Proliferative Disease Without Atypia Research Articles

Abstract PS07-02: Benign breast disease and microcalcifications in percutaneous biopsies and breast cancer risk

Abstract Objectives: Mammographic microcalcifications (calcs) are a sentinel marker of in-situ and invasive breast cancer (BC) but most calcs reflect benign breast disease (BBD). BBD comprises a diverse set of lesions, variably associated with increased BC risk. While calc frequency data for the modern era are limited, historically, calcs were reported in 11% of BBD biopsies. Some studies suggest that calcs in BBD impact BC risks; however, the frequency and BC risks associated with calcs during the percutaneous biopsy era have not been clearly established. Accordingly, we assessed the association of calcs with specific BBD lesions and BC risk in a large contemporaneous BBD cohort including detailed pathology review. Methods: A cohort of 4,819 patients with percutaneously diagnosed BBD from 2002-2013 at Mayo Clinic, were identified. The cohort was followed from 6 months after biopsy until censoring, BC diagnosis, or December 2021. Mean follow-up was 11.3 (SD=5.1) years for BBD patients who remained cancer-free in follow-up compared with 7.4 (SD=4.3) years for cases. Histology of all biopsies were reviewed microscopically to record pathologic findings. A natural language processing algorithm (NLPA) was developed and utilized to identify the presence of calcs based on pathology reports. NLPA results were compared to 300 matched biopsy reports, taken as ground truth. We performed age-adjusted Cox proportional hazards regression to assess hazard ratios (HRs) with 95% confidence intervals (CIs) for specific BBD lesions, stratified by the presence (calc+) or absence of calcs (calcs-), with estimation of an interaction term to test for differences in risks by calc strata. Standardized incidence ratios (SIRs) estimated risks for calc+ and calc- BBD lesions versus matched strata for Iowa SEER population-based BC incidence rates. Results: The NLPA achieved sensitivity=0.993 and specificity=0.986. Overall, 42.8% of BBD biopsies were calc+, including 49.1% of biopsies preceding BC and 42.4% of biopsies not preceding BC (Chi-square p=0.02). Overall, risks of BC among women with BBD calc+ biopsies did not differ significantly from those of women with calc- BBD: HR=1.13 (95% CI: 0.90,1.41), p=0.290. SIRs were also similar for the two groups; women with BBD calc+ biopsies had an SIR =2.00 (95% CI: 1.72, 2.33) and BBD calc- biopsies yielded an SIR= 1.91 (95% CI: 1.64,2.22) (Table 1). HRs were similar for specific calc+ and calc- BBD lesions, with progressively higher risks for non-proliferative disease (NP), proliferative disease without atypia (PDWA) and atypical hyperplasia (AH) (pinteraction=0.55). Interaction terms were not significant for any specific lesion, apart from a marginally significant result for dilated ducts, wherein risks were marginally higher for calc- lesions (pInteraction =0.048), perhaps representing a chance finding. SIRs for calc+ versus calc- BBD lesions were also similar. Overall, 77.3% of AH was calc+; for AH calc+, SIR=3.76 (95%CI: 2.74-5.17) and for AH calc-, SIR=4.41 (95%CI: 2.56-7.59). Conclusion: In this recent, larger percutaneous BBD cohort, calcs were present in 42.8% of all specimens, representing a marked increase compared with historical BBD data, particularly those dominated by surgical biopsy for diagnosis and preceding implementation of full-field digital mammography. In this study, calcs in percutaneously diagnosed BBD were not associated with increased BC risk. Table 1: Comparison of standard incidence ratio of subsequent breast cancer with and without microcalcifications in benign breast disease by histologic impression (NP = non-proliferative disease, PDWA = proliferative disease without atypia, and AH = atypical hyperplasia). (1) compared to Iowa SEER population Citation Format: Sarah Schrup, Robert Vierkant, Stacey Winham, Celine Vachon, Derek Radisky, Jodi Carter, Laura Pacheco-Spann, Matthew Jensen, Amy Degnim, Mark Sherman. Benign breast disease and microcalcifications in percutaneous biopsies and breast cancer risk [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-02.

Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era

Benign breast disease (BBD) comprises approximately 75% of breast biopsy diagnoses. Surgical biopsy specimens diagnosed as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) are associated with increasing breast cancer (BC) risk; however, knowledge is limited on risk associated with percutaneously diagnosed BBD. To estimate BC risk associated with BBD in the percutaneous biopsy era irrespective of surgical biopsy. In this retrospective cohort study, BBD biopsy specimens collected from January 1, 2002, to December 31, 2013, from patients with BBD at Mayo Clinic in Rochester, Minnesota, were reviewed by 2 pathologists masked to outcomes. Women were followed up from 6 months after biopsy until censoring, BC diagnosis, or December 31, 2021. Benign breast disease classification and multiplicity by pathology panel review. The main outcome was diagnosis of BC overall and stratified as ductal carcinoma in situ (DCIS) or invasive BC. Risk for presence vs absence of BBD lesions was assessed by Cox proportional hazards regression. Risk in patients with BBD compared with female breast cancer incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) program were estimated. Among 4819 female participants, median age was 51 years (IQR, 43-62 years). Median follow-up was 10.9 years (IQR, 7.7-14.2 years) for control individuals without BC vs 6.6 years (IQR, 3.7-10.1 years) for patients with BC. Risk was higher in the cohort with BBD than in SEER data: BC overall (standard incidence ratio [SIR], 1.95; 95% CI, 1.76-2.17), invasive BC (SIR, 1.56; 95% CI, 1.37-1.78), and DCIS (SIR, 3.10; 95% CI, 2.54-3.77). The SIRs increased with increasing BBD severity (1.42 [95% CI, 1.19-1.71] for NP, 2.19 [95% CI, 1.88-2.54] for PDWA, and 3.91 [95% CI, 2.97-5.14] for AH), comparable to surgical cohorts with BBD. Risk also increased with increasing lesion multiplicity (SIR: 2.40 [95% CI, 2.06-2.79] for ≥3 foci of NP, 3.72 [95% CI, 2.31-5.99] for ≥3 foci of PDWA, and 5.29 [95% CI, 3.37-8.29] for ≥3 foci of AH). Ten-year BC cumulative incidence was 4.3% for NP, 6.6% for PDWA, and 14.6% for AH vs an expected population cumulative incidence of 2.9%. In this contemporary cohort study of women diagnosed with BBD in the percutaneous biopsy era, overall risk of BC was increased vs the general population (DCIS and invasive cancer combined), similar to that in historical BBD cohorts. Development and validation of pathologic classifications including both BBD severity and multiplicity may enable improved BC risk stratification.

Abstract 4213: Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico

Abstract Introduction: Benign breast disease (BBD) is an important breast cancer (BC) risk factor, which may be classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH) for risk stratification. Data related to the frequency of specific types of BBD and their relationship to BC risk in the Hispanic American population are limited. To address this knowledge gap, we compared BBD and associated BC risk among Hispanic white (HW) and non-Hispanic white (NHW) in New Mexico (NM). Methodology: A retrospective IRB-approved study was performed of women 19 years or older residing in six counties in NM (Bernalillo, Sandoval, Sante Fe, Socorro, Torrance, Cibola/Valencia) between 1996 and mid-2007 to compare the frequency of BBD subtypes and BC risk among HW and NHW. We excluded women who had a history of BC prior to BBD diagnosis or who were diagnosed with BC within 6 months after BBD biopsy. Race and ethnicity were self-reported by women at the time of biopsy. BBD was categorized as NPD, PDWA, or AH based on medical records. Incident BC (in-situ or invasive) was ascertained via linkage to the NM Surveillance Epidemiology End Results (SEER) Registry and BC risk was assessed using standardized incidence ratios (SIRs), comparing the observed number of BC events to that expected based on the NM SEER six-county race- and ethnicity-specific incidence rates, accounting for age and calendar period. Results: Our analysis included 3,870 HW and 6,996 NHW women with BBD. The HW were younger (47.1 vs. 51 years) compared to NHW. HW women had slightly more NPD (69.4% vs. 66.6%) but less PDWA (26.2% vs. 29.4%) and similar frequency of AH (4.3% vs. 3.9%) as compared to NHW. Over a median post-BBD follow-up period of 13 years (range 6 months-17 years), 644 BCs were observed (4.81% in HW and 6.55% in NHW). The observed BC risk among women with BBD was higher than population-based expected rates (SIR 1.98, 95% CI 1.82-2.13, p<0.001) and showed expected increases in risk with increasing degrees of BBD abnormality: SIR=1.90 for NPD, 2.00 for PDWA, and 3.01 for AH. Comparing BC risk by ethnic subgroups, HW women had an overall risk of BC after BBD that was statistically indistinguishable from NHW women (SIR=2.17, 95% CI 1.86-2.48 in HW women, and SIR=1.91, 95% CI 1.73-2.08 in NHW women). Within the major subgroups of the BBD findings, there were no significant differences in risk of BC after BBD for HW versus NHW women. Conclusions: In this population-based study, benign breast disease subtypes and their associated breast cancer risk were similar among the Hispanic and non-Hispanic white women. Citation Format: Kush Raj Lohani, Andrea M. Nibbe, Robert A. Vierkant, Laura M. Pacheco-Spann, Lisa R. Seymour, Celine M. Vachon, Mark E. Sherman, Amy C. Degnim, Deirdre Hill. Comparison of benign breast disease subtypes and breast cancer risk among Hispanic and non-Hispanic white women in New Mexico. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4213.

