A Case-Control Study of Risk Factors for Fibrocystic Breast Conditions

Shanghai Nutrition and Breast Disease Study, China, 1995–2000

Chunyuan Wu1, Roberta M. Ray1, Ming Gang Lin1, Dao Li Gao2, Neilann K. Horner1, Zakia C. Nelson1, Johanna W. Lampe1,3, Yong Wei Hu4, Jackilen Shannon1,5, Helge Stalsberg6, Wenjin Li1, Dawn Fitzgibbons1, Peggy Porter1, Ruth E. Patterson1,3, Jessie A. Satia7 and David B. Thomas1,3 

1 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
2 Department of Epidemiology, Zhong Shan Hospital Cancer Center, Shanghai, China.
3 Department of Epidemiology, University of Washington, Seattle, WA.
4 Shi Dong Hospital, Shanghai, China.
5 Veterans Administration Medical Center, Portland, OR.
6 Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
7 Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Received for publication December 16, 2003; accepted for publication June 10, 2004.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 
This study was conducted to identify reproductive and dietary factors associated with benign proliferative mammary epithelial cell changes. Subjects were women enrolled in a randomized trial of breast self-examination in Shanghai, China. Women who developed fibrocystic breast conditions classified as nonproliferative (175 women), proliferative (181 women), or proliferative with atypia (33 women) between 1995 and 2000 and 1,070 unaffected trial participants were administered general risk factor and food frequency questionnaires. Conditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals. High parity and consumption of fresh fruits and vegetables were more strongly associated with a reduced risk of proliferative and atypical lesions than with nonproliferative conditions. For the fourth quartile of consumption versus the first, odds ratios for lesions diagnosed as nonproliferative, proliferative, and proliferative with atypia were 0.4 (95% confidence interval (CI): 0.2, 0.7), 0.2 (95% CI: 0.1, 0.4), and 0.1 (95% CI: 0.03, 0.5), respectively, for fruit intake and 0.6 (95% CI: 0.3, 1.1), 0.4 (95% CI: 0.2, 0.7), and 0.1 (95% CI: 0.1, 0.9), respectively, for vegetable intake. Reduced but nonsignificant risks in relation to soy products were observed for proliferative and atypical lesions. No single nutrient or botanical family was appreciably more strongly associated with proliferative conditions than with nonproliferative conditions, after results were controlled for total fruit and vegetable consumption. A diet rich in fruits and vegetables may reduce cellular proliferation in the mammary epithelium; this is one mechanism by which such a diet could reduce risk of breast cancer.

breast diseases; diet; estrogens; fibrocystic disease of breast; fruit; risk factors; soy foods; vegetables


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 
Fibrocystic breast conditions, formerly referred to as "fibrocystic breast disease" (1, 2), with proliferative epithelial cell elements have been associated with increased risk of subsequent breast cancer, especially if accompanied by atypical cellular changes (36). Since factors that stimulate cell proliferation may enhance the likelihood of malignant change, the identification of risk factors for proliferative mammary epithelial cell changes could provide insights into the early stages of mammary carcinogenesis.

Previous studies have shown increased risk of fibrocystic breast conditions in the aggregate to be associated with high social class (3, 4, 7, 8), late age at menopause (3, 4, 6, 8, 9), estrogen replacement therapy (3), nulliparity (3, 4, 6, 810), low body mass index (3, 4, 7, 8, 11), and family history of breast cancer (4, 69, 12), while high parity (3, 79), oral contraceptive use (3, 4, 6, 7, 10, 13), and physical activity (14, 15) have been related to decreased risk. Most reports have shown no substantial effect of ever, former, or current smoking on development of fibrocystic conditions, even across different grades of atypia (3, 6, 8). Results have been inconsistent for young age at first full-term pregnancy (3, 7, 9, 16) and lactation (7). Age at menarche has not been associated with risk (3, 4, 10).

Among the dietary factors studied, the most consistent finding is an apparently protective effect of fruits and vegetables (1720). Diets high in fiber (2123) and soy products (21) have also been associated with reduced risk, but a randomized trial showed increased cell division in lobular mammary epithelium after soy protein supplementation (24). Consumption of green vegetables has been inversely associated specifically with risk of proliferative benign breast disease (20). Results from studies of total fat are inconsistent (3, 19, 25, 26). In one study, high daily intake of energy was reported to be positively associated with benign epithelial cell proliferative disease (22).

