Frost, MH

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.

Abstract Background Women with atypical hyperplasia (AH) are at an approximately four-fold increased risk of subsequent breast cancer (BC). Mammographic breast density (MBD) is a well-established risk factor for BC, but its contribution to BC risk in women with AH remains an open question. We previously reported no association between MBD [measured by Wolfe's parenchymal pattern (PP)] and BC risk in a cohort of 147 women with AH. Here, we present results in an expanded cohort of 459 women diagnosed with AH between 1985 and 2001. Methods The Mayo Clinic Benign Breast Disease Cohort includes 13,485 women who had benign core and/or excisional biopsy 1967-2001. Biopsy tissues were reviewed by our study pathologist to determine presence of AH. MBD was available from clinical records starting in 1985, coded as PP (the standard for 1985-1996) or BI-RADS (1997-2001) density criteria. The original four-level PP (N1-fatty, P1-ductal prominence <25% of breast, P2-ductal prominence >25%, DY-dysplasia) and BI-RADS (fatty, scattered densities, heterogeneously dense, extremely dense) measures were re-categorized as low, moderate or high MBD by combining the middle two categories for each. BC events and clinical information were obtained by questionnaires, medical records and the Mayo Clinic Tumor Registry. Women were followed from benign biopsy to date of BC, death or last contact. Standardized incidence ratios (SIRs) were generated overall and within subgroups defined by density measure (PP vs. BI-RADS), number of atypical foci, and BMI by dividing the observed number of BCs by population-based expected values. Cox regression was used to estimate MBD hazard ratios after adjustment for demographic and clinical variables. Results Of the 551 women diagnosed with AH between 1985 and 2001, 459 (83%) had MBD data within 1 year prior to biopsy. Of these, 68 (15%) had low, 221 (48%) had moderate, and 170 (37%) had high MBD, respectively. Over a median follow-up of 11.7 years, 80 BCs were observed. SIRs for breast cancer did not differ significantly across density categories, overall or within any subgroups examined (see Table). Cox regression adjusting for age, BMI and density measure (PP vs. BI-RADS) also failed to identify an association with MBD (p=0.55). Low MBDModerate MBDHigh MBD N / BCsSIR (95% CI)N / BCsSIR (95% CI)N / BCsSIR (95% CI)P-valueOverall68/123.5 (1.8,6.1)221/393.6 (2.5,4.9)170/293.4 (2.3,4.8)0.97MBD Measure PP59/113.6 (1.8,6.5)85/153.0 (1.7,5.0)130/243.3 (2.2,5.0)0.87BI-RADS9/12.7 (0.1,14.7)136/244.0 (2.6,6.0)40/53.4 (1.1,7.9)0.90No. Atypical Foci 147/62.3 (0.9,5.1)123/182.8 (1.7,4.4)96/163.5 (2.0,5.8)0.63214/47.5 (2.0,19.1)58/134.8 (2.6,8.3)41/62.5 (0.9,5.5)0.213+7/26.7 (0.8,24.0)40/84.4 (1.9,8.6)33/74.0 (1.0,8.2)0.83BMI <2525/21.5 (0.2,5.4)75/184.9 (2.9,7.7)101/173.4 (2.0,5.5)0.1625-2919/54.9 (1.6,11.3)68/92.8 (1.3,5.2)36/42.1 (0.6,5.4)0.4530+23/54.8 (1.6,11.2)76/123.0 (1.6,5.3)32/74.0 (1.6,8.2)0.67SIRs compare observed numer of BCs to expected using Iowa SEER data. Analyses account for the effects of age and calendar period. P-value is test of heterogeneity in SIRs across columns. Conclusions We found no evidence of an association between MBD and subsequent BC in women with AH. Citation Format: Vierkant RA, Degnim AC, Hartmann LC, Frank RD, Radisky DC, Visscher DW, Frost MH, Winham SJ, Ghosh K, Vachon CM. No evidence of association between mammographic breast density and risk of breast cancer in women with atypical hyperplasia. [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 P6-09-05.