Abstract PD10-10: Epithelial proliferation score as an independent breast cancer risk predictor in benign breast disease

Abstract Background: Women with benign breast disease (BBD) experience an increased risk of breast cancer (BC). Histologic classification of BBD, as non-proliferative disease (NP), proliferative disease without atypia (PDWA) or atypical hyperplasia (AH), stratifies groups of patients into progressively higher categories of BC risk. However, this classification does not comprehensively assess the proliferative state of the epithelium throughout the biopsy. In addition, while AH is considered the most high-risk class of BBD, it is not always a highly proliferative lesion; atypical ductal lesions may reflect focal cytologic and architectural changes. We evaluated the association of an alternative classification of BBD severity and BC risk based on subjective grading of: 1) the maximal degree of epithelial proliferation and 2) multifocality of epithelial proliferation. Methods: Pathologists reviewed biopsies from participants aged 18 to 85 years in the Mayo BBD cohort (2002-2013), masked to BC outcomes, ascertained via questionnaires, tumor registry data and medical record review. Biopsies were classified as NP, PDWA or AH and semi-quantitatively scored for: 1) maximal degree of epithelial proliferation within a focus (DP) (0-3; none to severe) and 2) multifocality of proliferation (MP) (0-3; none to multiple foci). DP and MP scores were also summed to give a DP+MP score (0-6). Associations of DP and MP with BC risk were examined using Cox proportional hazards regression analyses, adjusting for age at BBD biopsy. Women were followed from date of initial biopsy to date of BC, death or last follow-up. Results: Of the 1529 assessable biopsies, 544 (35.6%) were classified as NP, 708 (46.3%) as PDWA and 277 (18.1%) as AH. Both DP and MP scores had significant positive correlation with increasing BBD severity (DP: r=0.51, p< 0.001; MP: r=0.52, p< 0.001). Mean (SD) DP scores were 0.6 (0.6) for NP, 1.6 (0.9) for PDWA, and 1.8 (0.7) for AH (ANOVA p<0.001). Mean (SD) for MP scores were 0.6 (0.6) for NP, 1.4 (0.8) for PDWA, and 1.8 (0.8) for AH (ANOVA p<0.001). Mean (SD) for DP+MP scores were 1.2 (1.2) for NP, 2.9 (1.5) for PDWA, and 3.6 (1.2) for AH (ANOVA p<0.001). With median follow-up of 8.8 years for controls and 5.3 years for cases, 10.6% of the women in the cohort developed BC. Compared to those with DP scores of 0, women with DP scores of 3 had significantly increased BC risk (HR 1.42, 95% CI: 1.16, 1.74, p=0.003). MP was associated with a non-significant increase in BC risk for scores of 3 versus 0 (HR: 1.20, 95% CI: 0.97,1.49, p=0.11). DP+MP scores of 6 conferred the highest BC risk (HR (score 6 vs. 0): 1.62, 95% CI 1.18,2.21, p=0.02). Results did not substantively differ after adjusting for BBD severity as NP, PDWA or AH. Conclusions: In this preliminary analysis within the Mayo BBD cohort, both proliferative degree (DP) and multifocality (MP) scores were correlated with histologic severity of BBD. DP and DP+MP scores were each associated with increased BC risk. We conclude that improved characterization of epithelial proliferation in BBD biopsies may enable refined prediction of individual BC risk. Citation Format: Jodi M Carter, Matthew R Jensen, Robert A Vierkant, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Karthik Ghosh, Derek C Radisky, Amy C Degnim, Mark E Sherman. Epithelial proliferation score as an independent breast cancer risk predictor in benign breast disease [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-10.

Mammographic breast density and risk of breast cancer in women with atypical hyperplasia: an observational cohort study from the Mayo Clinic Benign Breast Disease (BBD) cohort

BackgroundAtypical hyperplasia (AH) and mammographic breast density (MBD) are established risk factors for breast cancer (BC), but their joint contributions are not well understood. We examine associations of MBD and BC by histologic impression, including AH, in a subcohort of women from the Mayo Clinic Benign Breast Disease Cohort.MethodsWomen with a diagnosis of BBD and mammogram between 1985 and 2001 were eligible. Histologic impression was assessed via pathology review and coded as non-proliferative disease (NP), proliferative disease without atypia (PDWA) and AH. MBD was assessed clinically using parenchymal pattern (PP) or BI-RADS criteria and categorized as low, moderate or high. Percent density (PD) was also available for a subset of women. BC and clinical information were obtained by questionnaires, medical records and the Mayo Clinic Tumor Registry. Women were followed from date of benign biopsy to BC, death or last contact. Standardized incidence ratios (SIRs) compared the observed number of BCs to expected counts. Cox regression estimated multivariate-adjusted MBD hazard ratios.ResultsOf the 6271 women included in the study, 1132 (18.0%) had low MBD, 2921 (46.6%) had moderate MBD, and 2218 (35.4%) had high MBD. A total of 3532 women (56.3%) had NP, 2269 (36.2%) had PDWA and 470 (7.5%) had AH. Over a median follow-up of 14.3 years, 528 BCs were observed. The association of MBD and BC risk differed by histologic impression (p-interaction = 0.03), such that there was a strong MBD and BC association among NP (p < 0.001) but non-significant associations for PDWA (p = 0.27) and AH (p = 0.96). MBD and BC associations for AH women were not significant within subsets defined by type of MBD measure (PP vs. BI-RADS), age at biopsy, number of foci of AH, type of AH (lobular vs. ductal) and body mass index, and after adjustment for potential confounding variables. Women with atypia who also had high PD (>50%) demonstrated marginal evidence of increased BC risk (SIR 4.98), but results were not statistically significant.ConclusionWe found no evidence of an association between MBD and subsequent BC risk in women with AH.

