Sherman, Mark E.

Abstract Introduction: Terminal duct lobular unit (TDLU) involution, an age-related physiological process, is characterized by the reduction of size and numbers. Reduced involution is associated with higher mammographic density, a strong breast cancer risk factor. Both factors predict risk of developing breast cancer among women with benign disease. Given that prior studies have been conducted mainly in White women, we compared the extent of TDLU involution among Western and Asian breast cancer cases to describe potential racial heterogeneity in breast cancer etiology. Method: We obtained three TDLU involution metrics (count/100 mm2, mean span, and mean acini count/TDLU; all inversely correlated with TDLU involution) measured in benign breast tissue sections from 379 Chinese (254 luminal A and 125 core basal phenotype [CBP] cases) and 476 Polish (407 luminal A and 69 CBP) breast cancer cases. Polytomous logistic regression was performed using tertiles of TDLU measures as ordinal dependent variable and race as an independent variable. Covariates included age, body mass index, and parity. Analyses were performed separately by age group (<50, ≥50) and subtype (luminal A and CBP). Results: Among luminal A cases, Chinese had significantly greater TDLU count compared with Polish in both age groups (ORtrend= 11.0; 95% CI=2.80-43.2; Ptrend=0.001 for age<50; ORtrend= 12.1; 95% CI=5.12-28.7; Ptrend=1E-08 for age≥50). In addition, Chinese were more likely to have greater mean span and acini count among younger cases (ORtrend=2.5; 95% CI=1.44-4.28; Ptrend=0.001 for mean span and ORtrend=7.4; 95% CI=4.13-13.4; Ptrend=3E-11 for acini count) but not among older cases. Among CBP cases, Chinese were more likely to have greater acini count compared to Polish only among younger women (ORtrend=2.6; 95% CI=1.12-6.95; Ptrend=0.03 for age<50). Conclusion: We found Chinese were more likely to have reduced TDLU involution compared to Polish cases after accounting for potential confounders, with greater differences for luminal A and younger women. Studies of TDLU involution in diverse populations are needed to confirm and understand whether population difference in TDLU involution metrics are related to age at breast cancer onset and risks for specific tumor subtypes. Citation Format: Hyuna Sung, Changyuan Guo, Jennifer Guida, Shan Zheng, Erni Li, Jing Li, Nan Hu, Joseph Deng, Montserrat Garcia-Closas, Jonine Figueroa, Mark Sherman, Gretchen Gierach, Ning Lu, Xiaohong R. Yang. Racial variation in terminal duct lobular unit (TDLU) involution in Chinese and Polish breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5290. doi:10.1158/1538-7445.AM2017-5290

Abstract Background: Serous tubal intraepithelial carcinoma (STIC) is hypothesized to give rise to many cancers that have been historically classified as ovarian primaries. Although STIC is gaining status as a diagnostic entity, similar appearing lesions would likely have been reported as fallopian tubal carcinoma in-situ (FT-CIS) in the past. Accordingly to characterize patterns of reporting and behavior for tubal cancers, we analyzed population-based data for incidence rate trends, co-occurrence with cancer at other sites and survival of FT-CIS and invasive fallopian tube carcinoma (FT-Inv). Methods: We analyzed data for FT-CIS and FT-Inv included within 33 registries using the Cancer Incidence in North America Deluxe Analytical Files provided by the North American Association of Central Cancer Registries (1995-2012). Primary site of invasive carcinomas were defined according to the International Classification of Diseases for Oncology (3rd edition) topography codes (ovarian (C56.9), fallopian tube (C57.0), and primary peritoneal cancers (C48.1-.2, 48.8)). We excluded cancers with non-epithelial histology. Total counts, incidence rates per 1 million adjusted to the 2000 standard US population and age-standardized stage-specific survival were computed. Temporal incidence rate patterns were analyzed by joinpoint regression with estimates of annual percentage change (APC). Results: Cases in which the first cancer diagnosis was FT-CIS, included 98 FT-CIS alone; 27 FT-CIS followed by another cancer diagnosis within 1 year and 172 cases in which FT-CIS was diagnosed concurrently with another cancer as compared with 5513 invasive tubal carcinomas over the same period. The incidence rate of FT-CIS was stable from 1995-2002, then significantly increased from 2002-2012 [APC (95% CI) = 16.2% (10.9-21.7)]. Rates of early stage high-grade serous FT-Inv increased significantly