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Phytoestrogens and Breast Cancer
PHYTOESTROGENS AND BREAST CANCER Case-control study of phyto-oestrogens and breast cancer. Lancet 1997;350:990–4. Ingram D, Sanders K, Kolybaba M, Lopez D
(0.41, 1.98), 0.65 (0.29, 1.44), 0.36(0.15, 0.86) trend p ⫽ 0.013. This represents a three-fold reduction in risk for those individuals who for the highest compared with the lowest quartile of excretion. While the other phytoestrogens evaluated did show a reduction in risk, none reached statistically significance. The data were analyzed separately for premenopausal and postmenopausal women trends were analogous for each group. CONCLUSIONS
OBJECTIVE
To investigate the association between phytoestrogens and human breast cancer. DESIGN
Case-control study. SETTING
Perth, Western Australia—a single private clinic or the outpatient clinic of Sir Charles Gairdner Hospital. PATIENTS
Female residents of Perth, Australia with confirmed breast cancer, between ages 30 and 84. Exclusion criteria were pregnancy, antibiotic treatment in preceding 6 weeks, previous history of breast cancer, inability to speak or read English, planned surgery within 72 hours of diagnosis, or no definite diagnosis of breast cancer before surgery. Cases were matched to women according to 5-year age group selected randomly from 1993 Perth electoral roll and living in the same postal-code area. Exclusion criteria were the same except matched cases were not eligible if a personal history of breast cancer existed. METHODS
Collection of three consecutive 24-hour urine samples and a food frequency questionnaire. Analysis for lignans (enterodiol, enterolactone, matairesinol) and isoflavonoid (equol, daidzein) phytoestrogens were measured by gas chromatography—mass spectrometry (GC-MS). Total nitrogen excretion was measured to reflect general food intake. RESULTS
Notable associations existed in the risk for breast cancer even after adjustments were made for confounding variables (age at menarche, parity, alcohol intake, and total fat intake). Statically significant reduction in risk through the quartiles existed in the phytoestrogens equol and enterlactone. Specifically, equol adjusted odds ratios were 1.00, 0.45 (95% CI 0.20, 1.02), 0.52 (0.23, 1.17), and 0.27 (0.10, 0.69) trend p ⫽ 0.009. Those who had the highest quartile of excretion of equol had a four-fold reduction in risk. Similarly, enterlactone odds ratios were 1.00, 0.91 2000 Elsevier Science Inc. 1096-2190/99/$–see front matter PII S1096-2190(99)00020-7
A statistically significant reduction in breast cancer risk was associated with women who had a high urinary excretion over 72 hours of the phytoestrogens equol and enterlactone. COMMENT
Breast cancer is the most common cancer occurring in women in the US [1], with its incidence of increasing for the past several decades [2,3]. The frequency of breast cancer increases with age, family history, early menarche, late menopause, nulliparity, atypical lobar or ductal hyperplasia, tobacco usage, and alcohol consumption. In an effort to expand our knowledge and understanding of the many facets of breast cancer risk, scientists have logically turned to diet and it’s role in either promoting or preventing breast cancer. Epidemiological studies reveal a lower incidence and mortality in hormone-dependent cancers in Asian women and men compared with their Western counterparts [4]. Traditional Asian diets are strikingly different from traditional Western diets in the amounts of phytoestrogens consumed, primarily derived from soy. Phytoestrogens, which are structurally similar to estrogens and found in plants, have recently attracted attention as scientists hypothesized that they might play a role in the prevention of breast cancer. This hypothesis has been tested in both cell-culture as well as animal experiments, showing phytoestrogens to be tumor-inhibiting [5,6]. A case-controlled study of Singaporean women revealed a diet high in soy products conferred a lower risk of breast cancer in premenopausal women with no effect in postmenopausal women after adjustment for confounding variables [7]. Migration studies have also revealed an association between tofu, which is rich in phytoestrogens, and risk of breast cancer. Asian women, both premenopausal and postmenopausal, who migrated to US had a decrease risk of breast cancer with increasing frequency of tofu ingestion [8]. This study evaluated 144 pairs of Australian women in a case-controlled analysis to assess the association between phytoestrogen intake and risk of breast cancer by measuring urinary excretion of phytoestrogens over 72 hours. Integrative Medicine Vol. 2, Nos. 2/3, pp. 145–146, 1999
145
