Citations

18 Background: Benign breast disease (BBD) is diagnosed in 1-2 million women/year in the US, and while these patients are known to be at substantially increased risk for subsequent development of breast cancer, existing models for risk assessment perform poorly at the individual level. Here, we describe a DNA-microarray-based transcriptional model for breast cancer risk prediction for patients with sclerosing adenosis (SA), a lesion found in ¼ of all BBD patients that is characterized by epithelial proliferation, disordered acinar architecture, and stromal fibrosis. Methods: A training set was developed from 86 patients diagnosed with sclerosing adenosis (SA), of which 27 subsequently developed cancer within 10 years (cases) and 59 remained cancer-free at 10 years (controls). A diagonal linear discriminate analysis (DLDA)-prediction model for prediction of cancer within 10 years (SA TTC10) was generated from transcriptional profiles of formalin fixed, paraffin-embedded (FFPE) biopsy-derived RNA. This model was tested on a separate validation case-control set composed of 65 SA patients. Results: The SA TTC10 gene signature model, composed of 35 gene features, achieved a clear and significant separation between case and control with receiver operating characteristic area under the curve of 0.913 in the training set and 0.836 in the validation set. Conclusions: Our results provide the first demonstration that benign breast tissue contains transcriptional alterations that indicate risk of breast cancer development, and that essential precursor biomarkers of malignancy are present many years prior to cancer development. Furthermore, the SA TTC10 gene signature model, which can be assessed on FFPE biopsies, constitutes a novel prognostic biomarker for patients with SA.

247 Background: There are no prospective and few large retrospective studies of male breast cancer (MBC). This study’s aim was to describe our institutional experience with MBC and evaluate the ability of the AJCC staging system to stratify survival. Methods: All MBC cases were identified from our institution’s cancer registry from 1984-2008. Data collected included tumor characteristics, lymph node status, treatment, age, and survival. Results: During the study period 166 MBC cases were identified. Median age at diagnosis was 62 years (range 27-87). Most common presentation was a palpable breast mass (77%). Stage at diagnosis was stage 0 (6%), stage 1 (27%), stage 2 (36%), stage 3 (17%), stage 4 (5%), and unknown (9%). Procedure performed was mastectomy in 148 patients (89%), lumpectomy in 10 patients (6%) and unknown in 8 patients (5%). Median tumor size was 2.0 cm (range 0.2-11.0 cm). Most common histology was invasive ductal carcinoma (91%). Estrogen and progesterone receptor status assessed at diagnosis was positive in 93% and 86% of cases tested respectively. HER2/neu status was positive in 6 of 47 cases tested (13%). Nodal staging was performed by axillary dissection (AD) (70%), sentinel node biopsy (SN) alone (11%), SN and AD (11%) and no axillary staging (8%); 43% were node positive, 47% node negative and 10% unknown. Adjuvant chemotherapy was given to 40 patients (24%), adjuvant hormonal therapy to 42 patients (25%) and adjuvant radiation therapy was used in 33 cases (20%). With a median follow-up of 5.5 years, 86 patients (52%) have died: 44 due to breast cancer, 23 due to causes unrelated to breast cancer, and in 19 the cause of death is unknown. Median overall survival was 9.3 years. Median cancer-specific survival was 16.0 years. For patients initially diagnosed at stage 2, 3, and 4 median cancer-specific survival was 12.9, 7.2, and 0.8 years respectively. Median cancer-specific survival was significantly different for stages 2 vs. 3 (p = 0.03) and 3 vs. 4 (p = 0.0006). Conclusions: MBC most commonly presents as a palpable mass, is hormone responsive, and is most commonly treated with mastectomy. The TNM system appropriately stratifies men with MBC by duration of survival.

