Dietary phytoestrogen intake and premenopausal breast cancer risk in a german case-control study

Int. J. Cancer: 110, 284 –290 (2004)
Publication of the International Union Against Cancer DIETARY PHYTOESTROGEN INTAKE AND PREMENOPAUSAL BREASTCANCER RISK IN A GERMAN CASE-CONTROL STUDY INSEISEN ,* Regina PILLER , Silke HERMANN and Jenny CHANG-CLAUDE 1Unit of Human Nutrition and Cancer Prevention, Technical University of Munich, Freising-Weihenstephan, Germany2Department of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany A diet high in isoflavonoids (soy) is associated with lower
In Western populations with a low intake of isoflavonoids, breast cancer risk in Asian populations. Due to the low soy
dietary intake of another class of phytoestrogens, lignans, may be intake, dietary lignans may be the more important phy-
more important. Lignans, mainly secoisolariciresinol and mataires- toestrogen class in Western populations. We used a popula-
inol, are more widespread in plants and plant products (e.g., whole tion-based case-control study of breast cancer by age 50 in
grains, berries) that are frequently included in the usual Western southern Germany to evaluate the association between di-
etary intake of different phytoestrogens and premenopausal
diet.14,15 Analytic data for the lignan content of an acceptable breast cancer risk. Dietary information was collected from
range of foodstuffs have become available only recently, so few 278 premenopausal cases and 666 age-matched controls, us-
studies on the effect of lignan intake on breast cancer risk have ing a validated FFQ. Using multivariate logistic regression,
been performed.16,17 Additionally, lignans undergo bacterial me- the highest vs. lowest intake quartiles of daidzein and
tabolism in the human intestine, and only their metabolites entero- genistein yielded significantly reduced ORs (95% CI) for
diol and enterolactone are able to pass the intestinal barrier to exert breast cancer risk of 0.62 (0.40 – 0.95) and 0.47 (0.29 – 0.74),
biologic effects.18,19 Studies using enterolactone concentrations as respectively. The protective effects of daidzein and genistein
biomarkers of lignan intake (and intestinal microbial activity) have were found only for hormone receptor-positive tumors. High
given conflicting results: an inverse association with breast cancer intake of other isoflavonoids, e.g., formononetin and biocha-
nin A, as well as the sum of isoflavonoids were not associated
risk was found in 3 case-control studies,20–22 but no clear answer with a decrease in risk. Breast cancer risk significantly de-
creased with a high intake of the plant lignan matairesinol
Therefore, our aim was to assess the association of dietary (OR ؍ 0.58, 95% CI 0.37– 0.94) but not secoisolariciresinol or
intake of different phytoestrogens with premenopausal breast can- the sum of plant lignans. However, both estimated mamma-
cer risk in a German study population with a Western lifestyle, also lian lignans, enterodiol and enterolactone, were inversely
considering the hormone receptor status of breast cancer tissue. In associated with breast cancer risk, with ORs (95% CI) of 0.61
(0.39 – 0.98) and 0.57 (0.35– 0.92), respectively. No effect was
addition, the bioavailable intestinal lignan metabolites enterodiol found for total phytoestrogen intake. Our results suggest an
and enterolactone were calculated and related to breast cancer risk.
important role of dietary intake of daidzein and genistein,
despite low levels, as well as of matairesinol and mammalian
lignans to reduce premenopausal breast cancer risk in this
study population.