Abstract P6-10-19: Clinicopathologic features of breast cancers that develop in women with previous benign breast disease

Abstract Background Women with benign breast disease (BBD) have an increased risk for breast cancer (BC). Almost 30% of all BCs develop in women with prior BBD. Information about the features of the expected BCs after BBD would enable individualized surveillance and prevention strategies for these women. We sought to characterize BCs developing in a large cohort of women with BBD. Methods Our cohort includes 13,485 women who underwent breast biopsy for mammographic or palpable concern between 1967-2001. Biopsy slides were reviewed and classified as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. Results With a median follow-up of 15.8 years, 1273 women developed BC. Most BCs were invasive (81%), among which 61% were ductal, 13% mixed ductal/lobular, and 14% lobular. Two thirds were intermediate or high-grade, and 29% were node positive. Cancer characteristics were similar across the three histologic categories of BBD, with similar frequency of DCIS and invasive disease, tumor size, time to invasive BC, histologic type of BC, nodal positivity and HER2 positivity. Women with AH had a higher frequency of ER+ BC (91%) vs women with PD (80%) or NP (85%), p=0.02. Conclusion A substantial proportion of all BCs develop in women with prior BBD. We show that the majority of BCs after BBD are invasive tumors of ductal type, with a substantial proportion node positive. 84% of cancers were ER-positive. Chemoprevention should be strongly encouraged in higher-risk women with BBD. Citation Format: Visscher DW, Frost MH, Hartmanan LC, Frank RD, Vierkant RA, McCullough AE, Winham SJ, Vachon C, Ghosh K, Brandt KR, Farrell AM, Tarabishy Y, Hieken TJ, Haddad TC, Kraft RA, Radisky DC, Degnim AC. Clinicopathologic features of breast cancers that develop in women with previous benign breast disease. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-19.

Complex fibroadenoma and breast cancer risk: a Mayo Clinic Benign Breast Disease Cohort Study.

The purpose of this study is to examine the breast cancer risk overall among women with simple fibroadenoma or complex fibroadenoma and to examine the association of complex fibroadenoma with breast cancer through stratification of other breast cancer risks. The study included women aged 18-85 years from the Mayo Clinic Benign Breast Disease Cohort who underwent excisional breast biopsy from 1967 through 1991. Within this cohort, women who had fibroadenoma were compared to women who did not have fibroadenoma. Breast cancer risk (observed versus expected) across fibroadenoma levels was assessed through standardized incidence ratios (SIRs) by using age- and calendar-stratified incidence rates from the Iowa Surveillance, Epidemiology, and End Results registry. Analyses were performed overall, within subgroups of involution status, with other demographic characteristics (age, year of biopsy, indication for biopsy, and family history), and with histologic characteristics, including overall impression [nonproliferative disease, proliferative disease without atypia (PDWA), or atypical hyperplasia]. Fibroadenoma was identified in 2136 women [noncomplex, 1835 (85.9%); complex, 301 (14.1%)]. SIR for noncomplex fibroadenoma was 1.49 (95% CI 1.26-1.74); for complex fibroadenoma, it was 2.27 (95% CI 1.63-3.10) (test for heterogeneity in SIR, P = .02). However, women with complex fibroadenoma were more likely to have other, concomitant high-risk histologic characteristics (e.g., incomplete involution and PDWA). In analyses stratified by involution status and PDWA, complex fibroadenoma was not an independent risk marker for breast cancer. Complex fibroadenoma does not confer increased breast cancer risk beyond other established histologic characteristics.

