title: MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors.
abstract: 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, 58years (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 18months 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.
authors.affiliation: Department of PathologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France U1149 - University Paris DiderotParis, France.
authors.forename: J
authors.initials: J
authors.lastname: Cros
authors.affiliation: Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
authors.forename: O
authors.initials: O
authors.lastname: Hentic
authors.affiliation: U1149 - University Paris DiderotParis, France Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
authors.forename: V
authors.initials: V
authors.lastname: Rebours
authors.affiliation: Department of RadiologyAP-HP, DHU UNITY, Beaujon Hospital, Clichy, France.
authors.forename: M
authors.initials: M
authors.lastname: Zappa
authors.affiliation: Department of PathologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
authors.forename: N
authors.initials: N
authors.lastname: Gille
authors.affiliation: Department of Somatic GeneticAP-HP, DHU UNITY, Bichat University Hospital, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Theou-Anton
authors.affiliation: Methodology and Quality of Life in Oncology Unit (EA 3181)University Hospital of Besançon, Besançon, France.
authors.forename: D
authors.initials: D
authors.lastname: Vernerey
authors.affiliation: Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
authors.forename: F
authors.initials: F
authors.lastname: Maire
authors.affiliation: U1149 - University Paris DiderotParis, France Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
authors.forename: P
authors.initials: P
authors.lastname: Lévy
authors.affiliation: Department of PathologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France U1149 - University Paris DiderotParis, France.
authors.forename: P
authors.initials: P
authors.lastname: Bedossa
authors.affiliation: Department of PathologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France U1149 - University Paris DiderotParis, France.
authors.forename: V
authors.initials: V
authors.lastname: Paradis
authors.affiliation: U1149 - University Paris DiderotParis, France Department of Digestive OncologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
authors.forename: P
authors.initials: P
authors.lastname: Hammel
authors.affiliation: U1149 - University Paris DiderotParis, France Department of Gastroenterology and PancreatologyAP-HP, DHU UNITY, Beaujon University Hospital, Clichy, France.
authors.forename: P
authors.initials: P
authors.lastname: Ruszniewski
authors.affiliation: U1149 - University Paris DiderotParis, France Department of PathologyAP-HP, DHU UNITY, Bichat University Hospital, Paris, France anne.couvelard@bch.aphp.fr.
authors.forename: A
authors.initials: A
authors.lastname: Couvelard
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D000069287:Capecitabine / Q000494:pharmacology / Q000627:therapeutic use; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000077204:Temozolomide; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D000069287:Capecitabine; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: MGMT; methylation; pancreatic neuroendocrine tumors; temozolomide