Background: The development of effective chemopreventive strategies to reduce the risk of TNBC, is a critical unmet need. Obesity is associated with a chronic inflammatory condition in the white adipose tissue of the breast, characterized microscopically by crown-like structures of the breast (CLS-B). The presence and extent of these lesions is associated with a series of proinflammatory mediators, including tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and aromatase. Importantly these proinflammatory mediators are known to be involved in breast carcinogenesis. In translational studies to date, the strongest correlations have been seen between CLS-B and TNF-α. Therefore, we aim to evaluate whether treatment with a dietary supplement, DHA, an omega-3 fatty acid, with potent effects on TNF-α, can decrease obesity-related breast inflammation in women.
Trial design: This is a randomized phase II placebo-controlled, double-blinded study of DHA in overweight/obese patients (pts), defined as body mass index (BMI) ≥25 with a history of TNBC. Pts will receive DHA or placebo twice daily for 24 weeks and will undergo core biopsies from normal (non-irradiated contralateral) breast tissue before and after the treatment to determine whether DHA can decrease obesity-related breast inflammation.
Eligibility: Inclusion criteria: 1) Age ≥ 18. 2) BMI ≥ 25. 3) Completed treatment for stage I-III TNBC ≥ 6 months prior. 4) No clinical evidence of disease. 5) Adequate accessible breast tissue for pre- and post- treatment biopsy, consisting of one breast unaffected by invasive cancer, which has not been radiated or surgically augmented. 6) Adequate organ and bone marrow function. 7) ECOG status ≤2. Exclusion criteria: 1) DHA supplementation. 2) Aspirin/NSAID use in the month preceding and during the trial. 3) Therapeutic anticoagulation. 4) Regular use of statins, steroids, or immunomodulators.
Specific aims: The primary objective is to determine whether treatment with DHA for 24 weeks at 1,000 mg twice daily as compared to placebo reduces normal breast tissue levels of TNF-α in overweight/obese pts with a history of TNBC. The secondary objective is to evaluate the effect of DHA on the change from baseline in levels of the following tissue biomarkers: COX-2, IL-1β, aromatase, and CLS-B. Exploratory endpoints include assessment of age as a predictor of CLS-B and inflammatory biomarkers and the evaluation of red blood cell fatty acid levels as a surrogate of DHA compliance.
Statistical methods: Percent change in TNF-α mRNA levels in normal breast tissue between DHA and placebo arm will be compared using two-sample t-test. If normality assumptions are violated, a two-sample Wilcoxon rank-sum test will be used. With 30 subjects in each arm, we will have 80% power to detect effect size as small as 0.74 at 0.05 significance level using a two-sided, two-sample, Student t-test.
Accrual: A total of 60 evaluable pts will be enrolled. Assuming a 10% dropout rate and 10% non-evaluable rate, up to 76 participants will be randomized in this study. This trial is currently enrolling pts.
Contact information: For more information on this trial, please visit clinicaltrials.gov (NCT01849250) or contact Ayca Gucalp MD (firstname.lastname@example.org).
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-3-01.