Abstract
Keywords
Cigarette smoking is known to increase the morbidity and mortality for an increasing variety of cancers, including breast cancer, and an untold number of noncancerous disorders in both men and women, most prominent of which are hypertension and coronary artery disease.
Gender differences: cigarette smoking & health
Is cigarette smoking more dangerous in women than in men? Comparing the effects of cigarette smoking in males and females is difficult, given the gender differences of certain habit patterns. For example, historically, for more than 100 years, males have smoked more heavily than women, with a corresponding higher incidence of lung cancer. During the past half century however, there has been a significant rise in the cigarette smoking habit among women and, consequently, their rate of lung cancer is now almost equal to that of males. Clearly, this temporal difference in cigarette smoking habit patterns makes it difficult to assess male versus female differences in cancer consequences when considering the impact of cigarette smoking or, for that matter, any other carcinogenic exposure that is not unique to males or females. Prescott et al. note that the relative health risks observed in women indicate that they may be more sensitive than men to certain deleterious effects of cigarette smoking [1]. However, owing to a lower baseline mortality rate in women, differences in the results should be interpreted with caution.
In a Norwegian chronic obstructive pulmonary disease (COPD) study, the number of female smokers developing this disorder was found to be rapidly rising [2]. Findings demonstrate that women had a more severe lung function reduction than men among subjects who started smoking at a later age and who had early-onset COPD. This suggests a general gender difference in susceptibility to the lung-damaging effects of cigarette smoking. However, these authors recognized that there might be alternative explanations. Further support was given by Langhammer et al. who noted that when the prevalence of symptoms and current asthma among women and men with the same smoke burden or daily cigarette consumption were compared, women seemed to be more susceptible to the effect of tobacco smoking than men [3]. In a subsequent study, Langhammer et al. noted that females reported more symptoms in concert with lower self-rated health compared with males with similar smoking burden. Therein, “even if smoking in females was associated with a larger reduction in percent predicted lung function compared with males, this does not fully explain the higher symptom prevalence in females” [4].
Wilson et al. also note that the association of smoking with impaired quality of life “…is more marked in females than in males. There is a need to identify female smokers as a distinct target group in smoking cessation initiatives and programs” [5].
Summary of methods & results
Luo et al. [6] performed a well-conducted prospective observational study of active and passive smoking among 79,990 women aged 50–79 years during 1993–1998. A total of 3520 incident cases of invasive breast cancer were then identified during an average of 10.3 years of follow-up. Importantly, initial reports of cancer were ascertained by annual self-administered questionnaires. The reports of breast cancer were subsequently confirmed by medical records including pathology reports. The completion rate of annual questionnaires was 93–96%. Only invasive breast cancer cases were included, with exclusion of carcinoma in situ.
Biostatistical analysis among women who had never smoked, when compared with smokers, showed breast cancer risk to be increased among women who were former smokers, with a hazard ratio (HR) of 1.09, and by 16% among current smokers with a HR of 1.16. Active smokers showed a high breast cancer risk when smoking was initiated in the teenage years as well as for duration of smoking. Women who had smoked for 50 years or more were found to have the highest breast cancer risk; when compared with all lifetime nonsmokers, the HR was 1.35; the HR was 1.45 in comparison to nonsmokers who lacked exposure to passive smoking. This smoking-associated breast cancer risk persisted for 20 years following smoking cessation.
Among nonsmokers, those exposed to passive smoking for 10 years or more in childhood, 20 years or more as an adult at home, and 10 years or more as an adult at work, showed a 32% increased risk for breast cancer when compared with those who had low exposure to passive smoking. Interestingly, there was no significant breast cancer association in those individuals who had a lower exposure to the cumulative effects of passive smoking exposure. These findings merit serious attention for smoking cessation with respect to breast cancer risk among women.
The importance of family history of breast cancer as well as hormone therapy use inclusive of estrogen and progestin, age at menarche, and age at first live birth should be emphasized in a well-conducted study. For example, when compared with women who remained free of breast cancer, it was found that “…those who developed the disease were significantly more likely to be non-Hispanic white individuals, more highly educated, nulliparous, older age at first live birth, and to have a history of taking estrogen plus progestin hormone therapy, heavier alcohol intake and a family history of breast cancer (all p-values < 0.05). Women who developed breast cancer were also less likely to have never smoked than those who did not develop cancer (48 vs 51.4%). Among lifetime nonsmokers, 88.1% were exposed to passive smoking and most women had multiple types of passive smoking exposure. Childhood exposure only was slightly higher among the nonsmokers who developed breast cancer than those who did not, as with multiple types of passive smoking exposure…” [6]. These findings should emphasize the health risks associated with smoking.
