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

• To understand recommendations for soy intake for average risk women and also for women with a personal or family history of breast cancer

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

InterestsI 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.

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

Structure and Food Sources

• Flavonoids are plant-derived polyphenols

• Isoflavonoid subgroup weakly estrogenic

– examples: genistein, daidzein, equol

Structure of Isoflavonoids and Estradiol

Messina, Nutr Cancer 1994;21:113

Intake

• 1 gram soybeans 2 mg isoflavonoids

• Typical daily intake:

• Asian countries 50-100 mg

• Western countries <1 mg

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

Estrogenic Effects

• Weakly estrogenic 1/1000th -1/100,000th the strength of estradiol

• Produce estrogenic responses in mice

• May be antagonistic by competing for estrogen receptors

What is the evidence that isoflavonoids prevent breast

cancer?

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

In vitro Studies of Genistein

• Induces DifferentiationConstantinou A, 1990, Cancer Res

Kando K, 1991, Cancer Res

Watanabe T, 1993, Cancer Res

• Inhibits AngiogenesisFotis T, 1993, Proc Natl Acad Sci

0

1

2

3

4

5

Length,mm

bFGF, µg/L 0 30 30 30 30genistein, µmol/L 0 0 50 100 200

Fotsis,J. Nutr 1995,125;790S

Genistein as an Angiogenesis Inhibitor

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

Animal Studies: Isoflavonoids and Mammary Tumors

Study Results Study 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

Weeks after NMU administration

Mammary Tumor Incidence in Rats

Casein

SPI+Met

SPI

Percent of rats w

ith mam

mary tum

ors

0 5

NMU INJECTION

DIETCHANGE

268

100

10

Casein

Reference,Population

N cases Exposure RR (95% CI)

Hirohata, 1985Japan

212 Soybeans — Null

Lee, 1991Singapore

200 Soy protein 0.39 (0.19, 0.80)

Hirose, 1995Japan

1186 Bean curd 0.81 (0.65, 0.99)

Wu, 1996US (Asian women)

597 Total soy 0.85 (0.74, 0.99)

Ingram, 1997Australia

144 Equol* 0.27 (0.10, 0.69)

Zheng, 1999China

60 Isoflavanoid 0.14 (0.02-0.88)

Shu, 2001China

1459 AdolescentTotal Soy

0.51 (0.40-0.65)

*Measured in urine

Adolescent Soy Intake and Breast Cancer Risk

Shu, CEBP 2001

• 1459 cases and 1556 controls in China

• Diet age 13-15 by interview

• Separately asked mothers of 296 cases and 359 controls

Adolescent Diet

Quintile of Intake RR 95% 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

Cohort Studies of Soy and Breast Cancer

Reference Populations Cases Exposure RR

Nomura, 1978 Japanese in HI 86 Husbands diet Null

Hirayama, 1985 Japan - miso 0.46

Key, 1999 Japan 427 tofu, miso Null

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

Trials: Does Soy Lower Estrogens?

Reference N Duration: Months ResultCassidy, 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

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

RCTs of Soy and Estrogen

Nagata, 1998 Hi/Low Soy Duration/months Results

31/29 2 E2 and estrone

but N.S

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

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

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

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

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