My 64-year-old husband was diagnosed with GBM in his left temporal lobe after a successful resection in 1/2016. His tumor is unmethylated and IDH negative. He is TMZ-naive and has been on Keytruda and Optune for a year. The tumor was stable until late October, when it extended into a new area. It is slow-growing according to a PET scan yesterday.
Genomic testing of tissue retrieved from a second resection 11/16 highlighted mutations in NF1, PTEN, ASXL1, HNF1A, MLH1, NOTCH1 and SPEN. My husband's NO suggested Temsirolimus because of the PTEN mutation and TMZ starting in January.
My big research question is how to get the most kick out of TMZ, given his methylation status. It seems that either daily or 7-day/alternating Temodar have better clinical results than the standard protocol. I also wondering how best to sensitize GBM cells to TMZ and potentiate the treatment. Different studies suggest adding:
- Tamoxifen
- MGMT inhibitor O6-benzylguanine (O6-BG)
- Interferon-β (IFN-β)
- oncolytic adenovirus
- excision repair pathway enzyme apurinic/apyrimidine endonuclease/redox factor-1 (APE)
- Prozac/Fluoxetine
- antabuse/disulfiram
-Metformin
This all makes my head swim. Have any of you tried an alternative TMZ dosing schedule along with something to enhance its effectiveness against a unmethylated tumor?
Thanks for all your information and help.
Which company did the gene testing? Was it a commercial service like FoundationOne, or something else? Was there any commentary about the MLH1 mutation? This is a mismatch repair gene, and if the mutation is a deactivating one, it could put him at risk for an outgrowth of a hypermutated clone following TMZ treatment (because TMZ can induce hypermutation in cells with defective mismatch repair).
ReplyDeleteI would try to learn more about this MLH1 mutation (is it clonal- throughout the tumor, or subclonal - found in only a subset of the tumor cells). Did the report give a "variant allele frequency" for the mutations? What exact mutation is it (MLH1 _###_)? This would be a factor I would consider before deciding on TMZ therapy.
Low dose methadone could be a option
ReplyDeleteGlad I saw this post. None of my oncologists acknowledge my PTEN gene.is the temsorilimus another chemo agent? Have you looked into fasting to enhance the chemo?
ReplyDeletePTEN is a phosphatase that counteracts PI3K signalling. Almost all GBMs have a deletion of one copy of chromosome 10 (where the PTEN gene is located). Some GBMs additionally have a mutation in the second copy of PTEN, meaning they would have very little functional PTEN. Overactivation of PI3K signaling would then lead to downstream activation of mTOR (among other downstream effects).
DeleteTemsirolimus is an analog and prodrug of sirolimus (aka rapamycin) and they inhibit mTOR complex 1. Unlike rapamycin, temsirolimus is given intravenously, but is given once a week. So with temsirolimus you'd get high plasma levels, but for short durations, once weekly, and with sirolimus/rapamycin you could take smaller oral doses daily, leading to much lower but more constant plasma levels.
Some of the temsirolimus is converted into sirolimus inside the body. However some studies show the two substances have approximately equal efficacy.
http://onlinelibrary.wiley.com/doi/10.1111/j.1742-7843.2012.00923.x/pdf
As for lower grade gliomas, there has been more study with everolimus, another sirolimus/rapamycin analog, which is orally administered.
wow. as ever stephen, i owe you a lot. glad you're on our side.
DeleteFoundationOne did the gene testing. On the cover page, the report states "MLH1 splice site 1409+1G>A." There doesn't appear to be any indication whether it is clonal or subclonal and there is no specific information about the variant allele frequency of the specific mutations identified, nor any specific information about the mutation itself. And the initial bill for this was $26,000!
ReplyDeleteDo you think I should contact FoundationOne to get this information? I am very concerned. Thank you so much for asking these questions.
It appears as though this mutation could potentially be germline (found in all cells in the body) and associated with Lynch syndrome.
Deletehttps://www.ncbi.nlm.nih.gov/clinvar/variation/89718/
"About 50 percent of all cases of Lynch syndrome with an identified gene mutation are associated with inherited mutations in the MLH1 gene. Several hundred MLH1 gene mutations have been found in people with this condition."
https://ghr.nlm.nih.gov/gene/MLH1#conditions
I don't believe FoundationOne does matched testing on healthy cells. I would try to contact a clinic involved in hereditary cancer risk assessment, with the intention of finding out whether this MLH1 mutation is germline or somatic (found in all the cells of the body, or only in the tumor cells).
You could ask if Foundation Medicine has any more information on this, but you'll probably have to go somewhere else for the germline versus somatic assessment.
$26,000! I was told a month and a half ago that the list price for the FoundationOne testing is $5800 USD.
Also if this MLH1 mutation is germline, and is therefore found in all the tumor cells (as well as all his healthy cells), and this mutation renders mismatch repair ineffective, then temozolomide will also likely be ineffective, since the TMZ mechanism of action depends on mismatch repair, and mismatch repair defects can be a form of resistance to TMZ.
DeleteIn this scenario, MGMT unmethylated + defective mismatch repair = TMZ not a good idea.
