Patricia A. Thompson - US grants

DESCRIPTION (provided by applicant): Estrogen receptor positive (ER+), or luminal type, tumors account for 60-75% of all breast cancers and for more deaths than all other types of breast cancer combined. Aromatase inhibitors (AI) are recommended as first-line adjuvant therapy for hormone responsive tumors in postmenopausal women. In spite of significant success with hormonal therapies, ~20-25% of patients with ER+ disease will progress by 10 years with relapsed patients ultimately succumbing to their disease. Poor drug adherence, principally due to intolerance to side effects, remains a major challenge for achieving greatest drug benefit. A need to maximize AI efficacy is evident. Non-steroidal anti-inflammatory agents (NSAIDs), particularly sulindac, demonstrate potent and mechanistically supported anti-cancer activity for breast tumors in preclinical models. We hypothesize that sulindac, combined with AIs may act synergistically on breast density and breast tissue biomarkers as surrogates for relapse risk. The addition of sulindac to AI therapy may also have the added benefit of decreasing muscle and skeletal pain associated with AI use and thus improved adherence and long-term efficacy. To test our hypotheses, 150 breast cancer patients, stable on AI therapy for ER+ tumors, will be randomized to one of two intervention arms for 12 months: 1) AI + sulindac 150 mg bid or 2) AI + placebo bid. Our specific aims are: 1. To compare change in breast density as measured by Magnetic Resonance Imaging (MRI)-acquired fat-to-water ratio (FWR) (primary trial endpoint) within individuals and between treatment arms. We hypothesize that women treated with AI + sulindac 150 mg bid will show decreased breast density (i.e., increased FWR) over 12 months, whereas breast density in women receiving AI + placebo will not change. 2. To compare the apparent diffusion coefficient (ADC) of water within individuals and between treatment arms. We hypothesize that ADC values measured by diffusion weighted MRI (DW-MRI) will significantly change in women treated with AI + sulindac 150 mg bid over 12 months, whereas they will not change in women receiving AI + placebo. 3. To compare pain scores using the Brief Pain Inventory-Short form (BPI-SF) within individuals and between treatment arms. We hypothesize that women treated with AI + sulindac 150 mg bid will experience reduced pain scores over 12 months, whereas they will not change in women receiving AI + placebo. In addition, because the prodrug sulindac sulfoxide (Clinoril) has been shown to spare renal synthesis of the vasodilatory prostaglandins in patients with normal renal function, we hypothesize that daily sulindac use will not increase blood pressure (BP) in women on AIs with normal renal clearance and thus, will not elevate risk of CV toxicity mediated through drug-induced hypertension. Success in this phase II biomarker trial of sulindac combined with AI will serve as justification for a larger trial with cancer specific outcomes.

DESCRIPTION (provided by applicant): Colorectal adenomas (CRAs) are the benign precursors of most cases of colorectal cancer (CRC), a leading cause of cancer deaths; advanced CRAs are those most likely to progress to CRC. Although most CRAs can be removed at colonoscopy, 20-50% of individuals undergoing repeat colonoscopy 3-5 years later have metachronous, i.e. new, CRAs. Furthermore, a proportion of CRCs are not preventable through screening colonoscopy, necessitating alternative preventive strategies, such as chemoprevention. When given as a supplement, selenium (Se), a trace dietary mineral that is incorporated into specialized selenoproteins was previously shown to protect against CRC and prevalent CRAs as secondary endpoints in a non-melanoma skin cancer chemoprevention trial. Chemopreventive agents for CRC can be assessed in randomized controlled trials (RCTs) comparing metachronous CRA rates between intervention and placebo groups with results of effects on CRA recognized by the FDA as a CRC surrogate. No RCTs of Se supplements for CRC chemoprevention or for any other preneoplastic condition as the primary endpoint, have been reported. This application is for 3 years funding to complete The Selenium Trial (SeT); an RCT of Se, 200 5g daily as selenized yeast, for which randomization is completed. The primary study hypothesis is that treatment with Se yeast for 3 to 5 years will reduce the rate of metachronous CRAs without associated serious toxicities. Funding is requested to follow remaining SeT participants through study completion for all 1,800 participants in early 2014, and for data analysis and reporting. A major new study aim has been added to address the suggestion in recent published studies that excessive Se exposure may increase risk for type 2 diabetes (T2D). Although a mechanism for Se-related T2D in human is obscure, animal studies suggest that chronic activation of glutathione peroxidase 1 (GPX1), a potent anti-oxidant selenoprotein, may lead to the development of hyperinsulinemia, hyperglycemia, insulin resistance, and obesity. Therefore, the question of whether or not Se supplementation contributes to T2D has important public health implications. In the SeT cohort, we propose two approaches to studying the effects of Se on T2D, and insulin sensitivity and secretion: an epidemiological approach using the entire cohort; and assessment of the effect of Se supplementation on insulin secretion and sensitivity at the individual level using a modified oral glucose tolerance test in a sub- cohort of 300 subjects (150 on placebo and 150 on Se yeast). In secondary analyses, we will investigate whether or not baseline Se levels, genetic background, and/or use of low-dose aspirin modify Se effects on CRA occurrence or risk for T2D.

