Originally published as JCO Early Release 10.1200/JCO.2006.10.5023 on May 29 2007

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Tamoxifen, Soy, and Lifestyle Factors in Asian American Women With Breast Cancer

Anna H. Wu, Malcolm C. Pike, Lee D. Williams, Darcy Spicer, Chiu-Chen Tseng, Mona I. Churchwell, Daniel R. Doerge

From the Departments of Preventive Medicine and Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA; and the National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR

Address reprint requests to Anna Wu, PhD, Health Sciences Campus, Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033; e-mail: annawu{at}usc.edu

	ABSTRACT

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Purpose Soy foods have been a staple in Asia for centuries but the consumption of this food in the West is recent. Intake of soy among women at high risk for or with breast cancer has become a public health concern because genistein, a major component of soy, has weak estrogenic effects on breast epithelium, and has been found to negate the benefit of tamoxifen in some animal and in vitro studies.

Patients and Methods We conducted a cross-sectional study in Asian Americans with breast cancer who were tamoxifen users (n = 380) to investigate the association between soy intake and circulating levels of tamoxifen and its metabolites (N-desmethyl tamoxifen [N-DMT], 4-hydroxytamoxifen [4-OHT], and 4-hydroxy-N-desmethyl-tamoxifen [endoxifen]).

Results Serum levels of tamoxifen or its metabolites were unrelated to self-reported intake of soy or serum levels of isoflavones. Blood levels of tamoxifen were 81% higher in postmenopausal women age 65 or older compared with premenopaual women age 45 or younger (P = .005); similar patterns of results were observed for the tamoxifen metabolites. Levels of N-DMT were 27% (P = .03) lower among women in the highest tertile of body mass index (BMI, > 24.4 kg/m²) compared with those in the lowest category (BMI 21.5). Women who used hypertensive medications had higher levels of tamoxifen (P = .02) and N-DMT (P = .04) compared with nonusers.

Conclusion We found no evidence that soy intake adversely affected levels of tamoxifen or its metabolites. However, age, menopausal status, BMI, and use of hypertensive medications significantly influenced circulating levels of tamoxifen and its metabolites in this population.

	INTRODUCTION

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Intake of soy in Western populations has increased during the past decade, particularly since the US Food and Drug Administration issued a health claim on soy protein and coronary heart disease in 1999. However, because of reports of breast cell stimulation by isoflavones,^1,2 there are concerns about the safety of soy foods among breast cancer survivors, and for women at high risk for breast cancer. In some experimental studies the inhibitory effects of tamoxifen on growth of implanted mammary tumors were negated by concurrent dietary administration of soy isoflavones,^3,4 but in other rodent cancer models, soy appeared to enhance the beneficial effects of tamoxifen.^5,6 Little is known about the potential effects of soy intake for breast cancer survivors. Among Chinese women in Shanghai, usual soy food intake before breast cancer diagnosis was unrelated to disease-free breast cancer survival after a median follow-up of 5.2 years, but information on tamoxifen use was not included in this outcome study.⁷

We conducted a study to identify lifestyle factors that may influence prognosis of breast cancer among Asian-American women in Los Angeles County.¹ As part of this study, we measured serum levels of tamoxifen, its major metabolite, N-desmethyl-tamoxifen (N-DMT), and its two metabolites showing increased antiestrogenic activity, 4-hydroxy- tamoxifen (4-OHT) and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen), in a subset of breast cancer patients. In addition, serum levels of soy isoflavone (genistein, daidzein) and equol, a metabolite of daidzein, were measured. Our main objective of this cross-sectional analysis was to determine whether blood levels of tamoxifen and its metabolites were associated with blood levels of isoflavones and self-reported soy intake. We contend that if soy intake (or blood isoflavone levels) significantly influences blood levels of tamoxifen and its metabolites, soy intake may also adversely affect tamoxifen treatment. Previous studies mainly conducted in white women suggest that blood tamoxifen levels may be affected by age,^8,9 menopausal status,¹⁰ body size,¹¹ and use of various medications.¹² Thus, a secondary objective of this analysis was to evaluate whether these and other factors may influence tamoxifen metabolism in Asian women.

