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Background There is remarkable variation in the incidence of lung cancer among ethnic and racial groups in the United States.
Methods We investigated differences in the risk of lung cancer associated with cigarette smoking among 183,813 African-American, Japanese-American, Latino, Native Hawaiian, and white men and women in the Multiethnic Cohort Study. Our analysis included 1979 cases of incident lung cancer identified prospectively over an eight-year period, between baseline (1993 through 1996) and 2001.
Results The risk of lung cancer among ethnic and racial groups was modified by the number of cigarettes smoked per day. Among participants who smoked no more than 30 cigarettes per day, African Americans and Native Hawaiians had significantly greater risks of lung cancer than did the other groups. Among those who smoked no more than 10 and those who smoked 11 to 20 cigarettes per day, relative risks ranged from 0.21 to 0.39 (P<0.001) among Japanese Americans and Latinos and from 0.45 to 0.57 (P<0.001) among whites, as compared with African Americans. However, at levels exceeding 30 cigarettes per day, these differences were not significant. Differences in risk associated with smoking were observed among both men and women and for all histologic types of lung cancer.
Conclusions Among cigarette smokers, African Americans and Native Hawaiians are more susceptible to lung cancer than whites, Japanese Americans, and Latinos.
Previous studies have provided moderate support for the existence of ethnic and racial differences in the smoking-related risk of lung cancer, with black smokers and Native Hawaiian smokers having a greater risk than other populations.4,5,6,7 We examined the relationship between the incidence of lung cancer and smoking history among African-American, Japanese-American, Latino, Native Hawaiian, and white men and women in the prospective Multiethnic Cohort Study, focusing on population-based differences in the effects of the extent and duration of smoking and the time since quitting on the risk of lung cancer.
Methods
Study Population
The Multiethnic Cohort Study consists of more than 215,000 men and women in California and Hawaii and comprises mainly five self-reported racial and ethnic populations: African Americans, Japanese Americans, Latinos, Native Hawaiians, and whites living in Hawaii and California.8 Between 1993 and 1996, adults 45 to 75 years old enrolled in the study by completing a 26-page mailed questionnaire asking detailed information about dietary habits, demographic factors, level of education, occupation, personal behavior, prior medical conditions, and family history of common cancers. Potential participants were identified through driver's license files from the Department of Motor Vehicles, voter registration lists, and Health Care Financing Administration data files.
Incident cancers, histologic types of lung cancer, and the stage of lung cancer were identified by linkage to the Surveillance, Epidemiology, and End Results (SEER) cancer registries covering Hawaii and California. Deaths were identified by linkage to death-certificate files in Hawaii and California and the National Death Index. Case ascertainment and death information were complete through December 31, 2001, in both Hawaii and California. For each participant, the length of person-time in the study was determined from the time the questionnaire was returned until the earliest of the following: a diagnosis of lung cancer, the diagnosis of another smoking-related tumor, death from any cause, or the end of follow-up (December 31, 2001).
At baseline, participants reported whether they had ever smoked at least 20 packs of cigarettes in their lifetime, the average number of cigarettes smoked (fewer than 5, 6 to 10, 11 to 20, 21 to 30, or at least 31 per day), the duration of smoking (no more than 10, 11 to 20, 21 to 30, 31 to 40, or at least 41 years), and for former smokers, the number of years since quitting (less than 1, 1 to 2, 3 to 5, 6 to 10, 11 to 15, 16 to 20, or at least 21 years). Occupations suspected to entail exposure to lung carcinogens were defined on the basis of previous reports.9 The level of education was used as a proxy for socioeconomic status, and the highest level of education attained was classified in the following manner: no more than 8 years of school, 9 to 12 years of school, completion of vocational school, or some college or higher education. Intakes of specific food groups such as fruits and vegetables were calculated as nutrient densities (food intake divided by total energy) and evaluated in quintiles.
