Context Soy foods are rich in isoflavones, a major group of phytoestrogens that have been hypothesized to reduce the risk of breast cancer. However, the estrogen-like effect of isoflavones and the potential interaction between isoflavones and tamoxifen have led to concern about soy food consumption among breast cancer patients.
Objective To evaluate the association of soy food intake after diagnosis of breast cancer with total mortality and cancer recurrence.
Design, Setting, and Participants The Shanghai Breast Cancer Survival Study, a large, population-based cohort study of 5042 female breast cancer survivors in China. Women aged 20 to 75 years with diagnoses between March 2002 and April 2006 were recruited and followed up through June 2009. Information on cancer diagnosis and treatment, lifestyle exposures after cancer diagnosis, and disease progression was collected at approximately 6 months after cancer diagnosis and was reassessed at 3 follow-up interviews conducted at 18, 36, and 60 months after diagnosis. Annual record linkage with the Shanghai Vital Statistics Registry database was carried out to obtain survival information for participants who were lost to follow-up. Medical charts were reviewed to verify disease and treatment information.
Main Outcome Measures Total mortality and breast cancer recurrence or breast cancer–related deaths. Cox regression analysis was carried out with adjustment for known clinical predictors and other lifestyle factors. Soy food intake was treated as a time-dependent variable.
Results During the median follow-up of 3.9 years (range, 0.5-6.2 years), 444 deaths and 534 recurrences or breast cancer–related deaths were documented in 5033 surgically treated breast cancer patients. Soy food intake, as measured by either soy protein or soy isoflavone intake, was inversely associated with mortality and recurrence. The hazard ratio associated with the highest quartile of soy protein intake was 0.71 (95% confidence interval [CI], 0.54-0.92) for total mortality and 0.68 (95% CI, 0.54-0.87) for recurrence compared with the lowest quartile of intake. The multivariate-adjusted 4-year mortality rates were 10.3% and 7.4%, and the 4-year recurrence rates were 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. The inverse association was evident among women with either estrogen receptor–positive or –negative breast cancer and was present in both users and nonusers of tamoxifen.
Conclusion Among women with breast cancer, soy food consumption was significantly associated with decreased risk of death and recurrence.
Estrogen is believed to play a central role in breast cancer development and progression. Blocking the effect of estrogen, either by inhibiting estrogen action or by reducing estrogen production, has been widely used in breast cancer treatment as an adjuvant therapy.1 Soy foods are rich in phytoestrogens, mainly in the form of isoflavones, which are natural estrogen receptor modulators that possess both estrogen-like and antiestrogenic properties. Soy constituents have also been shown to have other anticancer effects, including the inhibition of DNA topoisomerase I and II, proteases, tyrosine kinases, inositol phosphate, and angiogenesis and may also boost immune response and possess antioxidative effects.2,3
Consumption of soy food has been inversely related to the risk of breast cancer in many epidemiological studies.4- 6 However, genistein, a major form of isoflavone, has been shown to enhance the proliferation of breast cancer cells in vitro and to promote estrogen-dependent mammary tumor growth in ovariectomized rats.3,7 In addition, breast cancer treatments often lead to a decrease in the endogenous estrogen supply of survivors, and a concern has been raised as to whether soy isoflavones may exert their estrogenic effects, promote cancer recurrence, and, thus, negatively influence overall survival.7,8 Furthermore, both in vivo and in vitro studies have suggested that soy isoflavones may interact with tamoxifen, although both synergistic and antagonistic interactions have been reported.3,9- 13
To our knowledge, only 1 epidemiological study, the Life After Cancer Epidemiology (LACE) study, has evaluated the association of postdiagnosis soy isoflavone intake with cancer recurrence. An inverse association was suggested for postmenopausal women who had used tamoxifen.14
Herein, we report a comprehensive evaluation of the association of soy food consumption after diagnosis of breast cancer with outcomes using data from a longitudinal study of 5042 breast cancer patients, with a particular focus on differences in the association according to the estrogen receptor (ER) status of the cancer and tamoxifen use by patients.
