We are looking for repurposed drugs for a family member and since most of the research has been done for GBM that is grade 4 tumor I wonder if there is anything to take into account while treating a grade 3 tumor. I once read somewhere, but can't remember where and how reliable this source was, to be careful with cytotoxic drugs for lower stage cancer as they may cause the tumor to develop to a higher grade. Could you let me know what are your opinions on this? What type of drugs would you chose or have you chosen for lower grade tumors? Thank you.
A more pertinent question than tumor grade is IDH1 status. Do you know if your family member's tumor is IDH1 mutant or non-mutant? It would say on the pathology report something like "IDH1 R132H immunonegative" or "immunopositive", which means it stained negative or positive for the most common IDH1 mutation in gliomas.
ReplyDeleteGrade 3 astrocytomas negative for IDH mutations tend to closely resemble glioblastoma and should be treated accordingly. IDH1-mutant gliomas tend to be more responsive to treatments such as radiation and chemotherapy than IDH non-mutant GBM, but they also have a higher rate of transition to temozolomide-induced hypermutated recurrence when treated with TMZ alone. There is little to no data on the risk of hypermutation when radiation and TMZ are combined, or when multiple cycles of TMZ follow combined radiation-chemotherapy. The studies on temozolomide-induced hypermutation so far have focused on IDH-mutant grade 2 gliomas (astrocytoma and oligodendroglioma) treated with multiple cycles of TMZ alone (without radiation).
It is something of a dilemma, as these IDH1 mutant tumors tend to be more responsive to chemotherapy than the typical GBM tumor, but there is also a need to avoid excessive reliance on temozolomide as a single therapy, to reduce the risk of hypermutated recurrence, which according to current data always takes the form of a grade 4 "secondary" GBM.
There is no data to show that any of the commonly used repurposed drugs can cause progression to a higher grade tumor. However, any drug that can effectively kill tumor cells tends to remove the most sensitive cells, leaving behind a more resistant subpopulation. Most repurposed non-oncology drugs are not particularly cytotoxic or are very mildly so. If they were strongly cytotoxic they'd be considered chemotherapy. The greater risk of inducing progression to higher grade tumors comes from excessive use of DNA-damaging chemotherapy (the risk is now well documented for IDH1 mutant grade 2 astrocytomas treated with TMZ as a single therapy in several studies from the Costello lab at UCSF).
Stephen, if I may ask in this thread:
Delete-one could speculate that hypermutation could also be caused by PCV chemotherapy?
-hypermutation is only caused by DNA damaging agents? I guess immunotherapy does not fall in this category, so it should be "safe" in this regard?
Thanks!
In fact there have been confirmed cases of hypermutated GBM recurrences following PCV and CCNU (lomustine) chemotherapy, however this is still understudied and we don't really know what the frequency of this outcome is following PCV or CCNU chemo, or how this relates to tumor MGMT methylation status.
Deletehttps://www.ncbi.nlm.nih.gov/pubmed/19584161
Most of the data on hypermutated glioma recurrence has only been published in the last few years (by the Costello lab at UCSF) and specifically focuses on temozolomide and low grade IDH-mutant gliomas. The data is sparse on the question of hypermutation following other alkylating agents like CCNU.
Hypermutation occurs specifically when tumor cells have defects in mismatch repair genes such as MSH6. In this case, temozolomide (and potentially other alkylating agents like CCNU) cause DNA mismatches that can't get repaired because of the defects in mismatch repair mechanisms.
As far as I've seen in the literature, hypermutation is only associated with DNA alkylating agents (mainly temozolomide, CCNU, and the PCV regimen which includes CCNU and procarbazine - both alkylating agents). Immunotherapy should definitely be safe in this regard.
Thank you, I understand it now.
ReplyDeleteStephen, were those TMZ induced hyper-mutated tumors accompanied by a shorter time to progression as well? Also, was there a median time from TMZ to mutation? One more question: was there a time where hypermutation wasn't likely if one made it to a particular threshold? Thanks,
ReplyDeleteDanny
Danny, we really only have full data for a very small group (6/10 IDHmut low grade astrocytomas treated with TMZ alone recurred with hypermutated secondary GBMs). Data for a larger cohort exists, but hasn't been published yet. Time from (end of?) TMZ treatment to (hypermutated) recurrence ranged from 1 to 81 months (median 15 months). So while it is possible to have a hypermutated recurrence occur up to 6 or 7 years after TMZ treatment, just looking at the numbers it seems that after 2 years or so, the chances of that happening is much less. Until the full study is published though it's impossible to say anything remotely definitive about this.
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