Jussi from Finland - Dx 2008 - 30.3.1991 - 23.8.2019 R.I.P.

[arojussi]

My oncologist has living brain tumor samble to test drugs with. We couldnt ask for better tissue to try find treatment for my brain tumors and looks like it isnt helping. So no liquid biopsy or lung met biopsy wouldnt help. Basically cancer always has mutations and that is why these results are so weird. We know that my brain tumor sample reacted to azd8186 medication, but trial requires mutations that my tumors obviously dont have.

I most likely just keep using sutent untill sideeffects turn untolerable. It all depends how many microscopic mets are left in my brains. 1 or 2no problem. Over 20 and It doesnt look good. My oncologist still tries to find drug combination that could work, but I am not very optimistic.

[D.ap]

Did a search of TP53 and scrolled to this link


Down several paragraphs

"The Mesenchymal subgroup contains the most frequent number of mutations in the NF1 tumor suppressor gene (37 percent). Frequent mutations in the PTEN and TP53 tumor suppressor genes also occurred in the group. Patients in the Mesenchymal group had significant increases in survival after aggressive treatment, unlike those in the Proneural, and to an extent, in the Neural subgroups."

https://cancergenome.nih.gov/researchhi ... ursubtypes

[arojussi]

I am desperate and when I am desperate I dont think well. They removed my mandibular met. Maybe in that met is mutation that is needed for trial. Basically if we find any mutation that eould be good. Bone met grew lot faster than any other mets, so in theory it should have more mutations.

[Olga]

Your thinking is pretty good actually - can you ask them to run the tests on a tissue from the mandibular met? It should be stored somewhere, ask the oncologist what they can do.
Re. PI3Kbeta Inhibitor AZD8186 that you brain tumor was found to respond to. There are two PI3Kbeta Inhibitors in testing now, and they now try to find if there is a correlation of the response to the specific mutations (which is often not the case). I found a pretty good review on this subject and it seems that a single agent trial for PI3Kbeta Inhibitors (PI3Kβ isoform-specific inhibitors) might be not the best clinical trial for you - not in your best interests, as they found that after initial response the tumors often shift from the PI3Kβ inhibitor sensitivity to PI3Kα inhibitor responsiveness, so the tumors stop to be responsive to the beta inhibitors but became responsive to the alfa inhibitors - which is an unfortunate clinical situation for the patient as he gets progression on the beta and probably can not get on the alfa? Read more here:
http://www.sciencedirect.com/science/ar ... 9215000600 it is a very interesting article.
Another thing I found interesting that there is some earlier less specific oral pan-Class I PI3K inhibitor pictilisib is already approved for other indication, with the knows anecdotal responses in melanoma...based on your testing you might try to get it off label? Ask the oncologist if your tumor was tested for the pan-Class I PI3K inhibitor. Another already approved PI3K inhibitor is idelalisib for other cancers.
Also there are concerns addressed in this article that there is a big difference in targets evaluation using two diff systems. also I have a concern that tissue might not have been stored properly and loose the viability?
You can also try to find a trial with this type of inhibitors that do not require the tissue testing, i.e. Phase 1 trials or combinations.
like this one https://clinicaltrials.gov/ct2/show/NCT ... =5&rank=32
make a wider search by "PI3K" because some of them use different way of wording - some say beta some put a sign for it etc.
I found the following interesting article on Pubmed by searching "PI3K brain"
https://www.ncbi.nlm.nih.gov/pubmed/28829592 re. some drug of this class that proven to penetrate the blood-brain barrier
ans this is the corresponding clinical trial:
https://clinicaltrials.gov/ct2/show/NCT ... 309&rank=4
so you can have fun reading on the subject.

[arojussi]

Thanks a lot. When I heard that they found no mutations at all my first thought was that something must have went wrong. Asps grows highly abnormal blood vessels and I strongly believe these blood vessels need at leat one mutation to grow so unusual way. My tumor sample was sent to America, because they cant test all mutations in Finland. Tumor sample has moved a lot and I had brain surgery in Summer, and saving tissue sample during that time was very difficult, so something could easily have gone wrong. We tell all this very valuable information to my oncologist.