2004 Wiley-Liss, Inc.
Participants in our population-based case-control study were recruited in the 2 study areas of Freiburg and Rhein-Neckar- Key words: dietary intake; phytoestrogen; isoflavonoid; plant lignan;
Odenwald between January 1992 and December 1995. All Ger- mammalian lignan; breast cancer; premenopausal women man-speaking women who were not older than 50 years at the timeof diagnosis of incident in situ or invasive breast cancer wereeligible. Patients were identified by frequent monitoring of hospital By definition, phytoestrogens are secondary plant components admissions, surgery schedules and pathology records of 38 hospi- that show structural similarity to mammalian estrogens and, there- tals. Among the 1,020 eligible patients in both study regions, 706 fore, are able to bind to mammalian estrogen receptors.1 Of the 3 (70.2%) completed the study questionnaire. Controls matched by main classes, isoflavonoids, lignans and coumestanes, the isofla- exact age and study region were selected from a random list of vonoids, namely daidzein and genistein, have received the most residents derived from the population registries. Of the 2,257 scientific attention in the last years due to their suggested health eligible controls, 1,381 (61.2%) participated in the study.25,26 The effects.2,3 Daidzein and genistein are found in high concentrationsin soybeans. Consequently, in Asian populations with a fairly highintake of soy and soy products, isoflavonoid intake might be high Abbreviations: BMI, body mass index; CI, confidence interval; EPIC, enough to reveal biologic effects in humans.4 Soy consumption has European Prospective Investigation into Cancer and Nutrition; FFQ, food- been suggested to contribute to the lower prevalence of breast frequency questionnaire; FSH, follicle-stimulating hormone; LH, luteiniz- cancer in Asian compared to Western populations.5,6 Since estro- ing hormone; OR, odds ratio; SHBG, sex hormone– binding globulin.
gen levels affect breast cancer,7 the early postulated anticarcino-genic mechanism is based on the weak estrogen-like activity Grant sponsor: Kurt-Eberhard-Bode-Stiftung; Grant sponsor: Deutsche (compared to endogenous estrogen) of genistein and, to a lesser extent, daidzein, as found in in vitro studies.1,8,9 These substanceshave since been shown to have hormonal receptor-independentanticarcinogenic effects in cancer cell lines and animal studies, *Correspondence to: Unit of Human Nutrition and Cancer Prevention, such as inhibition of angiogenesis, effects on endogenous hormone Technical University of Munich, Alte Akademie 16, 85350 Freising- concentrations and metabolism as well as antioxidant activity.10–12 Weihenstephan, Germany. Fax: ϩ49-8161-713931.
Stimulatory effects on carcinogenic processes as observed in invitro studies were not found in vivo.10 According to previous reviews,10,13 analytic epidemiologic stud- Received 4 August 2003; Revised 30 October 2003; Accepted 10 ies in humans support the view of a protective effect of soy consumption or related phytoestrogen intake on breast cancer riskwhen consumed at an early age (adolescence) or at very high doses. So far, only few investigations have been conducted in Published online 26 February 2004 in Wiley InterScience (www.
study was approved by the local ethical committee, and all partic- and total physical activity did not affect the estimates significantly and, thus, were not used for adjustment. For trend estimation, Both cases and controls filled in a self-administered risk factor categorized variables were entered into the regression models as questionnaire, collecting information on demographic factors, an- thropometric measures, menstrual history, reproductive history,breast-feeding history, family history of cancer, smoking history and alcohol consumption. If not otherwise specified, all informa-tion was truncated at the reference date, which was the date of A total of 278 cases and 666 controls were classified as pre- diagnosis for cases and the date of questionnaire completion for menopausal at the time of diagnosis (cases) or recruitment (con- controls. Menopausal status was assigned according to the reported trols) and were, therefore, included in the evaluation. A description state half a year before the reference date. The menopausal status of sociodemographic variables and known risk factors for breast of women with previous hysterectomy not accompanied by bilat- cancer is given in Table I. The mean age for cases and controls was eral oophorectomy was not identifiable and classified as unknown.
42.6 years (SD Ϯ5.48, Ϯ5.77, respectively). Total daily energy Information on hormone receptor status (estrogen, progesterone) intake was significantly different between cases and controls (Ta- of breast cancer tissue was obtained from pathology reports.
In addition, participants from Rhein-Neckar-Odenwald were Median dietary intake of phytoestrogens in cases and controls is asked to complete a self-administered FFQ, recording nutritional given in Table II. The higher intake of genistein among controls habits in the year prior to the diagnosis of breast cancer (cases) or compared to cases was statistically significant. Additionally, cases questionnaire completion (controls). The FFQ, consisting of 176 and controls differed significantly in formononetin intake. For all food items, is comparable to the FFQ used for the German part of other phytoestrogens, no significant differences existed. Secoiso- the EPIC study; it was validated for food group, energy and lariciresinol contributed nearly 50% of total phytoestrogen intake nutrient intake.27,28 A detailed description of this FFQ, including of about 1,000 ␮g/day. Relevant food sources for different phy- the treatment of missing values, was published previously.29 The toestrogens are listed in Table III.
