4133 Background: TMZ is an orally given drug used in patients (pts) with NETs, with encouraging results in pancreatic NETs in a recent study (Strosberg et al, 2011). Higher treatment efficacy seems to be correlated to MGMT tumor deficiency (Kulke et al, 2010). Aim-To assess MGMT expression in digestive NETs and to correlate with the efficacy of TMZ-based therapies. Methods: All pts with well differentiated, progressive, non resectable NETs treated with TMZ-based chemotherapy were included. Treatment efficacy was defined according to RECIST. Pts with progression or only stable disease were considered as “non-responders”. Nuclear expression of MGMT was assessed by immunohistochemistry on primary tumors or metastases and graded according the product of the intensity of staining (0 to 3) and the rate of positive cells (%), leading to a score comprised between 0 and 300. A score ≥ 80 was defined as “high” staining. Results: 22 pts (age 59 years (36-81)) with pancreatic (14 pts), small bowel (5 pts) or other (3 pts) NETs, grade 1 (5 pts) or 2 (17 pts) (WHO 2010 classification) were included. They received TMZ alone (19 pts) or combined with capecitabine (3 pts) as first line (3 pts) or 2+ line (19 pts).After a median of 6 cycles (3-16), objective response, stable disease and progression rates were seen in 32 % (7 pts, all with pancreatic NETs), 41% (9 pts, 5 pancreatic) and 27% (6 pts, 4 small bowel), respectively. Median (range) MGMT score was 10 (0-300). A “High” MGMT score was seen in 36% of pts (small bowel 4, pancreas 3 pts) ; it was correlated with primary tumor location (more frequent in small bowel NETs, p=0.02) and predictive of the absence of response (p=0.02). A “Low “MGMT score tended to be associated with objective response (p=0.06) whereas none of the pts with “high” score had tumor response. Response rate in pts with “low” MGMT score was 50%. Conclusions: MGMT deficiency is more frequent in pancreatic than small bowel NETs. Patients with pancreatic NET and low MGMT score are good candidates for TMZ, whereas those with high score should be treated with other drug in first intention. In patients with small bowel NET with most often high MGMT score, tumor stabilization using TMZ seems to be rare.
Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells.