	PATIENTS AND METHODS

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Between 1995 and 2001, we conducted a population-based case-control study in Los Angeles County and interviewed 1,277 Asian-American women who were diagnosed with histologically confirmed incident breast cancer.¹³ The purpose was to understand lifestyle factors for breast cancer in Asian Americans. The details of this parent case-control study and subject characteristics have been previously described.^13,14 Briefly, eligible cases were identified through the Los Angeles County Cancer Surveillance Program, a member of the National Cancer Institute's Surveillance, Epidemiology and End Results Program. At the time of interview (or follow-up visit), blood specimens were obtained for 894 women with breast cancer. Funding permitted testing blood specimens of 530 breast cancer patients of whom 380 were taking tamoxifen at the time of blood draw; these 380 women are the subjects for this cross-sectional analysis. As part of the parent case-control study, participants were interviewed in person using a standardized, structured questionnaire that covered demographic characteristics, migration history, menstrual and reproductive history, height and weight history, physical activity, and usual adult diet, including soy intake. Our food frequency questionnaire (FFQ) was modeled after a validated instrument,¹⁴ and asked about usual intake of 14 foods that are rich in soy. We used the questionnaire response to estimate usual total intake of isoflavones (mg per day).¹⁴ Subjects were also asked if they were diagnosed by a physician with hypertension, diabetes, high cholesterol, or arthritis, and about their use of medications including aspirin, acetaminophen, ibuprofen, diuretics, and other high blood pressure medications before their breast cancer diagnosis (for patients) or before the interview (for control subjects). Height, weight, and circumference of the waist and hip were measured at the time of interview.

At the time of blood collection, subjects were asked a few other questions, including an open-ended question about all the medications they took during the 2-week period before blood draw, including the name of medication, reason for taking the medication, number of days medication was used, and number of tablets per day. Information on tamoxifen use was obtained from this question. Of the 530 patients from the parent case-control study that we tested blood, 380 indicated taking tamoxifen (20 mg per day) during the 2 weeks before blood draw and they were the subjects of this analysis. To complement the information we collected on usual soy intake from the FFQ, subjects were also asked about their intake of soy foods in the 2 days before blood draw. We asked about soy intake before blood draw because peak plasma daidzein and genistein levels typically occur 6 to 8 hours after ingestion.¹⁵ Our study was approved by the institutional review board of the Keck School of Medicine of the University of Southern California (Los Angeles, CA).

Laboratory Assays of Serum Tamoxifen and Metabolites and Isoflavones and Metabolites
A previously published and validated method consisting of solid phase extraction and isotope dilution liquid chromatography/mass spectrometry with multiple reaction monitoring was used for the concomitant analysis for the major soy isoflavones (genistein, daidzein), and the important metabolite of daidzein (equol), tamoxifen, and its important metabolites (N-DMT, 4-OHT, and endoxifen). The limits of quantification achieved were sufficient to accurately and precisely determine concentrations of all these analytes in women consuming soy foods and/or therapeutic doses of tamoxifen.¹⁶ Detection limits were in the range of 5 to 10 nmol/L for isoflavones and 0.2 to 1 nmol/L for tamoxifen and its metabolites with coefficients of variation in the range of 0.9% to 11.4%.¹⁶

Statistical Analyses
We used analysis of variance and analysis of covariance to assess the relationships between serum levels of tamoxifen and select demographic and other variables of interest. These analyses were repeated for N-DMT, 4-OHT, and endoxifen (Table 1). Statistical analysis was performed on logarithmically transformed serum values and geometric mean serum levels (and 95% CIs) are presented. We first examined whether geometric mean serum levels of tamoxifen and its metabolites differed by race (Chinese, Filipino, and Japanese), age ( 45, 46 to 55, > 55 to 64, 65+), and menopausal status (premenopausal v postmenopausal). Age, menopausal status, and race were adjusted for in subsequent analyses. We examined whether geometric mean serum levels of tamoxifen and its metabolites differed by body mass index (BMI; kg/m²) and waist/hip ratio (WHR) obtained at the time of blood draw. Because BMI significantly influenced levels of tamoxifen and its metabolites, all subsequent analyses were adjusted for BMI. We investigated the relationship between soy intake (serum isoflavone levels and self-reported intake of soy) and serum levels of tamoxifen and its metabolites (Table 2). In addition, we investigated whether geometric mean tamoxifen (and its metabolites) levels differed by self-reported history of various physician diagnosed medical conditions and use of select medications (Table 3). All P values presented are two tailed and statistical significance was defined as P < .05. Calculations were performed using the SAS statistical software system, version 8.0 (SAS Institute, Cary, NC).