from 2002-2012 [10.4% (6.1-14.9)] and rates of late stage high-grade serous FT-Inv rose sharply from 2002-2012 [20.0% (17.5-22.6)]. Five-year age-standardized survival for women with FT-CIS only was 75.6% overall, reflecting 89.1% survival for women less than 50 years and 70.9% for women 50 years or older; survival for high-grade early stage serous FT-Inv was 77.8%. Conclusions: Diagnoses of FT-CIS and FT-Inv have increased dramatically, likely reflecting changes in diagnostic pathology practice. Developing standardized reporting for FT-CIS (and in the future, STIC) when present with concurrent invasive cancer are needed, given that this occurs often. Based on limited data, 5-year survival for FT-CIS and early stage FT-Inv are similar, but future studies to evaluate data for STIC will be required, which will likely be achievable only through national registries that are large enough to capture sufficient cases. Citation Format: Mark E. Sherman, Sally B. Coburn, Hannah Yang, William Anderson, Philip Rosenberg, Gretchen Gierach, Nicolas Wentzensen, Kathy Cronin, Britton Trabert. Incidence rates and outcomes of fallopian tube carcinomas: Data from the North American Association of Central Cancer Registries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 260. doi:10.1158/1538-7445.AM2017-260

Abstract Background: Estrogen receptor (ER) status in breast cancer is strongly associated with etiologic factors, prognosis and treatment response. Data suggest that population-based incidence rates of ER-positive (ER+) tumors are increasing and ER-negative (ER-) cancers have fallen over time in the United States (US), Denmark and Scotland. Whether these trends are consistent in other populations with different etiologic exposures and across ER±/HER2± subtypes is unknown. We, therefore, analyzed breast cancer secular trends in Ireland by ER expression; and for the first time, by joint expression of ER±/HER2±, a well-established clinical marker of uncertain etiological significance. Methods: This study included invasive breast cancers (n=24,845; 2004-2013) among women aged 20-84 years within the population-based National Cancer Registry of Ireland (97% coverage). The general population at risk (n=10,401,986) was obtained from the Irish Central Statistics Office. Using a validated approach to account for missing ER/HER2-status, we assessed ER± and ER±/HER2± secular trends with age-standardized incidence rates (ASR) and estimated annual percentage change (EAPC) with 95% confidence intervals (95%CI). Results: Over the 10-year follow-up period, 19,264 ER+ and 4,161 ER- breast cancers were diagnosed (1,420 were ER-unknown). ASRs increased significantly for ER+ (EAPC: 2.20%/year (95%CI: 0.97, 3.45%/year)) and decreased significantly for ER- cancers (EAPC: -3.43%/year (95%CI: -5.05, -1.78%/year)). The ER-specific trends were qualitatively similar among three age groups (<50, 50-64 and ≥65 years). With further stratification by HER2± expression, ER+/HER2- cancers rose (EAPC: 2.87%/year (95%CI: 1.33, 4.44%/year)), ER+/HER2+ cancers were statistically flat, while ER-/HER± cancers significantly declined. Conclusion: Secular trends for ER± cancers in Ireland were similar to those previously observed in the US and Denmark. Further, trends for ER/HER2 followed those for ER, although rates were constant for ER+/HER+ tumors. The divergence of cancer incidence patterns by ER among independent populations over time could reflect comparable changes in risk factor exposures with dual or opposite effects for risk of ER+ and ER- cancers (e.g., obesity, age at first birth/parity). Additionally, although HER2 is a well-established clinical predictive and prognostic marker for breast cancer outcome, it did not appear to substantively impact breast cancer incidence trends. Citation Format: Maeve Mullooly, Jeanne Murphy, Gretchen L. Gierach, Brittny Davis, Paul Walsh, Sandra Deady, Thomas I. Barron, Mark E. Sherman, Philip S. Rosenberg, William F. Anderson. Estrogen receptor positive and negative breast cancer secular trends in Ireland (2004-2013) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 257. doi:10.1158/1538-7445.AM2017-257

