Title of Project: Omega 3 Fatty Acids and Breast Cancer Prevention: Protective Benefits of Increased Fish Consumption

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1 Yee, isa D., he hio State University itle of Project: mega 3 Fatty Acids and Breast Cancer Prevention: Protective Benefits of ncreased Fish Consumption nvestigators: Principal nvestigator isa D. Yee, D, Associate Professor Division of Surgical ncology, Department of Surgery he hio State University, Columbus, H Co-nvestigators artha A. Belury, Professor Department of Human utrition Susan livo-arston, PhD, Assistant Professor Department of pidemiology Joanne ester, PhD, CP, Assistant Professor School of ursing bjectives: he primary objectives of this proposal are to: i.) Determine the effects of increased fish consumption on serum and breast fat tissue fatty acids in women at high risk for developing breast cancer; ii.) Assess compliance and tolerability of increased dietary intake of fish. While the addition of a specific nutrient or food component as a daily supplement may represent an effective means of raising serum and tissue levels of such a substance in humans, there may be added benefit to consumption of such substances as a whole food. solation of dietary components may offset or attenuate the desired health benefits associated with the whole food as a result of altered absorption or metabolism. Fish is a source of protein, vitamins D and A, and minerals such as choline and calcium in addition to long chain polyunsaturated fatty acids such as eicosapentaenoic acid (PA) and docosahexaenoic acid (DHA). Consumption of fish may promote other healthful food choices as opposed to use of ω-3 fatty acid supplements alone. We proposed a 3 month intervention of tuna and/or salmon consumption in high risk breast subjects to determine the effect of increased dietary intake of fish on breast adipose and serum fatty acid profiles, which would facilitate the incorporation of dietary fish consumption into the design of future trials testing the preventive benefits of fish oil/ω-3 fatty acids for breast cancer prevention. his work may help promote the increased consumption of fish and seafood as an important dietary intervention to reduce the risk of breast cancer. ethods: Women at high risk for breast cancer were recruited to participate in this study. As with our previous study of ω-3 fatty acid supplements in high risk patients, eligible subjects had a relative risk of developing breast cancer that is at least >2x that of the general population for their age group on the basis of family history, Gail model risk assessment, atypical histology, and/or gene mutation status. xclusion criteria included current cancer diagnosis or cancer therapy, co-morbid cardiac, pulmonary, renal, neurologic, endocrine or other condition that contraindicates participation or informed consent, 1

2 Yee, isa D., he hio State University pregnancy or lactation, allergies to fish or seafood, or use of fish oil/ω-3 supplements. Adherence was assessed by daily diaries and monthly 3 day diet records, and any adverse events were recorded in the daily logs and monitored. Physical examinations and anthropometric measurements (weight, height, waist) were obtained at baseline and 3 months. Baseline and 3 month visits included fasting blood for serum/plasma and erythrocyte fatty acid profiles and breast adipose fine needle aspiration to obtain fat samples for fatty acid profiles. Subjects were randomized to either 1) dietary fish in the form of canned salmon and albacore tuna or 2) ω-3 fatty acid capsule supplements as a control arm. Albacore was supplied in pouches (Starkist) and salmon in cans (Bumblebee) by the study sponsor, for an estimated DHA and PA content/6 ounce serving of ~1.5 g for white/albacore tuna canned in water, 2.7 g for pink canned salmon, 3.5 g red canned salmon to be combined to achieve ~12 g/week of PA + DHA in four 6 ounce servings per week. Women were provided with a printed chart of the possible weekly combinations and recipes. wo ovaza capsules per day provided ~1.68 g/day of PA + DHA (~12 g/week) to women on the control treatment. C U isk assessment, Physical exam, nformed consent A D Z A Fish diet (4 x six oz/wk) ω-3 fatty acid capsules (2 caps/day) C P 0 3 months esults: Between July 2010 to July 2012, 26 subjects were randomized to either dietary fish or ω-3 fatty acid capsules using a fixed-block 1:1 randomization with a block size of 8, with one woman ineligible because of ongoing endocrine therapy (fish = 12, capsules = 13). here were no significant differences between the study groups by age, menopausal status and anthropometric measures of B, waist-hip circumference (able 1). here were no dropouts. As determined by daily logs, pill or label counts, the overall adherence was 97.9% ± 3.5 (standard deviation, with adherence to the dietary fish regimen higher at 99.7% compared to control 96.3% (Student s t test, p = 0.01). able 1 Demographics All subjects (n=25) Dietary fish (n=12) Capsules (n=13) Age (years) 52 ± ± ± 13.5 Premenopausal B 25.9 ± ± ± 5 Waist-Hip ratio (waist-cm) 0.82 ± 0.06 (84.9 ± 11.6) 0.83 ± 0.06 (87.2 ± 8.7) 0.82 ± 0.06 (82.9 ± 13.8) Breast cancer risk factors Family history High risk histology Personal hx breast CA Gail score >1.67 n=20 evaluable