FFQ was returned by 1,288 of the 1,451 participants from Rhein- Except for genistein (4th vs. 1st quartile), formononetin and Neckar-Odenwald (88.8%). The median time between diagnosis biochanin A (3rd vs. 1st quartile), none of the crude estimates for and FFQ administration was 209 days for patients. Patients who breast cancer risk was statistically significant (Table IV). After filled in the FFQ more than 2 years after diagnosis were excluded adjustment for several risk factors for breast cancer and possible from analysis. Information about portion size and frequency of confounders, high intake of daidzein and genistein was inversely consumption for single food items was used to calculate mean food associated with premenopausal breast cancer risk (Table IV). For intake per day. Nutrient intake was computed by means of the the sum of daidzein and genistein, the risk estimates for both the German food composition table BLS II.3 (Bundesinstitut fu¨r ge- 3rd and 4th intake quartiles were significantly decreased compared su˘ndheitlichen Verbraucherschu¨tz und Veterina¨rmedizin, Berlin, to the lowest intake category, with ORs (95% CI) of 0.63 (0.41– Germany). Food items were classified into 14 groups.29 After 0.96) and 0.56 (0.36 – 0.87), respectively (p exclusion of the top and bottom 1% of the energy intake range formononetin and biochanin A was associated with increased (extreme over- and underreporting), 355 cases and 838 controls breast cancer risk in the 3rd intake quartile but not the 4th quartile; were finally included in the analyses.
overall, no significant effect was found for the sum of isofla- To estimate dietary phytoestrogen intake, a database of phy- vonoids (Table IV). Coumestrol intake was also not associated toestrogen-containing foods was established using the available analytic data from the literature, focusing on foodstuffs usually Of the lignans, no effect was found for secoisolariciresinol.
consumed in Europe.2,14,30–40 The food content of the isofla- However, premenopausal breast cancer risk decreased with in- vonoids (daidzein, genistein, formononetin, biochanin A), coumes- creasing intake of matairesinol (OR ϭ 0.58, 95% CI 0.37– 0.94 in tanes (coumestrol) and lignans (secoisolariciresinol, matairesinol) 4th vs. 1st intake quartile, p was included as aglycons in micrograms per 100 g edible food derived phytoestrogens did not affect breast cancer risk. A high portion. If more than one value for the same foodstuff was avail- estimated amount of mammalian lignans, enterodiol and enterolac- able, mean values were calculated. Additionally, in vitro data on tone, was inversely associated with breast cancer risk. ORs (95% the intestinal production of enterodiol and enterolactone after CIs) for the highest vs. lowest quartile were 0.61 (0.39 – 0.98, incubation with human feces were used to estimate the bioavail- ϭ 0.034) for enterodiol and 0.57 (0.35–0.92, p able intestinal lignan metabolites per 100 g of food ingested.41 When a particular phytoestrogen was found “in trace amounts” in If considering only patients who completed the FFQ within 1 a certain food, it was assigned to 0.01 ␮g/100 g food. After year after diagnosis (n ϭ 213), adjusted relative risks were only calculation of the phytoestrogen content of each FFQ item, mean slightly modified with few exceptions: relative risk estimates for daily intake of the different phytoestrogens was computed for each the 3rd quartiles of daidzein intake and total isoflavonoid intake became significant, while for matairesinol, enterodiol and en- The association between phytoestrogen intake and risk of pre- terolactone the point estimates for the 4th intake quartiles slightly menopausal breast cancer was estimated by means of conditional increased, with ORs of 0.64, 0.66 and 0.63, but were no longer logistic regression modeling. ORs and their corresponding 95% CIs were calculated using the PHREG procedure of the SAS We also examined the combined effect of daidzein and genistein statistical software package, version 8.2 (SAS Institute, Cary, NC) intake and intestinal lignan metabolites. Women were grouped by with stratification for exact age. Higher quartiles of phytoestrogen low (1st and 2nd quartiles) and high (3rd and 4th quartiles) consumption were compared to the lowest quartile of consump- consumption of daidzein and genistein and of enterodiol and tion, whereby the distribution of the phytoestrogen intake in con- enterolactone. High consumption of both phytoestrogen classes trols was used for quartile definition. Results were adjusted for showed the strongest risk reduction, with an adjusted OR (95% CI) first-degree family history of breast cancer (no, yes), number of of 0.57 (0.36 – 0.83) compared to low consumption of both groups births (3 categories of 0, 1 or 2, Ն3), duration of breast-feeding (4 categories of 0, 1– 6, 7–12, Ͼ12 months), energy intake (deciles), Further, we examined whether the phytoestrogen effect differed BMI [classified as underweight (Ͻ18.5 kg/m2), normal weight by hormone receptor status. Differentiated by estrogen and pro- (18.5–30 kg/m2) and obese (Ն30 kg/m2)], education level (low, gesterone receptor status of breast tissue, a significant inverse middle, high) and alcohol consumption (3 categories of 0, 1–18 association between daidzein and genistein intake and breast can- and Ͼ18 g ethanol/day). Age at menarche, smoking, sports activity cer risk was found only for breast tumors positive for estrogen or TABLE I – DISTRIBUTION OF SOCIODEMOGRAPHIC VARIABLES AND RISK
The observed effects of genistein and daidzein were largely FACTORS FOR PREMENOPAUSAL BREAST CANCER IN CASES (N ϭ 278) unexpected because the intake levels for these compounds are very low (150 –160 ␮g/day) compared to Asian populations (10 –30 mg/day).4 Concentrations necessary to reveal hormone receptor– mediated effects as determined in in vitro studies are unlikely to bereached by the estimated dietary intake range in this study popu- lation. This suggests a hormone receptor-independent mechanism of action of these isoflavonoids, which, however, appears to be contradicted by the clear results showing that the genistein and daidzein effects are restricted to hormone receptor-positive tumors.
Isoflavonoid effects on hormonal status and hormone metabolism may help explain the findings. Besides in vitro results, human intervention studies in premenopausal women and in men have found a decrease in plasma 17␤-estradiol, progesterone, FSH and LH and an increase in plasma SHBG concentrations after admin- istration of soy (isoflavonoids) or flaxseed (lignans).11,19,42–44 In addition, some studies have also shown increased ratios of urinary 2-(OH) to 16␣-(OH) and 2-(OH) to 4-(OH) estrogens associated with soy intake.11 The latter finding suggests reduced formation of genotoxic and potentially carcinogenic estrogen metabolites. Sev- eral enzymes involved in estrogen metabolism can be affected (mainly inhibited) by phytoestrogens, including aromatase and sulfotransferases.12 The effects were less pronounced in postmeno- pausal women.45 Thus, our present findings are compatible with the biologic mechanisms showing an important role for isofla- vonoids in protecting against hormone-dependent breast cancer through their effects on the generation, transport and removal of endogenous steroid hormones; furthermore, some of these actions are mediated by hormonal receptors and therefore dependent on receptor status. Surprisingly, intake of formononetin and biochanin A as precursors of daidzein and genistein was unrelated to breast cancer risk or even increased risk (3rd quartile, Table IV). This may indicate very limited conversion of these precursors to their In contrast to daidzein and genistein, the protective effect found for enterodiol and enterolactone was not modified by hormone receptor status. This implies that there may be differences between the 2 classes of phytoestrogens regarding the biologic mechanisms involved in reducing breast cancer risk. Isoflavonoids and mam- malian lignans show similar effects, such as competition with estrogen for binding to estrogen receptors (type II), induction of SHBG, inhibition of some steroid-metabolizing enzymes (aro- matase) and antioxidant activity.1,18 However, depending on the test systems used, differences between phytoestrogenic com- pounds have been reported. The possible underlying mechanism for the observed difference warrants investigation.
