GIST Support WikiQUESTION: How important is it to have the mutational testing to find out where your mutation lies in the c-kit gene?
"Exons" represent different regions of the KIT protein. Exon 9 is in a part of the protein that sticks up on the outside of the cell, like a little periscope looking for growth signals.
Exon 11 a part of KIT that is on the inside of the cell.
Exon 11 KIT's tend to be the most responsive to Gleevec. Exon 9 KIT GISTs tend to have intermediate responsiveness to Gleevec. Notice I am using the word "tend" as there is not a 100% correlation. I know of a person with exon 9 KIT GIST who started in the original phase II trial back in 2000, and is still going on 600 mg.
No one knows for sure why exon 9 KIT GIST is not as Gleevec responsive, but there are molecular theories...Exon 9 KIT GIST would be considered intermediately responsive to Gleevec.
SO, I think the answer is "some" for some people. We could think up various scenarios in which it was useful to have known. But we can also think up scenarios where the information did not affect what the doctor decided.
The mutational results can give you an estimate of general benefits from Gleevec or Sutent. Some mutations tend to have better results than others. The mutational information does not however, change the fact that your FDA approved treatment choices are Gleevec and then Sutent.
If you have benefited from Gleevec dosing initially...then that is the gold standard proof the drug works, regardless. For the very rare primary mutations like exon 17 KIT primary mutation, or PDGFRA mutations...I think the information can be somewhat more useful to rationalize why Gleevec may not have worked initially in the patient...I am not sure how much the information helps in selecting another treatment, however.
Intestinal exon 9 GISTs, which is 15% of all GIST cases, has longer progression free survival on higher dose of Gleevec. Patients like longer progression free survival, but there will be more toxicities too. It is still less clear how much a pre-emptive higher dosage before relapse improves the over all survival of the patient rather than waiting until after relapse on the lower dose before escalating to a higher dose. Still, many pts who know they are exon 9 would opt to go pre-emptively on the higher dose if they can tolerate it.
For the exon 11 KIT GISTers--two thirds of all GIST, I don't think the information is highly useful most of the time. Not to say it is useless, and certainly if someone wants to know the mutation for emotional coping..then go for it...have the test done.
If the Heat Shock 90 drugs end up working well for GIST, then they possibly make the mutational issue less important. These drugs work by different mechanisms, and in theory, the precise mutation in the c-kit gene should not affect the way the drug works. So if the HSP90 approach ends up working...we may end up with less mutational testing rather than more of it in the future...Stay tuned...
Drugs that bind more tightly to KIT than Gleevec would be helpful for exon 9 KIT GIST. I do not know how much AMN107 would bind differently than Gleevec itself. Also, possibly drugs that stop another important target in GIST, PI3K, could help. Or Heat Shock 90 Inhibitors. There are choices..
Marina