240 Background: Contralateral prophylactic mastectomy (CPM) is increasingly chosen by patients with breast cancer. Satisfaction after CPM is high. However, decreased satisfaction has been associated with reoperation after reconstruction. This study’s aim was to examine the adverse aspects patients attribute to reconstruction and the subsequent effect on psychosocial consequences and satisfaction with CPM. Methods: 487 unilateral breast cancer patients with a family history of breast cancer who underwent CPM between 1960 and 1993 were mailed a questionnaire evaluating QOL and satisfaction with CPM. Results: Of 269 respondents, 210 (78%) underwent reconstruction and 59 (22%) did not. Mean age at CPM was 46 and 50 years respectively (p=0.01). Mean follow-up was 20.2 years. Reconstruction was immediate in 96%, 98% with implants and 2% with tissue flap. Reconstruction was associated with lower satisfaction with CPM (p=0.03), but still only 7% (vs 2% in those without reconstruction) said they were dissatisfied. Most (83%) of those with reconstruction said they would choose reconstruction again while 7% were unsure and 10% said they would not. In those who did not undergo reconstruction, 18% said they would choose reconstruction if able to make the choice again while 5% were unsure and 77% said they still would not. 95 patients (45%) of those that underwent reconstruction required one or more reoperations for complications. Those with reoperation reported poorer responses for satisfaction with CPM (p=0.04), choice to have CPM again (p=0.008), and choice to have reconstruction again (p=0.004) when compared to patients with reconstruction and no reoperation. Those with and without reconstruction did not differ significantly with respect to femininity, sexual relationships or emotional stability, but those without reconstruction reported significantly poorer effects related to self esteem (p=0.04) and body appearance (p=0.002). Conclusions: In patients who undergo CPM, many years after surgery satisfaction with CPM is higher in those choosing not to have reconstruction than those with reconstruction although it was high in both groups. Reoperation is common after reconstruction and is associated with lower satisfaction.

144 Background: Many patients require hospitalization after mastectomy, predominantly for pain management and treatment of postoperative nausea and vomiting (PONV). In order to improve a woman's perioperative experience after mastectomy and facilitate mastectomy on an outpatient basis, we initiated a clinical pathway for perioperative management of unilateral mastectomy patients at Mayo Clinic Rochester. Methods: The clinical pathway consists of preoperative oral medications (celecoxib and gabapentin), preoperative ultrasound guided paravertebral block using bupivacaine, intraoperative anesthesia management with total intravenous anesthetic, and minimal use of long-acting opioids and postoperative acetaminophen and oxycodone. All patients are evaluated by the surgical team on the afternoon after surgery and if patients are recovering well are discharged on the day of surgery. The following morning, the surgical team telephones the patient to follow up on management of pain, nausea or vomiting, and drain output. Results: Eighteen patients have been treated on this clinical pathway. Mean age of patients was 66 (range 51-81). Majority of patients (n=16, 89%) underwent unilateral mastectomy with sentinel lymph node biopsy, with 1 patient undergoing bilateral mastectomy and 1 patient undergoing mastectomy and axillary dissection. All patients are evaluated by the surgical team on the afternoon of surgery. Fourteen patients (78%) were without evidence of hematoma or PONV, pain was well-controlled on oral medications and they were discharged on the day of surgery. On morning after telephone calls, pain scale ratings ranged from 1 to 3 and no patients verbalized complaints of nausea. Four patients (22%) treated on this clinical pathway required overnight observation in the hospital, one for urinary retention, two for pain control, and one for high sanguineous drain output. Conclusions: The clinical pathway presented provides preemptive analgesia and regional anesthesia for patients undergoing mastectomy, enabling the majority of patients to be discharged on the day of surgery. The clinical pathway is a safe and effective way to improve the perioperative experience of breast surgery patients and decrease hospital admission.

Abstract Purpose: Little is known about the role of the immune system in the earliest stages of breast carcinogenesis. We studied quantitative differences in immune cell types between breast tissues from normal donors and those from women with benign breast disease (BBD). Experimental Design: A breast tissue matched case–control study was created from donors to the Susan G. Komen for the Cure Tissue Bank (KTB) and from women diagnosed with BBD at Mayo Clinic (Rochester, MN) who either subsequently developed cancer (BBD cases) or remained cancer-free (BBD controls). Serial tissue sections underwent immunostaining and digital quantification of cell number per mm2 for CD4+ T cells, CD8+ T cells, CD20+ B cells, and CD68+ macrophages and quantification of positive pixel measure for CD11c (dendritic cells). Results: In 94 age-matched triplets, BBD lobules showed greater densities of CD8+ T cells, CD11c+ dendritic cells, CD20+ B cells, and CD68+ macrophages compared with KTB normals. Relative to BBD controls, BBD cases had lower CD20+ cell density (P = 0.04). Nearly 42% of BBD cases had no CD20+ B cells in evaluated lobules compared with 28% of BBD controls (P = 0.02). The absence of CD20+ cells versus the presence in all lobules showed an adjusted OR of 5.7 (95% confidence interval, 1.4–23.1) for subsequent breast cancer risk. Conclusions: Elevated infiltration of both innate and adaptive immune effectors in BBD tissues suggests an immunogenic microenvironment. The reduced B-cell infiltration in women with later breast cancer suggests a role for B cells in preventing disease progression and as a possible biomarker for breast cancer risk. Clin Cancer Res; 23(14); 3945–52. ©2017 AACR.

