Prognostic and Predictive Roles of MGMT Protein Expression and Promoter Methylation in Sporadic Pancreatic Neuroendocrine Neoplasms

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.

Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Cros

Hentic

Rebours

et al. 2016

“…(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

Self Cite

106

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.

“…The reported frequencies of MGMT promoter methylation (PCR or pyrosequencing) range between 0 and 40%, and for MGMT expression, between 24 and 51% depending on the method and study . Promoter hypermethylation seems to be associated with response to temozolomide in some studies; however, prospective validation is lacking (Schmitt et al 2014. Two ongoing prospective trials, one in GEP-NET (temozolomide + lanreotide, NCT02231762) and one in pNET (temozolomide vs temozolomide + capecitabine, NCT01824875) included MGMT expression and promoter methylation as a biomarker.…”

Section: Epigenetics In Netmentioning

confidence: 99%

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

Pavel¹,

Sers²

2016

Neuroendocrine tumors (NETs) are a group of heterogenous neoplasms. Evidencebased treatment options for antiproliferative therapy include somatostatin analogues, the mTOR inhibitor everolimus, the multiple tyrosine kinase inhibitor sunitinib and peptide receptor radionuclide therapy with 177-Lu-octreotate. In the absence of definite predictive markers, therapeutic decision making follows clinical and pathological criteria. As objective response rates with targeted drugs are rather low, and response duration is limited in most patients, numerous combination therapies targeting multiple pathways have been explored in the field. Upfront combination of drugs, however, is associated with increasing toxicity and has shown little benefit. Major advancements in the molecular understanding of NET based on genomic, epigenomic and transcriptomic analysis have been achieved with prognostic and therapeutic impact. New insight into molecular alterations has paved the way to biomarker-driven clinical trials and may facilitate treatment stratification toward personalized medicine in the near future. However, an improved understanding of the complexity of pathway interactions is required for successful treatment. A systems biology approach is one of the tools that may help to achieve this endeavor.