This prospective analysis of over 9000 women with invasive breast carcinoma suggests that BI-RADS density is not related to risk of breast cancer death or death from any cause. However, our data suggest that breast cancer patients with low density (BI-RADS 1) who are obese, or diagnosed with large tumors, or possibly have high-grade tumors are at increased risk of breast cancer death. Given that high breast density has been related to breast cancers with adverse prognostic features, we had hypothesized that elevated density might be related to reduced breast cancer survival, although that is not the finding in this analysis. Thus, our results raise additional questions regarding possible interactions between breast density, other patient characteristics, and subsequent treatment in influencing breast cancer prognosis.
The null finding we observed between breast density and breast cancer death is consistent with one (16
) of two previous studies to have evaluated this association (16
). In a British hospital–based study of 759 breast cancer patients, breast cancer–specific survival did not differ by BI-RADS density (the number of breast cancer deaths was not reported) (16
). In contrast, an analysis (17
) of 989 breast cancer patients identified within the Danish mammography screening program found that having mixed/dense breasts was associated with a reduced risk of breast cancer death compared with having fatty breasts (roughly equivalent to BI-RADS 1 or some BI-RADS 2; age-adjusted RR = 0.53, 95% CI = 0.34 to 0.82, n = 90 breast cancer deaths). The varying results for density and risk of death across these studies could be a result of small numbers of case patients, differences in density assessment and classification, or incomplete adjustment for confounding factors and effect modifiers, including BMI. In addition, international differences in populations or treatments may contribute to differing results.
In contrast to our results, previous studies have not reported an elevated risk of breast cancer death associated with low (BI-RADS 1) density among specific subgroups of breast cancer case patients. One explanation for the increased risks associated with low density among some subgroups is that breasts with a higher percentage of fat may contribute to a tumor microenvironment that facilitates cancer growth and progression. We found that the relation between BI-RADS density and risk of breast cancer death was in fact statistically significantly modified by BMI, an exposure that is directly associated with increased risk of advanced disease at diagnosis (24
), worse prognosis (22
), and lower breast density (11
). In our study, an adverse relationship between low density and risk of breast cancer death was most apparent among obese women. BMI and BI-RADS density are strongly and inversely related; however, only 10% of obese women in this analysis had BI-RADS 1 density. This subgroup constituted 2.5% of our breast cancer study population and included 4.5% of breast cancer deaths. Thus, findings particular to this group might be missed in a smaller study and require replication, particularly in light of the large number of statistical comparisons performed in our analyses. However, our data suggest that breast cancer patients with BI-RADS 1 density are at increased risk of breast cancer death irrespective of tumor characteristics, supporting the robustness of the finding. Given the rising prevalence of obesity worldwide, it is likely that the number of women who are obese and have low breast density will also likely rise, and therefore this group may benefit from modified treatment and increased surveillance efforts.
Proposed explanations for the poorer survival among obese breast cancer patients have included treatment with insufficient doses of chemotherapy, increased levels of factors produced in adipose tissue, such as estrogens and adipokines, and indirect effects resulting in higher concentrations of insulin-like growth factors and elevated bioavailability of hormones [reviewed in (22
)]. However, our data suggest that only a subset of obese women with fatty breasts (ie, 10% with low breast density) is at elevated risk of fatal cancers, thereby implicating the breast microenvironment in aggressive tumor biology. In support of this proposal, emerging data suggest that there are differences in metabolic and endocrine properties of adipose tissue between lean and a subset of obese women (25
. In postmenopausal women with cancer, BMI and testosterone levels in breast adipose tissue are directly associated (25
), and aromatase activity is increased in these patients (26
), suggesting that local aromatization of androgens to estrogens may provide stimulus for tumor growth.
Both animal models and studies of human breast tissues have suggested that there are relationships between elevated BMI, larger adipocyte size, inflammation in the breast (26
, and markers of increased cell proliferation (28
). Furthermore, laboratory studies have suggested that adipocytes interact with breast cancer cells to create a microenvironment conducive to invasion and metastasis [reviewed in (29
)]. It has been postulated that obesity-associated and cancer-associated adipocytes may share procarcinogenic attributes (30
). Therefore, it is biologically plausible to propose that increased fat content within the breast (ie, among obese women with low breast density) may enhance or complement obesity-related mechanisms that heighten tumor aggressiveness.
Our findings are consistent with the idea that both the fibroglandular and adipose tissue components, which are reflected radiologically in mammographic breast density, play a role in breast carcinogenesis. However, we were unable to quantify dense and nondense areas in this analysis. BI-RADS density assessment has moderate interobserver reliability (31
; any misclassification in this exposure would most likely have attenuated our findings, pointing to a need to replicate these findings using quantitative, reliable, and precise measurements of breast density. Furthermore, the growing evidence that the local tumor microenvironment is important in breast carcinogenesis points to the need for improved measures of breast density that account for its spatial distribution in localized regions in the breast.
In addition to the limitations of the BI-RADS density measure, our analysis was limited in that we lacked detailed, cumulative information on treatment, comorbidities, and changes in weight after diagnosis. Although we assessed numerous potential confounding factors, we cannot exclude the possibility of unmeasured confounding in our analysis. Nevertheless, we were able to account for mode of detection and many established prognostic factors collected in the BCSC.
Risk factors for the development of breast cancer may not necessarily be the same as factors influencing the risk of death from breast cancer once it has developed. It is reassuring that elevated breast density, a prevalent and strong breast cancer risk factor, was not associated with risk of breast cancer death or death from any cause in this large, prospective study. However, we identified subsets of women with breast cancer for whom low density was associated with adverse prognoses, highlighting the possibility of integrating breast density with epidemiological data and other measurements to understand mechanisms of breast carcinogenesis and to identify women who are likely to develop aggressive cancers, which might be preventable or detectable through specific interventions. Our findings underscore the need for an improved understanding of the biological characteristics of and the relationships between the breast tissue components that are responsible for the inter-individual variations in breast density. In future studies, evaluating targeted treatment and prevention strategies (such as use of aromatase inhibitors, metformin, weight control or exercise), assessment of breast density, epidemiological characteristics, and collection of tissues for bioassays may aid in the identification of patients most likely to benefit from these agents and enhance our understanding of breast carcinogenesis.