DESCRIPTION (provided by applicant): Estrogen receptor-negative (ER-), early stage breast cancer (ESBC) patients show marked clinical heterogeneity with regard to outcomes. Further, there have been no major advances in improving prognostication or prediction over the last decade. We have completed an extensive analysis of copy number imbalances (CNI) in ER- ESBC and have developed the first practical, robust prognostic model applicable to ER-ESBC. The primary goal of this project is to validate, and if necessary, refine our prognostic CNI model for ER-/ESBC. Overall the project is complementary to the TCGA in that the follow-up for patients is much longer, a requirement for breast cancer studies, and the samples are solely from ESBC whereas many of the samples in the TCGA are from large, advanced tumors due to the study design. The overarching hypothesis of our study is that inclusion of information on somatic events or tumor 'genotype' will improve risk discrimination and prediction model calibration for individual ER-/ESBC patients for recurrence, distant metastasis, treatment response, and overall survival. Secondarily, we hypothesize that the pattern of somatic events in ER-/ESBC will differ by epidemiological factors (race/ethnicity, age of onset, screening behaviors) providing important public health information. Three specific aims encompass the validation and refinement of prognostic/predictive models based on somatic events for ER-/ESBC considering population structure. In aim 1, we will validate our current model as a fixed model in three independent sample sets for prognostication. In aim 2, we will take advantage of advanced methods for variable selection to evaluate whether or not we can improve model accuracy by considering interactions between somatic events and clinical factors. In aim 3, we will conduct comparative analyses of the models to assess overlap in information content, prognostic accuracy. We will explore the models for the ability to predict response to contemporary treatment with and without inclusion of HER2+ cancers including taxanes and HER2-targeted therapy. The primary translational goal of this project is to validate and refine our prognostic CNI model for ER-/ESBC to reflect current therapeutic protocols. A second translational goal is to assess the performance of our CNI prognostic model(s) in predicting treatment response. Importantly, we propose novel methods for variable selection that allow consideration of the joint effects of somatic events, epidemiologic factors, and treatment on patient outcomes that can be generalized to other marker discovery efforts.

Project Abstract Despite advances in early detection and treatment, breast cancer remains a major cause of morbidity and mortality in women and prevention a major unmet need. Non-steroidal anti- inflammatory agents (NSAIDs), including aspirin (ASA), are among the most widely used drugs for minor pain and arthritis that demonstrate anti-tumor activity. Based on epidemiological data, low dose ASA is under investigation in clinical trials for the prevention of breast cancer recurrence. We were previously funded to perform a clinical trial of the NSAID, sulindac (SUL) at 150 mg BID, in postmenopausal women receiving aromatase inhibitor therapy as part of their breast cancer care. In an interim analysis, SUL significantly reduced breast density determined by MRI compared to an observation, control group after 12 months. Further, SUL reduced collagen straightness in breast tissue by second harmonic generation microscopy (SHG) microscopy and the change was significantly correlated with a decrease in breast density. Additional MRI based imaging of breast adipose tissue suggest novel SUL effects consistent with effects on anti-inflammatory/anti-tumor M2 type macrophages in adipose. SUL is a unique pro-drug with cyclooxygenase (COX) and non-COX activities. Because of unique anti-cancer activity in preclinical models and clinical trials, SUL has been studied for more than two decades and recently granted Fast Track Status by the FDA in combination with CPP-1X for approval as a chemoprevention agent for patients with familial adenomatous polyposis. Activity of SUL in preclinical models to prevent epithelial cancers support similar anti-cancer action in the breast. Our new data extend the preclinical findings to effects on breast density; an established risk factor for breast cancer. Here we propose to follow our promising preliminary data with the natural next step of a randomized, open label 3 arm study of SUL 150 mg BID, ASA 325 mg QD and no treatment control in postmenopausal women at increased risk of developing breast cancer. We will test the hypothesis that SUL at 150 mg BID for 12 months will significantly lower breast density in at-risk women and be superior to ASA, a cheaper, more accessible, and perhaps safer NSAID. Secondarily, paired breast biopsies (baseline and after 6 months) will be used to test the hypothesis that SUL effects on breast density are partly mediated through effects on breast tissue collagen alignment and collagen expression using highly innovative SHG and whole tissue slide matrix assisted laser desorption ionization (MALDI)-mass spectrometry. In addition, we will explore SUL and ASA effects on breast adipose including novel hypotheses that their action is in part mediated through activity on macrophages in breast tissue.