Molecular studies in asps. Why results seem disapponting.

[arojussi]

As molecular studies and matching cancer drugs based on cancer`s spesific mutations is popular I figured I share my personal opinion about the subject. Admin can remove or edit this freely if I am out of line. Genetic testing is popular and it might work in liquid cancers and more common cancers, but unfortunately I haven't seen much success with it in asps. There is obvious reasons. First of all in sutent trials they did molecular profiling and found out, that asps has very little mutations. Asps is caused by one fusion gene aspl-tfe3, that results in downstream signaling of angiogenesis. This alloves 2 drug treatment options. First palliative treatment with tki. Second surprisingly immunotherapy works well against cancers with high angiogenetic actitvity. At least axitinib and keytruda has been amazing success in asps. Here is the best part as asps mutates extremely slowly it is very unlikely to become resistant to immunotherapy.
Genetic testing can actually hurt as asps is often pd1-negative and msi low immunotherapy most likely look very unlikely to work in asps, so oncologist investigates other treatment options instead. As asps-patients often have limited resources I wouldn't spend my money in molecular profiling. Hopefully somebody can share amazing success story about molecular profiling in asps. Then I have to admit that I am wrong (again).

[Olga]

I actually agree that since in many cases ASPS tumors are often pd1-negative, it might be not in patient's best interest to get tested as it might disqualify the patient from the ICI treatments (are they really often pd1-negative? we will need to see the final results of the axitinib+keytruda trial as they come, I think they are testing the tumors on this if possible).
Base your request on stats not on the testing, as of now it is a better strategy.

[arojussi]

As we cant yet make reliable predictions if patient will respond to ici or not having pd1-status tested isnt yet very usefull for asps-patients. Of course in the future we might be able to predict which patients will response to immunotherapy, but we are not there yet. Also pd1 might not even be the best prognostic marker for asps. Naturally I am interested about, what trials find out.

[arojussi]

Indeed I dont know yet how often asps is pd1-negative my mistake.

[D.ap]

Morning Jussi and Olga
I agree that all should not hinge on the molecular profiling, as the verdict isn’t in on what drives ASPS .
However more than one medical article talks of mismatched repair of DNA , being the possible beginnings of ASPS?
FDA has approved Keytruda for dMMR and MSI cancers now , even though the trials excluded a lot of PD1 neg patients , so maybe the molecular studies were necessary to get to that point .Its quite a technicality involved science that I’ve only began to scratch .

https://www.onclive.com/web-exclusives/ ... nt-cancers

[D.ap]

Also it should be pointed out that some Opdivo trials, unlike Keytruda trials , weren’t exclusive(restricted ) to just PD1 positive patients, and so their numbers reported were further conveluded to show not true accuracy to the PD1 negative verses PD1 positive patients success.
Those were a life time ago( :)) in the immune check point time line , and so much more has come to light through the molecular profiling s . Number 1-
Some PD1 negative patients are reactive , showing excellent results , on PD1 checkpoint inhibitors .
Especially in melanomas.

As patients and caretakers , we need to educate doctors and or question them at the very least , to advocate to help in a cure, while keeping metastatic disease at bay.
We are the lucky sarcoma patient , that has a relatively indolent sarcoma , to watch thru scans and try and eliminate when they are at their smallest size.

Jussi interesting and wonderful thought to start a conversation on this important topic .
Thank you for it.

[arojussi]

Immunotherapies often work well against cancers with many neoantigens. That is why it works well in msi-high cancers. Asps is sometimes msi-high or mitch match repair deficient. But this was suprisingly rare. (I dont remember exact number.) To me msi-status alone doesnt explain keytruda and axitinib success in asps. I believed there would be some unknown explanation. Now I believe high amount of neoangiogenesis in asps explains why this compination works so well. It has been proven, that immunotherapy works well against cancers with many mutations and it is also proven that in general asps has very little mutations, so fact that immunotherapy works well in this cancer seems paradox.

[Olga]

Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis.
https://www.ncbi.nlm.nih.gov/pubmed/30201790
CONCLUSIONS:
PD-1 or PD-L1 blockade therapy is a preferable treatment option over conventional therapy for both patients that are PD-L1 positive and PD-L1 negative. This finding suggests that PD-L1 expression status alone is insufficient in determining which patients should be offered PD-1 or PD-L1 blockade therapy.
free full text

[D.ap]

Olga
Has the Keytruda-axitinib study given light to the number of pd1 /pdl1 positive and negative tumor successes, and their relationship to ASPS tumors that were analyzed ?