Lung Cancer, Smoke Exposure, and Sex

Lung cancer is the most preventable of all of the major forms of cancer because 85% to 90% of deaths from lung cancer are a result of active cigarette smoking. However, even in people who have never smoked, lung cancer accounts for approximately 15,000 deaths annually, similar to the number of deaths projected for ovarian cancer in 2006 and more than the number of deaths projected for brain cancer, bladder cancer, or multiple myeloma. Two important articles in this issue provide insights about sex differences in the epidemiology and molecular characteristics of lung cancer in lifelong nonsmokers. Nearly a decade ago, one of us (A.F.G.) postulated that differences in the histologic distribution of lung cancer between men and women signaled important differences in disease pathogenesis in response to tobacco smoke. Today, the evidence is substantially stronger, yet the issue seems more complex than ever. The report by Wakelee et al provides the first direct evidence that lung cancer incidence is higher among women than men who have never smoked based on five prospective cohort studies in the United States and one in Sweden. These data are particularly interesting because previous studies of lung cancer in lifelong nonsmokers have examined death rates but not incidence. Two massive American Cancer Society cohorts, together with other studies that are smaller or have shorter follow-up, collectively demonstrate that the death rate from lung cancer is approximately 25% higher in men than in women who have never smoked. It is important that other large cohorts attempt to replicate the observation by Wakelee et al that the opposite seems to be true for lung cancer incidence in never smokers age 40 to 79 years. Furthermore, replication would support the hypothesis by Henschke et al that women may be more susceptible to develop lung cancer than men but are less likely to die from the disease. Studies are also needed to determine whether the survival difference between male and female never smokers is large enough to account for the lower lung cancer death rates in women despite their higher incidence. Wakelee et al also note that the proportion of lung cancers that are adenocarcinoma is highest among male and female lifelong nonsmokers, intermediate in former smokers, and lowest in current smokers. It is well known that adenocarcinoma is the predominant cell type of lung cancer in women and in lifelong nonsmokers. What is less well known is that comparisons of proportions do not provide a direct comparison of risk. For example, although adenocarcinoma makes up a larger proportion of lung cancers in women than in men age 50 years and older, the incidence rate of adenocarcinoma is actually higher in men than women in the same age groups based on population-based cancer incidence registries in the United States. The reason why adenocarcinoma predominates in women is not that the risk of developing adenocarcinoma is higher in women than in men, but rather that the risk of developing other cell types of lung cancer, particularly squamous cell and small-cell cancers, is much lower. As Wakelee et al indicate, their study has certain limitations; it cannot assess whether the incidence of lung cancer among lifelong nonsmokers has changed over time or whether the pattern differs in geographic regions other than North America and northern Europe. Several prior studies have indicated that the proportion of never smokers in females with lung cancers is much higher than their male counterparts in certain parts of China and other Asian countries where women are exposed to indoor air pollution from unventilated fumes from cooking and heating at much higher concentrations than in the West. Here, too, comparisons of proportions are less informative than are comparisons based on incidence rates. In Asia, even more than in the United States, women comprise the majority of lifelong nonsmokers over age 60 years. The larger denominator, rather than any inherent sex difference in susceptibility, may explain why women outnumber men among never smokers with lung cancer. Subramanian and Govindan provide a comprehensive review of the current state of our knowledge about lung cancers in never smokers. Although they do not specifically point out the relationship between tobacco exposure and sex, many of the features of this disease, as discussed in their review, indicate a close interaction (Table 1). The higher incidence rate in women who have never smoked has already been discussed. Peripherally arising adenocarcinomas account for the majority of lung cancers occurring both in never smokers and in women. For practical purposes, centrally located small-cell carcinomas virtually never occur in never smokers, and squamous cell carcinomas are relatively rare. The role of estrogens and their receptors is complex and multifaceted, as summarized by Subramanian and Govindan and in other studies, and estrogens and their receptors may play a role in the pathogenesis of cancers occurring in smokers and never smokers. By influencing expression of polymorphic genes that regulate tobacco carcinogen metabolism, estrogens may play a role in carcinogenesis both by sex bias and at an individual level. Of interest, lung cancers may, on occasion, express relatively high levels of estrogen receptors alpha and beta, but their expression does not seem to show a sex bias (J. Minna and Y. Jeong, personal communication, October 2006). Studies from Taiwan suggest that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 5 FEBRUARY 1