Abstract Background: Age-related lobular involution (LI) is a physiological process, usually accelerated with menopause, in which the epithelial tissue of the breast gradually regresses. Our previous analysis of a cohort of more than 14,000 women who had a benign breast biopsy at the Mayo Clinic revealed that women who had undergone LI were at significantly reduced risk of subsequent breast cancer development. In our studies of postmenopausal women specifically, we found that more than 40% had not completed the process of LI, and that the increased breast cancer incidence in older women was strongly associated with incomplete LI. We sought to determine the potential protective mechanistic effects of lobular involution. Methods: We generated primary human mammary epithelial cell lines (HMECs) from breast biopsies of women who showed no LI (N = 6), partial LI (N = 7), or complete LI (N = 6). These cell lines were analyzed for proliferation in culture and profiled for genomic signatures using Affymetrix gene arrays. We also analyzed RNA isolated from a cohort of archived formalin-fixed, paraffin-embedded (FFPE) benign breast biopsy samples from postmenopausal women who had either completed the process of LI (N = 4) or who had not initiated LI (N = 8) for genomic signatures using Whole-Genome DASL Assays. Results: We found that LI was associated with decreased cellular proliferation and inhibition of processes associated with tumor development and progression. Specifically, we found that HMECs derived from benign breast biopsies in which LI was not evident showed increased proliferation and elevated expression of Twist (p = 0.002), a transcription factor associated with epithelial-mesenchymal transition (EMT) and breast cancer development. We are assessing differentially expressed genes for association with breast cancer risk using a nested case:control group of benign breast biopsies from women in our cohort who subsequently developed breast cancer (N = 85) vs those who did not (N = 142) and for whom LI status at the time of initial biopsy was known. Conclusions: LI may decrease cancer risk through inhibition of key tumorigenic processes. Identification of processes associated with the physiologic risk reduction seen with LI may provide insight into novel avenues for risk reduction. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-06-01.

Abstract Background: Fibroadenoma (FA) is a relatively common benign breast tumor that can occur in women of any age, with a peak incidence during the second and third decades. The only previous study of this lesion reported that FAs are associated with a 2.2 times increased risk of developing invasive breast cancer (BC) compared to matched controls [1]. This relative risk may increase to 3.1 among patients with complex FA, and remains elevated for decades after diagnosis. However, this study did not thoroughly account for other forms of concomitant risk factors. Our investigative team sought to examine breast cancer risk among women with non-complex and complex FA, overall and stratified by other BC risk factors. Materials and Methods: The study cohort included women between ages 18 to 85 in the Mayo Benign Breast Disease (BBD) Cohort who underwent excisional breast biopsy between 1967and1991 and were found to have a FA. FA was defined histologically as a combination of epithelial and stromal proliferation. Complex FA was defined as FA associated with any of the following features: sclerosing adenosis, epithelial calcifications, papillary apocrine change, and microcysts greater than 3.0 mm. The primary endpoint was a diagnosis of BC, determined using the Mayo medical record and questionnaire information from study participants. A single breast pathologist, blinded to the initial diagnosis and clinical outcome, performed pathology review. Observed vs. expected BC risk across levels of FA was assessed via standardized incidence ratios (SIRs), using age-stratified incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) registry. Analyses were carried out overall and within subgroups of involution status (none, partial, complete) and overall histology (non-proliferative disease [NP], proliferative disease without atypia [PDWA] or atypical hyperplasia [AH]). Results: Of 9097 women in the Mayo BBD Cohort, FA were identified in 2139- non-complex in 1903 (20.9%) and complex in 236 (2.6%). The greatest proportion of FA occurred in the 40–69 age range. The mean ages for women with non-complex FA and complex FA were 45.7 and 50.2 years respectively. The SIR of breast cancer in the overall BBD cohort was 1.5 (95% CI [1.4–1.6]). The SIR among women with non-complex FA was 1.5 (95% CI [1.3–1.8]), and for complex FA increased to 2.41 (95% CI [1.7–3.4]). However, women with complex FA were more likely to have other concomitant high-risk histologic features such as PDWA and incomplete involution. In stratified analyses accounting for involution status and PDWA, complex FA did not demonstrate an independent increase in BC risk. Conclusion: Complex FA does not confer an increased risk for BC beyond other established histologic features. Therefore, women with complex FA should be managed based upon a risk level consistent with the major histologic category of PDWA and/or AH. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-08.

