In this prospective study, we investigated the association of breast density with breast cancer risk according to tumor characteristics among 1042 postmenopausal women who were diagnosed with breast cancer between June 1, 1989, and June 30, 2004, and 1794 matched control subjects. Women with higher breast density (≥50%) showed 3.39-fold increased risk of breast cancer compared with women with lower breast density (<10%). The strength of the association between breast density and breast cancer risk varied by invasiveness, histological grade, tumor size, and ER status of the tumor. A stronger association was noted for in situ breast cancers, poorly differentiated invasive breast cancer, larger (>2 cm) tumors, and ER− breast cancers. We did not find differences in the associations of breast density with breast cancer risk by histological type, nodal involvement, and PR and HER2 status.
We report for the first time a stronger association between breast density and ER−
breast tumors compared with ER+
tumors. Findings on the association of breast density with receptor status of the tumor from previous studies are inconsistent (26
) (see ). In one study (27
), women with greater density were reported to have larger proportion of ER−
tumors; however, the association disappeared after adjustment for age. Although some other recent studies observed that women with greater breast density had an increased risk of ER+
, but not ER−
breast cancer (35
), others did not (28
). However, many of these studies were underpowered to investigate the differences in the association of breast density with the risk of breast cancer by ER status because of a smaller size as compared with our analysis. Higher levels of estradiol have been reported in the tissue from ER+
tumors compared with ER−
). Our findings suggest that regulatory factors other than estrogen may play an important role in the origins of ER−
tumors in denser breasts. Consistent with other studies, we did not see any differences in the associations between breast density and breast cancer risk by PR or HER2 status (28
). Breast cancer is a heterogeneous disease and ER+
tumors are believed to be etiologically different. Previous studies have found an association of hormone-related breast cancer risk factors with ER+
breast cancer subtype, but failed to find a similar association with ER−
breast cancers. Identifying the risk factors specific to ER−
tumors would help researchers understand the etiology of ER−
breast cancer and develop subtype-specific risk prediction models.
Inconsistent data exist on the association between mammographic breast density and breast cancer risk according to different tumor characteristics (see ). A recent study found an increased risk of both lobular and ductal carcinomas with increase in breast density, but there was no difference in the strength of the association across the histological subtypes (9
). Positive associations of breast density with tumor size, involvement of axillary nodes, and higher tumor grade have been reported in some (28
), but not all studies (30
). The results from our study indicate a stronger association of breast density with more aggressive subtypes of breast cancer, including tumors that are larger in size and of high grade. Previous studies report inconsistent findings when examining the association between breast density and these tumor characteristics (27
) (see ). Some of these differences may be explained by differences in study design, sample size (range in the number of breast cancer cases 286–19
119), and different definitions of breast density. If breast density is associated with more aggressive breast cancer phenotypes, it may suggest that the breast tissue environment underlying breast density allows for more growth and increased proliferation, than in more fatty breasts. In addition, because mammographic sensitivity decreases with increasing breast density, aggressive cancers occurring in denser breasts go undetected for longer periods permitting these already rapidly proliferating tumors to be larger at presentation (45
We found that breast density was more strongly associated with in situ breast cancer than invasive disease. This is in slight contrast with other studies that found similar associations for in situ and invasive tumors (34
). It is possible that our findings are the result of chance. The larger of the two studies (38
) had fewer in situ and invasive postmenopausal cancer case subjects than our study; the other study (34
) had reported the results for both pre- and postmenopausal women combined. Another possible explanation for the stronger association with in situ disease may be a difference in breast cancer detection rate in women with denser breasts. It is well known that the sensitivity of mammography is lower for women with dense breasts, and women with dense breasts are more likely to have an abnormal mammogram and undergo biopsies than women with fattier breasts (46
). Therefore, it is possible that the diagnosis of in situ carcinomas for many of these women is a serendipitous finding. In addition, the radiographic appearance of in situ tumors on mammogram results in higher sensitivity of screening mammography for detection of ductal carcinoma in situ compared with invasive cancer in both pre- and postmenopausal women (51
This study has a few limitations. The current analysis was restricted to women who were postmenopausal at the time of both mammogram and diagnosis, which constitutes the majority of the population assembled for the nested case–control study (77%). Our findings are thus limited to postmenopausal breast cancer subtypes and do not necessarily apply to premenopausal breast cancer. We did not investigate the associations between breast density and breast cancer risk by combined ER/PR or ER/PR/HER2 status because the small numbers of tumors in the subsets did not provide sufficient statistical power to draw meaningful conclusions.
Identification of the subtype-specific breast cancer risk factors would help to understand breast cancer etiology, develop subtype-specific risk prediction models, and eventually, to suggest novel prevention strategies. To our knowledge, this is by far the largest study with respect to the number of breast cancer cases that investigated the association of quantitative breast density with several breast cancer characteristics, including a tumor’s invasiveness, histology, grade, size, receptors status, and nodal involvement in the same population of women. The analysis used data from the Nurses’ Health Study, an established cohort with more than 30 years of follow-up, ascertainment of disease status, and comprehensive information on breast cancer risk factors, tumor characteristics, and breast density.
In conclusion, we investigated the association of mammographic breast density with subsequent breast tumor characteristics in postmenopausal women. Our results suggest that breast density influences the risk of breast cancer subtypes by potentially different mechanisms. Further studies are warranted to explain underlying biological processes and elucidate the possible pathways from high breast density to the specific subtypes of breast carcinomas.