A different alkylating agent such as lomustine (CCNU) could be used in place of TMZ, but in this case we're back to your original question about inhibiting MGMT.
DeleteYou could also consider VAL-083, an alkylating agent that does damage that is not subject to repair by MGMT, and is available in an expanded access protocol as well as clinical trials.
https://clinicaltrials.gov/ct2/show/NCT03138629
Stephen - Thank you so much for your thorough analysis! The discussion of the mutation in the FoundationOne report suggests that the mutation is germline. I am posing the question to our NO to see if he still thinks TMZ makes sense.
ReplyDeleteWe had discussed VAL-083, but he wanted to keep it in reserve in case the TMZ did not work. it looks very promising.
If there is defective mismatch repair, one can consider immunotherapy approaches. One should first active induce an anti-tumoral immune response, and then strengthen it with checkpoint blockers.
ReplyDeleteOf note, mTOR blockers completely block immune responsiveness, so this cannot be combined.
SVG - My husband is on Keytruda and his NO recommends that he stay on it, while adding a bi-weekly Temsirolimus infusion because of the PTEN alteration. Are you saying that Temsirolimus negates the efficacy of Keytruda? The NO believes that the combination of Optune and Keytruda have been restraining growth of the tumor.
ReplyDeleteDear Stephen and SVG - I am extremely grateful to you for raising super important issues and have written to FoundationOne raising concerns about the potential interactions of TMZ and Temsirolimus.
ReplyDeleteIn the meantime, I think we might hold off on using either chemotherapy. The genomic analysis states that my husband is a good candidate for PD-1 blockers based on his MLH1 alteration and he indeed appears to be responding to Keytruda. I certainly would not want to do anything that might inhibit that response, especially using Temsirolimus, which has had abysmal performance in clinical trials.
Does the Foundation One report give a quantification of Tumor Mutatational Burden (TMB, measured as number of mutations detected per megabase of DNA)? It was my understanding that this was added to all Foundation One reports sometime in 2016.
DeleteI would also prioritize confirming (rather than just speculating) that the MLH1 alteration is germline. This could be done with a blood sample at a clinic that does testing for hereditary cancer risk, for example
https://www.mskcc.org/cancer-care/risk-assessment-screening/hereditary-genetics/genetic-counseling/inherited-risk-colorectal
With an inherited germline defect in MLH1, or a diagnosis of Lynch Syndrome, (if either of these can be confirmed) I would definitely avoid temozolomide. It isn't just a matter of TMZ being ineffective, but also a matter of it inducing new mutations in both the tumor as well as other cells in the body that are dividing (in the bone marrow, gastrointestinal tract etc.)
https://www.ncbi.nlm.nih.gov/pubmed/25088490
Have you looked into clinical trials? There are lots of interesting trials in the US, including very interesting immunotherapy trials. A complication might arise however, given that he hasn't been exposed to TMZ - and most trials for recurrent GBM require having failed standard treatments (TMZ-based radiochemotherapy).
Thank you for that citation. Our NO had not encountered this report and is unfamiliar with this issue. This is a big help.
DeleteThe FoundationOne report states the Tumor Mutational Burden (TMB) is intermediate, with 9 Muts/Mb. I will contact MSK to inquire about testing to confirm whether it is an inherited germline defect in MLH1.
My husband was in a clinical trial of REGN2810 from 3/16 to 10/16. He left the trial after being diagnosed (incorrectly, apparently) with a recurrence. As I mentioned, he is responding well to Keytruda and Optune, so I would be very wary about dropping them to test something uncertain. I think adding to his cocktail is a better bet.
So he swapped one PD-1 inhibitor (REGN2810) for another one (Keytruda) at the time of "recurrence"? Was his entry in the REGN2810 trial the reason for him not being treated with TMZ?
DeleteThe 9 mutations per Mb is higher than average, but not hypermutated. One paper published by Foundation Medicine shows a median of 3.6 mutations/Mb across all cancer types, and a median of 2.7 for oligodendroglioma. (Glioblastoma wasn't included in this paper).
https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-017-0424-2
Hypermutated tumors commonly have 30-100 or more mutations/Mb.
I would be wary about dropping Keytruda and Optune as well. Hopefully you could get access to VAL-083 off trial.
"This unique N7-guanine targeting mechanism not only circumvents MGMT-mediated chemo-resistance but also maintains cytotoxic activity in cancer cells deficient in mismatch repair (MMR). These data suggest VAL-083 may offer a superior chemotherapeutic alternative in the treatment of MGMT-unmethylated or MMR deficient GBM."
Deletehttps://academic.oup.com/neuro-oncology/article-abstract/19/suppl_6/vi11/4590335?redirectedFrom=fulltext
I forgot to mention that he is ineligible for the MDNA55 trial because his tumor is multifocal. I have asked the NO about getting VAL-083 under compassionate care.
DeleteOpting for the Regeneron trial is the reason my husband was not initially treated with TMZ. The NO told us that because his tumor was unmethylated, TMZ would do him more harm than good.
DeleteEschewing TMZ is less an issue entering clinical trials now if your tumor is unmethylated. Last year he was foreclosed from participation instead bc of treatment with hypofractionated radiation. He had not met the minimum radiation Duke required.