Women with newly diagnosed breast cancer were paired with controls matched for age and area of residence. The authors compared the cases to controls and revealed no significant differences between several relevant clinical characteristics to breast cancer: age, age at menarche or menopause, age at first full-term birth, parity, months of lactation, alcohol intake, and fat intake. There was no mention of family history, benign breast disorders, menopausal status in this list, despite it being recorded from each participant in the study. Each woman collected three consecutive 24-hour urine specimens. Rather than using retrospective dietary questionnaire, phytoestrogen intake was assessed by measuring urinary excretion of daidzein, equol, and the lignans enterodiol, enterolactone, and matairesinol by gas chromatography-mass spectrometry (GC-MS). The authors did not mention whether those who carried out the GC-MS were blinded to the urine samples. However, since a great deal of judgment is not required for the measurement of GC-MS, blinding was probably not essential. After adjustments were made for confounding variables, the risk for the highest quartile of excretion of equol was associated with a fourfold reduction in risk of breast cancer development (trend P ⫽ 0.009). Similarly, a threefold reduction in risk (trend P ⫽ 0.013) was associated with those individuals with the highest compared with the lowest quartile of enterolactone excretion. While the other phytoestrogens evaluated did show a trend toward reduction in risk, none reached statistical significance. Additionally, the coefficient of variation for some phytoestrogens was large, making it difficult to detect small differences in populations. The weaknesses of the study are three-fold. Firstly, the short data collection period (72 hours) with uncertain correlation to daily phytoestrogen intake. There is an underlying assumption that having a high level of excretion over the 72 hours of collection reflects the patient’s habitual intake of phytoestrogens spanning a lifetime. In order to make an association between risk of breast cancer and phytoestrogens, this premise must be true. Breast cancer in these women had obviously developed over many years. So, the relevant dietary factors would be those factors which were in place prior to the patient developing the
146
Int Med 1999; 2(2/3)
breast cancer. A more accurate assessment of the relationship between phytoestrogens and breast cancer risk would need to be conducted prospectively monitoring who developed breast cancer and how much phytoestrogens were ingested. Secondly, genistein, a major phytoestrogen in soy, was not assessed because of technical difficulties with measurement. The evaluation of phytoestrogens cannot be considered complete since genistein was not measured. Lastly, the time period after diagnosis of breast cancer is obviously very stressful, leading to alterations in appetite and food selection. The authors measured total nitrogen excretion in an attempt to reflect general food intake and found no statically significant difference between patients and controls. A more precise reflection of food selection and intake is offered by a calorie-count coupled with nitrogen excretion. While this study does not offer the clinician grounds to make a concrete recommendation regarding phytoestrogen intake, it does add to the mounting evidence that there is some association between phytoestrogen intake and breast cancer risk. Joya Tillem, MD Cedars-Sinai Medical Center, Los Angeles, CA REFERENCES 1. Parkin DM, Muir CS, Whelan SL, Gao YT, Ferlay JL, Powell J, eds. Cancer in Five Continents, Vol. VI. Lyon, France: International Agency for Research on Cancer and International Association of Cancer Registries, 1992;IARC Sci. Pub. No. 120. 2. Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer. N Engl J Med 1992;327(6):390–8. 3. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997 [published erratum appears in CA Cancer J Clin 1997 Mar–Apr;47(2):68]. CA Cancer J Clin 1997 Jan–Feb;47(1):5–27. 4. Rose DP, Boyar AP, Wynder EL. International comparison of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 1986;58:2363–71. 5. Reddy K, Mangold G, Tandon A, Yoneda T, Mundy G, Zilberstein A, Osborne K. Inhibition of breast cancer cell growth in vitro by a tyrosine kinase inhibitor. Cancer Research 1992;52:3636–41. 6. Mayr U, et al. Validation of two in vitro test systems for estrogenic activities with zearalenone, phytoestrogens and cereal extracts. Toxicology 1992;74:135–49. 7. Lee HP, et al. Dietary effects on breast-cancer risk in Singapore. Lancet 1991;337:1197–1200. 8. Wu AH, et al. Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev 1996;5:901–12.