Abstract Purpose: Breast biopsies with benign findings (benign breast disease [BBD]) outnumber biopsies revealing in-situ or invasive cancer 4:1, providing an opportunity to identify histopathological features that predict breast cancer risk. Greater degrees of involution of terminal duct lobular units (TDLUs), the structures within the breast that produce milk and the primary source of breast cancer precursors, have been inversely associated with breast cancer risk among women with BBD. We recently developed measures to quantitate levels of TDLU involution, which demonstrate high inter/intra pathologist reproducibility. Here we assessed whether TDLU counts/100mm2 and median TDLU span (microns), two measures inversely related to degree of TDLU involution, are associated with subsequent breast cancer risk among women with BBD. Methods: From the Mayo BBD cohort (n = 9,376), we evaluated benign biopsies from 99 women who later developed breast cancer (cases) and 145 age-matched controls who did not develop breast cancer. Digitized images of biopsy sections were reviewed to enumerate TDLUs/mm2 and measure median TDLU span (microns) for up to ten normal TDLUs. Breast cancer risk factors were available from questionnaires or medical records. To assess associations with breast cancer risk, subjects were categorized into quartile levels of TDLU counts and median TDLU spans, based on data from controls. Odds ratios (ORs) and 95% confidence intervals (CI) were estimated using multivariable conditional logistic regression models, adjusted for histologic type of BBD, family history of breast cancer and menopausal hormone use. Results: Compared to controls, women who developed breast cancer had higher median number of TDLU counts/100mm2 (28 vs 20, p = 0.03) and larger TDLU spans (300 vs 267 microns, p = 0.14). In multivariable models higher TDLU counts (quartile4 vs. quartile1, OR = 2.44, 95%CI = 0.96-6.19, ptrend = 0.02) and larger TDLU span measures (quartile4 vs. quartile1, OR = 2.83, 95%CI = 1.13-7.06, ptrend = 0.03) were associated with subsequent diagnosis of breast cancer. Combinatorial metrics of TDLU counts with median TDLU span measures identified women at higher risk; specifically, women above the median for both TDLU span and TDLU counts had an OR = 3.75 (95%CI = 1.40-10.00, ptrend = 0.008), compared with women below the median for TDLU span and TDLU counts. Conclusion: These data show that lack of TDLU involution, as measured by increased persistence of TDLU counts, larger median TDLU spans and cross-classification using these measures was associated with increased breast cancer risk among women with BBD, extending prior work in this cohort based on other TDLU involution metrics. Future studies to identify determinants of TDLU involution, its association with breast cancer risk and its potential as an intermediate endpoint in prevention studies warrant consideration. Citation Format: Jonine D. Figueroa, Ruth Pfeiffer, Maya Palakal, Amy C. Degnim, Derek Radisky, Lynn C. Hartmann, Marlene Frost, Melody L. Stallings Mann, Louise A. Brinton, Daphne Papathomas, Daniel Visscher, Mark E. Sherman. Standardized measures of lobular involution and subsequent breast cancer risk among women with benign breast disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4682. doi:10.1158/1538-7445.AM2015-4682

Abstract Background Although a number of cancer chemopreventive agents have now been evaluated in phase II and phase III clinical trials that assess their efficacy and tolerability in both high risk and general populations, few have shown clear efficacy and uptake of approved agents has been disappointingly low. Therefore, chemopreventive agents should undergo rigorous screening prior to clinical trial evaluation in order to improve the selection of suitable agents for testing in large, expensive multi-center phase III trials. The aim of this study is to develop a descriptive method for prioritizing candidate agents for further development. Methods This framework was developed through a systematic literature review of Pubmed/Medline, Embase and The Cochrane Library. A semi-quantitative assessment focusing on efficacy and toxicity/tolerability was established based on expert input. Data from clinical trials, cancer epidemiological, observational and preclinical studies, including in vivo and in vitro basic research, was used to retrospectively evaluate the clinical application and effectiveness of cancer chemopreventive agents. Two chemopreventive agents with either a positive (aromatase inhibitors (AIs) for breast cancer) or negative (selenium for lung cancer) phase III clinical trial outcome were subsequently evaluated to determine the usefulness of the framework. Results Chemopreventive agents must reduce or reverse the process of carcinogenesis in normal or pre-malignant tissue with minimal toxicity. Evaluation of efficacy included data from preclinical and animal models, epidemiological studies, and clinical trials (both early