Clinical significance of molecular biomarkers in glioblastoma.
OBJECTIVE
To review the impact of molecular biomarkers on response to therapy and survival in patients with primary glioblastoma (GBM).


METHODS
Tissue specimens were analyzed for p53 mutations, EGFR amplification, loss of PTEN and p16, and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Demographic and clinical data were gathered from medical records.


RESULTS
Clinical and pathological data of 125 patients were collected and analysed. MGMT promoter methylation was associated with improved median overall survival (OS) (61 vs. 42 weeks, p = 0.01) and was an important prognosticator independent of age at diagnosis, extent of resection and post-operative ECOG performance status (HR 2.04, 95% CI 1.11-3.75). Among patients with MGMT promoter methylation, survival was significantly improved with chemoradiotherapy (CRT) over radiotherapy (RT) alone (71 vs. 14 weeks, p < 0.01). Furthermore, amongst those treated with temozolomide (TMZ) based CRT, the presence of EGFR amplification, maintenance of PTEN and wild-type p53 and p16 were each associated with trends towards improved survival.


CONCLUSIONS
MGMT promoter methylation is a strong, independent prognostic factor for OS in GBM. EGFR amplification, maintenance of PTEN, wild-type p53 and p16 all appear to be associated with improved survival in patients treated with CRT. However, the prognostic value of these biomarkers could not be ascertained and larger prospective studies are warranted.
Department of Oncology, McGill University and the Segal Cancer Centre - Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
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D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D012189:Retrospective Studies; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D018906:Antineoplastic Agents, Alkylating; D015415:Biomarkers; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide