Analysis of a small number of marker genes may determine in a matter of hours if a patient with gastrointestinal stromal tumors (GIST) would respond to a targeted molecular drug regimen. This analysis could allow clinicians to determine if they have chosen the best course of action or need to consider another alternative. Preliminary data from a genetic analysis of GIST cell lines showed that four marker genes reflected the effectiveness of treatment with sunitinib, a tyrosine kinase inhibitor that is used as second-line targeted therapy to stop the growth of GIST tumors after imatinib therapy has failed in patients with locally advanced, recurrent, or metastatic disease. The data were presented at the 2009 Clinical Congress of the American College of Surgeons.
In a previous study by Andrey Frolov, PhD, and Andrew Godwin, PhD, at Fox Chase Cancer Center in Philadelphia, PA, the same four genes were associated with the effectiveness of treatment of GIST with imatinib, which is given as front-line drug therapy for patients who are diagnosed with metastasis or who have GIST tumors that cannot be removed surgically. "We noticed four genes were similar in action when exposed to sunitinib as well as imatinib," said Derron Allen, MD, a research fellow in the department of surgery at the University of Alabama at Birmingham (UAB).
The UAB researchers are in the final stages of preparing for a clinical trial that will determine whether the genes can predict the outcome of patients who receive sunitinib for GIST. Details of the clinical trial, which should begin within the next 12 months, could not be disclosed at this time. However, the overall aim is to obtain FNA (fine needle aspiration) biopsies of live cells from GIST patients during an operation or a diagnostic procedure, culture them outside of the body, treat them with targeted molecular therapy, screen the cells for the expression of the four marker genes, and evaluate whether analysis of the genes can be used to make treatment choices. "This approach may help determine what would be the best treatment for a particular patient and to individualize drug therapy," said Dr. Andrey Frolov, an instructor in the department of surgery and associate scientist at UAB Comprehensive Cancer Center.
GISTs are the most common mesenchymal cancers in the gastrointestinal tract. Approx- imately 4,500 to 6,000 patients are newly diagnosed with GIST each year in the United States. Surgical removal of GIST is the primary form of therapy for localized primary tumors. However, more than half of GIST patients are diagnosed with locally advanced or metastatic disease.
GIST patients respond well to treatment with either imatinib or sunitinib—at least at first. "The drugs we use for these tumors are probably one of the pharmaceutical miracles of the last century," Dr. Frolov said. These forms of targeted therapy have been able to reduce the size of GIST by 50 percent or more or stabilize disease in most patients and they have increased survival by as much as four times when compared to the survival of patients who did not receive them.
However, imatinib and sunitinib do not directly kill cancer cells like nonspecific cytotoxic agents do; these drugs stop the growth of tumors. Moreover, the researchers note that this statement is specific to imatinib and sunitinib and cannot be generalized for all targeted therapies. Therefore, patients must receive treatment for prolonged periods, and over time, they often develop secondary resistance. "With these two drugs--imatinib and sunitinib--GIST patients are living much longer, but nevertheless, they may succumb to treatment resistance or disease recurrence," Dr. Frolov said.
Genetic analysis of marker genes has the potential to dynamically track treatment progress with imatinib or sunitinib. "The initial response [to treatment with tyrosine kinase inhibitors] is usually quite good. But then the tumor stops responding or another site develops or something else happens. A test, like the analysis of the marker genes, is needed to help physicians decide what to do when the drug they are using isn't a silver bullet anymore," he explained.
Genetic testing promises to be a less expensive alternative to positron-emission tomography (PET) scanning, which is one of the most common ways of assessing whether drug treatment is affecting GIST tumors. PET is an expensive examination, and it is not available in many parts of the country. "PET also is not a direct measure of treatment effectiveness. PET measures the metabolic activity of the tumor and whether a drug has shut down that metabolic activity or not," said Dr. Frolov. Therefore, PET scanning must be done after a course of treat-ment has been completed and the tumors have had time to react, which may take more than four weeks. "The analysis of the marker genes is a straightforward real-time reverse transcription polymerase chain reaction [the standard method of amplifying mRNA so it can be readily examined in a laboratory] that can be performed in any molecular function laboratory which has the necessary equipment. The cost would be similar to the cost of any pathology test," Dr. Frolov said.
Genetic analysis also has the potential to provide a specific molecular assessment of the effectiveness of targeted therapy almost immediately after it begins. "At the time the patient undergoes fine needle aspiration of a biopsy sample and cells are obtained, we might be able to check for the marker genes and compare them to baseline levels to see whether the tumor is responding or not in six to 12 hours," Dr. Frolov said.