Re: Are women more susceptible to lung cancer?

In a recent editorial in the Journal (1), Blot and McLaughlin criticize our case– control study (2) and other case–control studies in comparison with cohort studies addressing smoking-related lung cancer risks in males and females. In the same issue of the Journal, Bain et al. (3) also criticize our study. Both sets of authors point out that a number of carefully conducted cohort studies have shown no measurable excess of lung cancer cases among female smokers compared with male smokers, once amounts of smoking have been controlled, whereas our study showed statistically significantly and substantially higher risks for females than for males at every level of smoking. The authors offer various explanations for this discrepancy, including our use of relative risk measures, potential recall biases, interviews with next of kin, and so on (1). However, the answer lies elsewhere. Bain et al. (3) and the other cohort studies [reviewed in (3)] examined risks for males and females, adjusted for amount of smoking. In these studies, the scientific question addressed was, Adjusted for dose of smoking (in the same way for males and females), are males and females, or are male and female smokers, at the same risk? In other words, What is the (main) effect of sex, given adjustment for smoking? By contrast, the scientific question addressed by our case–control study and others was, At a given dose of smoking, is the effect of smoking different for males and females? That is, do males and females have different relationships between their smoking doses and risk of lung cancer (i.e., a different risk sensitivity to the effects of smoking)? This question is not addressed by the analyses of Bain et al. (3) and the others, which do not involve effect modification of smoking by gender. In a statistical model, if men and women are forced to have the same relationship between smoking and risk of lung cancer, then what is being examined is the intrinsic risk of sex itself, not of smoking. Because the major identified cause of lung cancer is tobacco smoking, we think the effect of sex by itself is of secondary importance. Should Bain et al. (3) examine different smoking dose–risk sensitivities between males and females in their data, they will face another issue. Ten cohort studies of lung cancer to date [cited by Bain et al. (3) and by us (4)] show that the baseline risk of lung cancer among female nonsmokers is approximately 75% of the baseline risk among male nonsmokers (Table 1). These 10 studies collectively identified thousands of lung cancer cases among nonsmokers in their cohorts. Bain et al. (3) found 99 female and 33 male lung cancer cases among their nonsmokers, with annual incidence rates per 100 000 of 16 and 12, respectively, or a female:male ratio of 1.33. This finding is at variance (approximately P .005) with the large amount of evidence from the other 10 cohort studies and suggests that some systematic biases underlie either the reporting of smoking or the incidence of lung cancer in their cohort. A nonsmoker baseline absolute risk higher for females than males will, by artifact, reduce any relative risks for females compared with males in the smoking-related risk sensitivities to lung cancer calculated with the data of Bain et al. (3). Thus, it is by no means clear that female smokers have the same smoking dose-related risks of lung cancer as males. Until sufficient analyses addressing this specific question show such a finding, the evidence to date indicates that female smokers are more sensitive than male smokers to the effects of smoking in inducing lung cancer.