| Comment This case was subjected to IDH1/2 mutation analysis performed at Moffitt. It was also sent for MGMT promoter methylation testing, for FISH testing of chromosomes 1 and 19, and of chromosome 10 (PTEN locus), as well as for EGFR vIII assessment. No IDH1 or IDH2 hotspot mutation was found by sequenom. MGMT testing was negative for methylation of the gene promoter. FISH testing was negative for codeletion of chromosomes 1p/19q, but positive for monosomy of C10 at the PTEN locus. The EGFR vIII deletion was negative. In addition oncogene testing by Next Generation Sequencing was performed at Moffitt and reported separately; in summary, no mutation was found in the assessed genetic 'hotspots'. The findings are characteristic of IDH-wildtype glioblastoma. The histopathologic diagnosis and interpretation are unchangedAddendum Pathology Report | ||||
| RIGHT TEMPORAL TUMOR Addendum IDH1 AND IDH2 MUTATIONAL STATUS: - NEGATIVE FOR IDH1 AND IDH2 MUTATIONS BY SEQUENOM 1p/19q STATUS: - NEGATIVE FOR 1p/19q CODELETION BY FISH MGMT PROMOTER METHYLATION STATUS: - NEGATIVE FOR MGMT PROMOTER METHYLATION PTEN/CHROMOSOME 10 STATUS: - POSITIVE FOR PTEN/C10 LOSS BY FISH EGFR vIII STATUS: - NEGATIVE FOR EGFR vIII NGS TRUSIGHT HOTSPOT MUTATION ANALYSIS: - NEGATIVE FOR ACTIONABLE MUTATIONS Any help would be much appreciated! | ||||
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Saturday, 26 September 2015
IDH Wild-Type GBM
I''ve copied over the addendum path report for my husbands tumor. I haven't been able to find any promising treatment throughout my research for his tumor type and feeling quite desperate! Any suggestions based on the additional information we have...I'm not liking what I've read so far and the outcome doesn't look good....
Hi Daphney,
ReplyDeleteThe majority of GBM cases have a very similar pathology. The majority are negative for IDH1 mutation, MGMT unmethylated, with monosomy of chromosome 10. This is typical GBM pathology. Unfortunately there was no testing for EGFR overexpression or amplification, which could be present even though the EGFRvIII mutation was negative.
Where is he at in his treatment now? Finished radiation? Starting monthly TMZ cycles?
Since MGMT status is unmethylated I would suggest at least adding Keppra (the anti-seizure drug) if he's not on it already. This seems to improve survival in GBM patients taking at during chemotherapy, perhaps because it inhibits MGMT. Disulfiram (Antabuse), valproic acid (Depakote, another anti-seizure med), and fluoxetine (Prozac) have also been shown to inhibit MGMT in preclinical work. Except for disulfiram, these are all central nervous system drugs that we know get into the brain. My first priority would be to sensitize the tumor to TMZ (Temodar), as this type of tumor is normally unresponsive to TMZ or other alkylating agents.
Hi Stephen,
ReplyDeleteWould you recommend combining valproic acid and Keppra even for a tumor that is methylated?
Thanks :)
Since a very large retrospective study published in 2016 found no survival benefit in GBM patients using valproic acid (for seizure control), the mainstream now considers valproic acid to have little anti-tumor benefit for GBM, and I doubt there will be randomized phase 3 trial to test it (the purpose of the retrospective study was to provide justification for a phase 3 trial). I've discussed this controversy in the valproic acid section of the Treatment Options for Glioblastoma and other Gliomas document, available at virtualtrials.com.
DeleteHowever, the dose was not controlled for in that retrospective study, and I suspect higher doses of valproic acid are necessary for the anti-tumor effects. For example in the phase 2 trial where valproic acid (Depakote) was given during the radiochemotherapy period, the dose was 25 mg/kg per day divided into 2 daily doses. Or 1750 mg per day for a 70 kg adult.
It's debatable whether higher dose valproic acid is most useful as a radiosensitizer or chemosensitizer, or both. The main mechanism proposed for its anti-cancer effects are as an HDAC inhibitor, so it could potentially be valuable regardless of MGMT status, but higher doses might be required, and not all patients might tolerate those higher doses very well. There are far more potent HDAC inhibitors on the market (vorinostat, panobinostat), but these are expensive and likely have limited penetration across the BBB. Valproic acid is more affordable, accessible, and likely has better brain uptake, but is also weaker as an HDAC inhibitor. The most compelling evidence for valproic acid was the phase 2 trial for GBM where it was combined with radiation (but was not continued during monthly TMZ cycles).
As for Keppra, retrospective studies in Korea have shown better outcomes for newly diagnosed GBM when taking Keppra. There is a small amount of human data showing it can reduce MGMT expression in the tumor. Whether or not the effect on MGMT expression is responsible for the improved outcomes seen in retrospective studies hasn't been proven. In any case, even in MGMT "methylated" tumors there are most likely some cells with lower levels of methylation, which are protected by MGMT activity. So theoretically, Keppra could still have some sensitizing effects even in "MGMT methylated" tumors.
Whether or not you should combine the two? It depends, does he need these agents for seizure control? And how tolerable is such a combination for him. It's the main dilemma for the cocktail approach in general, as the limiting factor is often how much and how many drugs a person can tolerate when combined.
Personally I lean toward valproic acid (following the dose used in the phase 2 trial, 25 mg/kg per day divided into two daily doses) during the radiation phase, and Keppra during the monthly cycles of TMZ.