Molecular testing in patients with rare cancer predicts response to Gleevec

May 15, 2005

PORTLAND, Ore. -- Patients with gastrointestinal stromal tumors (GIST) who have a particular genetic mutation are more likely to respond to Gleevec (imatinib) than those without the mutation, according to OHSU study results showcased at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO). The results confirm previous observations and provide a foundation for molecular testing that can predict who will best respond to treatment with Gleevec.

"Increasingly, there will be more drugs like Gleevec that are very specific in their action, and patients' responses to them will be dictated by their tumor biology," said Michael C. Heinrich, M.D., principal investigator of the study. "Performing molecular tests on patients' tumors will be useful for doctors in determining how patients should be treated."

Heinrich is a professor of medicine (hematology/medical oncology) in the OHSU School of Medicine and the Portland Veteran Affairs Medical Center (PVAMC) and a member of the OHSU Cancer Institute.

Gastrointestinal stromal tumors, which occur in the stomach and intestines, are diagnosed in about 5,000 Americans annually. Surgery is the treatment of choice for localized tumors, but in many patients the tumor recurs and spreads elsewhere, particularly to the liver. Without Gleevec, at this metastatic stage the disease is rapidly fatal because chemotherapy, radiation and surgery are ineffective in advanced cases.

Gleevec works by inhibiting a protein called KIT, which is abnormally expressed in GIST and fuels tumor growth by signaling cancer cells to keep growing. The majority of GIST patients have dramatic clinical improvement in their disease (tumor shrinkage) after beginning treatment with Gleevec. However, more than half of patients develop resistance to the therapy and experience disease progression after about two years.

In a previous study, Heinrich and colleagues identified differences in the clinical response to Gleevec among patients with different mutant forms of KIT protein, which is a type of tyrosine kinase. The purpose of this latest study was to further examine the relationship between the more common mutations and drug response in a much larger, dosage comparison Phase III study.

"We are pleased that the findings in this study substantiate our earlier observations," said Christopher L. Corless, M.D., Ph.D., who collaborated with Heinrich on the study. "Molecular subtyping of GIST is clearly important to understanding how Gleevec - and other drugs in the pipeline - affect growth signaling in these tumors." Corless is a professor of pathology in the OHSU School of Medicine and PVAMC and a member of the OHSU Cancer Institute.

Researchers analyzed tumor DNA samples from 324 GIST patients, obtained before they began treatment with Gleevec, and correlated the findings with subsequent patient outcome. Of 280 tumors with abnormalities of the KIT gene, those with a mutation in a segment called "exon 11" were significantly more likely to have a clinical response to Gleevec than patients whose tumor had a KIT "exon 9" mutation or had no mutations. Patients with the KIT exon 11 mutation responded to Gleevec for a longer period (576 days) than those with the KIT exon 9 mutation (308 days).

"However, there was no difference in the likelihood of clinical response between the two doses used in the study," said Heinrich. "The presence of an exon 11 type mutation was the single best predictor of clinical response to Gleevec, irrespective of dose."

The study also confirmed that new drugs are urgently needed for patients whose GIST genotype is less responsive to Gleevec. In response to this clinical need, future studies planned by Heinrich and colleagues will evaluate the use of Gleevec in combination with other agents to treat GIST patients.

"We have a powerful tool in Gleevec," said Heinrich. "However, we need to find ways to use the therapy so it doesn't just shrink tumors, but totally eliminates the cancer cells, so the tumors don't come back."

The OHSU Cancer Institute is one of only about 60 National Cancer Institute-designated cancer centers in the nation and remains the only such center between Sacramento and Seattle. It comprises some 120 clinical researchers and basic scientists who are working together to translate scientific understanding into longer and better lives for cancer patients.
ASCO abstract No. 7, "Correlation of clinical response to imatinib mesylate (IM) and target kinase genotype in patients with metastatic KIT+ GI stromal tumors (GISTs)."

Oregon Health & Science University

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to