNET patients; however, larger and randomized clinical studies should be performed to confirm these findings (Schmitt et al 2014, Walter et al 2015.…”

Section: Clinical Implicationmentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

101

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice

Dussol

Joly

Vercherat

et al. 2015

Cancer

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BACKGROUND:The alkylating agents (ALKYs) streptozotocin, dacarbazine, and temozolomide currently are the main drugs used in systemic chemotherapy for neuroendocrine tumors (NETs). The promising activity shown by gemcitabine and oxaliplatin (GEMOX) in previous studies prompted this study 1) to confirm the use of GEMOX in a larger population of NET patients, 2) to compare its efficacy with that of ALKYs, and 3) to explore whether the O 6 -methylguanine-DNA methyltransferase (MGMT) status could help in selecting the chemotherapy regimen. METHODS: One hundred four patients with metastatic NETs (37 pancreatic NETs, 33 gastrointestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin) were treated with GEMOX between 2004 and 2014. Among these patients, 63 also received ALKYs. MGMT promoter gene methylation was assessed via pyrosequencing in 42 patients. RESULTS:Patients received a median of 6 courses of GEMOX. Twenty-four (23%) had an objective response (OR). The median progression-free survival (PFS) and overall survival were 7.8 and 31.6 months, respectively. In the 63 patients treated with both ALKYs and GEMOX, the ORs (22% and 22%) and the PFSs (7.5 and 7.3 months) were similar. The response was concordant in 53% of the patients. Promoter gene methylation of MGMT was associated with better outcomes with ALKYs (P 5.03 for OR and P 5.04 for PFS) but not GEMOX. CONCLUSIONS: GEMOX is effective against NETs; its activity is comparable to that of ALKYs, and it is not influenced by the MGMT status. Our data suggest that GEMOX might be preferred for patients with unmethylated MGMT tumors. Cancer 2015;121:3428-34.

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O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents

Cited by 114 publications

References 42 publications

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice

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