phase trials in the organ of interest as well as secondary endpoints from other relevant studies). Agent suitability evaluation included assessment of toxicities, tolerability, and agent specific attributes (PK/PD, bioavailability, dosing, etc.). Examination of selenium and AI historical data in these categories revealed strong concordance with phase III outcomes. The detailed descriptive evaluation of the agents will be presented. Conclusion This framework provides a descriptive paradigm for cancer chemopreventive agent evaluation through systematic and rigorous interrogation. Thorough, standardized evaluation of all available preclinical, epidemiological, and clinical data should be strongly encouraged to better inform the investments required for clinical trials. Citation Format: Naomi Walsh, David S. Alberts, Powel Brown, Paul Limburg, Mark Sherman, Eva Szabo. Framework for clinical evaluation of chemopreventive agents: Defining criteria for future assessment. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4662. doi:10.1158/1538-7445.AM2015-4662

Abstract Introduction: Increased levels of circulating estrogens are associated with elevated risks of postmenopausal breast cancer. Previously, we showed that levels of sex steroid hormones in breast adipose tissue are positively correlated with circulating hormones. Further evaluation of hormone levels in breast tissues may help to explain the relationship between estrogens and breast cancer risk. Specifically, data suggest that focal breast lesions consisting of macrophages encircling dying adipocytes, referred to as “crown-like structures (CLS)”, are associated with increased aromatase activity, which could increase conversion of androgens to estrogens locally in the breast. Therefore, we assessed whether the presence of CLS affects the correlations between blood and breast adipose tissue hormone levels. Methods: Participants included 84 postmenopausal women with invasive breast cancer in the Polish Breast Cancer Study, a population based case-control study conducted from 2000 to 2003. We previously reported sex steroid hormone levels in cancer-free breast adipose tissue removed as part of breast excisions performed for cancer. Here, using immunohistochemical stains, we evaluated the number of CD68 positive macrophages and the presence of full CLS (i.e., complete adipocyte encirclement) in benign breast tissue sections prepared from surgical pathology specimens containing breast cancer. The relationship between the number of CD68 positive macrophages per unit area of fat and hormone levels was examined using Spearman rank correlations (rs). We assessed potential effect modification of the association between blood and tissue hormone levels by presence or absence of CLS by including an interaction term in linear regression models. Results: The number of CD68 positive macrophages per unit area of fat was not significantly correlated with levels of estrone, estradiol, androstenedione or testosterone measured in blood (rs = 0.001, -0.04, -0.07, and -0.09, respectively; p>0.05) or breast adipose tissue (rs = -0.15, 0.06, -0.06, and -0.08, respectively; p>0.05). Correlations between serum and adipose tissue hormones did not statistically significantly differ between women with CLS (n = 30) compared to those without CLS (n = 54). CLS were found more frequently in breast adipose tissue from overweight (i.e., women with a body mass index (BMI) between 25 and 29.9) (43%) and obese women (BMI >30) (30%) versus normal weight women, with (BMI between 18.5 and 24.9), (27%); (p = 0.04, χ2 test). The number of CD68 positive macrophages per unit area of fat was not significantly related to BMI (p = 0.31). Conclusion: Among postmenopausal women with invasive breast cancer, the presence of CLS was more common among overweight and obese women, but CLS did not influence the correlation between circulating and breast adipose tissue sex steroid hormone levels. Citation Format: Maeve Mullooly, Hannah P. Yang, Roni T. Falk, Sarah Nyante, Renata Cora, Ruth M. Pfeiffer, Derek C. Radisky, Daniel W. Visscher, Lynn C. Hartmann, Amy C. Degnim, Frank Z. Stanczyk, Jonine F. Figueroa, Montserrat Garcia-Closas, Jolanta Lissowska, Melissa T. Troester, Louise A. Brinton, Mark E. Sherman, Gretchen L. Gierach. Investigation of the relationship between crown-like structures and adipose tissue hormone levels among postmenopausal women with breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2767. doi:10.1158/1538-7445.AM2015-2767