Abstract Background: It has long been known that chemotherapy can result in premature menopause, causing follicular senescence and estrogen depletion with associated hot flashes and mood alterations. What is less well appreciated is whether the stroma of the ovary is equally impacted after chemotherapy, resulting in androgen deprivation. The aim of this pilot study was to evaluate whether androgen levels are adversely affected after chemotherapy and whether this is associated with unwanted symptoms. Methods: Women who were premenopausal, newly diagnosed with breast cancer, and about to undergo adjuvant chemotherapy were followed longitudinally. Women with adrenal insufficiencies, taking steroids, oral contraceptives, or had had previous chemotherapy were excluded. Self report questionnaires regarding sexual function, fatigue, mood, menstrual symptoms; menstrual diaries; and blood were collected at 4 points: before treatment, mid chemotherapy, post chemotherapy and 6 months later. Serum concentrations of dehydroepiandrosterone sulfate (DHEA-S) (adrenal hormone), bioavailable testosterone (bioT), androstenedione (Adione) (stromal hormone), estrone (E1), estradiol (E2) (follicular hormone), sex hormone binding globulin (SHBG), and follicle stimulating hormone (FSH) were evaluated. Descriptive statistics, comparisons of means by two sided t-tests and Pearson correlation coefficients were computed. Six month post treatment data are reported. Results: 24 women were accrued and 21 provided serum and questionnaires through 6 months. All sex steroid hormones decreased during chemotherapy and did not return to baseline by 6 months for the group as a whole. At 6 months, 14 women were postmenopausal per FSH, E2 and menstrual diaries and 7 had resumed menses. There were no significant differences in hormone concentrations at baseline between women who ended up menopausal from those who resumed menses. However, at 6 months, postmenopausal women had significantly lower concentrations than premenopausal women of E2 (289 pg/ml pre- 9 pg/ml post), E1 (132 pg/ml pre- 22 pg/ml post), and Adione (102 ng/dL pre- 56 ng/dL post), but not DHEA-S or bioT (all p < .01). E2 was significantly correlated with Adione (R = .47 p = .03), and E1 (R = .57, p = .007). Low to moderate correlations were found between hormone concentrations and symptoms. The use of tamoxifen was significantly, and negatively correlated with the total score on the Female Sexual Function Index (r = −.572, p = .005), indicating worse sexual function for women on tamoxifen. Conclusion: These data support the hypothesis that the post chemotherapy ovary suffers both follicular and stromal dysfunction, as noted by lower Adione, which is specific to the ovarian stroma. Adione concentrations in the postmenopausal group women are similar to published reports of women post oophorectomy. This is the first longitudinal study we are aware of to evaluate ovarian stromal function in women undergoing chemotherapy. This total hormone depletion may be why women experiencing chemotherapy induced menopause report severe and distressing menopausal symptoms such as hot flashes. Estrogen is often implicated, but androgen deprivation in this population should be taken into consideration when planning interventions to improve health related quality of life. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-01.

