Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation reactions and reduction of signals driving cell proliferation and survival responses. The objectives of this study were to examine the effects of statins on breast cancer cells, both in vitro and in vivo, and to begin to determine their mechanism of action. We evaluated the effects of statins on breast cancer cell growth, phosphoprotein signaling intermediates, survival/apoptosis regulators, cell cycle regulators, and activated transcription factors. We also examined the in vivo effect of statin administration in a mouse ErbB2 + breast cancer model. Only lipophilic statins had direct anticancer activity in vitro. Breast cancer cells with activated Ras or ErbB2 pathways seemed to be more sensitive than those overexpressing estrogen receptor, and this correlated with endogenous levels of activated nuclear factor KB (NF-KB). Key intermediates regulating cell survival by NF-KB activation, as well as cell proliferation by the mitogen activated protein kinase cascade, were among the earliest phosphoproteins influenced by statin treatment. These early effects were followed by declines in activator protein-1 and NF-KB activation and concordant changes in other mediators of proliferation and apoptosis. In vivo results showed that oral dosing of statins significantly inhibited the growth of a mouse mammary carcinoma. Lipophilic statins can exert direct anticancer activity in vitro by reducing proliferation and survival signals in susceptible breast cancer phenotypes. Tumor growth inhibition in vivo using a clinically relevant statin dose also seems to be associated with reduced tumor cell proliferation and survival. These findings provide supporting rationale for future statin trials in breast cancer patients.

Background: Recent guidelines suggest that chemoprevention with tamoxifen may be appropriate for women who have a 5-year risk of breast cancer greater than 1.66% calculated using the Gail model. Objectives: To determine whether nipple aspirate fluid (NAF) cytology combined with the Gail model provides breast cancer risk assessment that is superior to either method alone. Methods: Prospective observational cohort of 6,904 asymptomatic women. Breast cancer cases were identified through follow-up with the women and linkage to cancer registries. We used proportional hazards modeling to recalculate the coefficients for the predictor variables used in the Gail model. NAF cytology was added to create a second model. The two models were compared using the concordance statistic (c-statistic). Results: During 14.6 years of follow-up, 400 women were

This study sought to evaluate a shared decision-making aid for breast cancer prevention care designed to help women make appropriate prevention decisions by presenting information about risk in context. The decision aid was implemented in a high-risk breast cancer prevention program and pilot-tested in a randomized clinical trial comparing standard consultations to use of the decision aid. Physicians completed training with the decision aid prior to enrollment. Thirty participants enrolled (15 per group) and completed measures of clinical feasibility and effectiveness prior to, immediately after, and at 9 months after their consultations. The decision aid was feasible to use during the consultations as measured by consultation duration, user satisfaction, patient knowledge, and decisional conflict. The mean consultation duration was not significantly different between groups (24 minutes for intervention group versus 21 minutes for control group, p = 0.42). The majority found the decision aid acceptable and useful and would recommend it to others. Both groups showed an improvement in breast cancer prevention knowledge postvisit, which was significant in the intervention group (p = 0.01) but not the control group (p = 0.13). However, the knowledge scores returned to baseline at follow-up in both groups. Decision preference for patients who chose chemoprevention post consultations remained constant at follow-up for the intervention group, but not for the control group. The decision framework provides access to key information during consultations and facilitates the integration of emerging biomarkers in this setting. Initial results suggest that the decision aid is feasible for use in the consultation room. The tendency for the decision choices and knowledge scores to return to baseline at follow-up suggests the need for initial and ongoing prevention decision support.