Discussion
Luo et al. call attention to the fact that breast cancer is a heterogeneous disease with many subtypes that may vary in their etiologies [6]. For example, data suggest that lobular breast cancer may be more strongly associated with current smoking than ductal breast cancer and with tumors that were hormone receptor-positive for both estrogen and progesterone. Hence, when assessing cigarette smoking sequelae, one is compelled to consider these clinical and pathology variations and their influence on breast cancer.
Major strengths of the Luo et al. study include the prospective design, the large and broad geographical distribution of the cohort, the large number of cancer cases, pathological confirmation of cases, detailed information on potential confounders, and, particularly, detailed information on passive smoking, including quantitative measures of cigarette smoke exposure in childhood and adult exposure in residential and workplace settings [6]. They appropriately conclude that the association with passive smoking should be considered suggestive only, and needs confirmation with other studies. Their findings highlight the need for interventions to prevent initiation of smoking, especially at an early age, and to encourage smoking cessation at all ages. Importantly, they highlight the need for future studies to examine how genetic polymorphisms and other risk factors modify the effect of tobacco exposure on breast cancer risk, which are then likely to further our understanding of this important issue.
Other studies
Reynolds et al. studied passive smoke exposure by setting, namely the home, work or social settings, and by age of exposure, among 57,523 women who were lifetime nonsmokers and who had no history of breast cancer [7]. Following a decade, a total of 1754 women were diagnosed with invasive breast cancer. Considering all breast cancers, measures of high lifetime passive smoking intensity and duration showed a nonstatistically significant HR of 1.11–1.14. However, for the postmenopausal subset of women, HRs “…for lifetime low, medium and high cumulative exposure were 1.17 (95% CI: 0.91–1.49); 1.19 (95% CI: 0.93–1.53); and 1.26 (95% CI: 0.99–1.60). For women exposed in adulthood (age ≥20 years), risk was elevated at the highest level of cumulative exposure (HR: 1–18; 95% CI: 1.00–1.40), primarily among postmenopausal women (HR: 1.25; 95% CI: 1.01–1.56)…”. These findings showed a statistically significant dose response which was restricted to women with moderate-to-high levels of passive smoking exposure, thereby suggesting that cumulative exposure to high levels of passive smoking may increase breast cancer risk among postmenopausal women even though they had never smoked tobacco products.
A prospective cohort study from the Nurses' Health Study, identified 111,140 active smokers and 36,017 who had been exposed to passive smoking. During 3,005,863 person-years of follow-up, 8772 incident cases of invasive breast cancer were reported [8]. The HR of breast cancer was 1.06% for ever smokers relative to never smokers. Breast cancer incidence was associated with a higher quantity of current and past smoking, younger age at smoking initiation, longer duration of smoking, and more pack-years of smoking. Premenopausal smoking was associated with a slightly higher incidence of breast cancer. Interestingly, passive smoking in childhood or adulthood was not associated with increased breast cancer risk. The authors call attention to the fact that, while tobacco smoke contains carcinogens, which may increase breast cancer risk, conversely cigarette smoking offers antiestrogenic effects that may reduce breast cancer risk. They conclude that active smoking, particularly before a woman gives birth to her first child, may be associated with a modest increase in the risk of breast cancer. However, despite extensive epidemiologic studies dealing with cigarette smoking and breast cancer risk, this association remains controversial.
Risk factors
There are an increasing number of additional epidemiologic risk factors, including healthcare disparities, which may impact upon the cigarette smoking issue. Early age at first pregnancy affords protection to breast cancer. By contrast, breast cancer risks are increased by long-term estrogen exposure, as in oral contraceptives, or by exposure to radiation. For example, radiation exposure among those exposed to the atomic bombs at Hiroshima and Nagasaki, demonstrated that those individuals who were closer to the epicenter and who were younger in age at the time of exposure had a greater lifetime risk of breast cancer than those exposed more distantly from the epicenter and later in life.