[Olga]

After the surgery, they keep not a single but multiple samples of the tumor, so I would ask them to redo the test in Finland even with the limited number of the markers - what ever they can test it for locally. If they test the tissue and find ANY mutations that the testing in US also tried but did not find, it might be some indication that the tumor tissue was not viable when it got to us for testing.
Or may be in UK? that trial - may be they ask for the tumor samples to be sent and test them themselves? It is often done that way, they often do not accepts any off-site testing and want to get the tissue not the results.

[arojussi]

Thanks again. We will test different drug combinations for my asps sample here in Finland, so might as well test everything possible while we are at it.

I happen to stumble upon cediranib trial results. Looks like cediranib can alter gene expression in asps. I see no reason why pazopanib couldn't do that as well. cediranib down regulates angiogenic genes. Asps specific fusion gene ASPL-TFE3 is known to directly upregulate MET. Targeted by ARQ197. So America most likely missed mutation, that at least some time ago could have been targeted with experimental medication. Of course it is possible, that they no longer test MET. Even so, when they say they couldn't find any mutations at all maybe something truly went wrong.

[arojussi]

We got response from chinese neurosurgeon. He sees some new lesions when he makes picture bigger with computer. When mri is regular size lesions are still too small to see. I am not very optimisic.

[Olga]

Did he make any comment re. possibility of treating them too with the GammaKnife later, when they reach some bigger size that is convenient for him to target but small enough so the overall volume is still small?

[arojussi]

So far only plan is to scan again in 2 moths. But I have seen this kind of things before. First there is slight growth that can be either growth or not and then next scan shows exponential growth. Maybe if there isnt too many new mets gamma knife can still be option, but we dont know yet.

[D.ap]

Hi Jussi

I'm sorry for the report because as always , it is so unnerving to say the least , to know what's going on from the pictures .
You have been on sutent since the gamma knife proceedure , right ? And you took Keytruda as recently as 2 months ago ?
You used pazo along with Keytruda prior and I was wondering what you all thought about having changed to sutent and the possibility of it now aiding the residual Keytruda in attacking brain tumors?

With our limited but documentated understanding of how immune therapies continue to work after being discontinued , waiting for 2 months maybe isn't out of the question ? Pseudo progression happens

"Evaluating Pseudoprogression, Atypical Responses, and the Clinical Benefit of Cancer Immunotherapy"

The first bullet info

"Pseudo-progression may be associated with mixed responses, which include good response (shrinkage) concomitant with increased tumor size or even new lesions appearing elsewhere. Because it looks like progression on scans, clinicians may struggle with whether to discontinue potentially effective therapy based on a misinterpretation of scan results."

https://immunosym.org/daily-news/evalua ... unotherapy

[D.ap]

Maybe I'm going the wrong direction?

http://www.cureasps.org/forum/viewtopic ... 309#p10012

I'm thinking more vascular normalization and med reaction if that makes sense all

[Olga]

Jussi, was your tumor tested re. NY-ESO-1 expression? it is common for synovial sarcoma but can be also found in other tumors, patient specific. There are very good interim results from the trial with vaccine using NY-ESO-1 antigen.

[Bonni Hess]

Dear Jussi, I am so sorry for the newly found brain mets, but am grateful that they are still so small that they were unable to be detected by a regular MRI which will Hopefully allow you time to seek and begin another treatment. I know and share your concern that ASPS brain mets can grow more rapidly than mets in other parts of the body, so I agree that close scan monitoring is essential and perhaps Gamma Knife can be done on the new mets when they become large enough to successfully treat. In the meantime, I am grateful that you are so proactive and actively researching and networking to find an effective new systemic treatment that can cross the blood brain barrier to prevent the development of new brain mets and stabilize the progression of your increasingly challenging disease. Take care dear Jussi, stay strong, and know that you are not alone in your courageous battle which we all share. With special hugs, caring thoughts, healing wishes, and continued Hope, Bonni

[D.ap]

Jussi,
I like Olga's thinking

an article back in 2012

NY-ESO-1 expression in sarcomas
A diagnostic marker and immunotherapy target

" Individual cases of other sarcomas (angiosarcoma, malignant mesothelioma, chondrosarcoma, osteosarcoma, dedifferentiated liposarcoma, alveolar soft part sarcoma, and Ewing's sarcoma) were positive for NY-ESO-1. "


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518519/