Questions and answers from our members

What follows are a few recent questions-and-answers from members posting to the Life Raft listserv. The intent is to share this information more generally and to make the quality of such layperson discussions available for public scrutiny. As always, comments or corrections from readers are welcome.

The following questions were answered by Jerry Call, the Life Raft’s science coordinator

Does Gleevec change what the pathologist sees in a GIST biopsy? That could become important for me next week.
  J.C.: Yes, treatment with Gleevec can sometimes cause a change in what the tumor cells look like. A recent paper by Pauwes, et al, discusses this issue. In this study, they describe three cases (of 35) that change phenotype. In the cases described, the tumor cells changed from spindle shaped -- about 70 percent of GISTs are spindle cells, the rest are either epithelioid (more common with PDGFRA mutations) or mixed spindle/epithelioid) to epithelioid. They also lost expression of KIT, and two of three lost expression of CD34.
  My impression is that some of the tumors are possibly differentiating to a different phenotype. Importantly, two of the three also no longer responded to Gleevec.
  The most accurate way to verify that suspect tumors are still GIST and not a new second cancer is probably to have a biopsy and have it tested for KIT mutations.
  Even though the new/changed tumors don't express KIT, they still harbor the same KIT mutation (all of these cases had KIT mutations) as the original primary tumor.

The question that comes to mind is, how does this translate into preventative or proactive treatment? My father in law is down to four tumors in his liver, three identified as “dead” but one inexplicably lives on. Should we be looking at having these tested for c-kit and then ...? What are the potentialities of looking at the tumors like this? Is there something that can be done that logically makes sense but perhaps is in an untested state?
  J.C.: The most practical use of this information is when a new tumor appears in a location that is unusual for GIST. When GIST metastasizes, it usually goes to the liver. It can also spread to other areas in the abdomen. In rare cases it can spread to other areas including the lungs, bones, the brain, and the extremities (as two of our LFG members have reported GIST tumors of the arm). There is one case in the literature of subcutaneous GIST metastases.
  When a new tumor appears in one of these unusual places, the question that arises is whether it is GIST or a second type of cancer (do you have two different types of cancer at the same time)? It can become confusing for the pathologist if this new tumor has “changed its type” so that it no longer looks like GIST. The definitive way to tell if the new tumor is GIST is to have it analyzed to see if it has the same mutation (in KIT or PDGFRA) as the original primary tumor.
  The classic example of this was patient A. After a year on Gleevec she had growth in a long dormant nodule in the lung (remember it is rare for GIST to go to the lung). Several centers got involved in testing the tumor with somewhat different results, particularly over the issue of whether it was c-kit positive or negative GIST. Finally it was determined to be c-kit negative.
  But it was GIST. The single tumor was removed with a less invasive type of surgery, and patient A remained on the phase II trial (even though they could have kicked her off if they had strictly interpreted the protocol). A was one of the earliest GIST patients to take Gleevec and remains on the trial.
  Even though the GIST trials were only one year old, A’s example demonstrated at least two principals of excellence in GIST management. First, the suspect tumor was analyzed for ckit mutations, which proved that it was indeed GIST and not a second new cancer. Second, since only one tumor was progressing (local progression), the single resistant tumor was surgically removed and she continued on Gleevec.

Should we be looking at having these tested for c-kit and then what? What are the potentialities of looking at the tumors like this?
  J.C.: No I don’t think you should have those tumors tested for c-kit. This should generally be reserved for when there is a question of whether the tumor is GIST or something else.
  A GIST tumor losing expression of c-kit is just one of several ways that GIST can become resistant to Gleevec. The data is based on small numbers (so subject to change), but from what I have seen, I think that it might account for somewhere around 10 percent of resistant GIST. As for those “dead” tumors; even in tumors that respond very well to Gleevec, there are almost always at least a few residual cells that are still alive.

Is there something that can be done that logically makes sense but perhaps is in an untested state?
  J.C.: In my opinion, the two main choices that you have right now are to continue the Gleevec until resistance OR, if surgery is feasible, to remove all tumors and continue the Gleevec. I am not advocating either position. This is something to be discussed with GIST experts (surgeon and oncologist).