	RESULTS

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Serum levels of tamoxifen (and metabolites) were not associated significantly with self-reported usual adult soy intake, based on total isoflavone (mg/1,000 Kcal) habits before breast cancer diagnosis. Soy intake around the time of blood draw was also unrelated to levels of tamoxifen and metabolites. In addition, there were no significant associations between concentrations of tamoxifen or its metabolites and serum concentrations of total isoflavones or its components (genistein, daidzein, and equol; Table 2.)

Women with a history of high blood pressure that was diagnosed by a physician had higher levels of serum tamoxifen (23%; P = .08) and N-DMT (23%; P = .11) than those without a history of high blood pressure after adjusting for BMI and other covariates. This was largely related to use of blood pressure medications. Blood tamoxifen and N-DMT levels were 33% (P = .02) and 30% (P = .04) higher, respectively, in women who reported taking high blood pressure medications during the 2-week period before blood draw (Table 2). However, blood levels of 4-OHT and endoxifen were unrelated to use of blood pressure medication. Levels of tamoxifen (and metabolites) were unrelated to other conditions/medications we investigated (Table 3).

	DISCUSSION

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This is one of the first large, population-based cross-sectional studies of circulating levels of tamoxifen and it main metabolites and lifestyle factors in Asian Americans. Participants were breast cancer patients from a completed case-control study in Los Angeles County; these women (n = 380) provided a blood specimen at the end of interview and responded they were taking tamoxifen during the 2-week period before the blood draw. We investigated whether soy intake influenced metabolism of tamoxifen and used serum concentration of tamoxifen, N-DMT, 4-OHT, and endoxifen as outcome measures in this study.

Tamoxifen undergoes extensive metabolism through demethylation and hydroxylation, and there is large between person variation in the concentrations of tamoxifen and its metabolites.^17-19 The variable patterns of tamoxifen metabolism may explain, in part, the variable response to tamoxifen treatment.²⁰ Factors responsible for this wide variation are not well-understood; select lifestyle factors^9,10,12,21 and P450 genotype (specifically CYP2D6 and CYP3A4/5)¹⁹ have been implicated. CYP3A4/5 enzymes are predominantly responsible for the metabolism of tamoxifen to N-DMT; N-DMT is then hydroxylated by CYP2D6 to endoxifen.²² The frequency of poor CYP2D6 and CYP3A5 metabolizers is considerably higher in the white population than in the Asian population.^23,24 Poor CYP2D6 metabolizers with lower levels of endoxifen had increased recurrence and mortality rate in one study²¹ but this was not found in another study.²⁵ In a small study of postmenopausal patients, nonresponding patients had significantly higher blood levels of N-DMT and 4-OHT than responding patients,²⁶ but these results have not been confirmed. Thus, it is currently unclear whether circulating levels of tamoxifen and its metabolites could be used to predict treatment response and breast cancer outcome.

Relative to the blood tamoxifen levels, levels of N-DMT were about two-fold higher whereas levels of 4-OHT and endoxifen were approximately 2% and 18%, respectively, of the parent drug levels. Levels of the three metabolites relative to tamoxifen levels we found are comparable with results reported in other studies, including clinical trials in which the pharmacokinetics of tamoxifen were studied in a controlled manner.^27,28 The blood levels of tamoxifen, N-DMT, and 4-OHT in Asian-American women are comparable with levels that have been reported in white and African American women taking 20 mg/d dose regimens.^9,27 We are not aware of previous reports on endoxifen levels in different racial/ethnic groups.