Abstract P6-10-14: Association between mammographic breast density and histologic features of benign breast disease

Abstract Background: Mammographic breast density (MBD) reflects the proportion of fibroglandular tissue in the breast, and is an established risk factor for breast cancer. Benign breast disease (BBD) is also a known risk factor for breast cancer. We previously showed an association between lobular involution (physiologic atrophy) and MBD in a large cohort study of women with BBD. We performed a comprehensive evaluation of the association of histologic features of BBD with MBD. Methods: The Mayo BBD cohort includes women, 18 to 85 years, who were diagnosed with BBD at Mayo Clinic in Rochester, MN between 01/01/1967 and 12/31/1991. For this study, we included women who had a mammogram within 6 months of BBD diagnosis, and diagnosed with BBD between 1985 and 1991 when parenchymal pattern of breast density was clinically recorded. Risk factor information such as age, and body mass index (BMI) was collected from medical records. Parenchymal pattern, assessed clinically and previously used in multiple studies of MBD and risk, classified breast density based on extent and type of density, into four categories: N1 (non-dense, no ducts visible); P1 (ductal prominence occupying &amp;lt;25% breast); P2 (prominent ductal pattern occupying &amp;gt;25% of the breast; DY (homogenous plaque-like areas of density). All assessments of benign breast tissue were performed by expert breast pathologists blinded to both MBD and BBD reports. Histologic characteristics included overall impression (non-proliferative disease (NPD), proliferative disease without atypia (PDWA), and atypical hyperplasia (AH)), proportion of normal lobules that were involuted (no (0%), partial (1 to 74%), or complete (≥75%)), type of AH (ADH or ALH), ductal and lobular hyperplasia, calcifications, sclerosing adenosis, columnar alteration, cyst, fibroadenoma, marked fibrosis, intra-ductal papilloma, radial scar (number and size), duct ectasia, and mucocele like tumors. Associations of parenchymal pattern with BBD characteristics were examined using multicategorical nominal logistic regression models. We first examined associations after adjustment for age and BMI. All variables statistically significant (p&amp;lt;0.05) in these models were then simultaneously included in a fully-adjusted model. Results: Of 2,257 women in the study, 14% were &amp;lt;40 years old, 52.7% between 40- 59 years, and 32.9% were ≥60 years. In this sample, 55.2% of women had NPD, 36% had PDWA, and AH in 8.8%. MBD was classified as N1 in 21.8%, P1 in 12.6%, P2 in 23.7% and DY in 41.9%. Age- and BMI-adjusted analyses showed that there was an association of parenchymal pattern with overall impression, lobular involution, ductal hyperplasia, sclerosing adenosis, columnar alteration, cyst, duct ectasia and fibrosis. Multivariate analyses found that women of younger age (p&amp;lt;0.001) and with lower BMI (p&amp;lt;0.001), presence of fibrosis (p&amp;lt;0.001) and no involution (p=0.016) were more likely to have P2 or DY parenchymal pattern than women without those characteristics. Conclusion: Among women with benign breast disease, higher MBD is associated with younger age, lower BMI, fibrosis, and lack of lobular involution. These findings, concordant with other studies of MBD, provide insight into underlying mechanisms by which MBD and BBD contribute to breast cancer risk. Citation Format: Karthik Ghosh, Robert A Vierkant, Ryan D Frank, Daniel W Visscher, Vernon S Pankratz, Christopher G Scott, Derek C Radisky, Marlene H Frost, Lynn C Hartmann, Amy C Degnim, Celine M Vachon. Association between mammographic breast density and histologic features of benign breast disease [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-14.

Flat epithelial atypia and risk of breast cancer: A Mayo cohort study.

Based on its cytologic features, and its co-occurrence with atypical hyperplasia and breast cancer, flat epithelial atypia (FEA) has been proposed as a precursor lesion on the pathway to the development of breast cancer. It is often referred to as an "atypical" or high-risk lesion. However, to the authors' knowledge, the long-term risk of breast cancer in women with FEA is undefined. Specimens with FEA were identified among excisional breast biopsies in the Mayo Clinic Benign Breast Disease Cohort, which includes 11,591 women who had benign biopsy findings at the Mayo Clinic in Rochester, Minnesota between 1967 and 2001. Breast cancer risk among subsets of patients with FEA and nonproliferative, proliferative, and atypical hyperplasia (AH) was assessed using standardized incidence ratios (SIRs) compared with the Iowa Surveillance, Epidemiology, and End Results registry. FEA was identified in 282 women (2.4%); 130 had associated AH (46%) and 152 (54%) were classified as having proliferative disease without atypia (PDWA). With median follow-up of 16.8 years, the SIR for breast cancer in patients with AH plus FEA was 4.74 (95% confidence interval [95% CI], 3.17-6.81) versus 4.23 (95% CI, 3.44-5.13) for those with AH without FEA (P = .59). The SIR for patients with PDWA plus FEA was 2.04 (95% CI, 1.23-3.19) versus 1.90 (95% CI, 1.72-2.09) for patients with PDWA without FEA (P = .76). FEA is an uncommon finding in women with benign breast disease. FEA does not appear to convey an independent risk of breast cancer beyond that of the associated PDWA or AH.

