Cigarette Smoking and the Incidence of Breast Cancer. Arch Intern Med. Conversely, cigarette smoking also has antiestrogenic effects, which may reduce the risk of BC. The association between smoking and BC remains controversial. After adjustment for potential confounders, the hazard ratio HR of BC was 1. Conversely, the direction of the association between postmenopausal smoking and BC was inverse 0. Passive smoking in childhood or adulthood was not associated with BC risk.
Breast cancer BC is the most common cancer to affect women worldwide. Tobacco smoking is one of the leading preventable risk factors of cancer in respiratory and nonrespiratory sites.
The antiestrogenic effect of smoking has been supported by an increased risk of osteoporosis, 16 , 17 an early age at natural menopause, 18 and attenuated effects of hormone therapy HT among smokers.
Numerous epidemiologic studies 13 have been conducted on the association between cigarette smoking and BC risk, and results from these studies have inconsistently suggested positive, inverse, or null associations. The direction and magnitude of the overall association between cigarette smoking and BC may differ according to the hormonal profile and other characteristics of the study population. Lifetime smoking exposure consists of many facets, including active and passive smoking, as well as quantity, duration, cessation, and age at initiation of smoking, which are difficult to assess accurately.
In case-control studies, recall bias must be considered. Our group previously reported a slightly elevated relative risk of BC among active but not passive smokers from the Nurses' Health Study based on follow-up from to that included cases of BC, especially when smoking was initiated at a young age.
The Nurses' Health Study is a large prospective cohort established in Since , each participant has been mailed a questionnaire biennially to update information on demographic, anthropometric, and lifestyle factors and newly diagnosed diseases. Because questions on passive smoking were not asked until , the follow-up for passive smoking analysis started in All included women were followed up biennially from cohort entry for active smoking analysis and for passive smoking analysis until the earliest of the following events: diagnosis of invasive or in situ BC, loss to follow-up, death, or the end of the study period in Women who were lost to follow-up in each cycle were not followed up for that cycle but could reenter the analysis if they responded to the next questionnaire.
To eliminate the effect of active smoking in the analysis on passive smoking, the follow-up also ended when women started smoking. The follow-up rate calculated as eligible person-years divided by the maximum possible number of person-years and assuming no loss to follow-up was This study was approved by the institutional review board of the Brigham and Women's Hospital.
The status and quantity of current smoking were first assessed in and updated biennially. Past smoking status and quantity were asked only once in the questionnaire. In , current and past smokers were also asked about the age at which they started smoking, whether they had ever quit smoking for 6 months or longer, and the age at which they quit smoking. Questions related to passive smoking, including parental smoking status when living with them, the number of years they lived with a smoker in adulthood, and the status and frequency of exposure to cigarette smoke at home and work, were asked in Duration of smoking was derived by deducting the age at which they started smoking from their current age for current smokers and from the age at which they quit smoking for past smokers.
For past smokers, the number of years since quitting was calculated as the difference between current age and the age at which they quit smoking. Duration of smoking for current smokers and years since quitting were updated biennially. Pack-years of smoking from menarche to first birth, from first birth to menopause, and after menopause were derived from updated information on the age at which they started and stopped smoking and the amount of current and past smoking.
Participants were asked biennially whether they had been diagnosed as having BC during the past 2 years and, if so, to report the date of diagnosis. Deaths were reported by next of kin or by the US Postal Service in response to the follow-up questionnaires.
The National Death Index was also routinely searched for deaths among women who did not respond to the questionnaires. All women who reported new onset of BC were asked for permission to review their relevant medical records. Study physicians reviewed all medical records and pathology reports to confirm disease status and tumor details, including hormone receptor status and invasiveness.
In the present study, we included invasive BC confirmed by medical record or by the nurses themselves because self-reports of BC have been found to be highly reliable. Participants in the Nurses' Health Study were asked biennially about their reproductive factors, anthropometric characteristics, lifestyle, and diagnosis of other diseases. Current body mass index BMI and BMI at age 18 years were calculated as weight in kilograms divided by height in meters squared, using weight at the respective age and height in adulthood.