3 Yee, isa D., he hio State University Fatty acid analyses of plasma and erythrocyte membrane phospholipids and breast adipose tissue triglycerides were performed as previously described. PA, DHA, total ω-3 fatty acids and ω-3/ω-6 fatty acid ratio were analyzed for blood and breast fat specimens obtained at baseline and 3 months of study intervention. Plasma and erythrocyte membrane content of PA and DHA increased significantly with both treatment interventions, with corresponding significant increases in total ω-3 fatty acids and ω-3/ω- 6 fatty acid ratio (able 2). able 2, PA, DHA, ω-3 fatty acids and ω-3/ω-6 fatty acid ratio content following dietary fish % total plasma rythrocyte membrane Breast adipose tissue fatty month Fish Capsule Fish Capsule Fish Capsule acids* PA ± ± ± ± ± ± ± ± ± ± ± ± 0.12 P value** < < DHA ± ± ± ± ± ± ± ± ± ± ± ± 0.18 P value < < otal ω ± ± ± ± ± ± ± ± ± ± ± ± 0.45 P value < < < ω-3/ω ± ± ± ± ± ± 0.01 ratio ± ± ± ± ± ± 0.02 P value < < *average values for % total fatty acids **p values for comparison of 0 and 3 month values by the Student s t test, significance at p<0.05. PA and DHA content did not differ at baseline between the two treatment arms for plasma, erythrocytes, and breast fat samples. PA content of erythrocyte membranes and plasma was higher in the control capsule arm compared to dietary fish group (p = 0.02, 0.04, respectively), without significant differences between erythrocyte and plasma DHA at 3 months in women receiving ω-3 fatty acid capsules or canned fish (Figure 1). here were also no significant differences between the two treatment groups in total ω-3 fatty acids and ω-3/ω-6 fatty acid ratio. * * * * Figure 1, PA (C20:5n3) and DHA (C22:6n3) as percent of total fatty acids (average) in erythrocyte membranes and plasma, *------* = significant differences between 0 and 3 months, p = 0.02 and 0.04, respectively. 3

