GIST Management 2009 Update
|Posted by Julie Royster (jroyster) on May 13 2009|
|GIST In the News >>|
Evolving Molecular Medicine in GIST Management: A 2009 Update
by Genever Fox
I was fortunate to attend this 2 hour session on Wednesday evening, January 14, and to meet 2 list mates from GIST Support International, Nancy Berezin and Vicki Zuber, and Vicki's husband. It is so interesting and fun to put faces to the posts we read each day. I am sure we all took home some "pearls" of knowledge from the very interesting lectures in this continuing medical educational seminar held in conjunction with ASCO's GI Cancers Symposium. Webcasts of the CME presentations are available at THIS LINK.
The session was chaired by Dr. Demetri (from Dana-Farber). Drs. Jonathan Fletcher (Brigham & Women's), John Vetto (Oregon Health Sciences University), and Robert Benjamin (MD Anderson) all spoke about their respective areas of expertise in the GIST arena. They reviewed the history of GIST treatment and some of the early and still ongoing studies. I will try to summarize the points that I found the most interesting.
1. Although most GIST's are primarily driven by gain of function mutations in KIT (or less frequently in PDGFRA,) within each tumor there are small numbers of cells with other mutations. TK inhibitors are not effective on some of these mutations, especially the ones affecting the activation loop part of KIT (as opposed to mutations affecting the ATP-binding portion which tend to be sensitive to TK inhibitors.) Determination of the primary mutation will help prognosticate the initial response to therapy.
2. After a TK inhibitor knocks out the cells being driven by the primary mutation, the cells being driven by the less sensitive mutations are still able to grow into resistant tumors. Within one individual, there may be multiple resistant tumors each driven by different mutations. Some of these may be sensitive to a different TK inhibitor, such as Sutent or Nexavar, and some may not be sensitive to these drugs. That is why the response to the second and third line TK inhibitors is so variable among different patients. Mutation testing of the resistant tumors would be helpful in selecting the next drug to try but there may be multiple mutations found within a single patient.
3. Ultimately other targets within the resistant cells will have to be attacked for therapy to be effective. There is a lot of research going on looking at these potential targets (HSP-90, mTOR, PI3K, etc.)
4. All of the speakers seemed to feel that multiple drug therapy will ultimately be necessary to effect a long-lasting remission or cure in non-resectable GIST. Eventually new patients will be started on multiple drug regimes, similar to what is done with conventional chemotherapy.
5. Surgery is still the best shot at a cure now and the surgeons are getting better and more aggressive in excising tumors. Using a TK inhibitor (usually Gleevec) prior to surgery when the tumors are big is very helpful as long as you choose the right time to go to surgery. (An oncologist and surgeon with experience in this type of approach is likely to be crucial in getting the best outcome.)
6. Recurrent/metastatic tumors should be managed both surgically and medically if possible. For example, if a patient has multiple tumors and only 1 or 2 are growing while on a TK inhibitor, then the rogue masses should be removed if possible and the patient should stay on the TK inhibitor that is still controlling any remaining tumors.
7. For patients with tumors larger than 6 cm, 1 year of adjuvant Gleevec prolongs the interval before disease recurrence and is now FDA-approved. Studies where the adjuvant Gleevec is given for 2 years and 3 years are ongoing.
8. CT imaging is very good for monitoring response to treatment. PET scanning is also very helpful but doesn't need to be done on every patient. The speakers felt that PET scans are best used when CT results don't make sense or don't give the clinician the information they need to make appropriate therapeutic decisions.
9. The Exon 9 mutation is not as responsive to imatinib and requires 10 times as much imatinib at the cellular level in order to respond. Exon 9 patients should be taking more than 400 mg per day, ideally 800 mg if they can tolerate it, even if they are taking it in an adjuvant setting. When these patients progress, it is usually because they just aren't very sensitive to imatinib, not because of other mutations. That is why Exon 9 patients usually do well on sunitinib (Sutent.) When the Exon 9 patients progress while on sunitinib, it is because of other mutations.
Last changed: May 13 2009 at 2:46 PMBack