Short article: Evaluation of O6-methylguanine-DNA methyltransferase as a predicting factor of response to temozolomide-based chemotherapy in well-differentiated metastatic pancreatic neuroendocrine tumors.
OBJECTIVE
Temozolomide (TMZ) is an alkylating agent frequently used in well-differentiated metastatic pancreatic neuroendocrine tumors (PNETs) with very variable responses. O-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme whose loss of expression has been suggested to be predictive of response to TMZ in various human tumors. We evaluated the predictive value of MGMT status, assessed by immunohistochemistry (IHC) and methylation-specific PCR (MS-PCR), in well-differentiated metastatic PNETs treated by a TMZ-based chemotherapy.


METHODS
All patients with metastatic PNETs treated with TMZ-based chemotherapy between 2010 and 2016 in two academic centers, for whom the tumor samples were available, were included. Clinical data were collected and the MGMT status of the tumors was analyzed using MS-PCR and IHC.


RESULTS
Twenty-two patients (nine men, median age 61 years) were included. The loss of MGMT protein expression detected by IHC was observed in 13 (59%) patients and MGMT promoter hypermethylation was detected by MS-PCR in three (15%) out of 20 interpretable cases. MGMT status did not correlate significantly with the best radiological response according to the Response Evaluation Criteria In Solid Tumors criteria or with progression-free survival. There was no correlation between MGMT protein expression and MGMT gene promoter methylation.


CONCLUSIONS
These results indicate that a deficient MGMT status in PNETs, determined by loss of protein expression in IHC or by the presence of MGMT gene promoter methylation measured by MS-PCR, is not associated with a better response to TMZ-based chemotherapy and cannot be used as a predictive marker to lead treatment decisions.
aIMAD, Department of Gastroenterology & Digestive Oncology Departments of bPathology cSurgery, Nantes University Hospital dINSERM, U913 eINSERM, U1232, University of Nantes fIntegrated Center for Oncology, Centre René Gauducheau, Saint Herblain gDepartment of Gastroenterology & Digestive Oncology, CHU d'Angers, Angers, France.
Paul
P
Girot
Clotilde
C
Dumars
Jean-François
JF
Mosnier
Léa
L
Muzellec
Hélène
H
Senellart
Fanny
F
Foubert
François-Xavier
FX
Caroli-Bosc
Estelle
E
Cauchin
Nicolas
N
Regenet
Tamara
T
Matysiak-Budnik
Yann
Y
Touchefeu
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002454:Cell Differentiation; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000032:analysis* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000032:analysis* / Q000235:genetics; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005602:France; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D018579:Patient Selection; D016133:Polymerase Chain Reaction; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D000077204:Temozolomide; D013997:Time Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000235:genetics
D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide