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.
Breast cancer remains the second leading cause of cancer death and for many survivors, contributes to significant disease and treatment related physical and psychosocial side effects, medical costs and reduced quality of life. As such, primary prevention of breast cancer in women at increased risk with an agent that is safe and well tolerated is highly desirable. Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, demonstrate anti-cancer activity in breast cancer models, with observational evidence that supports lower odds of breast cancer among regular users. We have found that the NSAID sulindac, after one year of use, significantly reduces breast density, an established risk factor for breast cancer, and changes the structure of collagen in breast tissue in women taking aromatase inhibitors for the treatment of their breast cancer when compared to a control group. We propose a clinical trial using magnetic resonance imaging (MRI) and tissue biopsy to test the effect of sulindac on breast density and breast tissue in women at increased risk of breast cancer and we will compare its activity on breast density and breast tissue to aspirin and a control group. Ours is the first evidence of an effect of an NSAID on breast density, an established risk factor for breast cancer. Furthering our understanding of this activity is important to advancing the beneficial actions of NSAIDs observed in epidemiologic and animal studies to primary breast cancer chemoprevention in patients at increased risk of developing breast cancer.
