Title: On the Clinical Importance of Benign Breast Disease
Description: Breast cancer is thought to develop through progression of benign breast lesions, atypical hyperplasia (AH) and/or carcinoma in situ (CIS). Benign breast disease (BBD) is a group of heterogeneous breast abnormalities. This dissertation investigated the association between BBD and breast cancer risk in order to determine whether BBD should be considered a causal intermediary or susceptibility marker of breast cancer risk. We addressed BBD as a modifier of risk in four parts: a comprehensive review of previous cohort studies examining the association between BBD and mammographic density, an analysis of interactions between BBD and established breast cancer risk factors, and validation of currently used risk assessment models in a population of women with BBD. We used two longitudinal cohorts to assess these relationships, the Early Determinants of Mammographic Density study and Woman At Risk registry. Mammographic density and BBD are both important risk factors of breast cancer. We found that women with a history of BBD on average had 3.5% higher percent density on their mammograms than women without a history of BBD.

Women diagnosed with BBD prior to first pregnancy had 8.6% higher density than nulliparous women without a history of BBD. Few prior cohort studies have examined interactions between BBD and other breast cancer risk factors and all those that did only assessed multiplicative interactions, not additive interactions. BBD modified the association with parity and alcohol consumption. Nulliparous women with BBD had an almost 5-fold higher risk of breast cancer than nulliparous women without BBD. We found both multiplicative and additive interaction between alcohol use and BBD. Women with BBD who consumed alcohol had 2-fold higher risk of breast cancer compared to women without BBD who did not consume alcohol. We compared three widely used breast cancer risk assessment models, the Gail model, the International Breast Cancer Intervention Study (IBIS), and the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Mean estimated breast cancer risk based on IBIS model was significantly higher for women with any BBD as compared to mean predicted risk in Gail and BOADICEA models (IBIS 5.84%, Gail 4.79%, and BOADICEA 3.71%; p<0.001 for all pairwise comparisons).

All three models tended to under predict the number of breast cancer events in our cohort. Discrimination was also poor in all three models, for the total population, women with BBD and women with atypical hyperplasia. Overall, we found an association between BBD and mammographic density, as well as interactions between BBD and parity, and BBD and alcohol use. Furthermore, current breast cancer risk models have moderate calibration and discrimination in a population of women with BBD, and we saw that differences in calibration depended on type of BBD. Risk assessment models should include not only BBD, but also the interactions between BBD and other risk factors in order to adequately predict subsequent risk of breast cancer. Current breast cancer screening guidelines recommend against MRI or conclude there is insufficient evidence to make decisions regarding MRI screening in women with BBD, even though these women are known to be at a higher risk of breast cancer. Improving breast cancer risk models by including BBD, mammographic density, and their interaction could improve risk assessment and as a result improve screening and clinical care of these women.

Results from this dissertation support that BBD is more likely to be a susceptibility marker of breast cancer risk than a true precursor lesion. This suggests that changes in the BBD tissue that occur are more likely due to genetic or epigenetic factors that cause the breast to be more susceptible to the effects of other breast cancer risk factors.