GIST researcher shares 'our' Gleevec experience

Charles D. Blanke, M.D., F.A.C.P.
Director, GI Oncology Program
Oregon Cancer Institute

Dear Friends, I was very excited when asked to write a column for the Life Raft Group newsletter. Originally, I planned to discuss “my” experiences with Gleevec. On further reflection, I realized the whole process has been driven by you, the patients with the disease, and your supportive families. Obviously, the research could not have been done if so many had not been willing to travel extensively and to subject themselves to a wholly unproven cancer remedy. Likewise, the joy I had in presenting our study at the 2001 American Society of Clinical Oncologists’ Meeting in San Francisco was nothing compared with my day-to-day experiences in clinic, interacting with everyone touched by the trial. Thus, I want to discuss “our” collective experience in treating GIST.

Certain questions come up frequently in clinic, and many of these have been echoed by the editors of the newsletter. I have tried to answer the most common and/or important:

What is the importance of c-kit mutation?

We believe the mutation drives the malignant behavior of the GIST cell (to steal an analogy from Dr. Druker, think of a thermostat that is always stuck in the “on” position, continually causing a furnace to put out heat). It is true that patients with certain types of mutation have a higher chance of going in to remission (as high as 80 percent). However, that information is of little value for patients already on the study or drug — we already know what your chance of remission is (0 or 100 percent, depending on whether or not it happened). There is no group, with or without a mutation, in whom we can say Gleevec will work for sure OR that it cannot work and should not be tried.

Can patients become resistant after a remission? How long do responding patients need to take drug?

These are critically important questions. Unless a drug therapy eradicates every last cancer cell (“cure”), all tumors eventually become resistant. However, this has not happened in the CML early-phase population, and until recently, there was no evidence of this occurring in GIST patients. A solitary GIST patient has relapsed after achieving response, but there is reason to think she was not absorbing the drug. When re-administered Gleevec appropriately, her tumors immediately began shrinking again, and in a major way.

We don't know yet why those events happened-we merely speculate something was interfering with the drug, probably poor absorption.

Take home points: not all patients in remission are cured, and patients progressing after an initial good response should probably be tested to make sure they are properly absorbing the drug.

What is the importance of and validity of c-kit testing?

We believe that Gleevec is a targeted therapy. In other words, it cannot work if the target is not present in the cancer cell. Luckily, c-kit is fairly easy to test for, and we have seen only a few false positives. As we start looking for more sophisticated targets (e.g., activated KIT, or PDGF-R), the testing gets more complex and the likelihood of error is higher. Another important point: in non-GISTs, it is possible that KIT will be present, but it may not be driving the biologic behavior of that cancer cell. It is possible that Gleevec would not help that type of tumor; so merely having c-kit is not sufficient to guarantee success.

Are patient side-effects being addressed sufficiently?

The mere fact that this is being asked implies they are not. However, I have never found GIST patients to be particularly shy in telling me about problems, so I hope the situation is not too serious! I would encourage all readers to make concerns known to treating physicians and/or study nurses, and to not leave the office (or get off the phone) until a reasonable answer/ solution is obtained.

What are the implications of patientgenerated data?

This is powerful and compelling stuff! I remain incredibly impressed by the data-coordinating abilities of the Life Raft personnel. I see the major purpose of this sort of data as hypothesis- generating. Unfortunately, it cannot be free of bias and thus cannot stand by itself, but it certainly can point investigators and the Company in the right direction and let us know what we need to be looking at more closely. Thus, its importance cannot be overstated.

Again, I see the STI project as a victory for both patients and researchers. Participating myself has been the high point of my career. I thank you all and welcome e-mail or newsletter-directed questions.

The newsletter e-mail is linda@interpac.net
Dr. Blanke can be reached at blankec@ohsu.edu