Modulation of Breast Cancer Risk Biomarkers by High-Dose Omega-3 Fatty Acids: Phase II Pilot Study in Postmenopausal Women

Abstract

Higher intakes of the omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid (AA) have been variably associated with reduced risk of premenopausal breast cancer. The purpose of this pilot trial was to assess feasibility and explore effects of high dose EPA and DHA on blood and benign breast tissue risk biomarkers prior to design of a placebo controlled Phase IIB trial. Premenopausal women with evidence of hyperplasia +/- atypia by baseline random periareolar fine needle aspiration (RPFNA) were given 1860 mg of EPA + 1500 mg of DHA ethyl esters daily for 6 months. Blood and benign breast tissue were sampled during the same menstrual cycle phase pre-study and a median of 3 weeks after last dose. Additional blood was obtained within 24 hours of last dose. Feasibility which was pre-defined as 50% uptake, 85% retention and 70% compliance, was demonstrated with 46% uptake, 94% completion, and 85% compliance. Cytologic atypia decreased from 77 to 38% (p=0.002), and Ki-67 from a median of 2.1 to 1.0 % (p=0.021) with an increase in the ratio of EPA + DHA to AA in erythrocyte phospholipids but no change in blood hormones, adipokines, or cytokines. Exploratory breast proteomics assessment showed decreases in several proteins involved in hormone and cytokine signaling with mixed effects on those in the AKT/mTOR pathways. Further investigation of EPA plus DHA for breast cancer prevention in a placebo controlled trial in premenopausal women is warranted.

Measurement of red blood cell eicosapentaenoic acid (EPA) levels in a randomised trial of EPA in patients with colorectal cancer liver metastases

“…Baseline and post-treatment RBC PUFA levels in EMT study participants were similar to those reported previously in studies of omega-3 PUFA supplementation in healthy volunteers [13,19], women with breast hyperplasia [20][21] and in patients with lung cancer [22]. In particular, post-treatment % RBC EPA values were similar to those observed in an eight-week study of exactly the same EPA-FFA formulation and dose in healthy volunteers and inflammatory bowel disease patients [23].…”

“…Longer-term follow-up would have been required in order to confirm the return of the PUFA profile in RBCs to that observed pre-intervention. 'Washout' kinetics were not dependent on the prior degree of RBC incorporation or duration of EPA treatment and are similar (in these CRC patients) to the decay in RBC EPA content observed in at least three healthy volunteer studies, in which peak RBC EPA content was similar to that seen in the EMT study [13,19,27], as well as two more recent studies of pre-and post-menopausal women [20][21].…”

A Randomized Multicenter Phase II Study of Docosahexaenoic Acid in Patients with a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

“…Fabian and colleagues conducted two parallel pilot studies to evaluate omega-3 supplementation in pre- and postmenopausal women at increased risk for breast cancer; individuals were treated for 6 months with combined EPA and DHA ethyl esters (3.4g/daily) and underwent pre-and post-treatment biopsies. [44, 46] While feasibility was the primary endpoint, secondary endpoints included several blood and tissue-based biomarkers evaluating changes in cytomorphology, Ki-67, circulating inflammatory and adipokine markers, RBC and tissue fatty acid composition, and targeted mRNAs, chemokines, and peptides. Treatment with combined EPA/DHA resulted in favorable modulation in certain tissue and circulating markers in both cohorts to varying degrees.…”

“…Consistent with our findings, these investigators demonstrated little to no change in breast levels of proinflammatory gene transcripts in response to combined EPA and DHA supplementation. [44, 46] In this setting, comparison of the studies by Fabian et al . to our study is limited by differences in study population, dose, duration and formulation of omega-3 supplementation, and study endpoints.…”

Reducing the burden of obesity-associated cancers with anti-inflammatory long-chain omega-3 polyunsaturated fatty acids

“…Additionally, high dose omega-3 PUFAs supplementation (3,360 mg) over a six month period normalized adiponectin concentrations and decreased serum TNF-α and breast MCP-1 levels in postmenopausal women at risk of hyperplasia of the breast due to family history and/or an abnormal breast biopsy [67]. Omega-3 PUFA supplementation has also displayed potential in combating colon and prostate cancer.…”