METHODS
ABSTRACT | METHODS | RESULTS | COMMENT | ARTICLE INFORMATION | REFERENCES
Study Population
The current report includes participants of the Shanghai Breast Cancer Survival Study, a longitudinal, population-based study of women aged 20 to 75 years who were diagnosed as having primary breast cancer between March 2002 and April 2006 and were permanent residents of Shanghai, China. Patients were identified from the population-based Shanghai Cancer Registry and recruited into the study approximately 6 months after cancer diagnosis.
Of the 6299 cases identified, 5042 provided written informed consent and participated in the study (participation rate, 80.0%). Among the remaining cases, 757 (12.0%) refused to participate, 258 (4.1%) were absent during study enrollment, 83 (1.3%) could not be contacted, and 159 (2.5%) were excluded for other miscellaneous reasons such as health or communication problems. Nonparticipants were similar in age at cancer diagnosis but were more likely to have an advanced stage of cancer than study participants. Nine patients did not receive surgical therapy and were excluded from the analysis, leaving a total of 5033 participants for the current study. Cancer diagnoses were confirmed by a combination of medical record review and central review of pathological slides.
Data Collection
In-person recruitment and interviews using a structured questionnaire were carried out approximately 6.5 months (SE, 0.7 months) after cancer diagnosis by trained interviewers who were retired health care professionals. The baseline survey questionnaire covered demographic characteristics, reproductive history, disease history, medication use, selected lifestyle factors, diet, use of complementary and alternative medicine, and quality of life.
Clinical information collected included cancer stage, tumor ER and progesterone receptor (PR) status, and primary treatments (surgery/mastectomy, radiation therapy, chemotherapy, immunotherapy, and hormone therapy such as tamoxifen). Inpatient medical charts were reviewed to verify clinical information. Anthropometric measurements, including height, weight, waist circumference, and hip circumference, were taken according to a standard protocol.
Habitual dietary intake was assessed for specific time windows: the preceding 6 months for the baseline survey, the preceding 12 months for the 18-month survey, and the preceding 18 months for the 36-month survey. We used a validated food frequency questionnaire15 that was designed to measure consumption of soy foods commonly consumed in Shanghai, including tofu, soy milk, fresh soy beans, and other soy products, as well as meat, fish, and cruciferous vegetables. Nutrient consumption, including soy protein and isoflavone intake, was estimated by summing the product of food intake and the nutrient content of the food item based on the Chinese Food Composition Tables 2002.16
The cohort is being followed up by in-person interviews that take place at 18 months, 36 months, and 60 months after cancer diagnosis, supplemented by record linkage to the Shanghai Vital Statistics Registry (Figure). The follow-up interviews update soy food intake and complementary and alternative medicine use and collect information on disease progression and survival status.
Figure. Patient Flow
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As of June 30, 2009, the 36-month interview had been completed for 4354 of 4934 eligible patients (follow-up rate, 88.2%). The 60-month interview is still ongoing and has been completed for 1868 patients. Women who completed the 36-month follow-up and women who dropped out had similar intakes of soy food and other foods at the baseline survey. However, the 2 groups differed in age at diagnosis, body mass index (BMI), education level, and income, and these factors were adjusted for in the analyses.
Outcome information for dropouts was ascertained by annual linkage to the Vital Statistics Registry database. The most recent record linkage was conducted in October 2008. A Charlson comorbidity index was created for each woman based on a validated comorbidity scoring system17 and the diagnostic codes from the International Classification of Diseases, Ninth Revision, Clinical Modification.18 The institutional review boards of all participating institutions approved the study protocol.
Statistical Analysis
The major end points for the study were any death (total mortality analysis) and cancer recurrence/metastasis or death related to breast cancer (recurrence analysis). Survival status was censored at the date of last in-person contact or May 31, 2008 (5 months before the most recent linkage to the Vital Statistics Registry), whichever was most recent. For 15 participants who died of breast cancer but had missing information about disease recurrence, we used the disease stage (TNM)–specific median interval between disease recurrence and death to impute the date of disease recurrence. We excluded 20 patients who had a disease-free survival time of 0 from the recurrence analysis.
Cox proportional hazards models were used to evaluate the associations of soy intake with mortality an