Assessment of age, parity, current weight, alcohol consumption, physical activity, oral contraceptive use, menopausal status, age at menopause, HT use, history of benign breast disease, and family history of BC were updated during follow-up. A Cox proportional hazards regression model was used to assess the association between active and passive smoking and the incidence of BC. Active smoking was analyzed as smoking status, quantity of smoking, age at which participants started smoking, duration of smoking, years since quitting smoking, and pack-years of smoking in defined categories.
Passive smoking was analyzed as exposure to parental smoking when living with them, passive smoking at work, passive smoking at home, and the number of years participants lived with someone who smokes in defined categories.
We also derived an index of passive smoking that integrates frequency and years of exposure. All categorical variables of active and passive smoking were used as indicator variables, with the lowest level as the reference.
Trend tests for categorical measures of smoking were based on the midpoint value of each category. Potential confounding factors included age, family history of BC among first-degree relatives, age at menarche, height, BMI at age 18 years, oral contraceptive use, history of benign breast disease, leisure-time physical activity, alcohol consumption, a derived variable cross-stratifying age at first birth by parity, current BMI, age at menopause, menopausal status, and HT use.
Updated history of mammogram screening and types of HT estrogen, progesterone, or combined were also considered as potential confounders, but the adjustment for them did not substantially change the results. Passive smoking status at work and at home was also adjusted for in the analysis on active smoking. Active smoking status was additionally adjusted for in the analysis of the quantitative smoking measures quantity, age started, duration, and pack-years. Because smoking cessation is related to weight gain, 21 which may increase the risk of BC for postmenopausal women, 1 the potential effect modification of number of cigarettes a day when respondents started and stopped smoking by changes in BMI was assessed by stratified analyses, and the significance of effect modification was evaluated.
The potential heterogeneity in the association between smoking and BC across various reproductive periods was assessed using a fixed-effects meta-analysis of effect estimates derived from each period weighted by the inverse variance. Polychotomous logistic regression software 22 was used to test the heterogeneity of the association between smoking and subtypes of BC according to tumor estrogen receptor ER and progesterone receptor PR status.
Relative to person-years with other smoking status, current smokers were more likely to be postmenopausal and to have a lower current BMI; past smokers were more likely to have a family history of BC, to have a history of benign breast disease, and to have ever used oral contraceptives; and never smokers tended to consume less alcohol Table 1. Women with regular exposure to passive smoking had a higher BMI and were more likely to be nulliparous and to have used oral contraceptives.
Ever smokers had a marginally increased incidence of BC compared with never smokers, and the increase in incidence seemed to be comparable for past smokers and current smokers Table 2. Because the association between smoking and BC became stronger after adjusting for menopause-related factors, it is likely that this association was partially mediated by an early onset of menopause induced by smoking.
The covariate-adjusted HR was slightly elevated among women who smoked 25 or more cigarettes a day currently or in the past, who started to smoke at or before age 17 years, who smoked for 20 to 39 years or for 40 years or longer, or who had quit smoking within the past 10 years Table 3.
An indicator for heavy smoking that integrates all 3 measures of smoking was created. When we restricted the analysis to postmenopausal women without any HT at the person-level, the results were similar to those restricted to person-years without HT. Postmenopausal smoking in relation to the incidence of BC was not significantly different by PR status. The association between premenopausal smoking and the incidence of BC did not differ significantly by ER or PR status data not shown.
When analyses were stratified by menopausal status when BC was diagnosed, active smoking was not differentially associated with premenopausal BC relative to postmenopausal BC for various assessed smoking measures. Exposure to parental smoking when living with them, exposure to passive smoking at work or at home, the number of years living with someone who smokes, and the index of passive smoking were not related to the incidence of BC in covariate-adjusted analyses Table 5.
In the present study, various measures of smoking, including ever smoking, current and past quantity, age at which one started smoking, duration, years since quitting smoking, and pack-years of smoking after menarche were associated with a marginally higher incidence of BC.