Abstract Background: Women with hereditary breast cancer risk, who develop breast cancer, face complex surgical decisions related to their breast cancer and risk to their contralateral breast. The aim of this study was to prospectively evaluate the factors influencing decision making in these women and degree of decision conflict before and after consultation with breast specialized physicians (BSP). Methods: Women with hereditary breast cancer risk and recently diagnosed with unilateral breast cancer were enrolled in a prospective decision making questionnaire study. Questionnaires were completed prior to their initial breast clinic visit and after consultation with a breast clinic physician, nurse educator and a breast surgeon. Results: 68 women completed both questionnaires. Mean age was 52 (range 27–84). Prior to meeting with BSP, 10 (15%) women reported having made a decision for the cancer side and 18 (26%) reported being close to deciding. Of the 20 who expressed a surgical preference prior to consultation, 5 (25%) changed their decision after meeting with the BSP [1 to mastectomy (MTX), 4 to breast conservation (BC)]. After consultation with BSP, 65 (96%) reported having made a decision (BC in 29 (45%), MTX in 35 (54%), unspecified in one). The most commonly cited reasons influencing surgical choice were doctor's advice (79%), family history of breast cancer (74%) and worrisome findings on biopsy (50%). Prior to meeting with BSP, 9 (13%) women reported having made a decision regarding screening and/or risk-reducing options for the contralateral breast and another 11 (16%) reported being close to a decision. The choices in these 20 women were screening only in 10 (50%), contralateral prophylactic MTX (CPM) in 3 (15%), CPM and oophorectomy in 2 (10%), other combinations of options in 4, and unspecified in 1. After meeting with the BSP, 49 (72%) reported having made a decision regarding the contralateral breast; this decision was for screening only in 21 (43%), CPM only in 9 (18%), screening plus tamoxifen in 7 (14%), CPM and oophorectomy in 2 (4%), other combinations of options in 8, and unspecified in 2. The most commonly cited reasons for choices on the contralateral side were: family history (81%), doctor's advice (78%), and worrisome findings on biopsy (43%); only 25% cited psychological or emotional reasons. For both the cancer and contralateral sides, decisional conflict was significantly lower after meeting with BSP than prior to meeting with BSP. Decision-conflict scale total scores (possible range 0–100; higher scores indicate more decisional conflict) summarized for each side and compared between timepoints Conclusion: The BSP consult and family history have the greatest influence on decision making among women with hereditary risk diagnosed with breast cancer. After consultation most women felt they had made decisions for both the cancer and contralateral sides and reported significantly lower decision conflict compared to prior to the consultation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-15-05.

Abstract Invasive breast carcinoma in African American (AA) women differs significantly from their Caucasian (CA) counterparts in its incidence, morphology and outcome. These tumors are more likely to be high grade, hormone receptor negative, present at a younger age and at a higher stage. Evaluation and a better understanding of precursor lesions may help delineate the mechanisms underlying the development of breast cancer in these two groups. Atypical hyperplasia (AH) in the breast has been associated with an increased risk of developing cancer (relative risk∼4.0). Risk stratification of these women by identification of predictive biomarkers would be beneficial for optimal patient care. In our study we evaluated the expression of the following prognostic biomarkers: estrogen receptor (ER), Cyclooxygenase-2 (COX-2) enzyme and Ki-67 in AH in a cohort of AA women with benign breast biopsies. AA women with benign breast biopsies from years 1997–2000 were retrieved from our departmental database. Clinical and follow up data was obtained from the SEER database. The hematoxylin and eosin (H & E) slides for these cases were reviewed by 2 pathologists, who were blinded to the outcome, and those with atypia were included in this study. Paraffin blocks were retrieved for immunohistochemical (IHC) analysis and standardized scoring methods applied. A total of 1608 AA women had benign breast biopsies during the study period. We performed IHC analysis on 37 (2.3%) who were diagnosed with atypia (25 cases of atypical ductal hyperplasia (ADH) and 12 cases of atypical lobular hyperplasia (ALH)). Increased COX-2 expression was seen in 19 of 28 (67.8%) cases with AH. Of these, 13 of 19 cases (68.4%) were of ADH and 6 of 9 cases (66.7%) were of ALH. Twenty of 25 cases had a high expression of ER overall. Of these, 15 of17 (88.2%) of the positive cases was in the ADH category and 3 of 7 (42.8%) was in the ALH group. Of 32 cases, only 3 cases showed a proliferation rate of > 2% (9.4%) with Ki-67 IHC stain. All of these cases belonged to the ADH (21) category. In summary, the majority of AH cases showed increased COX-2 expression, although no differences were observed between lobular and ductal lesions. In contrast, ADH lesions appeared to exhibit increased reactivity for ER compared to ALH. Similarly, although rare, more ADH cases showed an increased proliferation rate compared to ALH. From our data, COX-2 and ER might be of prognostic significance in AA patients with AH. Larger studies with follow up are needed to understand this disease further. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-07.