Changed lineage composition is an early event in breast carcinogenesis.

The epithelium compartment of the human breast is made up of a branching ductal-lobular system, which is lined by a single layer of luminal epithelial cells surrounded by contractile myoepithelial cells. The co-ordinated development of these two cell types, and maintenance of their relative proportions, is fundamentally important for normal breast morphogenesis. Changes in cell type composition is one of the hallmark features of breast cancer progression, and the vast majority of breast tumors are comprised of luminal cells only, with a complete absence of myoepithelial cells. Despite this striking alteration in relative proportions of luminal and myoepithelial cells in invasive breast cancers compared with normal breast tissue, the steps in this dramatic change in cellular composition remain poorly characterised, nor is it known whether loss of myoepithelial cells is an early event in carcinogenesis. In a panel of breast tissues, we quantitated the proportion of luminal cells relative to the surrounding myoepithelial cell layer in a panel of normal and pre-invasive breast tissue samples, including lesions with proliferative disease without atypia (PDWA), columnar cell lesions (CCL), atypical ductal hyperplasia (ADH), and DCIS, and correlated these findings with proliferation in the same lesions. The study findings showed that changes in lineage composition correlate with increased proliferation, and are one of the earliest events in breast carcinogenesis. Therefore not only are myoepithelial cells important in distinguishing between invasive and non-invasive tumors, their relative proportion compared with luminal cell numbers may provide a new potential indicator of which premalignant lesions are at higher risk of progression to invasive disease.

Clinicopathological characteristics of subsequent breast cancers in patients with benign breast disease

1061 Background: Benign breast disease (BBD) is a significant risk factor for breast cancer (BC); however little is known about the aggressiveness of the BCs these patients develop. Shared features between select atypias and low-grade DCIS have led some to speculate that a history of BBD portends the development of well-differentiated BCs. Methods: The Mayo BBD cohort includes 9,376 women who had benign breast biopsies from 1967–1991. Data on BC events were obtained from medical records and questionnaires. Tissue from the BCs was reviewed by a single breast pathologist (DWV). Results: Our cohort included 6,244 patients with nonproliferative disease (NP), 2,801 women with proliferative disease without atypia (PDWA), and 331 with atypical hyperplasias (AH). With a median of 18 years of follow-up, 799 patients with BBD have developed breast cancer, 416 initially had NP, 313 had PDWA, and 70 AH. BC tissue was available for 703 of the women. The cancers were invasive ductal in 76.1% (n = 535), invasive lobular in 9.4% (n = 66), and DCIS alone in 14.5% (n = 102) patients. Grade is currently available for 500 women, and is well differentiated in 29.4% (n = 150), moderately differentiated in 42.7% (n = 218) and poorly differentiated in 27.8% (n = 142). In 537 cases the malignant tissue had a concurrent benign component consisting of NP in 24% (n = 129), PDWA in 25.1% (n = 135), and AH in 50.8% (n = 273). In regards to tumor size, 69.6% had T1 tumors, 24.9% T2 tumors, and 5.5% T3 disease. Metastasis to lymph nodes occurred in 25% of patients. Median time to BC was 12.3 years and did not differ across the different benign entities. Breast cancer developed within 5 years from the initial BBD in 163 women (20%). In this group, tumor size was greater (p = 0.02), and there were more poorly differentiated tumors (p = 0.006) than in those who later developed BC. Conclusions: In the BCs that have developed in our BBD cohort, we do not see a preponderance of well-differentiated, good-risk BCs. Patients diagnosed within 5 years of BBD appear to have BCs with more aggressive features. No significant financial relationships to disclose.

Benign breast disease and breast cancer risk in young women.