Beginning in 2003, participants received an updated version of the original baseline questionnaire to update information on diet and personal exposures. The follow-up questionnaire again asked about smoking status, the level and duration of smoking, and the participant's age at the initiation of smoking (younger than 15, 15 to 16, 17 to 18, 19 to 21, 22 to 25, or older than 25 years). In the current analysis, we included such data on 5090 participants who reported a history of smoking at baseline to clarify sex and ethnic and racial differences in age at the start of smoking and the rates of smoking cessation since the first questionnaire. All questionnaires were approved by the institutional review boards at the University of Southern California and the University of Hawaii.
Excluded from this analysis were approximately 14,000 participants with other ethnic or racial backgrounds, approximately 2300 participants with a history of lung cancer or other smoking-related cancer as reported on the baseline questionnaire or from the cancer registries, approximately 8000 participants with missing data on smoking, and approximately 7600 participants with missing dietary data. A total of 183,813 participants contributed person-time to the analysis, and 1979 cases of lung cancer (1135 in men and 844 in women) were recorded. Cases were classified histologically as adenocarcinoma, squamous-cell carcinoma, small-cell carcinoma, large-cell carcinoma, or other. Disease stage was categorized as localized, regional, or distant.
Statistical Analysis
We used Poisson regression to model the absolute risk of lung cancer among participants who had never smoked, former smokers, and current smokers simultaneously (Hirosoft Sofware) as monomial functions of age and smoking duration, following the general approach of Doll and Peto.10,11 Our data indicated that the risk of lung cancer among participants who had never smoked was well fit as proportional to age to the fourth power and that the excess risk of lung cancer among former and current smokers was adequately described as a function of smoking duration to the fourth power multiplied by the number of cigarettes smoked per day. The effect of the level and duration of smoking in the model could be modified by race or ethnic group, sex, time since quitting, and an interaction between race or ethnic group and the smoking variables. We found the interaction between race or ethnic group and the number of cigarettes smoked to be significant (P<0.001). Additional terms for occupation, level of education, and dietary intake of fruits and vegetables were included in the multivariate models and evaluated as potential confounding factors. The specific details of the model we used are described in the Supplementary Appendix, available with the full text of this article at www.nejm.org.
Results
Study Population
The mean age at baseline was 60.1 years for men and 59.6 years for women. The level of education varied widely among the groups (Table 1). Among men, the rate of current smoking was highest among African Americans (28.5 percent) and Native Hawaiians (20.1 percent) and lowest among Japanese Americans (15.5 percent) and whites (15.9 percent) (Table 1). Among women, African Americans and Native Hawaiians were the most frequent current smokers, whereas Latinos and Japanese Americans had the lowest percentage of current smokers. Among both men and women, African Americans and Latinos reported smoking the fewest cigarettes per day, with whites being the heaviest smokers.
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We found significant yet fairly small differences in age at the initiation of smoking in a subgroup of 5090 participants (P<0.001) (Table 2). As compared with African-American women, Japanese-American women reported being older and whites younger when they began smoking. The same was true for men. Among both men and women, the mean age at smoking initiation was similar in African Americans, Native Hawaiians, and Latinos.
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Observed Risk of Lung Cancer According to Histologic Type and Stage of Disease
In age-adjusted analyses that did not account for smoking history, African-American and Native Hawaiian men had the highest incidence of lung cancer, whereas the incidence was similar among Native Hawaiian, white, and African-American women (Table 3). The incidence was significantly lower among Japanese Americans and Latinos than among African Americans — from 54.0 percent lower among Japanese-American men (P<0.001) to 71.0 percent lower among Latino women (P<0.001). The incidence of lung cancer among white women was similar to that among Native Hawaiian women (17.0 percent and 20.0 percent lower than that among African-American women, respectively), whereas the incidence among white men was 40.0 percent lower than that among African-American men.
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Ethnic and racial differences in relative risks were observed for all histologic types of lung cancer. Subtype-specific risks among Native Hawaiians were similar to those among African Americans except for the risk of small-cell carcinoma (relative risk, 1.92; P=0.003) and large-cell carcinoma (relative risk, 0.31; P=0.03). The relative risks of all subtypes of lung cancer were substantially lower among Japanese Americans and Latinos than among African Americans and ranged from 0.19 for large-cell carcinoma (P<0.001) to 0.58 for adenocarcinoma (P<0.001). As compared with African Americans, whites had significantly lower relative risks of all subtypes except small-cell carcinoma (Table 3).