Age/menopausal status, body mass index, and use of hypertensive drugs emerged as factors that significantly influenced circulating tamoxifen and its metabolites in this study. Blood levels of tamoxifen and its metabolites were at least 50% higher in older postmenopausal women (age 65 or older) than in younger premenopausal women (age 45 or younger) even after adjusting for body size. These age-related differences have been reported previously in studies of white and African American women.^8,9 The consistency in findings in different racial/ethnic groups suggest that this age effect may indicate more than simply better compliance among older women but may reflect slower excretion and metabolism with increasing age.

Levels of tamoxifen, N-DMT, 4-OHT, and endoxifen were inversely associated with BMI among Asian-American women; the finding with N-DMT was statistically significant (Table 1). A similar, but weaker pattern of association was observed using WHR. The lowest BMI tertile in our population was less than 21.5 kg/m² whereas the highest tertile was more than 24.4 kg/m². No significant associations between BMI and levels of tamoxifen and metabolites were reported in two smaller cross-sectional studies. In one study, levels of tamoxifen, N-DMT, and 4-OHT did not differ between women with BMI < 30 versus those with BMI 30.⁹ In another study, levels of tamoxifen, N-DMT, and 4-OHT were unrelated to BMI, but levels of another demethylated tamoxifen metabolite (N-didesmethyl tamoxifen) were significantly inversely associated with BMI.²⁷ Sample size of this study was almost three times larger than the two previous studies and the BMI of our subjects was considerably lower. We also had two measures of body size (BMI and WHR) and both yielded similar results. In earlier studies, small sample sizes and heterogeneous patient populations may have contributed to the differences in results.

Women who reported taking high blood pressure medications showed significantly higher blood concentrations of tamoxifen and N-DMT (Table 3). This difference was specific to blood pressure medications and was not found in relation to use of other medications. In another study where medication use was abstracted by medical chart review, levels of tamoxifen and N-DMT were significantly higher and levels of 4-OHT were nonsignificantly higher among women taking diuretics compared with nonusers.¹² Among the 125 women who took antihypertensives in our study, nine took diuretics exclusively, 38 took diuretics in combination with another hypertensives, and 78 took nondiuretic hypertensives. Levels of tamoxifen, N-DMT, and 4-OHT were highest among those who took only diuretics (137.5, 254.8, 2.74 ng/mL, respectively), and intermediate among those who took diuretics in combination with another hypertensive (137.0, 251.9, and 2.61 ng/mL, respectively). Endoxifen was not measured in the previous study¹² their levels did not differ by type of hypertensives in this study. Because many of the hypertensive medications have effects on the cytochrome P450 isoforms, and tamoxifen is metabolized via cytochrome P450-mediated pathways, further studies are needed to confirm the effects of hypertensives on circulating levels of tamoxifen and its metabolites and to determine whether they adversely influence outcome.

Circulating levels of tamoxifen, N-DMT, 4-OHT, and endoxifen were unrelated to intake of soy, measured in three ways in this analysis (Table 2). We had two measures of self-reported soy intake; one was usual adult soy intake (mg of isoflavones/1,000 Kcal) before breast cancer diagnosis (obtained from the FFQ)¹⁴ and the second question related to soy intake 2 to 3 days before the time of blood draw (obtained at blood draw). A third measure of soy intake in this analysis was based on serum isoflavone levels, determined using the same blood specimen we used to measure blood tamoxifen (and metabolite) levels. The correlation between serum isoflavone and usual self-reported soy intake was 0.31 (P < .001). We also previously showed that subjects can reliably recall their usual soy intake on the basis that blood isoflavone levels increased significantly in association with self-reported intake of soy.²⁹ The fact that we did not observe any association between all three measures of soy and circulating tamoxifen levels provide evidence that it is unlikely that soy intake significantly affected internal exposures to tamoxifen and its metabolites. The primary limitation of our study is that it utilized serum levels as the end point; assessment of direct antagonistic effects of soy on tamoxifen at a receptor or cellular level would not be excluded.

