CHICAGO --- Tobacco use in American women rose dramatically during the 20th century, resulting in a 600 percent increase by the year 2003 in the number of women who died of lung cancer. In the same period, the number of lung cancer deaths in men declined.

Lung cancer has now surpassed breast cancer as the leading cause of cancer death, accounting for one fourth of all female cancer deaths last year. In 2004, lung cancer will cause as many deaths in women as breast and all gynecologic cancers combined.

Several studies have reported that women are more susceptible than men to the lung cancer-causing effects of cigarette smoking, although this issue remains somewhat controversial.

What is not controversial, according to Northwestern University researcher Jyoti D. Patel, M.D., is that lung cancer appears to be a different disease in women.

In an article in the April 14 issue of The Journal of the American Medical Association, Patel and colleagues from Memorial Sloan-Kettering Cancer Center, New York, discuss differences in the biology of lung cancer between the sexes, including genetic mutations, increased production of certain enzymes that help trigger cancer growth and hormonal changes.

“Genetic, metabolic and hormonal factors all are important to the way women react to carcinogens and lung cancer. This information should impact how we evaluate and screen patients who smoke and how we direct smoking cessation and lung cancer prevention programs,” Patel said.

For example, women are more likely than men to develop adenocarcinoma, a subtype of lung cancer. Adenocarcinoma, once a rare type of lung cancer, is now the most common type of lung cancer and is less associated with smoking than other types of lung cancer. Adenocarcinoma is the most common form of lung cancer present in young persons, those who never smoked and women of all ages.

Patel said that this difference in prevalence between sexes suggests basic differences in lung cancer.

“Mounting evidence suggests that these differences could be due, in part, to estrogen,” Patel said.

Research has found that lung cancer cells have more estrogen receptors on their surface than normal lung cells. Other studies have shown an association between estrogen replacement therapy and development of adenocarcinoma of the lung and a positive interaction between estrogen replacement, smoking and development of adenocarcinoma of the lung, Patel said.

Patel also noted that once women have lung cancer, they experience a survival benefit that is not accounted for solely by a longer life expectancy or imbalance of other prognostic factors.

Most major studies for lung cancer prevention in the past have excluded women. The researchers believe it is critical that future lung cancer research specifically include a portion of women that reflects the true incidence of lung cancer in females.

“Given these differences, it is critical that future lung cancer research specifically include a proportion of women that reflects the true incidence of lung cancer in females,” they said.

Perhaps the biggest challenge lies in avoiding a similar sad story in other parts of the world, the researchers said. Sociocultural constraints that previously discouraged tobacco use by women continue to weaken in many developing countries. Around 20 million women have started smoking in China in the past 10 years, and after aggressive promotional campaigns in Japan that targeted women and girls, smoking among women there has doubled in just five years.

Patel and co-authors caution that the extraordinary increase in lung cancer rates seen in American women in the 20th century will be repeated in women of developing countries during this century unless effective tobacco control measures are implemented.

Patel is instructor in medicine in the division of hematology/oncology at the Feinberg School of Medicine, a researcher at The Robert H. Lurie Comprehensive Cancer Center of Northwestern University and an attending physician at Northwestern Memorial Hospital.

Her co-researchers on the study were Peter B. Bach, M.D., assistant attending physician in the department of epidemiology and biostatistics, and Mark G. Kris, M.D., chief, thoracic oncology service, Memorial Sloan-Kettering Cancer Center. Kris was senior author on this article.