Two reviews dealing with the health effects of phytoestrogens concluded that protective effects on breast cancer risk might be found in women who consume soy phytoestrogens at an early age (adolescence) or at very high doses.10,13 Most of the included studies evaluated the relationship between intake of soy/soy prod- ucts and disease risk, predominantly in Asian populations. Studies which assessed isoflavonoid or lignan metabolite concentrations in plasma or urine samples in relation to breast cancer yielded incon- MET, metabolic equivalents; data available for 187 cases and 525 sistent results. While 2 prospective studies failed to find a signif- icant inverse association between high urinary isoflavonoid excre-tion or serum enterolactone concentrations and breast cancer progesterone receptor (Table VI). The effects of enterodiol and risk,23,24 5 case-control studies reported a protective effect on enterolactone were independent of hormone receptor status (data Two studies in Asian populations, living in Japan (prospective study)48 and the United States (case-control study),49 that assessed overall isoflavonoid intake reported an inverse association with We found a protective effect of a high intake of genistein and breast cancer risk. The effect of dietary intake of isoflavonoids and daidzein (isoflavonoids) and matairesinol (lignan) on breast cancer lignans on breast cancer risk has been assessed only recently in 2 risk. The effect of genistein and daidzein was limited to hormone studies in the United States but not yet in Europe.16,17 Both US receptor-positive breast tumors. Additionally, a high amount of studies, one with a prospective design,17 failed to find a significant estimated enterodiol and enterolactone (mammalian lignans) is association with breast cancer or an effect modification by meno- inversely related to premenopausal breast cancer risk.
pausal status or hormone receptor status of the tumor.
TABLE II – DIETARY INTAKE (MEDIAN, 25%–75% PERCENTILE) OF SELECTED PHYTOESTROGENS AND ENERGY IN PREMENOPAUSAL
BREAST CANCER CASES (N ϭ 278) AND POPULATION-BASED CONTROLS (N ϭ 666)1 1Units are ␮g/day except for “Energy”, kcal/day.–2Mann-Whitney U-test.
TABLE III – CONTRIBUTION OF FOOD GROUPS AND SUBGROUPS TO THE DIETARY INTAKE OF SELECTED PHYTOESTROGENS IN PREMENOPAUSAL
BREAST CANCER CASES AND CONTROLS (AVERAGE PERCENTAGE OF TOTAL INTAKE IN CASES/CONTROLS) For the calculation of individual phytoestrogen intake, analytic pumpkin seeds) and coffee. Potatoes, leafy vegetables, cabbages, data from the literature were used, as described by other onion/garlic, nuts/seeds, wine, tea and especially bread contributed groups.15,38,50,51 With the exception of daidzein, the dietary intake to the total matairesinol intake. The proportional contribution of estimates for the different phytoestrogenic compounds in our sub- food groups to the mammalian lignans is spread over a broad jects are compatible with the results from a Dutch study in women variety of foods like different kinds of vegetable, potatoes, fruits, 49 –70 years old participating in the Utrecht EPIC cohort.15 Data nuts/seeds and bread, indicating differences in lignan sources.
on isoflavonoid intake in 4 European countries (Ireland, Italy, the There are 2 major concerns over possible biases that may have Netherlands, UK) also estimated an average intake of Ͻ1 mg/day, affected the results. First, a case-control study design of nutritional which was somewhat higher than that found in Germany.52 Studies studies may suffer from recall bias in cases. This cannot be from central Europe reporting lignan intake data are not available.
excluded for the present study. However, limited modification of Finnish data regarding dietary lignan intake vary widely but show the diet over time has been indicated, also after a diagnosis of distinctly lower secoisolariciresinol intake levels than we found cancer. The type of food consumed can be regarded as a personal here.50,53 Reported lignan and coumestrol intake values from 1 of dietary preference, so intake levels of most persons are likely to be 3 studies in the United States are similar to our results,51 while relatively stable over time.54 Zheng et al.47 observed that Ͼ90% of others are not;16,17 however, isoflavonoid intake was higher in the cases reported no appreciable dietary change during the time period from initial cancer diagnosis to urine collection. Addition- Differences in phytoestrogen intake between studies can be ally, results from EPIC-Heidelberg, obtained with the same nutri- explained by differing dietary habits but may also be affected by tional assessment tool, were comparable to the present results in differences in the phytoestrogen content of food (e.g., soy protein terms of energy and nutrient intake ranges55 and, therefore, give as an ingredient) or differences in the ability of the FFQ employed some reassurance for the validity of the data. Further, dietary to assess relevant food items for phytoestrogen intake. As shown assessment was not the main topic of the original study project, so in Table III, the important (Ͼ5% contribution) sources of daidzein patients may not have been sensitized to nutrition. The descriptive and genistein in the diet of our study population were soy sprouts, data show few differences between the original study population legumes, soy products, sauces and coffee (daidzein). Secoisolar- and the subgroup with FFQ data; thus, selection bias can largely be iciresinol is predominantly provided by nuts and seeds (flaxseeds, excluded as a source of error.29 Second, phytoestrogen data in- TABLE IV – CRUDE AND ADJUSTED1 ORS AND 95% CIS FOR PREMENOPAUSAL BREAST CANCER RISK BY PHYTOESTROGEN INTAKE
1Adjusted for first-degree family history of breast cancer, number of births, duration of breast-feeding, energy intake, BMI, alcohol TABLE V – ADJUSTED1 ORS AND 95% CIS FOR PREMENOPAUSAL BREAST
food additives used in food manufacturing before 1995 were used CANCER RISK BY COMBINATIONS OF LOW AND HIGH2 mainly for technologic reasons and pertain largely to soy protein DIETARY INTAKE OF DAIDZEIN AND GENISTEIN AND OF preparations (with widely varying isoflavonoid concentrations).