(0.41, 1.98), 0.65 (0.29, 1.44), 0.36(0.15, 0.86) trend p ⫽ 0.013. This represents a three-fold reduction in risk for those individuals who for the highest compared with the lowest quartile of excretion. While the other phytoestrogens evaluated did show a reduction in risk, none reached statistically significance. The data were analyzed separately for premenopausal and postmenopausal women trends were analogous for each group. CONCLUSIONS
OBJECTIVE
To investigate the association between phytoestrogens and human breast cancer. DESIGN
Case-control study. SETTING
Perth, Western Australia—a single private clinic or the outpatient clinic of Sir Charles Gairdner Hospital. PATIENTS
Female residents of Perth, Australia with confirmed breast cancer, between ages 30 and 84. Exclusion criteria were pregnancy, antibiotic treatment in preceding 6 weeks, previous history of breast cancer, inability to speak or read English, planned surgery within 72 hours of diagnosis, or no definite diagnosis of breast cancer before surgery. Cases were matched to women according to 5-year age group selected randomly from 1993 Perth electoral roll and living in the same postal-code area. Exclusion criteria were the same except matched cases were not eligible if a personal history of breast cancer existed. METHODS
Collection of three consecutive 24-hour urine samples and a food frequency questionnaire. Analysis for lignans (enterodiol, enterolactone, matairesinol) and isoflavonoid (equol, daidzein) phytoestrogens were measured by gas chromatography—mass spectrometry (GC-MS). Total nitrogen excretion was measured to reflect general food intake. RESULTS
Notable associations existed in the risk for breast cancer even after adjustments were made for confounding variables (age at menarche, parity, alcohol intake, and total fat intake). Statically significant reduction in risk through the quartiles existed in the phytoestrogens equol and enterlactone. Specifically, equol adjusted odds ratios were 1.00, 0.45 (95% CI 0.20, 1.02), 0.52 (0.23, 1.17), and 0.27 (0.10, 0.69) trend p ⫽ 0.009. Those who had the highest quartile of excretion of equol had a four-fold reduction in risk. Similarly, enterlactone odds ratios were 1.00, 0.91 2000 Elsevier Science Inc. 1096-2190/99/$–see front matter PII S1096-2190(99)00020-7
A statistically significant reduction in breast cancer risk was associated with women who had a high urinary excretion over 72 hours of the phytoestrogens equol and enterlactone. COMMENT
Breast cancer is the most common cancer occurring in women in the US [1], with its incidence of increasing for the past several decades [2,3]. The frequency of breast cancer increases with age, family history, early menarche, late menopause, nulliparity, atypical lobar or ductal hyperplasia, tobacco usage, and alcohol consumption. In an effort to expand our knowledge and understanding of the many facets of breast cancer risk, scientists have logically turned to diet and it’s role in either promoting or preventing breast cancer. Epidemiological studies reveal a lower incidence and mortality in hormone-dependent cancers in Asian women and men compared with their Western counterparts [4]. Traditional Asian diets are strikingly different from traditional Western diets in the amounts of phytoestrogens consumed, primarily derived from soy. Phytoestrogens, which are structurally similar to estrogens and found in plants, have recently attracted attention as scientists hypothesized that they might play a role in the prevention of breast cancer. This hypothesis has been tested in both cell-culture as well as animal experiments, showing phytoestrogens to be tumor-inhibiting [5,6]. A case-controlled study of Singaporean women revealed a diet high in soy products conferred a lower risk of breast cancer in premenopausal women with no effect in postmenopausal women after adjustment for confounding variables [7]. Migration studies have also revealed an association between tofu, which is rich in phytoestrogens, and risk of breast cancer. Asian women, both premenopausal and postmenopausal, who migrated to US had a decrease risk of breast cancer with increasing frequency of tofu ingestion [8]. This study evaluated 144 pairs of Australian women in a case-controlled analysis to assess the association between phytoestrogen intake and risk of breast cancer by measuring urinary excretion of phytoestrogens over 72 hours. Integrative Medicine Vol. 2, Nos. 2/3, pp. 145–146, 1999
145
