There are few BBD cohort studies with comprehensive follow-up and detailed characteristics on subsequently diagnosed invasive tumors. Among a large, well-characterized cohort of patients diagnosed with BBD, we expanded upon previous analyses in this population [7],[8] that evaluated associations of well-established breast cancer risk factors and BBD features with breast cancer risk to determine herein if there exists possible etiologic heterogeneity using tumor characteristic data obtained from the longstanding high quality Kaiser tumor cancer registry [16]. Determining risk associations by tumor subtypes has been increasingly recognized as an important area of research [20, 21]. We comprehensively analyzed histopathologic features of the BBD biopsy and clinicopathologic characteristics of the breast tumors that developed subsequent to BBD diagnosis. We found that most breast cancers diagnosed among BBD patients within this general community healthcare plan were the low stage, ER-positive tumors that tend to be highly responsive to treatments. Compared with patients with non-proliferative BBD, those with proliferative BBD with atypia had an over five-fold increased risk of ER-positive breast cancer. Our analyses provided limited evidence for heterogeneity in risk factor associations that we evaluated by tumor characteristics. Importantly, histology and presence of CCLs at the time of BBD were independently associated with subsequent breast cancer risk irrespective of ER status, or tumor size or grade. These data provide further support for CCLs as a breast cancer risk factor, especially for postmenopausal BBD patients.
Patient characteristics and breast cancer risk
We extended prior findings by evaluating etiologic heterogeneity for risk factors thought to be most relevant for subsequent risk among BBD patients. Consistent with multiple studies of women diagnosed with sporadic breast cancer [9-12] and with the Mayo Clinic BBD cohort [6], we observed that parity/age at first birth was significantly associated with future breast cancer risk. Also consistent with limited data from other BBD cohorts [6], we found that history of bilateral oophorectomy was associated with reduced breast cancer risk, whereas positive family history of breast cancer in a 1st degree relative tended to be associated with increased breast cancer risk. We were able to further evaluate potential etiologic heterogeneity in risk associations, because our BBD study is nested within a single, large, well-defined population with access to healthcare and with a long-standing tumor tissue registry that has collected data since the 1960’s. Although the number of ER-negative tumors was limited, we confirmed patterns of association by ER status that have also been observed among women diagnosed with sporadic breast cancers [9-12]. For example, early age at first birth showed an inverse association with ER-positive tumors suggesting that reproductive risk factor associations among BBD patients may be similar to those observed in the general population.DH
It has long been established that ADH is a high-risk precursor lesion, conferring a 4-5-fold increase in risk of breast cancer development [3]. Indeed, our analysis of BBD patients showed that compared to non-proliferative lesions, a diagnosis of ADH was associated with over 5-fold increased breast cancer risk; however, this association was limited to risk of ER-positive breast cancer, with little or no risk observed for ER-negative disease. Limited data from cohorts have reported on the relation of ADH by hormone receptor subtype. Consistent with our results, a previous population-based case-control study, CASH, found that history of any benign breast disease was associated only with increased risk of ER-positive luminal A tumors (OR = 1.89, 95% CI 1.43-2.50) [22]. These findings support the hypothesis that benign lesions are more likely to be hormone receptor positive with less genomic instability [23-26]. Moreover, the finding that ADH might be more relevant for ER-positive breast cancer risk is also consistent with hormonal chemoprevention trials which show a significant reduction in risk in women diagnosed with ADH [5, 27].
Proliferative BBD without atypia
Proliferative disease without atypia is a conglomerate of multiple different pathologies. Radial scars are proliferative lesions that visually appear similar to tumors on mammograms. Pathologically, they are associated with epithelial elements and/or other proliferative lesions such as sclerosing adenosis. Recent analyses in two Swedish cohorts recruited through mammography screening programs from 2001-2013 with over 75,000 subjects did not find any significant heterogeneity when evaluating the associations of non-proliferative or proliferative BBD lesions with risk of molecularly defined subtypes of breast cancer; however, a limitation in this study was that there was no separation of proliferative lesions with or without atypia [28]. Our analysis using the Page classification of BBD histology showed that PDWA was associated with increased risk of both ER+ and ER- disease. This is consistent with the hypothesis that these lesions serve as precursor lesions in the natural history of breast cancer [3]. The Nurses’ Health Study and the Mayo BBD study showed radial scars to be one of the PDWA lesions associated with breast cancer risk, with an almost 2-fold increased risk [6, 29]. The Nurses’ Health study cohorts showed an independent association after adjusting for BBD histology. After restricting analyses to BBD patients with proliferative disease, we did not find a significant increase in risk associated with sclerosing adenosis or radial scar. Reasons for these discrepancies could be differences in the study populations as the calendar periods for all three of the cohorts overlap; the Nurses BBD cohort were women who reported a first diagnosis of BBD between 1976-1998; the Mayo BBD cohort is a hospital-based referral center that may see more high-risk women but with a similar calendar period to our study with BBD diagnoses occurring between 1967-2001. As our study was embedded in a health care organization where the women are actively followed and had access to mammography screening, breast cancers detected in our study may be found earlier than in other cohorts which makes direct comparisons difficult.
