Lung cancer fact

We are all painfully aware of the ongoing epidemic of lung cancer throughout the world. Despite the noble efforts of interested parties to reduce smoking rates, we still read the depressing statistics reporting that lung cancer is the leading cause of cancer death in the United States and throughout the world. Indeed, in United States lung cancer in women is responsible for as many deaths as breast cancer, and as many as all gynecologic cancers combined. (1)

The typical stereotype of the individual with lung cancer is a middle-aged to elderly man who smokes and lives in a Western country. While there is obviously still some truth to this, the present article in CHEST (see page 1750) by Toh et al, along with data from multiple other studies challenges this prototype. Toh and colleagues, who are from Singapore, set out in a retrospective analysis to assess the impact of smoking status on both the response to chemotherapy and on overall survival. No differences were found between smokers and nonsmokers with respect to these two end points. There are inherent biases in this study in that it was a retrospective study of patients who had been referred to a tertiary medical oncology service, and therefore no conclusions can be made from this study about the prognosis of individuals with earlier stage lung cancer. However, the demographic data in this study are of major interest to those interested in reducing lung cancer incidence and mortality. Challenging the typical lung cancer prototype is the fact that 36.3% of the study population were nonsmokers. Further, 73.9% of these nonsmokers with lung cancer were women, and adenocarcinoma comprised 74.5% of the cell types. To my mind, these staggering statistics raise the following three critical issues that require further exploration:

1. Are there gender differences in lung cancer?

2. Are there race differences in lung cancer?

3. Is lung cancer different in smokers vs nonsmokers?

As will be discussed, these three issues are to a large extent interrelated.

GENDER DIFFERENCES IN LUNG CANCER

In the study by Toh et al, women comprised 33.8% of the total group of patients with lung cancer, but in the subgroup of nonsmokers with lung cancer 73.9% were women. Controversy exists as to whether there are gender differences with respect to susceptibility to lung cancer. A case-control study (2) of 442 female and 362 male Canadians with lung cancer demonstrated an odds ratio (OR) of lung cancer for female smokers of 27.9, compared with 9.6 for male smokers. Another case-control study (3) of nearly 15,000 patients with lung cancer demonstrated a higher OR for women (12.7) than for men (9.1). In contrast, several cohort studies (4) have not shown a higher relative risk of lung cancer in female smokers, but these studies may have suffered from lack of adjustment for the duration of cigarette smoke exposure.

Whatever the situation is for smokers with lung cancer, there seems to be little doubt that women are considerably overrepresented in the group of nonsmokers with lung cancer. This is particularly true of Asian populations. (5) There are also differences in the prevalence of cell type, with adenocarcinoma being the most common form of lung cancer in both women and nonsmokers. (6)

There may be sex-related biological differences in lung cancer patients. Nicotine, a precursor for carcinogens in the lung, is subject to a lower total plasma clearance in women than in men. (7) Various investigators have reported significantly more tobacco-related mutations in women smokers than in male smokers, including specific mutations in the p53 and CYPIAI genes. (8,9) The role of estrogens in lung cancer also has been studied, with inconsistent results. Estrogens may be implicated in lung carcinogenesis by acting as estrogen receptor ligands and activating cell proliferation. (10) A possible interaction between estrogen therapy and smoking, and the development of adenocarcinoma of the lung has been postulated by some investigators. (11) These authors reported an OR of 13 for women who smoke and did not receive hormone replacement therapy, compared with an OR of 32.4 for women who smoke and received hormone replacement therapy.

Another potential gender difference in lung cancer is that of survival. Women have been reported to have longer survival times after surgical resection of early stage lung cancer (12,13) and following chemotherapy for advanced non-small cell lung cancer and small cell lung cancer. (14,15) Not all studies, however, have demonstrated this survival advantage for women. (16)

RACE DIFFERENCES IN LUNG CANCER

There seem to be not only race differences with respect to the incidence of lung cancer, but also a complex interaction between race and gender. In the current study by Toh et al, 73.9% of the nonsmokers with lung cancer were women, and this high incidence of female nonsmokers with adenocareinoma is often only seen in Asian populations. (5) Chinese women in all countries have a relatively high lung cancer incidence despite the fact that very few of these women smoke. Whether this is a genetic predisposition based on race, or whether it is due to environmental factors, is still uncertain. One study (18) of families with female nonsmoking lung cancer probands in Taiwan suggested that there may be a rare autosomal-codominant gene that influences the risk of lung cancer in nonsmokers. Environmental factors also may play a role in certain races, however. Several studies (17,19) in Chinese populations have suggested exposure to oil fumes during cooking as a risk factor for lung cancer. Obviously, there may well be an interaction between genetics and environmental factors to explain these racial differences in lung cancer difference.

SMOKING STATUS AND LUNG CANCER

In a review of > 3,000 new patients with lung cancer, the Edinburgh Lung Cancer Group found that only 2% of cases occurred in nonsmokers. (20) This is in stark contrast to the current Singapore study by Toh et al, in which 36.3% of patients with lung cancer were nonsmokers. This again reflects the complex interactions among gender, race, and smoking status in the subsequent development of lung cancer.

Why do nonsmokers develop lung cancer? The answer is, obviously, uncertain at present. While there may be genetic factors involved, (18) a number of environmental factors have also been implicated. In Asian women, the role of exposure to cooking oils has been implicated in a number of studies but is as yet unproven. (17,19) Environmental tobacco smoke, or "passive smoking," has been the subject of intense scrutiny. In most studies, the relative risk for lung cancer has been on the order of 1.2 to 1.3, suggesting a modest increase in lung cancer risk. (21) Passive smoking, however, is unlikely to explain the high incidence of lung cancer in nonsmokers in this Singapore study, as the mean age at diagnosis for nonsmokers compared to smokers was almost 10 years younger. As there is a clear dose-response relationship between smoking exposure and lung cancer, one would expect lung cancer due to passive smoking to occur at a later age than that for smokers. Other environmental factors implicated in lung cancer in nonsmokers include exposure to radon, arsenic, asbestos, chromium, nickel, and other occupational carcinogens. (22) Critical analysis of the currently available literature would suggest that exposure to such carcinogens is probably associated with a low risk of lung cancer and is almost certainly not relevant to the current Singapore study by Toh et al.

SUMMARY

The study by Toh et al has demonstrated no difference in both response to chemotherapy and overall survival between smokers and nonsmokers with non-small cell lung cancer. Of considerable concern is the fact that nonsmoking women in this Asian population are at considerably greater risk of developing lung cancer than their Western counterparts. There is clearly a complex interaction among gender, race, smoking status, and cell type in the subsequent development of lung cancer, and this interaction requires urgent attention from both researchers and public health authorities in order to slow the current epidemic of lung cancer in certain parts of the world. Perhaps more important than this research is the need to reverse the current push by tobacco companies into developing countries and Asia. It has been estimated that 20 million women have started smoking in China since 1990, (23) and a doubling of smoking rates has been documented in Japanese women in recent years. (24) If these trends continue, the prototype of the lung cancer patient (middle-aged to elderly Western man who smokes) may rapidly be replaced by the alternative (younger Asian women who both smoke and do not smoke). Urgent action is required!

David J. Barnes, MBBS, FCCP

Sydney, Australia

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