Women with newly diagnosed breast cancer were paired with controls matched for age and area of residence. The authors compared the cases to controls and revealed no significant differences between several relevant clinical characteristics to breast cancer: age, age at menarche or menopause, age at first full-term birth, parity, months of lactation, alcohol intake, and fat intake. There was no mention of family history, benign breast disorders, menopausal status in this list, despite it being recorded from each participant in the study. Each woman collected three consecutive 24-hour urine specimens. Rather than using retrospective dietary questionnaire, phytoestrogen intake was assessed by measuring urinary excretion of daidzein, equol, and the lignans enterodiol, enterolactone, and matairesinol by gas chromatography-mass spectrometry (GC-MS). The authors did not mention whether those who carried out the GC-MS were blinded to the urine samples. However, since a great deal of judgment is not required for the measurement of GC-MS, blinding was probably not essential. After adjustments were made for confounding variables, the risk for the highest quartile of excretion of equol was associated with a fourfold reduction in risk of breast cancer development (trend P ⫽ 0.009). Similarly, a threefold reduction in risk (trend P ⫽ 0.013) was associated with those individuals with the highest compared with the lowest quartile of enterolactone excretion. While the other phytoestrogens evaluated did show a trend toward reduction in risk, none reached statistical significance. Additionally, the coefficient of variation for some phytoestrogens was large, making it difficult to detect small differences in populations. The weaknesses of the study are three-fold. Firstly, the short data collection period (72 hours) with uncertain correlation to daily phytoestrogen intake. There is an underlying assumption that having a high level of excretion over the 72 hours of collection reflects the patient’s habitual intake of phytoestrogens spanning a lifetime. In order to make an association between risk of breast cancer and phytoestrogens, this premise must be true. Breast cancer in these women had obviously developed over many years. So, the relevant dietary factors would be those factors which were in place prior to the patient developing the
146
Int Med 1999; 2(2/3)
breast cancer. A more accurate assessment of the relationship between phytoestrogens and breast cancer risk would need to be conducted prospectively monitoring who developed breast cancer and how much phytoestrogens were ingested. Secondly, genistein, a major phytoestrogen in soy, was not assessed because of technical difficulties with measurement. The evaluation of phytoestrogens cannot be considered complete since genistein was not measured. Lastly, the time period after diagnosis of breast cancer is obviously very stressful, leading to alterations in appetite and food selection. The authors measured total nitrogen excretion in an attempt to reflect general food intake and found no statically significant difference between patients and controls. A more precise reflection of food selection and intake is offered by a calorie-count coupled with nitrogen excretion. While this study does not offer the clinician grounds to make a concrete recommendation regarding phytoestrogen intake, it does add to the mounting evidence that there is some association between phytoestrogen intake and breast cancer risk. Joya Tillem, MD Cedars-Sinai Medical Center, Los Angeles, CA REFERENCES 1. Parkin DM, Muir CS, Whelan SL, Gao YT, Ferlay JL, Powell J, eds. Cancer in Five Continents, Vol. VI. Lyon, France: International Agency for Research on Cancer and International Association of Cancer Registries, 1992;IARC Sci. Pub. No. 120. 2. Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer. N Engl J Med 1992;327(6):390–8. 3. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997 [published erratum appears in CA Cancer J Clin 1997 Mar–Apr;47(2):68]. CA Cancer J Clin 1997 Jan–Feb;47(1):5–27. 4. Rose DP, Boyar AP, Wynder EL. International comparison of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 1986;58:2363–71. 5. Reddy K, Mangold G, Tandon A, Yoneda T, Mundy G, Zilberstein A, Osborne K. Inhibition of breast cancer cell growth in vitro by a tyrosine kinase inhibitor. Cancer Research 1992;52:3636–41. 6. Mayr U, et al. Validation of two in vitro test systems for estrogenic activities with zearalenone, phytoestrogens and cereal extracts. Toxicology 1992;74:135–49. 7. Lee HP, et al. Dietary effects on breast-cancer risk in Singapore. Lancet 1991;337:1197–1200. 8. Wu AH, et al. Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev 1996;5:901–12.