Abstract Abstract #62 Background: Breast cancer is the leading cause of cancer deaths in younger women (25 to 49 years of age). Young women with breast cancer also have worse overall survival and increased risk of recurrence compared to older women with breast cancer. Innovative approaches to understanding risk factors and tissue characteristics for the younger population can improve understanding of breast cancer etiology and enhance risk-stratification for these women. This study was aimed at examining breast cancer risk factors among young women (&amp;lt;50 years) with BBD. Materials and Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had benign excisional breast biopsy between January 1, 1967 and December 31, 1991 were identified. The diagnosis of breast cancer served as the study endpoint and was determined using the Mayo medical record and questionnaire information from study participants. The breast pathologist, blinded to the initial diagnosis and clinical outcome, performed pathology review. BBD was classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). Age-related lobular involution (reduction in number and size of acini per lobule) was classified as none-0%, partial- 1 to74%, or complete- &amp;gt;75% involution. Relative risk (RR) was estimated by comparing the number of observed breast cancers with the number expected, based on breast cancer rates in the Iowa Surveillance, Epidemiology, and End Results registry. Results: Of the 9376 women in the Mayo BBD cohort, 4460 women were aged &amp;lt;50 years at BBD diagnosis and formed the study cohort. The mean age at BBD diagnosis was 39.4 (+ 8.3) years. With a median follow-up of 20 years, 326 breast cancer cases were identified. The histologic findings were NPD in 72% of women, PDWA in 26%, and AH in 2%. The relative risk of breast cancer for the overall cohort of young women with BBD was 1.5 (95% CI [1.4, 1.7]). The relative risk among those with AH was 6.9 (95% CI [4.6, 10.1), compared with a RR of 2.0 (95% CI [1.7, 2.4]) for PDWA, and RR of 1.2 (95% CI [1.0, 1.4]) for NPD. Risk was associated with extent of lobular involution (RR for no involution was 1.7 (95%CI [1.4, 2.1]); partial involution 1.4 (95%CI [1.2, 1.7]); complete involution 0.7 (95%CI [0.3, 1.4]). Family history was available for 83% of the cohort and RR was 2.2 (95% CI [1.7, 2.8]) for women with strong family history and was 1.3 (95% CI [1.1, 1.6]) for women with no family history. Discussion: Young women with BBD are at increased risk of breast cancer. Risk is high in women with atypical hyperplasia, and those with a family history of breast cancer. Lobular involution is associated with reduced breast cancer risk in this population, suggesting a role in modifying breast cancer risk. These findings suggest the need for further research in this population, along with tissue-based studies to examine the processes leading to breast cancer, and enable identification of those women at highest risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 62.

Breast cancer risk in women with radial scars in benign breast biopsies

The risk for subsequent breast cancer in women diagnosed with radial scar lesions (RS) on benign breast biopsy remains controversial. We studied the relative risk of radial scar lesions in a large cohort of patients with benign breast disease (BBD). Radial scars were identified in a BBD cohort of 9,262 patients biopsied at Mayo Clinic between 1967 and 1991. Radial scar lesions were classified as proliferative disease without atypia (PDWA) unless atypia was present (classified as atypical hyperplasia [AH]). The observed number of breast cancers developing among those with RS was compared to that expected in the general population using standardized incidence ratios (SIRs, mean follow-up interval 17 years). RS were identified in 439 (4.7%) of the cohort members; 382 (87.0%) contained one RS, 42 (9.6%) contained two, 9 (2.0%) contained three, and 6 (1.4%) contained four or more. The majority of RS (356, 82.4%) were less than 5.0 mm in diameter; 60 (13.9%) were 5.0-9.9 mm, and 16 (3.7%) were 10.0 mm or greater. The relative risk for women with PDWA and RS was 1.88 (95% CI, 1.36-2.53), no different than PDWA without RS [relative risk 1.57 (95% CI, 1.37-1.79) (P=0.29)]. Women with atypical hyperplasia and RS (n=60) had a relative risk of 2.81 (95% CI, 1.29-5.35), while those with atypia but without RS had a relative risk of 3.97 (95% CI, 2.99-5.19). RS imparts no increased breast cancer risk above that of PDWA or AH without RS.

Loss of co-ordinate expression of progesterone receptors A and B is an early event in breast carcinogenesis.

Progesterone receptor (PR) mediates the effects of progesterone in mammary tissues and plays a crucial role in normal breast development and in breast cancer. PR proteins are expressed as two isoforms, PRA and PRB, that have different capacities to activate target genes, yet it is unknown whether progesterone action in normal and malignant breast is mediated by PRA and/or PRB. This study determines the relative expression of PRA and PRB in normal breast and in benign, premalignant and malignant archival breast lesions by dual immunofluorescent histochemistry. In normal breast and in proliferative disease without atypia (PDWA) PRA and PRB were co-expressed within the same cells in comparable amounts, implicating both isoforms in progesterone action. In atypical lesions, however, there was a significant increase in predominant expression of PRA or PRB, with lesion progression from the normal state to malignancy. PR isoform predominance, especially PRA predominance, was evident in a high proportion of ductal carcinomas in situ (DCIS) and invasive breast lesions. In the normal breast and in PDWA, the relative expression of PRA and PRB in adjacent cells was homogenous. There was a significant increase in cell-to-cell heterogeneity of PR isoform expression in ADH and DCIS lesions and in the majority of breast cancers. Heterogeneous cell-to-cell expression of PR isoforms occurred prior to overall predominant expression of one isoform in premalignant breast lesions, demonstrating that loss of control of relative PRA:PRB expression is an early event in the development of breast cancer. PRA:PRB ratios within a breast lesion are likely to be important as both markers and effectors of tumor growth and development, and progressively aberrant PR isoform expression may play a role in the etiology of breast cancer.

Progesterone receptor A and B isoforms in the human breast and its disorders.