Regarding the lignans secoisolariciresinol and matairesinol, the most important food sources were considered but there may be other foods not analyzed so far. Several other plant lignans (e.g., pinoresinol, syringaresinol, lariciresinol) have been identified as precursors of enterodiol and enterolactone,57 but their concentra- tions in different foods are not available. This probably explains why the food sources of secoisolariciresinol and matairesinol are (0.46–1.10) (0.54–1.25) (0.36–0.83) distinctly different from those of mammalian lignans (Table III).
The most critical point, however, may be the production of en- Adjusted for first-degree family history of breast cancer, number of terodiol and enterolactone from ingested lignans in the human births, duration of breast-feeding, energy intake, BMI, alcohol con-sumption and education.–2Low levels refer to 1st and 2nd quartiles, intestine. The extent of lignan conversion in the gut depends and high levels refer to 3rd and 4th quartiles.
largely on the quantity and composition of the gut microflora.18Here, we used data from Thompson et al.41 based on incubatingdifferent foods with freshly gained human feces. It has been cluded in the database and used for intake calculations may be reported that plasma enterolactone concentrations are decreased incomplete for several reasons. In the case of isoflavonoids, the for several months after antibiotic therapy.58 Additionally, gut most important though unsolved question is the use of soy and soy transit time and fat content of the diet appear to modulate the components (e.g., soy protein) as food additives.56 The discussion availability of mammalian lignans.18,59 Therefore, when calculat- of possible health effects of soy was not yet popular during the ing the available amount of mammalian lignans in the present field period of the study. Thus, it can be assumed that soy-derived study, the reported high inter- and intraindividual differences in the TABLE VI – ADJUSTED1 ORS AND 95% CIS FOR TOTAL DAIDZEIN AND GENISTEIN INTAKE AND PREMENOPAUSAL
BREAST CANCER RISK BY ESTROGEN AND PROGESTERONE RECEPTOR STATUS OF THE TUMOR 1Adjusted for first-degree family history of breast cancer, number of births, duration of breast-feeding, energy intake, BMI, alcohol production of mammalian lignans53,60 could not be taken into monal profile.64,65 This supports the view that a “healthy” diet account. Isoflavonoids also undergo intestinal metabolism, and the provides more bioavailable mammalian lignans but does not ex- question of bioavailability of dietary isoflavonoids and their me- clude the possibility that mammalian lignans exert their own tabolites may also be important for understanding their health effects.61,62 Equol is the intestinal isoflavonoid metabolite with the In conclusion, our results give clear epidemiologic evidence for strongest estrogenic activity, but it is produced in only about a protective role against premenopausal breast cancer of a diet high one-third of Caucasian people, depending largely on the intestinal (albeit low compared to Asian populations) in daidzein, genistein or matairesinol as well as estimated mammalian lignans enterodiol Due to the difficulty in accounting for sources, metabolism and and enterolactone. The association between isoflavonoid intake bioavailability of dietary lignans, it is not surprising that the and breast cancer risk was found only for hormone receptor- association with breast cancer in our study was not the same for positive tumors, while the effect of mammalian lignans was inde- mammalian and plant lignans. Both approaches suffer from im- pendent of receptor status. Whether phytoestrogens are the under- precision: the lignan intake data do not reflect the bioavailable lying causal agents of a favorable diet or a favorable gut microflora fraction of lignan metabolites, and the enterodiol and enterolactone or both in relation to reduced breast cancer risk remains to be in vitro data used for calculation may be biased due to differences in the physiologic gut flora between subjects.
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