4 Yee, isa D., he hio State University Breast adipose tissue PA and DHA did not differ between baseline and 3 months for either treatment arm. Combining the control and dietary fish arms (n=25) revealed increased PA and DHA at 3 months for the overall study group (Figure 2). An end of study questionnaire designed to ascertain the tolerability of the study interventions indicates that consumption of canned salmon/pouched albacore in an amount less than 4 six ounce servings per week would be more easily followed on a long term basis. Conclusions: o the best of our knowledge, this study represents the first prospective evaluation of fish as a whole food intervention in women at high risk for cancer. he dietary intervention of 4 six ounce servings of canned fish, as a combination of sockeye, Coho salmon and albacore designed to approximate the ω-3 fatty acid content of 2 capsules per day of ovaza, was generally well tolerated with excellent adherence over a 3 month study period. * * Figure 2, PA (C20:5n3), DHA (C22:6n3), total ω-3 fatty acids and ω-3/ω-6 ratio as average percent of total fatty acids in breast adipose tissue, overall combined n = 25. * = significant differences between 0 and 3 months for PA and DHA by Student s t test, p = and 0.046, respectively. ur data demonstrate that dietary fish in the form of canned wild sockeye and Coho salmon and pouched albacore tuna at 4 six ounce servings per week can significantly increase plasma and erythrocyte PA, DHA, total ω-3 fatty acids and ω-3/ω-6 fatty acid ratio at 3 months. Although the control group of an ω-3 fatty acid supplement at 2 capsules/day led to a greater increase in PA than the dietary fish arm at 3 months in plasma and erythrocytes, DHA, total ω-3 fatty acids and ω-3/ω-6 ratio of these samples did not differ significantly between the two treatment groups. he lack of significant increase in PA, DHA, total ω-3 fatty acids and ω-3/ω-6 ratio in breast adipose tissue by treatment group (n=12 versus n=13), despite a significant rise in breast fat PA, DHA for the combined arms (n=25), may relate to the sample size and study duration. As the fatty acid profile of fat reflects long term dietary intake, in comparison to shorter term changes detected in plasma and erythrocyte membrane phospholipids, modulation of breast adipose PA and DHA by diet or supplements may occur over a more extended time period at the dose levels (i.e. canned fish, 2 capsules per day) selected for this study. ultiple factors such as background diet, lifestyle, and fatty acid metabolism may contribute to incorporation of these long chain PUFAs into breast adipose tissue. his study, as supported by the Seafood ndustry esearch Foundation, provides novel data regarding the use of a diet high in fish consumption compared to a capsule dose of PA and DHA in a cohort of women at high risk for breast cancer. he study data show significant increases in plasma, erythrocyte and breast adipose tissue PA and DHA with both treatment strategies and excellent adherence and tolerability demonstrating that dietary fish represents a viable ω-3 fatty acid strategy in our high risk target population to carry forward in future clinical trials for breast cancer prevention. 4

5 Yee, isa D., he hio State University Future Plans: Additional funding secured from the Food nnovation Center of he hio State University is supporting analysis of breast adipose tissue and blood samples for changes in inflammatory gene expression (e.g. interleukin 6, cyclooxygenase 2, and macrophage marker CD-68) for potential biomarkers of response, which we will correlate with the fatty acid results. We also received funding for an intramural Pelotonia grant from he hio State University Comprehensive Cancer Center to pursue metabolomics analyses of breast adipose tissue and peripheral blood mononuclear cell (PBC) samples as novel biomarkers of increased consumption of ω-3 fatty acids, and we will also evaluate these data for associations with plasma, erythrocyte membrane and breast adipose tissue fatty acid profiles. hese analyses will provide additional information regarding differential effects of dietary fish versus ω-3 fatty acid capsules on plasma and breast fat markers of response. We would like to analyze the fatty acid content of samples of the canned wild sockeye and Coho salmon and pouched albacore tuna, as well as capsules of ovaza, to compare with our estimates for PA and DHA intake with the canned fish. he specific PA:DHA composition of ovaza relative to salmon and albacore may account for the increased PA in plasma and erythrocytes at 3 months. We plan to submit the manuscript for publication in a journal regarding cancer prevention or nutrition, such as Cancer Prevention or American Journal of Clinical utrition. he data from this trial will guide our future clinical investigations of the preventive benefits of fish oil/ω-3 fatty acids for high risk molecular subtypes of breast cancer, such as estrogen, progesterone (P) negative, H-2/neu overexpression positive or P-H-2/neu- (triple negative) breast cancer. he results are also applicable to the development of dietary versus supplement strategies for increasing circulating and tissue levels of DHA and PA in other study populations. 5