Head and Neck Cancer Patients Fare Worse When Missing a Copy of Tumor Suppressor Gene
DURHAM, N.C. -- Patients with head and neck cancers who are missing one copy of an important tumor suppressor gene called IGF2R have much poorer survival rates than patients with two copies of the gene, according to a study at the Duke Comprehensive Cancer Center.
But survival can be greatly increased among gene-deficient patients by adding chemotherapy to the standard treatment regimen of radiation, the study showed.
If further clinical trials confirm the findings, doctors will ultimately be able to test their patients before treatment to select the best therapy for each person's genetic composition, said Randy Jirtle, Ph.D., professor of radiation oncology at Duke. Patients who need chemotherapy would receive it, while those who would not benefit from chemotherapy could be spared its toxic and potentially life-threatening side effects.
Results of the study are published online in the March, 2003, issue of BMC Cancer.
"Our study is yet another fine example of translating laboratory research into a clinical tool that can have direct patient impact," said David Brizel, M.D., professor of radiation oncology and a co-author of the study. "We now have strong evidence showing that patients with only one copy of the IGF2R gene will have much better survival if they receive both chemotherapy and radiation together. On the contrary, patients with the gene intact do not appear to benefit from chemotherapy and may only need radiation."
In the study of 116 patients with advanced head and neck cancers, originally published in the New England Journal of Medicine, the researchers subsequently found that half of patients had lost one copy of the tumor suppressor gene known as IGF2R. Patients with one copy had a 5-year survival rate (without relapse) of only 23 percent. Patients with both copies of the gene had a 5-year survival rate (without relapse) of 69 percent.
That ratio changed dramatically when the gene-deficient patients were given chemotherapy plus radiation. The dual treatment regimen boosted their 5-year survival rates to nearly the same as patients with both copies of the gene intact, the study showed.
"Our results are very tantalizing, because they suggest that we could increase survival for patients who have a poor prognosis, while we could spare half of patients from needlessly receiving drugs that are associated with significant morbidity and mortality," said Timothy A. Jamieson, M.D., a former Duke resident in radiation oncology and first author on the study.
Brizel said the cure rate has never been good for patients with advanced head and neck cancers -- some 40,000 people per year. For reasons unknown, some patients respond well to radiation while others do not. So in 1990, Brizel and his colleagues launched a clinical trial to compare twice-a-day radiation against combined and concurrent radiation and chemotherapy. The combination clearly worked better overall, but nearly 40 percent of patients still fared poorly.
"I wanted to know if there was some way to determine who needed the more intensive treatment and what made them less receptive to radiation alone," said Brizel.
So Jamieson, Jirtle, Brizel, Mitch Anscher, M.D., and other researchers in the Departments of Radiation Oncology and Pathology at Duke University Medical Center conducted a retrospective study of the patients from the original clinical trial, plus additional patients who fit the study entry criteria but did not actually enroll in the trial. They analyzed the genetic composition of tumors and found that patients with poor survival had lost a copy of IGF2R. Patients with good survival had both copies of the gene intact.
"We have long known that some patients respond well to radiation therapy while others don't. Now we have a strong hypothesis as to why that disparity exists, and we hope to use these data as a clinical tool for selecting patients who truly need chemotherapy," said Anscher.
The team studied IGF2R because it is a well-known tumor-suppressor gene. IGF2R is either mutated or partially loses its function in many breast, liver, lung, gastrointestinal and endometrial cancers. Its normal functions are to inhibit growth-promoting proteins that enable cancers to multiply; and to enhance a process called apoptosis, in which cells are programmed to die at the end of their natural life spans.
But when IGF2R is mutated or loses its expression, it cannot perform these tumor- suppressing activities, and cancer cells grow uncontrollably. The researchers also postulate that losing a copy of IGF2R can impact the activity of other genes along its pathway, thereby compounding its primary deficit in suppressing cancer.
They speculate that chemotherapy may improve patient prognosis in two ways: first, by directly killing cancer cells; and second, by sensitizing the cancer cells to the radiation itself.
In the future, the team hopes to conduct another clinical trial in a larger population to confirm their previous findings. Their ultimate goal is to develop a simple blood test that will identify patients with IGF2R gene loss, and to base their treatment decisions upon that information. Other Duke University Medical Center researchers involved in this study are Robert Clough, Xiaolong Fu, M.D., Ph.D., Hong-Seok Jang, M.D., Ph.D., Keith Killian, M.D., Ph.D., Yoshihiko Oka, M.D., Ph.D., and Robin Vollmer, M.D.