All three potentially modifiable risk factors we investigated were positively related to risk of second primary contralateral breast cancer. The 40% to 50% elevation in risk associated with obesity we observed is consistent with the 58% elevation in contralateral breast cancer risk women with a BMI ≥ 30 kg/m2
had compared with women with a BMI lower than 25 kg/m2
enrolled in the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial of adjuvant tamoxifen in patients with node-negative invasive ER+ breast cancer.5
It is also consistent with the 56% elevation in risk of second primary breast cancer observed for women in the highest BMI quartile compared with women in the lowest quartile in a large population-based cohort of breast cancer survivors.7
Thus, our study adds to the growing body of evidence from recent studies that obesity may be an important risk factor for second primary contralateral breast cancer. The mechanisms through which obesity confers an increased risk of contralateral breast cancer are likely to be quite similar to those which govern its well established relationship with risk of first primary breast cancer.10
In postmenopausal women, adipose tissue is the primary producer of endogenous estrogens, and this is thought to be the primary pathway through which obesity confers an elevation in breast cancer risk. In addition, there is growing data to suggest that hyperinsulinemia may also be an important contributor to the relationship between obesity and breast cancer.11
We observed that consumers of ≥ 7 alcoholic beverages per week had a 90% increased risk of contralateral breast cancer. Our result is broadly consistent with the increased risk of contralateral breast cancer observed among women who had ever regularly consumed alcohol in a large recently published multicenter patient-control study.9
Our risk estimate is higher though than the 20% increase in risk this prior study observed among women who on average consumed ≥ 1 drink per day. Other smaller studies have also observed modest positive associations that were not statistically significant.3,7,8
While the reasons for this difference in the magnitude of the association are unclear, one potential explanation is that our study was restricted to women whose first breast cancer was ER+. Similar to obesity, the relationship between alcohol use and risk of first breast cancer is well established.12
The primary mechanism through which it is thought to elevate risk is hormone since alcohol consumption directly increases endogenous estrogen levels in postmenopausal women.13,14
There is also some evidence that alcohol use is more strongly related to risk of ER+ versus ER-negative breast cancer.15,16
Thus, based on the available biologic and epidemiologic evidence, the relationship between alcohol use and contralateral breast cancer may be stronger among women whose first breast cancer was ER+.
Our observation that current smokers have a substantial 2.2-fold increased risk of contralateral breast cancer is somewhat consistent with the results of two previous reports, although the magnitude of the association we observed is again higher. One of these studies observed a 70% increased risk among women who smoked more than a pack a day,4
and the other reported a 24% increased risk among ever smokers3
(compared with never smokers), but neither result was statistically significant. In contrast, the previously mentioned large multicenter case-control study that found a positive association with alcohol, did not observe a relationship between ever having smoked during the interval between first breast cancer diagnosis and reference date and contralateral breast cancer risk.9
However, it did not separate former and current smokers, making it somewhat difficult to directly compare our results. Lastly, a study evaluating risk of second primary breast cancer regardless of laterality found that current smoking was not related to risk.7
Unlike obesity and alcohol use, smoking is not a well established risk factor for postmenopausal breast cancer despite biologic plausibility for a positive association. Tobacco smoke contains carcinogens that are genotoxic to the rodent mammary gland,17
and in humans tobacco carcinogen DNA adducts have been found in breast tissue18,19
and these carcinogens can be metabolically activated in breast epithelial cells.20,21
Inconsistency in published results from epidemiologic studies may due to evolving smoking patterns in women. Several recent studies indicate that smoking initiation at a young age and/or before a first full-term pregnancy may be more strongly related to breast cancer risk than is initiation at older ages.22–25
In addition, greater intensity and duration of smoking appears to be positively associated with risk in several recent cohort and patient-control studies.24–28
Thus, earlier studies of smoking and breast cancer may have failed to find an association with risk because too few women included started smoking at a young age or had smoked at sufficient intensities or durations to detect an association. The interaction between alcohol consumption and smoking in relation to contralateral breast cancer observed here has not been previously reported. While our study had limited statistical power to assess interactions, our results suggest that smoking may confer an increased risk of contralateral breast cancer independent of alcohol use, alcohol's effect may depend on concurrent smoking, and women with higher levels of alcohol consumption who are current smokers may have particularly high risks of contralateral breast cancer. However, these relationships require confirmation.
A potential limitation of all patient-control studies is recall bias. Our BMI results were not impacted by this bias because our primary source of anthropometric data was medical records and risks were unchanged when analyses were restricted to data only from medical records. In contrast, data on smoking and alcohol use could not be reliably obtained from medical records and so analyses are based only on self-reported data. Consequently, data from enrolled deceased women could not be included. The extent of the potential resulting biases is unknown. Encouragingly, when we restricted our BMI analyses to self-reported data from alive women, the same association was observed when women with a BMI ≥ 30 kg/m2 at first breast cancer diagnosis were compared with women with a BMI lower than 25 kg/m2 (OR based on medical record data including both alive and deceased women: 1.6; 95% CI, 1.1 to 2.2 v OR based on self-reported data from alive women only: 1.6; 95% CI, 1.0 to 2.5). Given the considerable correlation within our three exposures between the two time points of interest, date of first breast cancer diagnosis and reference date (particularly for BMI and alcohol use), it was difficult to evaluate how changes in these exposures over time influenced contralateral breast cancer risk. However, in a subanalysis of women who were current smokers at the time of their first breast cancer diagnosis, but had quit smoking by reference date, the fact that they were current smokers at their first breast cancer diagnosis did not impact their risk of contralateral breast cancer. This suggests that recency of smoking may be most relevant to contralateral breast cancer risk. With respect to the generalizability of our results, this study was limited to women with ER+ first primary breast cancers, so the extent to which the risk factors studied influence risk of contralateral breast cancer among women with ER-negative first breast cancers could not be assessed. Also, this study included women diagnosed with their first breast cancer as long ago as 1990 when patterns or hormone therapy use were different then they are now. As a result fewer women ever used hormone therapy, or used if for a duration conferring maximal clinical benefit, than women today. While our analyses were adjusted for use of hormone therapy, interactions with hormone therapy could not be assessed given the size of our study.
Few studies, most with relatively small sample sizes, have evaluated the influence that potentially modifiable lifestyle factors have on risk of second primary contralateral breast cancer. Identifying such factors could be both of broad public health relevance and of individual importance to the growing number of breast cancer survivors. Our population-based study adds to the limited available literature and suggests that obesity, smoking, and alcohol are all positively related to risk affording breast cancer survivors three means of potentially reducing their risk of contralateral breast cancer.