The distribution of distant, regional, and localized disease was similar across groups (Table 3). The distribution among African Americans and whites was consistent with SEER data.12 Ethnic or racial differences in the risk of lung cancer were observed across all stages of disease, with African Americans and Native Hawaiians having similarly elevated risks. As compared with African Americans, Latinos and Japanese Americans had significantly lower relative risks for all stages, ranging from 0.28 for regional disease (P<0.001) to 0.54 for localized disease (P<0.001). Among whites, the relative risk of distant disease (P<0.001), but not of localized disease (P=0.59) or regional disease (P=0.07), was significantly lower than that among African Americans (Table 3).
Risk of Lung Cancer Related to Cigarette Smoking
Figure 1 shows the predicted risks of lung cancer among current smokers as a function of age in the different ethnic and racial groups at various smoking levels. At low levels of smoking (10 cigarettes per day) (Figures 1A and 1C), Japanese Americans and Latinos had one third the risk of lung cancer of African Americans or Native Hawaiians (global P<0.001). These differences essentially disappeared with higher levels of smoking (30 cigarettes per day) (Figures 1B and 1D). Similar patterns were observed for former smokers.
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A total of 13.1 percent of the cohort reported an occupation suspected to entail exposure to lung carcinogens (11.1 percent of African Americans, 12.0 percent of Native Hawaiians, 18.6 percent of Latinos, 12.8 percent of Japanese Americans, and 10.2 percent of whites). In analyses adjusted for smoking status, we found no strong associations between occupation and the risk of lung cancer (relative risk, 1.12; P=0.14). However, as compared with participants who completed no more than eight years of school, significant associations were observed among those who reported higher levels of education: both vocational training (relative risk, 0.73; 95 percent confidence interval, 0.56 to 0.95) and attending some college (relative risk, 0.70; 95 percent confidence interval, 0.58 to 0.84) were associated with a decreased risk of lung cancer. Total fruit intake (P=0.03) and vegetable intake (P=0.11) were not strong predictors of risk. Adjustment for these potential confounding factors did not influence the strong ethnic or racial differences in the risk of lung cancer associated with smoking.
These patterns were unchanged when we excluded 459 incident cases diagnosed within the first two years of follow-up. Among participants who had never smoked, we found no significant ethnic or racial differences in the rates of lung cancer in either sex (see Table 1 of the Supplementary Appendix).
Although statistical power was limited in some subgroup analyses because of the small numbers of cases, the ethnic or racial differences in the risk of lung cancer according to the histologic type were also more evident at lower levels of smoking (see Figures 1 through 4 of the Supplementary Appendix).
Discussion
We found significant differences in the association between cigarette smoking and the risk of lung cancer among five self-reported ethnic and racial populations. These differences were not evident among heavy smokers (those who smoked more than 30 cigarettes per day), a group that comprises between 2 percent and 19 percent of all smokers in the Multiethnic Cohort Study. The findings could not be explained by differences between populations in known or suspected risk factors, including diet, occupation, and socioeconomic status as assessed according to the level of education.
Previous comparisons of blacks with whites yielded moderate support for the existence of differences between these self-identified groups in the relative risk of lung cancer associated with cigarette smoking.4,5,6 We found the risk among whites to be significantly lower than that among African Americans among participants who smoked no more than 10 cigarettes per day (relative risk, 0.45) and those who smoked 11 to 20 cigarettes per day (relative risk, 0.57). Few studies have compared the smoking-associated risks of lung cancer among Native Hawaiians, Asians, and Latinos.7,13,14,15,16 In a population-based case–control study conducted in Hawaii, the risk of lung cancer among smokers after adjustment for the duration and level of smoking was more than twice as high among Native Hawaiians and 46 percent higher among whites as among Japanese Americans.7 Our prospective analysis corroborates these findings at low-to-moderate levels of smoking. The smoking-associated risk of lung cancer among Hispanics has previously been reported to be similar to that among whites,14 but we observed striking differences in risk, with Latinos and Japanese Americans having significantly lower risks than whites, Native Hawaiians, and African Americans at smoking levels of less than 30 cigarettes per day (Table 4).
