Dec. 2, 1999 Scientists at UC San Francisco and Harvard University tracking people after lung cancer surgery have discovered that those who bear a common cancer-causing mutation tend to have particularly aggressive tumors early on and are four times more likely to die of the disease. The mutation strikes women smokers three times more often than men, the researchers found.
The findings suggest that this mutation, known as K-ras, helps the tumor proliferate in response to the body's natural growth hormones, particularly estrogen in women, they conclude. K-ras is detected in about 10 percent of all lung cancers,
The sobering report, by scientists at Harvard University and the University of California, San Francisco appears in the December issue of the Journal of the National Cancer Institute.
The scientists urge research to determine whether vigilant screening for the K-ras mutation can lead to improved chances of survival for patients with non-small cell adenocarcinoma, the lung cancer in the study which accounts for 40 percent of all lung cancers. Incidence of adenocarcinoma is on the rise and is more common in women than men, they noted.
"The striking thing is how early the K-ras mutation seems to act on tumors, how aggressive tumors are when under its influence, and how vulnerable women are to this mutation," said John K. Wiencke, PhD, professor of epidemiology and biostatistics at UCSF and a senior author of the study.
While the K-ras mutation is found in about 10 percent of all lung cancers, it is detected in about one fourth of adenocarcinomas, and almost exclusively among smokers, Wiencke said. Lung cancer is the leading cause of cancer death, both in the U.S. and worldwide.
"It seems appropriate to try to detect the mutation as early as possible in patients with adenocarcinoma and then treat those patients quickly and with as many of the armaments we now have against cancer," he said.
First author on the scientific paper is Heather H. Nelson, PhD, research associate in cancer cell biology at the Harvard School of Public Health.
The scientists studied patients who were about to undergo surgery for non-small cell adenocarcinoma. They found the K-ras mutation only among the lung cancer patients who had been smokers, yet those who had smoked relatively lightly or briefly and then quit were just as prone to the mutation as those who smoked for many years. The pattern, Wiencke said, highlights the importance of avoiding smoking in the first place.
The particularly aggressive nature of the early stages of K-ras-associated lung cancer challenges the view that smokers will always benefit if they quit, he added.
"Among those with non-small cell adenocarcinoma who have the mutation, it appears that the ability of the tumor to grow quickly and aggressively develops in the early stage of the disease, possibly even before metastasis can be detected," Wiencke said. "The most crucial behavioral decision would be to never take up smoking, rather than quitting" (in hopes of reducing cancer risk.) This finding applies only to this type of cancer, he stressed, and quitting has definitely been shown to decrease the likelihood or severity of other serious illnesses such as heart disease and emphysema.
The lung cancer study involved 365 newly diagnosed patients. All were tested for K-ras mutation and other traits and then tracked for four years after undergoing lung cancer surgery.
After taking into account a well-known link between the K-ras mutation and occupational exposure to asbestos among men, the researchers found that women were three times more likely than men to have the K-ras mutation.
Following surgery, those patients with a K-ras mutation were almost twice as likely to die compared to those without a K-ras mutation, the researchers discovered. Most distressingly, those patients whose cancer was operated on when it was in a relatively early phase - called stage 1 -- were nearly four times more likely to die if they had a K-ras mutation.
The striking prevalence of the K-ras mutation among women smokers and the grim survival statistics among patients with the K-ras, particularly in the early stages of cancer, lead the team to suspect that estrogen may play a role either in the initiation or the selection of K-ras mutant cells in the lung tumors.
It is likely, they report, that tobacco carcinogens cause essentially all K-ras mutations and that the mutations occur quite early in the cellular growth of lung cancers. Pre-adenocarcinoma cells are known to produce receptors for estrogen, and the researchers hypothesize that estrogen and the body's other growth-promoting hormones may be used by the early-stage cancer to spur its growth. Such a mechanism would account for the disproportionate number of women smokers with lung cancer who bear the K-ras mutation, they suggest.
Wiencke says the scientists want to understand how to prevent the K-ras gene from mutating in the first place, on the assumption that blocking the mutation might be a more promising strategy to save lives than trying to combat the effects of the mutation once it has occurred.
Collaborators on the research along with Nelson and Wiencke are Karl T. Kelsey, MD, professor of cancer cell biology, and David C. Christiani, MD, professor of occupational health, both at the Harvard School of Public Health; Eugene J. Mark, MD, professor of pathology, and John C. Wain, MD, professor of surgery, both at Harvard Medical School. Wain is in the thoracic surgery unit at Massachusetts General Hospital.
The research was funded by the National Institutes of Environmental Health Sciences and the National Cancer Institute.
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