Apr. 20, 2004 STANFORD, Calif. - Radiation therapy is a powerful tool for treating cancer, but for 5 percent of patients that lifesaving treatment comes with serious side effects. Screening blood for the activity level of 24 genes may identify those patients most likely to react badly to radiation, say Stanford University School of Medicine researchers. With this tool, doctors may soon be able to tailor-make treatments for individual patients.
"We've been treating cancer patients as if one treatment fits all," said Gilbert Chu, MD, PhD, professor of medicine and of biochemistry who led the study. "Cancer patients need to be treated for their particular cancer and their own bodies."
Some factors are a tip-off that a patient may have an unusually severe reaction to radiation. Patients who have autoimmune diseases such as diabetes or lupus, or who have certain rare genetic diseases need to be monitored carefully or avoid radiation altogether.
Even beyond these obvious signs, some patients suffer disfiguring, disabling or extremely painful effects. These may include wounds that don't heal, skin burns so severe they require plastic surgery, or brain damage. Past attempts to identify these patients by screening the cancer cells themselves have failed, according to Chu. In his study, published in this week's online edition of the Proceedings of the National Academy of Sciences, Chu and colleagues describe 24 genes that can be used to single out these patients for alternate therapies or lower radiation doses.
Chu said screening blood rather than cancer cells means the test would be more accessible to patients. "To be most useful it had to be done on peripheral blood and with a small number of genes," he said.
Chu, whose research revolves around how cells repair damaged DNA, thought that patients who respond poorly to radiation might have cells that don't properly recognize or repair radiation-induced DNA damage. These cells may turn on different genes, or the same genes at different levels, compared with normal cells exposed to radiation.
A group of graduate students and medical students consisting of Kerri Rieger, Wan-Jen Hong, Virginia Goss Tusher and Jean Tang tested this idea in blood samples taken from 57 cancer patients who had recently received radiation treatment. Of these, 14 patients had unusually severe radiation toxicity. The students used a gene microarray, which provides a snapshot of gene activity, to analyze which genes were active in blood cells.
In the initial analysis, Chu said the group couldn't identify genes that were consistently different between patients who did and didn't suffer serious side effects. He worked with Robert Tibshirani, PhD, professor of health research and policy, to develop a new statistical method of analyzing the microarray data. With this improved analysis, the group found 24 genes that behaved differently in patients who suffered radiation toxicity.
When Chu and his colleagues tested the patients' blood samples for these 24 genes, they identified nine of the 14 people with severe reactions. Of the remaining five patients, two were later found to have been treated with new approaches that carried high risks for toxicity. That left only three of 14 patients who the test failed to identify. Most important, the test did not mistakenly pinpoint any of the other patients.
Knowing which patients may have severe radiation toxicity could make treatment decisions easier. For cancers of the breast or prostate, Chu said surgical options can be as effective as radiation. "If you knew one of the options carried a big risk, that might alter your decision," he said.
For other cancer patients, radiation may be the best treatment. However, Chu added that patients at risk for high toxicity may also have cancers that die in response to much lower radiation doses. In such cases, radiation - though at greatly reduced doses - may still be an option.
Those who don't have severe radiation toxicity may also benefit from this study. "If you eliminate those patients with toxicity you may be willing to use higher doses for the remaining patients," Chu said. He said doses are set by what an average person can handle. If patients are treated individually rather than as averages, many could receive higher, more effective doses.
Chu said that before personalized treatment becomes possible, researchers must validate the 24-gene test on a larger number of samples. A biotech company must also commercialize the screen and make it available to medical labs.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.
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