This study demonstrated that higher BMI was significantly associated with all-cause death among premenopausal patients after adjustment for clinical and known factors that are associated with the mortality risk of breast cancer patients. Analysis stratified according to hormonal receptor status showed that higher and lower BMI were associated with increased risks of all-cause and breast cancer-specific death only for patients with ER
tumors. Previous studies that investigated the relationship between BMI and outcome in Japanese breast cancer patients considered only a few known risk factors as covariates, included only a small number of cases, and did not assess hormone receptor status [25
]. Our study is of importance in having assessed the relationship between BMI and all-cause or breast cancer-specific death by taking into account multiple risk factors for breast cancer, in addition to menopausal status and hormone receptor status, in Japanese women.
Our results demonstrated that higher BMI was significantly associated with all-cause death among premenopausal patients, and were consistent with several previous observational studies of premenopausal or younger women that demonstrated poorer overall survival with increased BMI [2
]. A meta-analysis including 43 studies showed that the effect of obesity on higher all-cause or breast cancer-specific death was larger among premenopausal than among postmenopausal women [21
]. Our present results demonstrated that the effect of higher BMI was greater for all-cause death than for breast cancer-specific death (HR
2.61; 95% CI: 1.01–6.78 for BMI ≥25.8
for all-cause death; HR
1.68; 95% CI: 0.61–4.65 for BMI ≥25.8
for breast cancer-specific death). One possibility is that women with higher BMI have poorer overall survival because of a higher risk of comorbidities. Therefore, we reanalyzed the data after excluding patients who had comorbidities. Within the limited statistical power, the effect of higher BMI was significant for all-cause death among premenopausal patients (HR
3.42; 95% CI: 1.23–9.47 for BMI ≥25.8
for all-cause death, p for trend for BMI ≥21.2
0.0068) and not significant for breast cancer-specific death. These were perhaps potential mediators of the adverse effect of higher BMI in premenopausal breast cancer patients, independent of comorbidities.
In the present study, an association of higher BMI with poorer outcome was seen in women with ER
tumors. This result is consistent with previous studies that have indicated an association of higher BMI with poorer outcome, being especially pronounced among women with hormone receptor-positive tumors [9
]. Several hypotheses to explain why obese breast cancer patients show poorer survival can be considered. Firstly, there may be differences in sensitivity to estrogen among tumors with different types of hormone receptors. A previous study found that hormone receptor-positive tumors showed a better response to endocrine therapy than ER-/PgR- tumors [34
], indicating that ER
tumors are the most sensitive to estrogen hormone. Secondly, it has been postulated that higher estrogen concentrations may confer increased biological aggressiveness on hormone receptor-positive tumors, as BMI is directly related to circulating estrogen levels [22
]. Thirdly, higher BMI is associated with upregulation of a number of cellular proliferation pathways [37
]. Consequently, obesity might lead to an increase of tumor cell proliferation and metastasis through undefined adipokine effects on tumor cells [17
]. For example, leptin, an adipocytokine, is produced mainly by adipose tissue and is known to act as a cancer growth factor [38
], as well as promoting angiogenesis and potentially stimulating the growth of breast cancer cells, thus possibly leading to reduced patient survival [39
Our present multivariate-adjusted analysis showed that BMI <21.2
, i.e. low BMI, was associated with elevated risks of both all-cause and breast cancer-specific death among women with ER
tumors. The relationship between low BMI and higher cancer mortality risk might be at least partly explained by the presence of circulating tumor cells (CTCs) in the peripheral blood of patients [40
]. CTCs are derived from clones in the primary tumor [41
] and are thought to become scattered to various organs, leading to the development of distant metastasis [42
]. In patients showing chronic undernutrition, cytokine reactions and subsequent activation of the immune system are compromised, which might affect the tumor-immune system interaction in distant organs [43
]. In this study, the BMI <21.2
category might have included undernourished patients as well as properly nourished, naturally lean patients. This may have partly contributed to the increased risk of all-cause and breast cancer-specific death. Another reason for the relationship between the BMI <21.2
category and higher risk of cancer mortality might have been the slightly higher proportion of patients with advanced-stage breast cancer. Therefore, we attempted to analyze the data by omitting cases of advanced breast cancer. However, this analysis yielded almost the same results (data not shown).
The major strengths of the present study were that no subject was lost to follow-up during the study period. The MCCH Cancer Registry conducts active follow-up by accessing hospital visit records, resident registration cards and permanent domicile data. In cases of death occurring outside the hospital, information on the date and cause of death was obtained with permission from the Ministry of Justice. Another strength was the relatively low proportion of patients for whom data on hormone receptor status were missing (10.6%). In previous studies, the proportion of patients for whom data on ER and/or PgR status were missing ranged from 5.0% to 48.1% [2
]. Distribution of receptor status for ER and PgR was roughly the same as those in previous studies which investigated 3,089 patients from ten hospitals in Japan [44
]. A further strength was that it gave consideration not only to clinical stages but also to treatments such as chemotherapy, endocrine therapy and radiation therapy from an epidemiological viewpoint.
Several limitations of our study should also be considered. First, although BMI has been accepted as an index of obesity, it cannot be used to identify the distributions of fat and muscle tissue. Second, we used self-reported BMI at the baseline, and there may have been a misclassification of exposure due to self-reported weight and height. However, the self-reported current height and weight data were highly correlated with measured data, and therefore any possible bias was likely small. Third, stratification by hormone receptor status may have resulted in false positive or false negative results. The 95% CIs were wide for HRs by hormone receptor status, suggesting that statistical power might be limited because of relatively small number of patients and all-cause and breast cancer-specific deaths. To obtain reliable results with this stratification, subsequent recruitment of patients and follow-up will be required. Fourth, the generalizability of our results to the Japanese population as whole may be limited because our study was conducted among a population living in a rural area. More studies are needed to verify our results instead of to assess the generalizability.