We believe these results obtained from breast cancer patients who consume considerable amounts of soy and are on tamoxifen therapy add new information to a public health question that has been controversial and inadequately studied. Tamoxifen is the most widely prescribed selective estrogen receptor modulator. Soy-derived genistein is structurally similar to 17 beta-estradiol with binding affinity for both estrogen receptors and may compete with tamoxifen for the estrogen receptors, and could reduce the efficacy of tamoxifen through its estrogen agonist activity.¹ To date, the strongest evidence that genistein may negate the beneficial effects of tamoxifen is based on a series of studies conducted in ovariectomized immune-compromised rats implanted with estrogen receptor-positive breast cancer cells. In these studies, genistein intake by athymic mice abrogated the ability of tamoxifen to inhibit the proliferation of estrogen receptor-positive breast cancer cells.³ In addition, a common dose of genistein given in different forms (soy molasses, Novasoy, mixed isoflavone) was associated with varying degrees of stimulated tumor growth.³⁰ In another study using an erbB2/neu transgenic mice model, dietary isoflavones abrogated tamoxifen-associated mammary tumor prevention.⁴ However, no adverse effects of soy on tamoxifen were reported in other studies which used different animal models. Gotoh et al⁵ found that tamoxifen in combination with a diet containing miso (fermented soybean paste) inhibited the development of MNU-induced mammary cancer. In another study,⁶ DMBA-induced mammary carcinogenesis was reduced in association with both tamoxifen and soy; the largest reduction in risk was in relation to administration of tamoxifen and soy in combination.

In summary, this is one of the largest cross-sectional studies of lifestyle determinants of circulating levels of tamoxifen and its metabolites in Asian women. We did not find soy intake to positively or negatively influence circulating levels of tamoxifen and its metabolites. However, age/menopausal status, body weight, and use of hypertensive medications significantly influenced circulating levels. Because approximately one third of patients with estrogen receptor-positive tumors do not respond to tamoxifen therapy, and ultimately even those that do respond become resistant to the treatment, better understanding of factors that influence tamoxifen metabolism is warranted. Future studies that include genotype information of the key CYP450 enzymes known to influence the production of the important antiestrogenic tamoxifen metabolites, 4-OHT and endoxifen, should be informative.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Anna H. Wu

Financial support: Anna H. Wu

Administrative support: Chiu-Chen Tseng

Collection and assembly of data: Anna H. Wu, Lee D. Willliams, Chiu-Chen Tseng, Mona I. Churchwell, Daniel R. Doerge

Data analysis and interpretation: Anna H. Wu, Malcolm C. Pike, Darcy Spicer, Chiu-Chen Tseng, Daniel R. Doerge

Manuscript writing: Anna H. Wu

Final approval of manuscript: Anna H. Wu, Malcolm C. Pike, Lee D. Willliams, Darcy Spicer, Chiu-Chen Tseng, Mona I. Churchwell, Daniel R. Doerge

	ACKNOWLEDGMENTS

 
We are grateful to all the study participants for their contributions and support. We thank the entire data collection team, especially Annie Fung, Lydia Tran, June Yashiki, and Sushma Jain.

	NOTES

 
published online ahead of print at www.jco.org on May 29, 2007.

Supported by grants from the Susan G. Komen Foundation (POP02-1896), the California Breast Cancer Research Program (9PB-0089), and the National Institute of Environmental Health Services (5P30 E207048). Incident breast cancer cases for this study were collected by the USC Cancer Surveillance Program (CSP), which is supported under subcontract by the California Department of Health. CSP is also part of the National Cancer Institute's Division of Cancer Prevention and Control Surveillance, Epidemiology, and End Results Program, under contract number N01CN25403. D.R.D. is supported in part by the National Institute on Aging (P01-AG024387) with additional support from the National Institute for Complementary and Alternative Medicine, Office of Dietary Supplements, and the Women's Health Initiative.

The views presented in this article do not necessarily reflect those of the US Food and Drug Administration.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 27, 2006; accepted April 19, 2007.

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