Abstract Background: Age-related lobular involution (LI) is a physiological process in which the terminal duct lobular units of the breast regress as a woman ages. Analyses of breast biopsies from women with benign breast disease (BBD) have found that extent of LI is negatively associated with subsequent breast cancer development. Here we assess the natural course of LI within individual women, and the impact of progressive LI on breast cancer risk. Methods: The Mayo Clinic BBD cohort consists of 13,455 women with BBD from 1967-2001. The BBD cohort includes 1115 women who had multiple benign biopsies, 106 of whom had developed breast cancer. Within this multiple biopsy cohort, the progression of the LI process was examined by age at initial biopsy and time between biopsies. The relationship between LI progression and breast cancer risk was assessed using standardized incidence ratios (SIRs) and by Cox proportional hazards analysis. Results: Women who had multiple biopsies were younger age and had a slightly higher family history of breast cancer as compared with the overall BBD cohort. Extent of LI at subsequent biopsy was greater with increasing time between biopsies and for women age 55+ at initial biopsy. Among women with multiple biopsies, there was a significant association of higher breast cancer risk among those with involution stasis (lack of progression, HR 1.63) as compared with those with involution progression, p = 0.036. Conclusions: The multiple biopsy BBD cohort allows for a longitudinal study of the natural progression of LI. The majority of women in the multiple biopsy cohort showed progression of LI status between benign biopsies, and extent of progression was highest for women who were in the perimenopausal age range at initial biopsy. Progression of LI status between initial and subsequent biopsy was associated with decreased breast cancer risk. Citation Format: Derek Radisky, Daniel W. Visscher, Ryan Frank, Robert A. Vierkant, Stacey J. Winham, Melody L. Stallings-Mann, Tanya L. Hoskin, Aziza Nassar, Celine M. Vachon, Lori A. Denison, Lynn C. Hartmann, Marlene H. Frost, Amy C. Degnim. Natural history of age-related lobular involution and impact on breast cancer risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-364.

BACKGROUNDWomen with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.METHODSAll samples containing AH were included from 2 cohorts of women with benign breast disease (Mayo Clinic and Nashville). Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). The BC risk was stratified for the number of AH foci within AH subtypes.RESULTSThe study included 708 Mayo AH subjects and 466 Nashville AH subjects. In the Mayo cohort, an increasing number of foci of AH was associated with a significant increase in the risk of BC both for ADH (relative risks of 2.61, 5.21, and 6.36 for 1, 2, and ≥3 foci, respectively; P for linear trend = .006) and for ALH (relative risks of 2.56, 3.50, and 6.79 for 1, 2, and ≥3 foci, respectively; P for linear trend = .001). In the Nashville cohort, the relative risks of BC for ADH were 2.70, 5.17, and 15.06 for 1, 2, and ≥3 foci, respectively (P for linear trend < .001); for ALH, the relative risks also increased but not significantly (2.61, 3.48, and 4.02, respectively; P = .148). When the Mayo and Nashville samples were combined, the risk increased significantly for 1, 2, and ≥3 foci: the relative risks were 2.65, 5.19, and 8.94, respectively, for ADH (P < .001) and 2.58, 3.49, and 4.97, respectively, for ALH (P = .001).CONCLUSIONSIn 2 independent cohort studies of benign breast disease, the extent of atypia stratified the long‐term BC risk for ADH and ALH. Cancer 2016;122:2971‐2978. © 2016 American Cancer Society.

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.