This study, the largest cohort study of BBD to date, indicates that women with proliferative breast lesions without atypia have a slightly increased risk of breast cancer, whereas women with atypical hyperplasia have a substantially increased risk. When atypical hyperplasia was examined by histologic subgroup, both atypical ductal and atypical lobular hyperplasia were associated with increased risk, although the estimates of association were imprecise. Our estimates of the risk of breast cancer among women with proliferative lesions without atypia and with proliferative lesions with atypia relative to women with nonproliferative lesions are similar to those of other large cohort studies of BBD [3
We found no clear association between side of the BBD lesion and side of the subsequent breast cancer. Among women with proliferative disease without atypia and atypical hyperplasia, odds ratios for subsequent breast cancer in the ipsilateral breast were somewhat higher than among those for breast cancer in the contralateral breast, but the CIs were wide and overlapping. Our findings concerning laterality should to be interpreted cautiously because information on laterality of the breast cancer was missing on one-third of cases. Furthermore, the numbers of ipsilateral and contralateral breast cancers among women with atypical hyperplasia were small (n
= 15 for both ipsilateral and contralateral). Previous cohort studies have also found higher risk of breast cancer in the ipsilateral breast, particularly among women with atypical hyperplasia [8
Studies that have assessed the risk associated with of specific histologic entities within the broad category of proliferative disease without atypia, including fibroadenoma [4
], sclerosing adenosis [16
], radial scar [14
], and papilloma [10
], have given conflicting results. Some of these discrepancies may be due to the use of different referent groups (non-proliferative disease versus general population), difference in how advanced the lesions were, small numbers of breast cancer cases with specific lesions, and small effect sizes associated with these lesions. Thus, it is unclear whether these specific entities increase the risk of breast cancer independent of their association with proliferative disease without atypia. In this study, the presence of multiple columnar lesions and complex fibroadenoma without atypia were associated with a non-significantly increased risk of breast cancer, whereas sclerosing adenosis, radial scar, and papilloma showed no association with risk.
Some studies have indicated that the risk associated with atypical lobular hyperplasia is greater than that associated with atypical ductal hyperplasia [7
], whereas others have found no difference in risk [9
]. Although our point estimate for atypical lobular hyperplasia was higher than that for atypical ductal hyperplasia, there was considerable overlap between the CIs for the two estimates.
Our finding that the association of atypical hyperplasia with breast cancer was stronger among younger women and premenopausal women compared to older women and postmenopausal women, respectively, agrees with the results of several other studies [1
]. A modifying effect of age or menopausal status on risk among women with proliferative disease without atypia is less clear. We found no difference in risk among younger and older women with proliferative disease without atypia, whereas Hartmann et al. [8
] reported a somewhat higher risk among women <45 years of age compared to women >55 years of age. Other studies [5
] have found that the risk of breast cancer did not differ in premenopausal and postmenopausal women with proliferative disease without atypia, and Ashbeck et al. [13
] noted a tendency toward higher risk among presumed postmenopausal women (≥55 years) compared to presumed premenopausal women (<55 years).
Proliferative disease without atypia and atypical hyperplasia were more strongly associated with risk for follow-up of <15 years compared to follow-up of ≥15 years, and the interaction was statistically significant (p
= < 0.01). In women followed for ≥15 years the ORs for both proliferative disease without atypia and proliferative disease with atypia were elevated but not statistically significant. Our finding is in agreement with those from several studies which suggest that the risk of breast cancer decreases with increasing length of follow-up [10
]; however, other studies have observed no clear decrease [5
Several issues affecting studies of the association of specific BBD features with risk of breast cancer deserve comment. First, some studies which examined the risk of breast cancer among women with biopsy-diagnosed BBD have used non-proliferative disease as the referent group [3
]. However, several studies which have used the general population or women who have not undergone biopsy as the reference group suggest that women with non-proliferative disease may be at slightly increased risk of breast cancer [4
]. Thus, our risk estimates based on including non-proliferative lesions in the reference group may be underestimates of the true risk (expressed relative to that for women with no breast pathology). Second, the classification of specific lesions may differ between different diagnostic centers and pathologists [30
]. We tried to counteract this by having all pathologists use the same classification scheme; in addition, pathologists from Portland and London, but not Toronto, had a joint session to standardize criteria. For this reason, we carried out a sensitivity analysis excluding Toronto from the analysis, and the results were unchanged. In addition, the consistency of our results with those from studies which have included centralized pathology review is striking. Furthermore, the study results did not differ by study center (p
A number of limitations of this study should be mentioned. Due to the small numbers, the risk estimates for ductal, lobular, and columnar atypical hyperplasia were imprecise, a limitation common to most previous studies. Small numbers of atypical hyperplasia also restricted our ability to examine it in combination with other histologic features, such as sclerosing adenosis, radial scar, and papillomas. In addition, small numbers precluded assessment of the interaction between family history and proliferative disease with atypia. We lacked information on features, such as calcifications, which some studies [3
] have found to be associated with increased risk. Finally, information on some breast cancer risk factors was either not available (breastfeeding) or was missing for some women (body mass index, hormone therapy).
In conclusion, this large cohort study of BBD demonstrated that, compared to women with normal pathology or non-proliferative disease, women with proliferative disease without atypia have a modestly increased risk of breast cancer, whereas women with atypical hyperplasia have a substantially increased risk. Our results also suggest that menopausal status and time since biopsy may modify the risk of breast cancer among women with BBD. In view of the small numbers of some lesions (e.g., radial scar, multiple papilloma, complex fibroadenoma, columnar cell hyperplasia, and atypical hyperplasia) in this and other cohorts, it would be valuable to undertake a pooled analysis of data from existing cohorts of women with biopsy-confirmed BBD who have been followed for the development of breast cancer, using uniform pathologic criteria.