Prognostication of newly diagnosed glioblastomas
Identifying newly diagnosed glioblastomas that may respond to alkylating chemotherapy (ie, temozolomide)
Guiding therapy decision making for newly diagnosed glioblastomas in elderly patients (>60 years)
Glioblastoma (WHO grade IV astrocytoma) is the most frequent malignant primary central nervous system tumor in adults. It has a very poor prognosis, with median survival of less than a year. Current standard of care consists of surgical resection followed by radiotherapy in addition to alkylating chemotherapy with temozolomide.
MGMT (O[6]-methylguanine-DNA methyltransferase) is a DNA repair enzyme. This enzyme rescues tumor cells from alkylating agent-induced damage, and this leads to resistance to chemotherapy with alkylating agents. Epigenetic silencing of the MGMT gene by promoter methylation results in decreased MGMT protein expression, reduced DNA repair activity, and potential increased sensitivity to therapy. MGMT promoter methylation status has been most widely evaluated by methylation-specific PCR method, which is both sensitive and specific.
In newly diagnosed glioblastomas, the presence of MGMT promoter methylation has been shown to be an independent favorable prognostic factor and a strong predictor of responsiveness to alkylating chemotherapy (ie, temozolomide). This is particularly relevant for elderly patients (>60 years), who usually have decreased tolerance for combined aggressive chemoradiation. For this group of patients, recent clinical trials have provided strong evidence supporting an alternative therapeutic strategy consisting of monotherapy with the alkylating agent temozolomide for patients whose tumors show MGMT promoter methylation and radiotherapy alone for patients whose tumors lack MGMT promoter methylation. Thus, in addition to the significant prognostic and predictive value, MGMT methylation status has emerged as a valuable biomarker to guide therapy decision making for newly diagnosed glioblastoma in elderly patients, preventing unnecessary treatment toxicities and costs.
MGMT promoter methylation has been reported to high rates in oligodendrogliomas and astrocytomas of lower grade, in which they variably correlate with 1p19q codeletion and IDH mutations. Prognostic and predictive significance of MGMT promoter methylation status in these tumors has been shown in some studies, but not in others.
Not all patients whose tumors have MGMT promoter methylation will respond to alkylating chemotherapy.
MGMT promoter methylation status should not be used as the sole determinant of alkylating therapy eligibility.
Test results should be interpreted in context of clinical findings, tumor sampling, and other laboratory data. If results obtained do not match other clinical or laboratory findings, contact the laboratory for possible interpretation. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.
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