Abstract Background: Terminal duct lobular units (TDLU) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009–2011). Methods: We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n = 390): TDLU counts, median TDLU span, and median acini counts per TDLU. RRs (for continuous measures), ORs (for categorical measures), 95% confidence intervals (95% CI), and Ptrends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone–binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. Results: Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18; 95% CI: 1.07–1.31; Ptrend = 0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80; 95% CI: 0.72–0.89; Ptrend < 0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61; 95% CI: 1.32–1.97; Ptrend < 0.0001) and testosterone (RRT3vsT1: 1.32; 95% CI: 1.09–1.59; Ptrend = 0.0043) were associated with higher TDLU counts. Conclusions: These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. Impact: Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis. Cancer Epidemiol Biomarkers Prev; 23(12); 2765–73. ©2014 AACR.

Abstract Background: Terminal ductal lobular units (TDLUs), the functional units of the breast for lactation, are the structures from which most breast cancers arise. TDLU involution, reflecting atrophy and loss of TDLUs, has been related to lower subsequent breast cancer risk. The predictors of such breast tissue aging, however, are not well defined. Given that estrogens and other hormones play a central role in the etiology of postmenopausal breast cancers, we conducted a study to assess the relationship between four hormones and sex hormone-binding globulin (SHBG) with markers of TDLU involution. Methods: Subjects included healthy women who volunteered between 2009 and 2011 to participate in the Komen Tissue Bank Study. Participants completed a risk factor questionnaire, provided a blood sample, and donated breast tissue for research. Our analysis was restricted to postmenopausal women who were not currently taking menopausal hormones (n=153). A pathologist, masked to patient data, assessed tissue sections for the presence of TDLUs and, among sections containing TDLUs (n=88), measured TDLU diameters for up to ten TDLUs per section. Both presence of TDLUs and TDLU diameter are inversely related to involution. Chemiluminescent immunometric assays were used to measure serum levels of estradiol (E2), SHBG, follicle-stimulating hormone (FSH), and prolactin. Percent free E2 was calculated from measured E2 and SHBG levels. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the presence of TDLUs (none or any) associated with tertiles of serum hormone and SHBG levels. Multivariable ordinal logistic regression was used to calculate ORs, 95% CIs, and p-trend for TDLU diameter categorized as tertiles (≥218.4, 218.4-281, and ≥281 microns) with serum hormone and SHBG levels. All models were adjusted for potential confounding factors. Results: The study population was 87.6% Caucasian with a mean age of 59.5 years, and >2/3 of the women were overweight or obese. Increasing percent free E2 was significantly associated with larger TDLU diameter (OR>2.53 vs. ≥1.99: 5.58, 95% CI: 1.48-21.07; p-trend=0.01), whereas increasing SHBG was associated with smaller TDLU diameter (OR>73nmol/L vs. ≥38 nmol/L: 0.19, 95% CI: 0.05-0.74; p-trend=0.02). Total E2 (p-trend=0.49), FSH (p-trend=0.85), and prolactin (p-trend=0.58) were not associated with TDLU diameter. We did not find significant relationships between the presence of TDLUs and any of the serum levels. Our observed relationships were not modified by age or other breast cancer risk factors, including BMI, years since menopause, and history of bilateral oophorectomy. Conclusion: Based on limited data, these findings suggest that sex hormones may play a role in TDLU involution. Thus, TDLU involution may represent one mechanism by which hormone levels influence breast cancer risk. TDLU measurements may therefore be helpful in assessing breast cancer risk as a marker of breast tissue aging. Analysis of the relationships between hormones and TDLU involution among premenopausal women may provide additional insights into early events in breast carcinogenesis. Citation Format: Zeina G. Khodr, Mark E. Sherman, Ruth M. Pfeiffer, Gretchen L. Gierach, Louise A. Brinton, Roni T. Falk, Deesha Patel, Laura Linville, Susan E. Clare, Daniel Visscher, Carolyn Mies, Stephen Hewitt, Anna Maria Storniolo, Jonine D. Figueroa. Endogenous hormone levels and lobular involution of the breast among healthy, postmenopausal women in the Komen Tissue Bank Study. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B89.