Carcinogens are notorious for their interaction with each other. An excellent example of this phenomenon is asbestos exposure in addition to cigarette smoking, which leads to a significant increase in the production of mesothelioma. Is the effect of radiation exposure impacted by cigarette smoking? The list of such interactions may be very long.
Genetic susceptibility
It is extremely important to appreciate the fact that the findings mentioned are based on population studies, and therein they raise many questions from the host factor standpoint. For example, one must carefully evaluate whether a subset of this population is more vulnerable to cigarette smoking effect owing to their familial risk. In testing the cigarette smoking effect with respect to hereditary cancer syndromes, Watson et al. investigated whether tobacco use would alter colorectal cancer risk in carriers or Lynch syndrome-associated mismatch repair mutations MLH1 or MSH2 in a retrospective cohort study [9]. Their findings showed that tobacco use, MLH1 mutation carrier status (compared with MSH2 carrier status), and male sex were significantly associated with an increased risk of colorectal cancer with HRs of 1.43, 2.07 and 1.58, respectively. Interestingly, alcohol consumption did not alter colorectal cancer effect. They concluded that smoking cessation must be an integral part of the management of Lynch syndrome, therein highlighting the genetic–environmental interactions in cancer development and, in this case, tobacco use.
Carcinogens & breast cancer risk: individual variation
Harris places appropriate emphasis on the person-to-person variations of carcinogenic effects secondary to an individual's type of enzymatic activities [10]. Specifically, he emphasizes the fact that repair rates of DNA damage owing to carcinogens vary among those so exposed, wherein there exist individual differences in their metabolism and repair rates which are relevant to their degree of carcinogen-induced DNA damage; these effects are, in turn, mediated by acquired as well as inherited host factors which influence an individual's risk for cancer occurrence. Herein, Harris credits Charles Darwin in The Origin of Species, 1859, who stated “No one supposes that all the individuals of the same species are cast in the very same mold. These individual differences are highly important to us” [11].
The phenomenon of individual differences in patients' inherited endowments of biochemical make-up has been emphasized by Ambrosone et al. [12], who show that the cigarette smoking effect is associated with an increase in breast cancer risk among women who inherit NAT2 slow acetylation genotypes, which are present in approximately 50–60% of Caucasian populations. Herein, it is reasoned that smoking is likely to play an important etiologic role in breast cancer, particularly among those who are so-called ‘slow acetylation genotypes’.
Conclusion
A series of population-based studies of the effects of cigarette smoking and breast cancer risk in women have shown a significant association between cigarette smoking and breast cancer risk. Factors impacting this risk are the following: duration of smoking; young age of smoking onset; continuation of lifetime smoking and postmenopausal smoking. Evidence for passive smoking effect, while highly significant in some studies [6,13], is controversial in others [8]. In addition to the carcinogenic effects of cigarette smoking on breast cancer, there are also data showing that all individuals exposed to carcinogens are not affected in the same way [10,14].
Future perspective
Clearly, men and women should avoid active cigarette smoking and, whenever possible, passive smoking. Indeed, legal constraints against cigarette smoking are being put into practice worldwide, with smoking prohibition in public and private establishments; these new laws are designed to protect and to hopefully dissuade active cigarette smoking and to protect individuals from the effects of passive smoking. There is a need for further governmental regulation of the sale of cigarettes to those younger than the consenting age. Finally, the evidence for an increasingly wide variety of diseases, including multiple cancer sites, is so overwhelming as to erase any skeptical theoretical causal factors since we can now clearly establish on a factual basis the significant and, indeed, tragic carcinogenic effects of this drastic life-threatening habit pattern.
Executive summary
Population-based studies of the effect of cigarette smoking on a variety of cancers, inclusive of carcinoma of the breast, have shown risk to be impacted heavily by smoking duration, early age of smoking onset, its continuation throughout a patient's lifetime and, for women, postmenopausal smoking.
Conversely, the effect of passive smoking remains controversial, although some data demonstrate that passive smoking does impact on differing cancer sites inclusive of the breast.
All individuals exposed to carcinogens are not affected in the same way, with some being more susceptible to cancer and other smoking-related diseases than others.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.