By Wallace Ravven on November 30, 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

“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.