Variation in the metabolism of nicotine among different ethnic and racial populations may underlie differences in smoking behavior (i.e., the depth and frequency of inhalation) and, thus, the uptake of carcinogens. Blacks have higher cotinine levels than white or Hispanic smokers after having smoked the same number of cigarettes.17,18 Blacks have also been reported to inhale more nicotine per cigarette smoked than whites and perhaps therefore have increased exposure to tobacco carcinogens, which may account in part for their high rates of lung cancer, despite a low number of cigarettes smoked per day.19
Greater dietary intake of fruit and vegetables has been associated with a reduced risk of lung cancer.20,21 There were considerable dietary differences among the ethnic and racial populations in our study; however, adjustment for mean daily fruit and vegetable intake among these groups could not explain the strong differences in risk among the populations. The level of education was related to risk, with the highest risk among those with less than eight years of schooling. Education is very likely a surrogate variable for other important exposures, but what these are and whether they are distributed disproportionately in the observed high-risk groups of African Americans and Native Hawaiians are not clear. Our findings are unlikely to be explained by differences in socioeconomic status, since over 50 percent of the African Americans in the Multiethnic Cohort Study had some college education, as compared with only 20 to 30 percent of Latinos.
Another explanation for the increased risks among African Americans and Native Hawaiians at lower levels of smoking is that they are constitutionally more susceptible to the effects of tobacco carcinogens. Our data suggest that these differences may be most relevant at lower levels of smoking, perhaps because, at high levels (more than 30 cigarettes per day), metabolic or other relevant pathways become saturated. Inflammation or other pathophysiological processes may also differ between populations and influence susceptibility to lung cancer. Further research is needed to understand the underlying mechanisms.
Other differences in smoking behavior may affect cumulative tobacco exposure. Black smokers have typically preferred menthol brands, although most studies do not support the hypothesis that menthol cigarettes are associated with a greater risk of lung cancer than other types of cigarettes.6,22 As previously mentioned, the intensity of smoking may differ among ethnic and racial groups, although in the previous case–control study in Hawaii, the type of cigarettes smoked and the depth of inhalation did not explain the observed differences in risk among Native Hawaiians, whites, and Japanese Americans.7
There may have been inconsistencies in the self-reported levels of smoking in our study, although the errors in reporting would have had to be substantially different between some groups to explain our findings. In a study among black, Hispanic, and white adolescents, the validity of self-reported levels of cigarette smoking was found to be similar across groups when compared with levels of expired carbon monoxide.23 Another study of self-reported smoking frequency among black adults and white adults also found no significant differences in the validity of self-reports as compared with the number of cigarette butts collected.24
In summary, our data provide further support for the existence of ethnic and racial differences in the smoking-associated risk of lung cancer. Studies assessing differences in the metabolism of nicotine and tobacco carcinogens may help explain differences between populations in the susceptibility to smoking-related lung cancer.
Supported by a grant (CA 54281) from the National Cancer Institute.
No potential conflict of interest relevant to this article was reported.
We are indebted to Faye Nagamine, Dr. Kristine Monroe, Hank Huang, Peggy Wan, Stuart Wugalter, Judith Tom, Hongshi Chen, and Maj Earle for their assistance and to the participants in the Multiethnic Cohort Study for their participation and ongoing commitment.
Source Information
From the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (C.A.H., D.O.S., M.C.P., B.E.H.); and the Cancer Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu (L.R.W., L.N.K., L.L.M.).
Address reprint requests to Dr. Haiman at USC/Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Rm. 4441, Los Angeles, CA 90089-9175, or at haiman{at}usc.edu.
References
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Related Letters:
Racial Differences in Lung Cancer
Epstein R. J., Zhao Y., Foulds J., Williams J. M., Gandhi K. K., Haiman C. A., Stram D. O., Le Marchand L.
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N Engl J Med 2006;
354:1951-1953, May 4, 2006.
Correspondence
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