Smoking before menopause, especially before the first birth, was associated with a slightly increased incidence of BC. The associations of BC risk with quantity of smoking, 25 - 38 duration of smoking 19 , 32 , 35 - 37 , 39 and age at which one started smoking 19 , 29 , 32 , 33 , 35 - 39 have been investigated in many previous studies. The results remain partly conflicting, but positive associations have been reported among heavy smokers, long-time smokers, and smokers who started at an early age.
In most of the previous studies, these smoking measures were not mutually adjusted. In the present study, we created an index of active smoking that integrates quantity, age at which one started smoking, and duration of smoking. The results suggested that, although an elevated risk for light smokers and moderate smokers was not apparent, heavy smokers who started smoking early in life, smoked for a long duration, and smoked a high quantity were at the highest risk of BC, supporting an independent and additive effect from various smoking measures on breast carcinogenesis.
Results from the present study suggest that the initiation of smoking before menopause and particularly before the first birth was most strongly associated with an increased risk of BC. Early age at the first birth has been found to convey a long-term protection against BC, possibly because of the terminal differentiation of breast epithelium late in the last trimester of the pregnancy. All previous studies that have separately evaluated smoking before and after the first birth have found a similar pattern, suggesting that smoking before the first birth may be more important to breast carcinogenesis than smoking after the first birth.
Smoking before menopause was positively associated with BC risk, and there were hints from our results that smoking after menopause might be associated with a slightly decreased BC risk.
This difference suggests an antiestrogenic effect of smoking 15 among postmenopausal women that may further reduce their already low endogenous estrogen levels. Conversely, among premenopausal women, any antiestrogenic effect of smoking may not be strong enough to significantly reduce endogenous estrogen levels, leaving the dominant carcinogenic effect of smoking.
Extensive exposure to passive smoking has been suggested to induce BC development because N -nitrosamines and other carcinogens found in tobacco smoke appear to be more concentrated in passive smoke than in mainstream smoke.
In the present study, incidence of BC was not related to frequency or duration of passive smoking in adulthood or to exposure to parental smoking in childhood. Our results combined with the evidence from previous prospective cohort studies collectively suggest that passive smoking may not play an important role in the etiology of BC.
Nonetheless, we found that regular exposure to passive smoking may magnify the effect of active smoking. This effect was not explained by higher smoking intensity among smokers who were also regularly exposed to passive smoking because we found the same pattern of effect modification for all smoking measures, including duration, quantity, and age at which one started smoking.
Such interaction has not been explored in previous studies, and further evidence is warranted to confirm our finding and to explore potential mechanisms. A limitation of the present study is the limited quantitative and updated assessment of passive smoking, which introduces the potential for misclassification. Compared with active smoking, passive smoking is more difficult to assess because of its ubiquitous presence.
Previous studies 19 , 37 , 38 , 45 - 56 on passive smoking have used various quantitative measures, such as quantity and duration of husband's smoking, pack-years of lifetime exposure, and hours per day—years, but none of these measures has been suggested to be superior. Any nondifferential misclassification of passive smoking in our study would bias the association toward the null.
To our knowledge, the present study is the largest so far on the association between smoking and BC risk. The substantial statistical power allows us to detect even a modest association. The prospective cohort design and updated information on quantity and status of active smoking prevented recall bias and minimized the chances for selection bias and nondifferential misclassification of smoking due to changes in behavior over time.
The Nurses' Health Study provides information on a variety of covariates, including potential confounders, effect modifiers, and hormone receptor status of BC, and allows exploration of mechanistic associations.
Despite the extensive research on cigarette smoking in relation to BC risk, this association remains controversial. Results from the present study suggest that the potential effect of active smoking on BC risk is modest. The risk of BC may increase with younger age at smoking initiation and longer duration of smoking. Antiestrogenic effects of smoking, which may convey a reduced risk of BC, are suggested to be more dominant among postmenopausal women.
Growing evidence suggests that carcinogen-metabolizing genes may modify the potential effect of smoking on risk of BC. Acquisition of data : Willett and Hankinson. Drafting of the manuscript : Xue. Critical revision of the manuscript for important intellectual content : Xue, Willett, Rosner, Hankinson, and Michels.