Radisky, Derek C.

BACKGROUNDWomen with benign breast disease (BBD) have an increased risk of developing breast cancer (BC). Nearly 30% of all BCs develop in women with prior BBD. Information regarding features of the expected number of BCs after BBD would enhance individualized surveillance and prevention strategies for these women. In the current study, the authors sought to characterize BCs developing in a large cohort of women with BBD.METHODSThe current study cohort included 13,485 women who underwent breast biopsy for mammographic or palpable concerns between 1967 and 2001. Biopsy slides were reviewed and classified as nonproliferative disease, proliferative disease without atypia, or atypical hyperplasia. BCs were identified by follow‐up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed.RESULTSWith median follow‐up of 15.8 years, 1273 women developed BC. The majority of BCs were invasive (81%), of which 61% were ductal, 13% were mixed ductal/lobular, and 14% were lobular. Approximately two‐thirds of the BC cases were intermediate or high grade, and 29% were lymph node positive. Cancer characteristics were similar across the 3 histologic categories of BBD, with a similar frequency of ductal carcinoma in situ, invasive disease, tumor size, time to invasive BC, histologic type of BC, lymph node positivity, and human epidermal growth factor receptor 2 positivity. Women with atypical hyperplasia were found to have a higher frequency of estrogen receptor‐positive BC (91%) compared with women with proliferative disease without atypia (80%) or nonproliferative disease (85%) (P = .02).CONCLUSIONSA substantial percentage of all BCs develop in women with prior BBD. The majority of BCs after BBD are invasive tumors of ductal type, with a substantial number demonstrating lymph node positivity. Of all the BCs in the current study, 84% were estrogen receptor positive. Prevention therapy should be strongly encouraged in higher‐risk women with BBD. Cancer 2016;122:378–385. © 2015 American Cancer Society.

Abstract Introduction: CD56+ lymphocytes (a defining marker of natural killer cells) have a predominantly cytotoxic phenotype and a hypothetical role in breast tumor immunosurveillance. Here we investigate whether CD56+ staining density varies in nonmalignant breast lobules according to confirmed breast cancer risk factors- age, and histologic features of fibrocystic change and lobular involution. Methods: Archived breast tissue samples were obtained from 94 women with benign breast disease (BBD). The sample set was selected as a nested case-control study (47 cases, 47 controls) from within a large BBD cohort; cases were those who developed breast cancer subsequent to their benign breast biopsy; controls were matched to cases on age at biopsy, year of biopsy, and length of breast cancer free follow-up at least as long as the time-to-cancer in the matched case. Up to 10 representative lobules in each sample were characterized by H&E for fibrocystic changes and the degree of epithelial proliferation (normal, nonproliferative, proliferative, atypia) and for degree of lobular involution (none, partial, complete). Consecutive sections were immunostained for CD56 and hematoxylin. Using digital image analysis, CD56 staining was quantified on a per lobule basis by pixel ratio (PR) (positive stain:total lobule). Statistical analysis was performed using linear mixed effects regression on the rank transformed density to account for correlations among multiple lobules from the same patient in assessing the association of density with lobule characteristics and using conditional logistic regression for association with case-control status. Results: Among 94 women (median age 52, range 35-73), 876 lobules were evaluated: 431 in BBD cases and 445 in BBD controls. Overall, 391 lobules (45%) were normal and the remaining 485 (55%) demonstrated fibrocystic changes. Among fibrocystic lobules, 247 (51%) had nonproliferative changes, 218 (45%) had epithelial proliferation, and 20 (4%) had atypical hyperplasia. Among normal lobules, 61 (16%) had no involution, 139 (36%) had partial involution, and 191 (49%) had complete involution. The vast majority of lobules (861/876, 98%) demonstrated presence of CD56+ cells, while only 15 of 876 lobules in 11 patients had zero CD56+ cells [7 cases (15%) versus 4 controls (8.5%) OR 1.75, p = 0.37]. The median CD56+ PR was 0.55% overall. Fibrocystic lobules as a group showed significantly lower median CD56+ PR compared to normal lobules (0.37% vs 0.85%, p < 0.0001). Among subcategories of fibrocystic lobules, the median CD56+ PR was lower in proliferative lobules (0.29%) compared to non-proliferative (0.42%), but this difference was not statistically significant (p = 0.55). Older women (age > 55) showed the highest CD56+ PR (median of 0.92%), as compared to 0.38% in women 45-55 (p=0.02), and 0.52% in women age <45 (p = 0.26). Among normal lobules, median CD56+ PR was similar between lobules with no involution (0.55%) and partial involution (0.52%) but was considerably higher among lobules with complete involution (1.3%, p = 0.09 and p = 0.05, respectively). In a multivariable model, CD56+ PR differences between fibrocystic and normal lobules remained significant (p = 0.0002) and also remained significant between age groups of > 55 and 45-55 (p = 0.02), while involution was non-significant. Median CD56+ PR was lower in cases (0.43%) compared to controls (0.72%), but this was not statistically significant (p=0.19) in our sample of 47 case-control pairs. Conclusions: Breast lobules with fibrocystic changes show less CD56+ cells, raising a question of possible immune suppression induced by early epithelial abnormalities. These findings encourage further investigation to improve understanding of the immune microenvironment in premalignant breast tissues. Citation Format: Rushin D. Brahmbhatt, Daniel Kerekes, Tanya L. Hoskin, Alvaro Pena, Daniel W. Visscher, Melody L. Stallings-Mann, Derek C. Radisky, Linda M. Murphy, Vernon Shane Pankratz, Keith L. Knutson, Marlene Frost, Amy C. Degnim. CD56+ immune cell infiltration is decreased in benign breast lobules with fibrocystic changes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B34.

