Q&A: Targeted Gleevec Therapy for GIST
CancerWise - August 2007
Doctors know what drug to use in treating a patient with gastrointestinal stromal tumors (GIST). Now they know how much of this drug to prescribe, thanks to a new standard practice of identifying the location of gene mutations on the tumor.
Answering questions about the therapy targeting the dosage of imatinib (Gleevec®) is Jonathan Trent, M.D., an assistant professor in the Department of Sarcoma Medical Oncology.
What is GIST?
GIST is a type of sarcoma involving the soft tissues of the body, including the muscles, tendons, fat, nerves and tissue around the joints. GIST is a sarcoma that arises in the gastrointestinal tract. More than half of GIST tumors are found in the stomach, but they also can occur in the small intestine, esophagus, colon and rectum.
The cancer actually develops in the cells lining the walls of the gastrointestinal tract. These are the cells that tell muscles to contract to move food and liquid.
Most of these tumors have a protein on their surface called "KIT" that is activated (made to grow) by a mutation in the gene that makes this protein.
How many people are diagnosed with GIST each year?
GIST is a very rare type of cancer. It affects approximately 4,000 to 6,000 men and women a year in the United States. The average age at diagnosis is about 60, although some of my patients are teenagers and some are in their 90s.
How does the targeted therapy work for patients with GIST?
If a patient is newly diagnosed with GIST, we conduct a molecular analysis (called DNA sequencing) of the DNA from their tumor. This test does not usually require a new biopsy or surgery since material already collected by the pathologists works well. If a mutation of the KIT gene is found at one of two locations of the gene (exon 11 or exon 9), the dose of Gleevec can be optimized.
Patients with mutations located at:
- exon 11 – Receive 400 mg of Gleevec (most common initial dose)
- exon 9 – Receive increasing daily doses of Gleevec:
- 400 mg the first four weeks
- 800 mg after four weeks
Why is the KIT gene targeted?
More than 90% of GIST cells have mutations in one of two genes, called KIT and PDGFRa, according to the National Cancer Institute. Gleevec targets both of these mutated genes. Previous clinical trials have shown that Gleevec can kill GIST cells that have spread (metastasized) to other parts of the body and cannot be removed with surgery.
Is this targeted therapy standard at other cancer centers?
No. There are only a few places in the country treating patients with GIST using this targeted therapy dosing based on the site of mutation. It is really cutting-edge treatment.
Centers across the country see GIST patients and conduct mutation testing, but
M. D. Anderson is the largest, which is important since the disease is so rare.
How long have you been using this approach?
We initiated our individualized approach to targeted therapy six months ago, and it has quickly become our standard treatment for patients with GIST.
What led M. D. Anderson to implement this treatment?
We started our individualized targeted therapy based on our own clinical experience, opinions from other experts and information that was published about a year ago from a large study in Europe.
Results from a phase III trial conducted by Maria Debiec-Rychter, M.D., in Belgium [European Journal of Cancer 42 (2006) 1093-1103] showed that identifying the locations of gene mutations could help pinpoint effective dosages of Gleevec in patients with advanced GIST. The report shows that using the targeted therapy led to improved progression-free survival in patients taking Gleevec.
Are you conducting any follow-up studies to refine treatment for GIST?
We are continually searching for new markers that we can use to further refine the dose of Gleevec and whether there is a subset of patients that should not receive Gleevec but rather an alternative agent such as sunitinib (Sutent®) as first-line therapy.
What is the benefit of the new targeted therapy?
We are able to provide personalized patient care. We hope that being able to tailor the drug dosage for each patient, based on their individual tumors, right from the beginning will help improve survival.
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