BACKGROUND. Ductal lavage (DL) does not routinely identify cytologically malignant cells. For this study, the authors asked whether molecular analyses of DL specimens from women with cancer would identify abnormal cells, even if they appeared cytologically normal. METHODS. DL was performed and yielded fluid in 29 of 45 consenting women who were undergoing breast cancer surgery. Array comparative genomic hybridization (CGH) was performed on the corresponding tumor tissue from 14 women. There was no single, common alteration; thus, bacterial artificial chromosome‐specific fluorescence in situ hybridization (FISH) probes were selected based on CGH alterations. RESULTS. FISH copy number changes were detected in tumor sections in 9 women. In the corresponding 9 DL samples, 1 sample was clearly malignant on cytology, 1 showed marked atypia, 1 showed mild atypia, and the rest were benign. Five of the 9 DL samples had epithelial cells that showed genetic changes identical to those observed in the tumor by FISH. The remaining 4 of 9 DL samples that did not show molecular changes were probably (N = 1) or possibly (N = 3) from the same duct as the tumor. CONCLUSIONS. Although only 11% of the DL samples were identified as malignant cytologically, 55% showed molecular changes that were identical to those observed in the tumor. FISH was more sensitive for finding tumor in DL specimens than cytology. However, the ductal system in which the tumor was located did not always yield fluid, limiting the sensitivity of DL. The results from this study showed that genetic changes can be detected in the absence of morphologic changes in cytologically benign cells, but the application will be limited without a better approach for acquiring cells and a common set of probes for detecting molecular abnormalities that are found in breast malignancies. Cancer (Cancer Cytopathol) 2007. © 2007 American Cancer Society.

Introduction: The purpose of this study is to examine whether participation in a personalized screening trial is associated with anxiety or breast cancer worry. The Patient Centered Outcomes Research Institute recently funded WISDOM (Women Informed to Screen Depending On Measures of risk), which is a randomized trial that tests the safety and efficacy of basing starting age, stopping age, frequency and modality of breast cancer screening on individual risk (Clinical Trials Identifier NCT02620852). Methods: In WISDOM, participants can be randomized to annual screening or personalized screening arm, or self-select an arm an observational cohort. This interim analysis examined the first 1817 participants to determine if the personalized risk arm is acceptable and to explore whether baseline anxiety was associated with study arm. For acceptability our target was to have >60% of participants agree to randomization. Participants completed questions about their Risk Perception, the PROMIS Anxiety short form 8a (total scores 8-40 with higher scores indicating more anxiety), and Breast Cancer Risk Worry (BCRW) survey (total scores 5-20) with higher scores indicating more worry) at baseline and before they were given information on their personal risk or study assignment. For the purposes of these analyses, we defined high anxiety to be the percentage of participants scoring =>22 on the PROMIS and >8 on the BCRW. Results: The participants were recruited from three sites (UCSD, UCSF, Sanford Health). Of the 1817 initial participants, 1643 completed the baseline questionnaire. Participants has a mean age of 57 years (SD 9). 15.8% felt their chances of developing breast cancer was high, 19.5% felt their chance of developing breast cancer was greater than the average women, and 56.6% felt their lifetime risk of developing breast cancer was >25. Risk perception was not significantly different between women who opted to be randomized versus the observational arm. The majority of participants were willing to be randomly assigned to an arm (1071/1643, 65.1%). Of those who joined the observational cohort, the majority selected personalized risk arm (474/572, 82.9%). Overall, PROMIS anxiety scores were low at baseline (14.0 MEAN (SD 4.6)) as were the Breast Cancer Risk Worry scores (5.7 MEAN (SD 1.05)). Less than 8% of participants had PROMIS scores >22 and that did not vary across the randomized or observational groups (P=0.2)). About 2% of participants had a BCRW scores >8. Women who worried with breast cancer were more likely to select to be in the observational (3.5%) than randomized (1.7%) arm of the study (P=0.02). Conclusions: For the women approached to participate in Wisdom, personalized screening was acceptable alternative to annual mammography. Participants in general overestimated their lifetime risk of breast cancer, had very low anxiety and low breast cancer worry. Those who were worried about breast cancer opted more often for the observational arm of the study to allow them to choose between the personalized versus annual arm. Future analyses will follow participants prospectively to determine adherence to assigned or selected arm, and whether anxiety changes after receipt of their personalized risk information. Citation Format: Naeim A, Sepucha K, Wenger N, Eklund M, Annette S, Madlensky L, van't Veer L, Parker B, Yau C, Cink T, Anton-Culver H, Borowsky A, Petruse A, Sarrafan S, Stover-Fiscalini A, LaCroix A, Adduci K, Wisdom Advocate Partners, Laura E. Participation in a personalized breast cancer screening trial does not increase anxiety at baseline [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD2-14.