Abstract African American (AA) women have higher mortality rates from breast cancer (BrCa) and are diagnosed at younger ages than their Caucasian counterparts. Women who have had a benign breast biopsy are at increased risk of the disease, although less is known about the risk of BrCa associated with benign breast disease in AA women. We examined 1428 breast biopsies from AA women which occurred from 1997–2000 and assessed various pathologic markers including: apocrine metaplasia, ductal hyperplasia including atypia, evidence of cysts, duct ectasia, fibrosis, intra-ductal papilloma, sclerosing adenosis, columnar alteration, and involution (atrophy). These women were followed for later BrCa through the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology and End Results (SEER) program through 2008. Women who developed BrCa were compared to those in the cohort who did not, and to other AA women with BrCa in the SEER registry. AA women in our study were also compared to Caucasian women in the Mayo Clinic cohort. Differences in variables were assessed by chi-squared tests and 95% confidence intervals. Of the 1428 biopsies, 52 (3.6%) subsequent incident breast cancers were reported in SEER. The mean age at diagnosis was 59, and the mean time from biopsy to BrCa diagnosis was 6.1 years. Individuals with atypical ductal hyperplasia at biopsy (n=37, 2.6%) were more likely to develop breast cancer (n=7, 13.5%, p<0.01). No other pathologic variables were associated with increased risk. Women in our cohort with breast cancer did not differ from AA in the SEER database with respect to age at diagnosis, stage at diagnosis, or receptor positivity. Compared to the Caucasian women in the Mayo Clinic BBD cohort, AA women in our study were younger at biopsy (p<0.01), but had similar percentages of involution and atypia (p=0.50 and 0.15, respectively). Our preliminary findings among a relatively small group of AA women with prior benign breast biopsies and incident breast cancers suggest that results from the Mayo Cohort study are likely to apply to AA populations. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-08-16.

Abstract The association between hormone replacement therapy (HRT) and breast cancer risk in women with benign breast disease (BBD) is unclear. However, others have shown that HRT use is associated with the development of proliferative breast disease (Rohan et. al, CEBP 2008). To better clarify potential risks associated with postmenopausal hormone use in women with BBD, we performed a nested case control study within the Mayo Clinic Benign Breast Disease Cohort. In the cohort, there are 11,079 women who had benign breast biopsies between 1967 and 1996 and for whom we have outcome and risk factor data, including use of HRT. We studied 947 cases (breast cancer after BBD) and two controls matched to each case based on age and year of BBD. Information on use of HRT was obtained through use of questionnaires and medical record review with a mean time of follow up of 17.4 years. HRT use, histology, involution status, and family history were all evaluated for impact on breast cancer risk in a multivariate model. As shown in Table 1, when looking at effects of histology, involution, and family history, we confirmed previously reported findings of risk (Hartmann LC et. al, NEJM 2005). Specifically, we saw increased risk in women with AH vs. PDWA or NP, decreased risk with complete involution vs. partial or no involution, and increased risk with strong family history vs. weak or no family history. Associations of hormone replacement therapy and other relevant clinical variables with risk of breast cancer Multivariate model simultaneously including all variables listed in the table. HRT=hormone replacement therapy. NP=non-proliferative. PDWA=proliferative disease without atypia. AH=atypical hyperplasia We found that women who had used HRT had no higher risk of developing breast cancer than women who had not used HRT. Specifically, with Never Users as the reference group, those with 5 years or less exposure had OR 0.80 (0.56-1.15); 6-10 years, 0.85 (0.56-1.28) and 11+ years, 0.51 (0.36-0.72), p =0.002. In conclusion, we found that HRT use among postmenopausal women with BBD was not associated with an increased risk of breast cancer. In this case-control set, we confirmed previous findings regarding well established risk factors of histology, involution status, and family history. While HRT use may contribute to the development of proliferative breast disease, we do not see that HRT is associated with additional breast cancer risk, beyond that of the proliferative disease itself. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-09-03.

