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Isoflavonoids and Breast Cancer Risk

Isoflavonoids and Breast Cancer Risk. Michelle D. Holmes , MD, DrPH. michelle.holmes@channing.harvard.edu. Learning Objectives To understand the structure and food sources of isoflavonoids To understand the different types of research studies supporting an isoflavonoid-breast cancer link

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Isoflavonoids and Breast Cancer Risk

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  1. Isoflavonoids and Breast Cancer Risk Michelle D. Holmes, MD, DrPH michelle.holmes@channing.harvard.edu

  2. Learning Objectives • To understand the structure and food sources of isoflavonoids • To understand the different types of research studies supporting an isoflavonoid-breast cancer link • To understand recommendations for soy intake for average risk women and also for women with a personal or family history of breast cancer

  3. Performance Objectives • Students should be able to evaluate new research findings on isoflavonoids and breast cancer in light of the previous evidence • Be able to make recommendations on soy intake for average risk and high risk women based on the weight of present research evidence

  4. Interests I was trained as a primary care physician and have always had a strong interest in public health. I have always been interested in the impact of diet, exercise, and other lifestyle factors on chronic disease. I became an epidemiologist in mid career. My research focus is diet and cancer.

  5. Overview • Structure, food sources of isoflavonoids • Different types of studies supporting a isoflavonoid-breast cancer link • international • in vitro and animal • case-control and cohort • trials • Recommendations

  6. Structure and Food Sources • Flavonoids are plant-derived polyphenols • Isoflavonoid subgroup weakly estrogenic • examples: genistein, daidzein, equol

  7. Structure of Isoflavonoids and Estradiol Messina, Nutr Cancer 1994;21:113

  8. Intake • 1 gram soybeans  2 mg isoflavonoids • Typical daily intake: • Asian countries  50-100 mg • Western countries  <1 mg

  9. International Data • Asian countries: high soy intake and lower breast cancer rates • Japanese migrants assume host country rates of breast cancer • Western diet: minimal soy • Vegetarians in the US have lower cancer rates

  10. EstrogenicEffects • Weakly estrogenic 1/1000th -1/100,000th the strength of estradiol • Produce estrogenic responses in mice • May be antagonistic by competing for estrogen receptors

  11. What is the evidence that isoflavonoids prevent breast cancer?

  12. In vitro studies of Genistein • Inhibits Tyrosine Kinase (important for cell proliferation, transformation) Markovits J, 1989, Cancer Res Linnasier C, 1993, Biochemical Pharmacology • Inhibits DNA topoisomerase II (causes DNA breaks) Markovits J, 1989, Cancer Res

  13. In vitro Studies of Genistein • Induces Differentiation Constantinou A, 1990, Cancer Res Kando K, 1991, Cancer Res Watanabe T, 1993, Cancer Res • Inhibits Angiogenesis Fotis T, 1993, Proc Natl Acad Sci

  14. Genistein as an Angiogenesis Inhibitor 5 4 3 Length, mm 2 1 0 bFGF, µg/L 0 30 30 30 30 genistein, µmol/L 0 0 50 100 200 Fotsis,J. Nutr 1995,125;790S

  15. In vitro Studies of Genistein • Affects Growth of ER+ human breast cancer cells: • Stimulates at low dose • Inhibits at high dose Miodini P, 1999, Br J Cancer Nakagawa H, 2000, J Cancer Res Clin Oncol • Inhibits growth of ER- human breast cancer cells Shen F, 1999, Anticancer Res

  16. Animal Studies: Isoflavonoids and Mammary Tumors Study ResultsStudy Results Carroll, 1975 Null Barnes, 1990  Troll, 1980  Barnes, 1990  Gridley, 1983 Null Constantinou 1998  Hawrylewics, 1989  Fritz, 1998  Hsueh, 1989 Null Hilakivi-Clarke 1999  Baggott, 1990  Hakkak, 2000  Santell, 2000 Null

  17. Mammary Tumor Incidence in Rats Casein SPI+Met SPI Percent of rats with mammary tumors Weeks after NMU administration 100 Casein NMU INJECTION DIET CHANGE 10 8 0 5 26

  18. Adolescent Soy Intake and Breast Cancer RiskShu, CEBP 2001 • 1459 cases and 1556 controls in China • Diet age 13-15 by interview • Separately asked mothers of 296 cases and 359 controls

  19. Adolescent Diet Quintile of IntakeRR95% CI 1 1.00 - Total 2 0.75 (0.60-0.93) soy 3 0.69 (0.55-0.87) foods 4 0.69 (0.55-0.86) 5 0.51 (0.41-0.65) p-trend <0.01

  20. Cohort Studies of Soy and Breast Cancer Reference Populations Cases ExposureRR Nomura, 1978 Japanese in HI 86 Husbands diet Null Hirayama, 1985 Japan - miso 0.46 Key, 1999 Japan 427 tofu, miso Null

  21. Problem:Assessment of dietary isoflavonoids is difficult in epidemiological studies Amoung U.S women, large amounts of isoflavonoids come from “hidden” soy: - soy protein isolate - soy concentrate - soy flour (white bread and donuts) Frequent in processed foods and is brand-dependent Horn-Ross, CCC, 2000

  22. Trials: Does Soy Lower Estrogens? Reference N Duration: Months Result Cassidy, 1994 6 1  FSH, LH follicular E2 Duncan, 1999 14 3 FSH, LH Martini, 1999 36 2 No change Lu, 2000 8 1 shifted metabolism to more favorable estrogens metabolites Lu, 2000 10 1  progesterone levels Wu, 2000 20 7  luteal E2 only in 10 Asian women

  23. Cont’d Reference N Duration: Months Result Duncan, 2000 14 -  estrogens only in 5 equol excreters regardless of soy intake Xu, 2000 18 9 shifted metabolism to more favorable estrogen metabolites

  24. RCTs of Soy and Estrogen Nagata, 1998 Hi/Low SoyDuration/monthsResults 31/29 2 E2 and estrone but N.S

  25. Does Soy Increase Breast cell Proliferation? McMichael-Phillips, AJCN, 1998 - RCT of 48 premenopausal women scheduled for breast biopsy - 2 weeks soy supplemented diet - Normal breast tissue labelled for markers of proliferation - High soy group had  proliferation Hargreoues, J Clin Endoc Metab, 1999 - Sequential trial of 84 premenopausal women - Underwent nipple aspiration (NA) -  markers of proliferation in NA fluid after soy intake

  26. Does Soy Increase Breast cell Proliferation? Maskarinec, Br Cancer Res, 2001 - Cross-sectional study in HI - Soy intake assessed by questionnaire vs. density on mammogram -Results: - High soy  density - High soy  breast size

  27. Hypothesis: Could early-life soy exposure induce early breast maturation making it resistant to carcinogenesis? Evidence: • Isoflavonoids promote differentiation in vitro • Some animal studies have shown large effects with pre-pubertal exposure • International differences persist until 2nd generation • Shu, 2001 case-control study of adolescent soy intake

  28. Isoflavonoids and Breast Cancer Risk: Conclusions • Biologically plausible: • estrogenic effects • effects on angiogenesis, cell growth • Animal data suggestive • Epidemiologic data suggestive but cohort studies are poor • Adverse effects possible, balance between proestrogen/anti estrogen effects is unclear

  29. What should clinicians recommend? • Modest intake of soy products similar to Asian cultures (1-2 servings/day) unlikely to be harmful in the average women and may be helpful • Many clinicians, NCI website suggest that high risk women avoid soy: • Women with breast cancer, particularly ER+ or on tamoxifen • Women with a strong family history

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