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, 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.

Gastroenteropancreatic Neuroendocrine Tumors

“…The combination of temozolomide and capecitabine was associated with a significantly improved PFS (median PFS, 14.4 months in the temozolomide arm vs 22.7 months in the temozolomide/capecitabine arm; hazard ratio, 0.58 [ P = .023]) and OS (median OS, 38 months in the temozolomide arm vs not reached in the temozolomide/capecitabine arm; hazard ratio, 0.41 [ P = .012]). It is currently unclear whether expression of the DNA repair enzyme methyl‐guanine‐methyltransferase may predict response to temozolomide‐based regimens …”

“…It is currently unclear whether expression of the DNA repair enzyme methyl-guanine-methyltransferase may predict response to temozolomide-based regimens. 142,[145][146][147]…”

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasms: Systemic Therapy - Chemotherapy

“…Chemotherapeutic options after failure of STZ-based chemotherapy include the following: temozolomide (TMZ) ± capecitabine [7][8][9][10][11][12] , dacarbazine [13][14][15] , oxaliplatin combinations with fluoropyrimidines (5-FU or capecitabine) [16,17] and irinotecan-based therapy [18] . Although data for TMZ-based chemotherapy are still limited, it may replace STZ-based therapy in pancreatic NEN, if STZ is not available, and may be considered in NET G3 and in high-risk NET of other primary sites (e.g., pulmonary NET) [19][20][21] .…”

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment

“…The MGMT gene product 06-methylguanine DNA-methyltransferase provides resistance to treatment with alkylating agents such as temozolomide (36). MGMT promoter methylation could increase sensitivity to temozolomide and serve as a predictive biomarker of response to chemotherapy in MEN1 patients with advanced disease (37).…”