Abstract Background: Women with benign breast disease are at elevated breast cancer risk. In order to accurately predict a woman's individual risk of breast cancer, a breast cancer risk-prediction model is needed that incorporates significant breast cancer risk factors. This report describes two factors: tissue based assessment of lobular involution, and radiological marker- mammographic density (MD). Lobular involution, or physiologic atrophy of the breast glandular epithelium, is inversely associated with breast cancer risk. MD is a strong positive risk factor for breast cancer. With increasing age, the extent of lobular involution increases while MD decreases. However, it is unclear whether involution and MD represent independent breast cancer risk factors. We examined breast cancer risk associated with lobular involution and MD in women with benign breast disease (BBD) to determine whether these features are independently associated with breast cancer risk.Methods: Using the Mayo Clinic Surgical and Pathology Indices, 9376 women ages 18 to 85 with benign excisional breast biopsy between January 1, 1967 and December 31, 1991 were identified and formed the Mayo BBD cohort. We studied a sub-cohort of women diagnosed with BBD between 1985 and 1991 (when MD was clinically assessed and recorded) who had a mammogram within 6 months of the BBD diagnosis. Breast cancer outcomes were determined through the Mayo medical records and a study-specific questionnaire. Lobular involution extent was assessed in background tissue as 'none' (0% lobules involuted), 'partial' (1-74% lobules involuted) or 'complete' (≥75% lobules involuted). MD was classified as Wolfe's parenchymal pattern (PP) as N1/ fatty; P1; P2; and DY/ homogenously dense. Hazard ratios and confidence intervals were calculated using Cox regression analyses, adjusting for confounders: age, parity, BMI, BBD histology, menopausal status, family history, PP and involution extent.Results: A total of 2666 women in the Mayo BBD cohort, with biopsies between 1985 and 1991, had a mammogram within 6 months of the breast biopsy. The mean age at biopsy was 54.6 years. After a mean follow-up of 13.3 years, 172 (6.5%) women developed breast cancer. After adjustment for PP and other confounders, women with no or partial involution had elevated risk compared to women with complete involution (HR 2.62 [95% CI 1.39, 4.94] for no involution and 1.61 [95% CI 1.03, 2.53] for partial involution; complete involution as reference group; p for trend 0.003). Moreover, women with dense breasts were at greater risk compared to women with nondense breasts (HR 1.67 [95% CI 1.0, 2.73] for DY pattern, 1.96 [95% CI 1.2 – 3.21] for P2, 1.23 [95% CI 0.67, 2.26] for P1; N1 category as reference group; p for trend 0.02). Multivariate analyses also showed that women with the combination of no involution and dense breasts had greater risk compared to those with complete involution and nondense breasts (HR 4.08 [95% CI 1.72, 9.68]).Conclusion: Lobular involution and MD are both risk factors for breast cancer; this report is the first to demonstrate that each provides unique information about breast cancer risk. These findings emphasize the potential for inclusion of both these factors in future breast cancer risk-prediction models. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6064.