By Deborah L. Shelton, St. Louis Post-Dispatch

About one in five women who get lung cancer have never smoked.

Researchers know that smoking causes cancer, but they don''t know why people who never smoke get it.

And they have no idea why more women who have never touched a cigarette get lung cancer than men who have never smoked.

Lung cancer killed Dana Reeve on Monday. She was 44 and had never smoked. People know her as the constant caregiver and support for her husband, actor Christopher Reeve, whose fall from a horse in 1995 paralyzed him. He died in 2004.

Now, her own early death is bringing attention to another tragedy: Lung cancer among people who have never smoked, especially its disproportionate impact on women.

One in five women with lung cancer have never touched a cigarette. One in 10 men with the cancer have never smoked.

Lung cancer kills more men and women in the United States than any other cancer, with more than 150,000 new cases diagnosed every year, according to the American Cancer Society. The overwhelming number of cases - from 80 percent to 90 percent - are diagnosed in smokers.

Lung cancer deaths in women surpassed breast cancer deaths in 1987 for the first time.

"Dana Reeve''s death highlights the fact that lung cancer is the leading cause of cancer death in women in the U.S., claiming 30,000 more lives annually than breast cancer," said Regina Vidaver, executive director of Women Against Lung Cancer, a research and advocacy group in Madison, Wis.

Vidaver said women make up a majority of lung cancer patients under 50. Most of them haven''t smoked. Because lung cancer typically takes years - even decades - to develop, the younger the patient, the less likely it came from smoking.

Experts make a distinction between never-smokers and nonsmokers, people who may have smoked in the past and quit.

"We simply don''t know what accounts for lung cancer in never-smokers," said Dr. Ramaswamy Govindan. He is chief of the lung cancer program in the division of medical oncology at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "There are speculations ranging from hormones to radon exposure to viral infections."

Govindan said two-thirds of the lung cancer patients at Siteman who have never smoked are women.

Dr. Richard Battafarano said genetic differences might account for a higher prevalence among women.

"One of the factors that might come into play is the possible contribution of estrogen to lung cancer," said Battafarano, a thoracic surgeon and assistant professor of surgery at Washington University medical school. "But a lot of these hypotheses need to be validated scientifically."

The good news is that newer drugs designed to treat lung cancer appear to work dramatically better in women and never-smokers. The trade names of the drugs are Tarceva, Iressa and Xyotax. Iressa is prescribed only to a limited group of patients who have already responded well to it.

Vidaver, a molecular biologist, said lung cancer develops differently in men and women and the sexes react differently to treatment.

"The question is why, and we don''t know the answer to that," she said. "We need to understand these sex differences better, because we are already seeing treatment differences."

Researchers believe that patients who develop lung cancer who have never smoked are probably biologically different than smokers, Govindan said.

Cindy Erickson, CEO of the American Lung Association of Missouri, said Reeve''s death brings home that even nonsmokers can be in danger of lung cancer from cigarette smoke.

"In Dana Reeve''s case, there was no stated cause," Erickson said. But she questioned whether second-hand smoke might have played a role.

Govindan discounted the role of second-hand smoke, saying it likely was not a factor unless the patient had excessive exposure from living with a lifelong smoker.

He also doubted that lung cancer diagnosed in never-smokers is more deadly.

A more important factor, he said, is the stage of the cancer at diagnosis. The earlier the diagnosis, the greater the chance of survival.

Doctors said they will continue to encourage people not to smoke because most lung cancer occurs in smokers or previous smokers.

"We can''t lose sight of that," Battafarano said.

Harry Jackson Jr. of the Post-Dispatch contributed to this report.