Test to predict Gleevec response expands

Testing includes virtually all possible mutations that drive GIST growth

PORTLAND, Ore. — As reported in the June 2003 issue of the Life Raft Group newsletter, an international team of researchers has developed testing that can forecast how well gastrointestinal stromal tumor patients will respond to Gleevec (imatinib mesylate).

Now the tests have been expanded to more accurately predict how GIST patients will fare on Gleevec (Glivec outside the U.S.A.)

“These results demonstrate that the most important predictor of tumor shrinkage during Gleevec therapy is not age or tumor size, but rather the specific type of mutation causing the tumor,” said Dr. Michael Heinrich of the Oregon Health & Sciences University (OHSU), co-principal investigator of the study.

“The majority of GI stromal tumors have a mutant form of KIT that acts like a gas pedal stuck to the floor, providing a constant stimulus for GIST cells to grow,” Heinrich said.

Among GIST tumors that lack a KIT mutation, some (5 to 7 percent) had a mutation in a different (but closely related) tyrosine kinase called PDGFRA. (platelet-derived growth factor receptor alpha). Gleevec is effective against some of these PDGFRA mutations.

Approximately 7 to 12 percent of GISTs have no detectable KIT or PDGFRA gene mutation. GISTs with no KIT or PDGFRA mutations are called “wild-type” (for KIT/ PDGFRA). Found in about 7 percent of patients, it isn’t clear what supports the growth of this subset of GISTs.

The information in genes is divided into different sections called exons and introns. Exons contain coding information and introns do not. Mutations in different exons in the gene cause changes in shape in different parts of the receptor. Mutations are known to occur in the c-KIT gene in exon 11, exon 9, exon 13, and exon 17. Mutations in the PDGFRA gene are known to occur in exon 12, and exon 18.

Clinical testing for mutations in exon 11 and exon 9 of the c-KIT gene has been available at OHSU for about a year. This mutation testing service has recently been expanded so that it adds exons 13 and 17 in KIT and exons 12 and 18 in PDGFRA

.

“In effect, this expanded testing closes the loop on mutation testing,” says Jerry Call, science coordinator for the Life Raft Group. “Before, they could say you had an exon 11 mutation (about 67 percent of patients) or exon 9 (about 18 percent), but if both of these were negative, you were left without knowing if you had wild-type or one of the other mutations. The expanded testing now accounts for the other 15 percent of people whose mutation was previously unknown.”

“If they find that you don’t have any of the four types of KIT mutation or the two types of PDGFRA mutations,” added Call, “then you know (with less than a 1 percent chance for error) that you are ‘wild-type’ for KIT and PDGFRA.”

Regardless of the test results, however, all patients eligible for treatment should undergo a therapeutic trial or treatment with the drug. Even among patients with tumors lacking a detectable KIT or PDGFRA gene mutation, the response to Gleevec is higher than the response to traditional chemotherapy (less than 5 percent).

“Mutational testing can be helpful in confirming the diagnosis of GIST and in defining the prognosis for patients who need Gleevec therapy,” said Dr. Christopher Corless, associate professor of pathology in the OHSU School of Medicine and co-investigator in the GIST research.

“As Gleevec is used more and more in combination with surgery, we believe that testing for mutations in GIST will be important in deciding whether Gleevec therapy should be used before and/or after surgery for GIST,” added Heinrich.

How to Order the Test

Requests for KIT and PDGFRA mutation screening must originate from a pathologist or treating physician. One paraffin block of the tumor (either biopsy or surgical specimen) or 15 unstained sections of the tumor should be sent to address listed below. A copy of the original pathology report as well as the patient’s insurance information must be included.

Dr. Christopher Corless
OHSU Dept. of Pathology (mailcode L471)
3181 SW Sam Jackson Park Rd
Portland, OR 97239
Tel. 503-494-6776
Email: corlessc@ohsu.edu