Two different isoforms of progesterone receptor (PR), PRA and PRB, are expressed in target tissues at comparable levels. In this study, we first examined PRA and PRB immunoreactivity in human breast cancer and various intraductal proliferative epithelial lesions, and correlated these findings with clinicopathologic parameters. We then examined mRNA expression of PRA and PRB in six cases of invasive ductal carcinoma using RT‐PCR. Immunoreactivity for both PRA and PRB was positive in the great majority of proliferative disease without atypia (PDWA) (85% for PRA and 96% for PRB) and atypical ductal hyperplasia (ADH) (100% for PRA and 100% for PRB), but the ratio of immunopositive cases and immunohistochemical (IHC) scores was significantly smaller in ductal carcinoma in situ (DCIS) (65% for PRA and 75% for PRB) and invasive ductal carcinoma (IDC) (66% for PRA and 55% for PRB) than in PDWA and ADH. There was a significant positive correlation between IHC scores for PRA and estrogen receptor α (ERα) in IDC, DCIS and ADH but not between PRB and ERα. In IDC, both PRA and PRB IHC scores were significantly associated with histological grade, but there was no association between PRA or PRB status and lymph node involvement, tumor size, or prognosis of the patients. The expression of mRNAs for both PRA and PRB was detected in all six cases of IDC examined. These results suggest that both PRA and PRB are strongly associated with ERa in human breast and this relation may be disturbed in breast cancer.

Retinoic Acid Receptor and Retinoid × Receptor in Ductal Carcinoma in situ and Intraductal Proliferative Lesions of the Human Breast

Retinoic acid (RAR) and retinoid × receptors (RXR) are essential in the transcriptional actions of retinoids. To date, RAR and RXR have not been examined in precancerous lesions and/or ductal carcinoma in situ (DCIS) in human breast. Therefore, we examined RAR and RXR subtypes in DCIS (58 cases), atypical ductal hyperplasia (ADH) (32 cases), and proliferative disease without atypia (PDWA) (32 cases) to study the status of these RARs and RXRs. Immunoreactivities for RAR α, RXR α, RXR β, and RXR γ were all detected in the nuclei of normal ductal epithelia. Immunoreactivity for RAR β was detected exclusively in the nuclei of myoepithelial cells, but not in normal ductal epithelia. Immunoreactivity for RAR γ was not detected in any of the breast tissues examined except for a few cases of PDWA and ADH, and 11 cases of DCIS. The RXR α labeling index (LI) was significantly higher in both DCIS (mean 77.9) and ADH (mean 77.7) than in PDWA (mean 62.8) (P<0.001). RXR β LI was significantly lower in DCIS (mean 81.5) than in both ADH (mean 91.1) and PDWA (mean 91.9) (P=0.0001). Immunoreactivity for RAR α, RXR α, RXR β and RXR γ was widely distributed compared to that of RAR β and RAR γ in DCIS, ADH and PDWA. RAR α LI was significantly correlated with Ki67 LI in DCIS (P=0.0040), especially in estrogen receptor (ER)‐positive DCIS. Our results suggest that RXRs are much more widely distributed than RARs in intraductal proliferative lesions of the human breast, but ER‐positive DCIS cases with high cell proliferative activity are associated with RAR α, suggesting the possible involvement of retinoids through RAR α in tumor cell proliferation in DCIS.

Estrogen replacement therapy in women with a history of proliferative breast disease.

Little information is available regarding the invasive breast carcinoma risk associated with estrogen replacement therapy (ERT) in women with histories of histologically defined breast lesions. A retrospective cohort study of a consecutive series of women who underwent breast biopsies that proved to be benign between 1952-1978 was conducted. Follow-up data were obtained for 9494 women (87.6% of women eligible for follow-up). To investigate the effect of ERT on invasive breast carcinoma risk, the analysis was restricted to women with premenopausal breast disease whose follow-up extended through menopause and who did not develop premenopausal breast carcinoma. Relative risks were calculated with respect to women who took ERT but whose benign breast biopsies had neither atypical hyperplasia (AH), complex fibroadenoma (CFA), nor proliferative disease without atypia (PDWA). During 190,845 woman-years of follow-up there were 444 confirmed cases of invasive breast carcinoma in the entire cohort. Women with a history of AH had relative risks of invasive breast carcinoma of 2.87 (95% confidence interval [95% CI], 1.3-6.3) and 2.53 (95% CI, 1.0-6.3) if they did or did not take ERT, respectively. For women with a history of CFA these risks were 1.57 (95% CI, 0.72-3.4) and 1.46 (95% CI, 0.53-4.0), respectively, whereas for women with a history of PDWA they were 1.37 (95% CI, 0.88-2.1) and 1.13 (95% CI, 0.69-1.9), respectively. ERT does not significantly elevate the risk of invasive breast carcinoma in women with previous histologically defined benign breast disease. Therefore, ERT is not contraindicated in these women.