Changes in the MGMT gene expression in patients with primary glioblastoma after relapse. Influence of clinical characteristics and MGMT expression on survival of patients

Background. Over the past 10-15 years, there has been a clearer understanding of the processes occurring in cells of the primary glioblastoma. However, the change in MGMT gene expression and its role after disease relapse remain understudied. Purpose: to study changes in MGMT gene expression in case of recurrent primary glioblastoma after the standard therapy; to determine influence of clinical factors and MGMT gene expression on relapse-free survival of patients. Materials and Methods. We carried out a prospective analysis of clinical and molecular genetic characteristics of 21 patients aged from 28 to 63 with primary glioblastoma before and after recurrence. Relative mRNA expression of MGMT gene and mutations in IDH1/IDH2 genes were determined in surgical biopsies using PCR techniques. After the first surgery, all patients received radiation therapy (60 Gy) and chemotherapy with adjuvant temozolomide (2-18 cycles). The second-line chemotherapy was performed in 17 (80.9 %) patients, and 8 patients received (47 %, 8/17) temozolomide. Results. The relationship between the progression-free survival (PFS) and mRNA expression of MGMT gene (73.5 vs 33 weeks, p=0.013) and objective response to therapy (88 vs 36 weeks, p=0.046) was found. The number of cycles of first-line chemotherapy with temozolomide influenced the duration of the first PFS (65 weeks vs 21.5 weeks, p=0,07). The first PFS was not affected by patients' age (p=0.64), sex (p=0.17), Karnofsky performance scale index (p=0.43), extent of brain damage (p=0.41) and extent of the resection (p=0.27). After onset of relapse, mRNA expression of MGMT gene remained the same, being 66.7 % (14/21). The increased expression was observed in 23.8 % (5/21) of cases, and decreased gene expression was observed in 9.5 % (2/21) of cases. The second PFS was affected by the extent of tumor resection, although there were no statistically significant differences (p=0.52). The effect of mRNA expression of MGMT gene on the median second PFS was not revealed (p=0.39). No objective response to therapy was found in patients with a low mRNA expression of MGMT gene. Conclusion. Recurrent glioblastoma becomes more resistant to further therapy. With the development of tumor recurrence, the predictive value of MGMT gene is lost and the role of the extent of cytoreductive surgery increases.