Concordance and clinical value of the MGMT promoter methylation pattern in tissue with paired serum and MGMT protein expression in a series of glioblastoma (GB) patients

2037 Background: MGMT (O6-methyl-DNA-methyltransferase) gene promoter methylation and MGMT tissue expression predict benefit from alkylating chemotherapy in GB. Tumoral MGMT promoter methylation can be detected in patients’ serum. We studied the concordance of tissue MGMT methylation pattern (t-MGMT+ or -) with paired MSP (methylation specific polymerase-chain reaction) in serum DNA (s-MGMT+ or -) and with the expression of MGMT protein measured by quantitative immunohistochemistry (q-IHC) in a series of GBs with complete clinical follow-up. Methods: MSP was performed in 70 patient samples and 37 paired patient's serums. Sixty-three patients were assessed for tissue nuclear q-IHC expression (2 tissue microarrays) giving 3 values per patient: minimum (min-q-IHC), maximum (max-q-IHC) and average (ave-q-IHC) of positive cells. Clinical factors were age (≥ 50, < 50), surgery (biopsy, resection), KPS (< 70, ≥ 70%), radiotherapy (< 40Gy, 60 Gy), base chemotherapy (BCNU, TMZ), chemotherapy benefit (P, SD+PR+CR), progression-free survival (PFS) and overall survival (OS). Results: t- MGMT+ patients (38.6%) had longer PSF (P=0.03), OS (P=0.04) and benefited from chemotherapy (P=0.09) compared with t-MGMT- patients. Multivariate analysis disclosed t-MGMT+ status and radiotherapy as independent factors for better OS and longer PFS (where age <50 was also significant). An s-MGMT+ status (27% of patients) was an independent factor of better survival and longer PFS in multivariate analysis. A high concordance between t-MGMT and s-MGMT was found (P<0.0001, Cohen's Kappa = 0.586). The sensibility to detect t-MGMT- of MSP in serum was 95.4% with a specificity of 60%. There were not significant differences between max-IHC, min-IHC and ave-IHC (Long-test P=0.65). Max-IHC had the best sensibility to predict t-MGMT- status. The cut off point was >12 positive cells for a sensibility of 97.4 % but a specificity of only 8.9% (ROC ((0,70; (0,56–0.84) P=0.007)). Conclusions: t-MGMT is the gold standard to identify patients who benefit from alkylating therapy. In the case of no tissue available, s-MGMT MSP assay has a good sensibility to detect t-MGMT- patients. MGMT q-IHC is not a good surrogate of t- MGMT status. No significant financial relationships to disclose.