In this analysis of the BCSC cohort, we examined the independent contribution of benign breast diagnoses and breast density to breast cancer risk in 42818 women with at least one benign breast biopsy; over 6.1 years of follow-up, 1359 breast cancers developed. This represents the largest study to date of benign breast biopsies and breast density and the only study using data collected after 1990, thus reflecting contemporary mammography and pathologic evaluation of breast lesions. We found that benign breast disease and high breast density independently predict incident breast cancer. Women found on breast biopsy to have atypical hyperplasia and very high breast density had the highest risk for breast cancer. Notably, women with the more common proliferative forms of benign breast disease without atypia were at statistically significantly increased risk for breast cancer in all but the lowest category of breast density, that is, average density, high density, and very high density categories. Women with low breast density, whose breast tissue is almost entirely fat, were at low risk for future breast cancer regardless of the histology of their breast biopsy. However, the number of women with low breast density and proliferative disease was small and the test for interaction did not achieve statistical significance, indicating that this may represent a chance finding.
It is known that simply having a history of a breast biopsy increases a woman's risk for future breast cancer. Previous breast biopsy is incorporated as a risk factor in the majority of risk assessment models for breast cancer including the Gail model, the revision of the Gail model that incorporates breast density, our own BCSC model, and the Tyrer-Cuzick model. However, some models do not include the histopathological diagnosis of the biopsy in the risk calculation, and those that do only modify a woman's predicted risk if her histopathological diagnosis is atypical hyperplasia. In our study, proliferative lesions without atypia were identified in one-quarter of all breast biopsy results and the increased risk for breast cancer associated with these diagnoses, particularly in the presence of high breast density, is not included in current risk assessment models. These findings suggest that breast cancer risk assessment models have the potential to be improved by incorporating the full range of biopsy results into the risk calculations.
Our results could be used to better tailor prevention to individual patients. For example, tamoxifen is recommended for women with atypical ductal hyperplasia (ADH) according to the American Society of Clinical Oncology and the US Preventive Services Task Force. This recommendation is based on results from the Breast Cancer Prevention Trial showing that women with ADH reduced their risk of breast cancer by 86% when taking tamoxifen. Our results suggest that tamoxifen may not be appropriate for all women with ADH. Women with ADH and low breast density are not at increased risk of breast cancer compared to women with nonproliferative lesions and average breast density; women with ADH and average breast density have a modest increased risk of breast cancer. However, women with ADH and high or very high breast density are at high risk of breast cancer and would likely benefit the most from tamoxifen. Given that women have been reluctant to take tamoxifen for prevention because of medication side effects and the poor discrimination of risk prediction models, results from our study may assist women and their providers when deciding on tamoxifen therapy for prevention.
One prior study examined the combined effect of breast density and benign breast disease on risk for incident breast cancer in a case-control study nested in the Breast Cancer Detection Demonstration Project (BCDDP). In that study, breast density and benign breast disease were both associated with breast cancer. However, women with both high breast density and atypical hyperplasia were at statistically significantly lower risk for breast cancer than both the group of women with low breast density and atypical hyperplasia and the group of women with high breast density and either nonproliferative or proliferative disease without atypia (Pinteraction = .002). There are several important differences between the two studies: 1) The BCDDP data collection took place between 1973 and 1980 with follow-up through 1989, whereas the mammograms and biopsies for our BCSC analysis occurred between 1994 and 2009 and are more representative of current practice. 2) The BCDDP study of benign breast disease and breast density also had limited statistical power because it included only 347 women with benign breast disease who developed cancer and 410 age-matched control subjects. In the BCDDP there were only 13 women with both high breast density and atypical hyperplasia, compared to 267 in our BCSC analysis. Thus, the confidence interval around the risk estimate for women in the BCDDP was wide. 3) The BCDDP used a different referent group than our study, women with nonproliferative histopathology and a percentage breast density less than 50%, and adjusted for additional covariates including family history, alcohol consumption, nulliparity, years of education, weight, menopause status, age of menopause, and postmenopausal hormone use. We performed sensitivity analyses to mirror this approach using the BCSC data, but they did not change our findings.
When comparing the relative hazards reported in this paper to those of benign breast disease reported in prior publications, it is important to keep in mind that all women included in this analysis were required to have undergone at least one breast biopsy. This was done to avoid introducing any bias due to a propensity to biopsy based on breast density. Because having a biopsy itself is a risk factor for breast cancer, the relative risk for women with high density and proliferative disease on biopsy will be even higher than that reported in this paper when the referent group is women who have never had a breast biopsy. The distribution of benign breast disease observed in the BCSC is almost identical to that of the large prior cohort study reported by the Mayo Clinic. When women with nonproliferative findings are used as the referent group, the relative risk estimates for proliferative lesions in the Mayo Clinic study are very similar to those in our study.
A second study from the Mayo Clinic investigated the relationship between lobular involution on breast biopsy and breast density. They hypothesized that lobular involution might explain some of the relationship between breast density and breast cancer risk because lobular involution increases with age and is associated with the replacement of epithelial tissue with adipose tissue (fat). Although they did find some association of the degree of lobular involution with breast density, both were independent risk factors for breast cancer. As in our analysis, the Mayo Clinic study demonstrates that clinically relevant changes in breast histology are associated with breast cancer risk independent of breast density.
There are several potential limitations to our study. Community radiologists reported breast density as part of routine clinic practice. Thus, the results are likely less precise than they would be if performed at a central facility by one trained reader. There was also a transition from film mammography to digital mammography during the study period, but we have demonstrated in a prior article that this has not affected the qualitative BI-RADS measure of breast density. Similarly, community pathologists read and reported the histopathological findings of the breast biopsies as part of routine clinical care. We did not perform any central review of pathology diagnoses or mammographic density assessment, nor did we perform any training to encourage standardization in the interpretation of the biopsies or mammograms. Several studies have documented poor agreement between pathologists for some histologic diagnoses. The decreased precision from lack of standardization would tend to bias the results toward the null. Thus, our associations may underestimate or overestimate the true strength of the associations between breast density, benign breast disease, and breast cancer because of misclassification of breast density and histologic findings. Finally, the small number of women with LCIS on biopsy precluded meaningful evaluation of the contribution of LCIS to risk within breast density subgroups.
In summary, we found that BI-RADS breast density and benign breast disease were independent risk factors for breast cancer associated with a stepwise increase in risk with increasing density and increasing proliferation. Women with high breast density and proliferative lesions with atypia were at highest risk for future breast cancer. The nearly 16% of women with proliferative lesions without atypia in the upper two categories of breast density had twice the risk of women with non-proliferative breast diagnoses. Women with low breast density were at low risk even if their biopsy results indicated the presence of proliferative lesions with or without atypia. The potential benefits and harms of screening mammography are directly influenced by the level of breast cancer risk. Women at higher risk will have greater absolute benefit and fewer harms and women at low risk will have lower absolute benefit and greater harms. To maximize the potential benefit and minimize the potential harms of primary and secondary preventions for breast cancer, facilities and screening programs are starting to implement risk-based screening programs. Women and providers may use our results when discussing their breast cancer risk and the potential benefits and harms of interventions and choices for primary and secondary breast cancer prevention.