Background: Lung cancer incidence is gradually leveling off in U.S. men but is continuing to rise in U.S. women. This increase in U.S. women exceeds that expected from a slower decline of smoking among women. Recent epidemiologic and biochemical studies suggest gender differences in susceptibility to tobacco carcinogens.

Purpose: We conducted an up-to-date, more in-depth evaluation of our earlier observation of a potential gender difference in relative risk (RR) of lung cancer due to smoking. We added information from several additional case and control subjects and included more precise histologic classification of the cancer type, accurate quantitation of smoke exposure, and adjustments for body size.

Methods: The present investigation was a part of an ongoing hospital-based, case-control study by the American Health Foundation. It included data from 1889 case subjects (1108 males and 781 females) with lung cancer of squamous/epidermoid, small-cell/oat cell, large-cell, and adenocarcinoma types and 2070 control subjects (1122 males and 948 females) with diseases unrelated to smoking. The case and control subjects were admitted to participating hospitals from 1981 to 1994 and were pair-matched by age, sex, hospital, and the time of hospital admission. Ex-smokers and non-Caucasians were excluded from analyses to avoid confounding. The RRs and 95% confidence intervals were estimated from adjusted odds ratios (ORs) by use of unconditional multiple logistic regression analysis, and statistical significance was determined by two-sided tests. The ORs for major histologic types were estimated at increasing levels of exposure to cigarette smoke.

Results: Our results indicated that women were more likely to be never-smokers than men, particularly those with the squamous/epidermoid-type cancer (8.3% for women versus 2.9% for men 55 years old or older). Men started smoking earlier, reported inhaling more deeply, and smoked more cigarettes per day than women. In contrast, dose-response ORs over cumulative exposure to cigarette smoking were 1.2-fold to 1.7-fold higher in women than in men for the three major histologic types; these differences were more pronounced for small-cell/oat cell carcinomas and adenocarcinomas than for squamous/epidermoid carcinomas. Adjustments for weight, height, or body mass index did not alter the ORs.

Conclusions: These results confirm our earlier finding that the ORs for major lung cancer types are consistently higher for women than for men at every level of exposure to cigarette smoke. Furthermore, this gender difference cannot be explained by differences in base-line exposure, smoking history, or body size, but it is likely due to the higher susceptibility to tobacco carcinogens in women.