Abstract Background: Terminal duct lobular units (TDLUs) are the anatomical source of most breast cancers. TDLU involution, manifested as atrophy and loss of TDLUs, is associated with reduced breast cancer risk. We hypothesize that breast cancer susceptibility loci are associated with TDLU involution. Accordingly, we evaluated relationships between 25 established breast cancer susceptibility markers and their association with TDLU involution in the Susan G. Komen for the Cure® Tissue Bank (KTB). Methods: Subjects were women ages 18-84 (N=680), who had no personal history of any cancer, were not currently taking menopausal hormones, completed a risk factor questionnaire, provided an Oragene® saliva sample, and donated a 10-guage needle tissue core from the upper outer breast quadrant for research. We genotyped 25 known single nucleotide polymorphisms (SNPs) associated with breast cancer risk using TaqMan® assays. Pathologists masked to risk data classified three features inversely related to TDLU involution using one histological section of breast tissue/subject: number of TDLUs per section (TDLU density), TDLU diameters and number of acini per TDLU. SNPS were compared to metrics of TDLU involution categorized in tertiles: TDLU density (0-1, 2-8, 9+), mean TDLU diameter (53-291, 292-415, 416-1143 microns), and mean number of acini per TDLU (2-10, 11-20, 21+). We estimated age-adjusted per-allele odds ratios (ORs) and 95% confidence intervals (CIs) using ordinal logistic regression models with TDLU measures as the outcome and SNPs as the explanatory variables. Associations with TDLU density were based on up to 680 women with genotype data, while associations with diameter and acini measures were based on up to 469 women with observed TDLUs. Results: The rs3803662 (TOX3/TNRC9) SNP risk allele showed an association with increased TDLU density, larger TDLUs, and more acini in TDLUs (TDLU density per-allele OR=1.29 95%CI=1.04-1.60; TDLU diameter OR=1.32 95%CI=1.00-1.74; and TDLU acini OR=1.34 95%CI=1.02-1.77), consistent with previous observations of significant associations seen for this SNP with mammographic density (a well-established risk factor for breast cancer), breast cancer risk, and survival of breast cancer. In addition, we observed associations for four other SNPs with TDLU density (rs311499, rs10483813, rs2981582, rs3817198), for one other SNP with mean TDLU diameter (rs11249433), and for three other SNPs with mean TDLU acini number (rs704010, rs10941679, rs11249433). Conclusion: These data suggest that breast cancer susceptibility SNPs may be associated with TDLU involution levels, and could represent a mechanism by which they influence breast cancer risk. These findings warrant replication in other studies and provide support for the concept that levels of TDLU involution represent an intermediate marker of breast cancer risk. Citation Format: Jonine D. Figueroa, Gretchen L. Gierach, Ruth Pfeiffer, Stephen Chanock, Louise Brinton, Deesha A. Patel, Daniel Visscher, Carolyn Mies, Stephen Hewitt, Susan Clare, Anna Maria Storniolo, Mark Sherman. Associations between breast cancer susceptibility markers and terminal duct lobular unit involution in normal breast tissues among women from the Susan G. Komen for the Cure® Tissue Bank. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 58.