Abstract Introduction: Estrogen receptor beta (ERβ), which is highly expressed in benign breast epithelium, is postulated to function as a tumor suppressor of breast cancer. Atypias of the breast increase the lifetime risk of breast cancer four-fold. However, little is known about ERβ expression in association with atypias or whether ERβ plays a role in mitigating breast cancer risk in high-risk individuals. We therefore undertook this study to examine the relationship of ERβ expression in atypias and adjacent normal lobules with the risk of subsequent breast cancer. Methods: We studied women in a well-characterized benign breast disease cohort with atypical ductal hyperplasia (ADH) or atypical lobular hyperplasia (ALH) diagnosed from 1967 to 1991. Nuclear and cytoplasmic ERβ expression was assessed via immunohistochemistry in both the atypical hyperplasia epithelium (atypia) and background normal lobules for percent (scores 0-4 for <1%, 1-25%, 26-50%, 51-75%, >75%, respectively) and intensity (scores 0-3 for negative, weak, intermediate, strong, respectively) using a highly specific ERβ monoclonal antibody (PPG5/10). For nuclear staining, an ERβ sum score (percent + intensity, range 0-7) was created and grouped as low (0-2), moderate (3-5) or high (6-7). Competing risks regression was used to assess the association of ERβ expression with future breast cancer risk while also accounting for the competing risk of death from other causes. Results: 171 women, median age 56, were studied (79 ADH and 92 ALH). Median follow-up was 15 years overall, and 36 women developed breast cancer at a median of 13 years after their atypia biopsy. ERβ expression was lower in the atypia versus normal lobules whether evaluated by nuclear percent stained, nuclear intensity or cytoplasmic intensity (all p < 0.001). For nuclear staining specifically, ERβ expression in the atypia was low in 44 (26%), moderate in 117 (68%) and high in only 10 (6%) based on the sum score. In contrast, ERβ was higher in the normal lobules with a majority showing high expression (n = 96, 56%), moderate expression in 74 (43%) and low expression in only 1 (0.6%). Lower ERβ nuclear expression in the atypia was associated with increased breast cancer risk, whether evaluated by percent staining, intensity or sum score; the same was true for ERβ nuclear expression in the background normal lobules. Low ERβ expression in the atypia (sum score 0-2) was associated with a 2-fold increased risk of subsequent breast cancer compared to atypia with moderate-high expression (sum score 3-7), HR 2.0, 95% CI: 1.02-3.8, p = 0.04. Lower ERβ expression in the normal lobules was also associated with an increased risk of future breast cancer: HR = 2.5 (95% CI: 1.3-5.1, p = 0.009) for low-moderate versus high expression. Conclusions: Increased ERβ expression in normal and atypical lobules was associated with a significantly decreased risk of breast cancer in our high-risk patient cohort. These data suggest that in women with atypical hyperplasia, ERβ expression is protective against the future development of breast cancer. ERβ may serve as a useful biomarker to further stratify breast cancer risk in women with benign breast disease. Citation Format: Tina J. Hieken, Jodi M. Carter, John R. Hawse, IV, Tanya L. Hoskin, Marlene Frost, Lynn C. Hartmann, Derek C. Radisky, Daniel W. Visscher, Vernon S. Pankratz, Amy C. Degnim. ERβ expression and breast cancer risk prediction for women with atypias. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A03.