MGMT status of glioblastomas: Is PCR or IHC better?

Back in February '08 I wrote a post arguing that MGMT testing on glioblastomas is still not ready for clinical use outside of clinical trials. Since not all of our oncologist colleagues are Neuropathology Blog disciples, I continue to occasionally get a request from a clinician for MGMT testing on glioblastoma specimens. MGMT stands for O(6)-methylguanine DNA methyltransferase. Why are they asking for this test? Alkylating agents, like temazolamide, are more effective when MGMT is not active in a tumor because MGMT normally acts to remove the toxic methylguanine adducts provided by temozolamide. So MGMT silencing, usually due to gene promoter hypermethylation, predicts better response to temazolamide.

What's the best method for assessing MGMT activity in a tumor? According to a review article in the July 2009 issue of Archives of Pathology and Laboratory Medicine by Drs. Peter Pytel (pictured) and Rimas Lukas (Vol133:1062-1077) "immunohistochemical staining for MGMT does not offer a reliable way to stratify glioblastomas, and polymerase chain reaction-based assays are therefore necessary." Pytel and Lukas, of the University of Chicago Medical Center, provide the following two references for this position:

-- Yip S, Iafrate AJ, Louis DN. Molecular diagnostic testing in malignant gliomas: a practical update on predictive markers. J Neuropathol Exp Neurol. 2008;67:1-15.
-- Preusser M, Janzer RC, Felsberg J, et al. Anti-O6-methylguanine methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as a clinical biomarker. Brain Pathol. 2008;18(4):520-532.

On the other hand, some would argue that immunohistochemistry picks up more cases of MGMT than does PCR. Since its still really an experimental test, the issue ultimately may come down to what insurance will pay for. Immunohistochemistry is cheaper, so the patient may have an easier time getting his or her insurance to pay for it. My position is this: I will continue to discourage clinicians from getting the test until it becomes standard practice. If they insist on getting it, I would recommend immunohistochemistry for cost reasons and send it out to the Duke University laboratory of Dr. Roger McLendon to have it done. If, however, PCR is specifically demanded, I will send it to LabCorp, a commercial reference laboratory, which offers the MGMT PCR assay on paraffin-embedded tissue.