Columnar cell lesions
While its generally accepted that ADH, lobular neoplasia and ductal carcinoma in situ (DCIS) are precursor lesions for breast cancer [30, 31], evidence is accumulating that CCLs may also be a precursors, although conveying lower risk particularly among populations with access to mammography screening [32-34]. Our data support CCLs as a common risk factor for both ER-positive and ER-negative breast cancers with relative risk estimates of around 1.5 after accounting for BBD histology, for both tumor types. Molecular analyses of CCLs suggest that some alterations occur early and mimic those observed in coincident established precursor lesions such as DCIS [3, 8, 23, 33, 35-42]. There are three other studies that have evaluated CCLs in BBD cohorts, Nashville, Nurses, and Mayo and our data are consistent with the findings of all three [23, 35, 36, 40]. Only the Nurses BBD cohort obtained tumor characteristics on cases and also did not find any significant differences by ER status or grade, which is consistent with our data. Current management of CCL, according to the Mayo Clinic review, suggests that these patients should be managed with annual clinical breast exams and mammography [3]. Our data suggest CCL might be a risk factor for both ER+ and ER- disease, which has not been observed previously and requires further investigation.
Involution status
Reduced lobular involution has been previously shown to be a significant factor associated with elevated breast cancer risk among women with BBD [19, 43, 44]. In the present study, we found that involution was weakly inversely related with breast cancer risk for ER+ disease. Further, higher levels of lobular involution were inversely and significantly associated with risk for well-differentiated tumors, a finding which was not observed for moderately or poorly differentiated tumors. As there were relatively few hormone negative cases in this population, we had limited power to test for differences by ER status. A limitation of this study is the absence of data on menopausal hormone therapy (MHT) use after BBD diagnoses, as MHT uptake was rising at the same time that mammography screening was increasingly being adopted [16]. Given previous studies showing that recent MHT use reduces involution levels among current but not former users [45], we hypothesize that MHT use post BBD diagnosis may be an unmeasured negative confounder attenuating involution associations towards the null. Overall, it is unclear whether screening practices, unmeasured MHT use, or/and both might confound observed associations with involution. Additional contemporary studies in other populations with managed health care might help clarify the relationship of involution with future breast cancer risk.
This is a unique cohort of women enrolled in a general community health care plan, providing the population access to screening and preventative services that may not be typical for other subsets of the US population. It is not currently known whether women with BBD are followed and screened more closely compared to women without BBD diagnoses. Current data from a study of over 42,000 screened women in Spain found that women with a previous benign breast disease diagnosis had a higher cumulative risk of screen-detected cancer and interval cancers, consistent with data supporting BBD as a risk factor for breast cancer regardless of mode of detection [46]. Whether women with BBD in our cohort are more likely than the general population to participate in screening is not known but could be the subject of future research.
Strengths/Limitations
A limitation of our study is that risk estimates are based on a BBD patient population diagnosed on excisional biopsies during a calendar period spanning the adoption of widespread mammography screening, which became more commonplace in KPNW around 1993; thus, associations may not be reflective of BBD diagnosed in more recent years. Since 1995, advances in breast imaging technologies have resulted in a shift in diagnostic biopsy procedures to core needle biopsies, which currently comprise about 80% of biopsies in the US [47]. Based on data from the US Breast Cancer Surveillance Consortium, risks associated with high-risk ADH lesions on excisional biopsy were lower when diagnosed via core biopsy (6.7% vs 5.0%), perhaps reflecting the size of the ADH focus [47]. Another limitation as noted earlier, was the absence of risk factor data after BBD diagnosis and in particular on MHT use, which has been noted to be prevalent at KPNW at this time [16] and could have biased the results, especially with respect to the findings for involution. The small number of patients with ER-negative breast cancers is another limitation. Our study had multiple strengths: it was a nested-case control study embedded within a large, well-characterized BBD cohort with lengthy follow-up and access to archival BBD tissues and well-established detailed tumor registry data, the latter aspect allowing us to provide one of the most detailed analyses to date of tumor characteristics of breast cancers diagnosed among the vast majority of patients. Moreover, because we studied women in a healthcare management organization we could also evaluate temporal changes in access to mammography screening, data that are limited in other cohorts.
Summary and conclusions
Within this BBD cohort, the largest to date with longitudinal follow up, we provide breast cancer risk factor associations within an HMO patient population [7]. Our data provide further evidence that PDWA is associated with both ER-positive and ER-negative disease. Further, we show CCLs are associated with moderate increases in breast cancer risk, independent of BBD histology, and irrespective of ER status, in agreement with previous studies. Given the predominance of low-stage ER-positive tumors that developed among this cohort, our findings suggest that invasive cancers that develop subsequent to a BBD diagnosis are likely highly treatable with low mortality. Histologic evaluation of BBD biopsies is a promising avenue for the identification of new risk factors for different molecular subtypes of breast cancer and could inform the natural history of disease; however, given complex relationships between screening and diagnosis, along with secular changes in risk factor prevalence, contemporary prospective studies are needed to clarify the relationships of factors that may influence progression of BBD to cancer.