July 2, 2003 Patients with the earliest form of the most common type of lung cancer are more than twice as likely to die of the disease within four years if they have a mutation in a well known cancer-causing gene, scientists have found. The study in the July 2 issue of the Journal of the National Cancer Institute also shows that lung cancer patients who both smoke and consume alcohol frequently are more likely to have the mutation.
A team led by surgeon Steven A. Ahrendt, M.D., of the James P. Wilmot Cancer Center at the University of Rochester analyzed tumors from 188 patients with non-small-cell lung cancer. The team found that the status of the p53 gene plays a pivotal role in distinguishing which patients are most likely to survive four years or more. The discovery comes at a time when complex molecular markers are beginning to play a role along with more traditional features such as the extent of cancer in a patient's body in determining the treatments that cancer patients receive.
"We need to confirm these results through a larger study, but this difference is large enough to be clinically meaningful," says Ahrendt, associate professor of surgery, oncology, and pathology.
The ability to predict which patients are more likely to live or die could cause doctors to re-think how they treat certain lung cancer patients Ahrendt says. Currently, patients with early-stage lung cancer commonly receive surgery but not chemotherapy or radiation unless the cancer recurs. If scientists know that certain patients – for instance, those with a p53 mutation – are much more likely to die of the disease, preventive chemotherapy might be considered earlier in treatment.
The study creates a bright spot for a disease where the overall survival rate is dismal. Lung cancer is the leading cause of death by cancer in both men and women, and overall, fewer than one in five patients live five years after diagnosis. For people whose lung cancer is caught in the earliest stage, the news is somewhat better: Generally about 40 to 60 percent of such patients live five years. Ahrendt's study identifies a sub-group of patients – those whose cancer is caught early, who don't have a p53 mutation – in which 78 percent of patients, nearly four in five, lived four years or more, a survival rate four times higher than for lung cancer patients overall.
Ahrendt and colleagues base the findings on an extensive study of tumor samples from 188 patients with non-small-cell lung cancer, which make up 80 percent of lung cancers. The team found mutations of the p53 gene – a gene whose normal function is to produce a protein that helps repair or destroy damaged cells before they can become troublesome – in 55 percent of the tumors. In the study, 48 percent of early-stage lung cancer patients with a p53 mutation died within four years, compared to 22 percent of patients without the mutation.
The team found that the type of p53 mutation matters as well. Patients with mutations that simply substituted one chemical base for another fared better than patients with more complicated mutations that completely knocked out the function of the tumor-suppressing protein made by p53.
The finding pertains only to those patients with very early lung cancer, which has not spread to lymph nodes or any other organs. The status of the p53 gene does not appear as crucial for later-stage cancers, probably because mutations in the p53 gene are overshadowed by the larger number of genetic abnormalities in these tumors.
The scientists also found that people who smoked and consumed alcohol frequently were 50 percent more likely to carry the mutation than smokers who did not regularly drink alcohol. While it's widely known that most people who get lung cancer are smokers, the evidence points out that once they get lung cancer, smokers who drink alcohol are more prone to have p53 mutations that make it more likely that they will die from the disease.
Ahrendt says the results of several dozen other studies that have looked at the relationship between p53 and lung cancer have varied widely, with some suggesting a link between p53 and survival, and others finding no such link. Some of the factors that set apart the current study, Ahrendt says, are its large size and its design as a "prospective" study in which scientists did not know the patient outcomes when the study began.
Most important, he says, the team used two very different techniques to check p53. In addition to conventional sequencing technology to check whether p53 had mutated, the team also used gene-chip technology to analyze the gene's genetic sequence. Together the techniques picked up more p53 mutations than previous studies.
Currently there is no easy, inexpensive blood test to check one's p53 status, Ahrendt says. The molecule is a popular pharmaceutical target for drugs in development because it's involved in many types of cancerous tumors, including breast, ovarian, bladder, brain and prostate cancers.
Other authors on the paper include researcher Yingchuan Hu and statistician Michael McDermott of the University of Rochester, and David Sidransky, Martin Buta, Nicole Benoit, Stephen C. Yang, and Li Wu of Johns Hopkins. With funding from the National Cancer Institute, the team analyzed tumors from patients where Ahrendt previously worked, at Johns Hopkins in Baltimore and at the Medical College of Wisconsin in Milwaukee.
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