We conducted this study to evaluate the role that reproductive and dietary factors, particularly antioxidants and certain phytoestrogens, may play in the development of mammary epithelial cell proliferation in Chinese women with fibrocystic breast conditions.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 
Study setting and subjects
Subjects for this case-control study were selected from women who were enrolled between 1989 and 1991 in a randomized trial of breast self-examination among textile workers in Shanghai, China (27, 28). When a woman in the trial detected a breast lump, she was evaluated by a medical worker in her factory who, if indicated, referred her to one of three hospitals operated by the Shanghai Textile Industry Bureau or to other hospitals that had contractual agreements with individual factories. Study personnel reviewed the pathology reports and other medical records of all women found to have a histologically confirmed benign breast lesion, recorded tumor size and histologic classification on a standardized form, and obtained slides of all tumors for shipment to Seattle, Washington, for review. Women in the trial who received a breast biopsy in any of the three Shanghai Textile Industry Bureau hospitals and were subsequently diagnosed with a fibrocystic breast condition between September 1995 and July 2000 were eligible for the present study.

A total of 622 women with fibrocystic breast conditions were identified for this study, and in-person interviews were completed for 551 (89 percent) of them. Of these women, 389 (71 percent) had satisfactory slides for review (at least five scanning power fields) and were included in the analyses for this report.

Women whose breast conditions were diagnosed between September 1995 and August 1997 were simultaneously enrolled in an ongoing immunocytochemical study of mammary cell proliferation (unpublished data). Controls for the present study were selected from unaffected women in the breast self-examination trial cohort. For each benign and malignant case also enrolled in the previous study of cell proliferation, 20 potential controls of the same age were randomly selected. Women were contacted, starting with the first two names on the list, until two women of the same age and menstrual status as their matched case were recruited. All 367 controls recruited in this manner (64 percent of the eligible women contacted) were included in the analyses for this report. Controls for the cases who were not enrolled in the study of cell proliferation were frequency matched to cases eligible for this study, as well as to cases also eligible for two concurrent studies of breast cancer and fibroadenoma, by 5-year age group and hospital affiliation of their factories at baseline. In-person interviews were completed for 704 (82 percent) of 862 controls selected in this manner.

Data collection
A baseline questionnaire was administered orally to all women in the breast self-examination trial by factory medical clinic workers between October 1989 and October 1991. The women who participated in the present study were reinterviewed from 1995 through 2001 by members of a team of specially trained former medical clinic workers, utilizing a detailed general risk factor questionnaire and a food frequency questionnaire. Cases were interviewed in hospitals or clinics, usually at the time of their initial visit for their breast problem, before the histologic diagnosis was made. Controls were interviewed in their homes or factories. Information was elicited on demographic characteristics, reproductive and gynecologic history, smoking and alcohol habits, medical history, family history of breast cancer, and occupational and recreational physical activities. Because prior breast surgery reported by many women erroneously included the surgery conducted for the present disease, information from the baseline questionnaire on prior breast surgery was utilized. The food frequency questionnaire was based on a previously validated instrument (29, 30) and ascertained data on the frequency of intake of 99 food items during adult life. Respondents provided information on their usual frequency of intake (per day, week, month, or year) of each item. The seasonality of fruit and vegetable consumption was accounted for by asking subjects to report the number of months of the year in which they consumed each item.

Informed consent was obtained from each woman prior to interview. The study was approved by the institutional review boards of the Fred Hutchinson Cancer Research Center and the Station for Prevention and Treatment of Cancer of the Shanghai Textile Industry Bureau, in accordance with assurance filed with the Office for Human Research Protections of the US Department of Health and Human Services.

Validation of diagnosis and histologic classification
A single study pathologist (M. L.) read slides from all cases without knowledge of their original diagnosis. He recorded the number of scanning power fields examined and classified the women’s conditions into three different types of fibrocystic breast conditions according to the scheme developed by Stalsberg (31). Cases with atypia were those with atypical ductal hyperplasia, atypical lobular hyperplasia, or moderate apocrine atypia (33 cases). Cases with proliferative changes were those with moderate or florid ductal hyperplasia or moderate or predominant sclerosing adenosis and no atypia (181 cases). Subjects with mild or no ductal hyperplasia and subjects with mild or no sclerosing adenosis were classified as having nonproliferative fibrocystic breast conditions (175 cases).

Randomly selected slides from the three major groups of fibrocystic breast conditions were read by a reference pathologist (H. S.). There was a satisfactory level of agreement between the readings made by the study pathologist and the reference pathologist on the presence or absence of proliferation and atypia (weighted {kappa} = 0.4), and the benign conditions were categorized into 1) nonproliferative, 2) proliferative without atypia, and 3) proliferative with atypia for analysis. In all instances, the diagnoses made by the study pathologist were used.

Data analysis
All individual food consumption frequencies were converted to annual frequencies. Intake of fruits and vegetables was computed by weighting the frequency of intake by the number of months per year during which the food item was eaten. The 99 foods were grouped into 19 mutually exclusive food groups (Appendix 1). The individual annual frequencies of intake for the foods in each group were summed to create values for consumption of the food group. Amounts of sesame and soybean oils consumed were estimated by dividing the amounts used by the woman’s family per day by the number of family members. Nine fried food items were combined into a separate high-fat group. Fruits and vegetables were further classified into mutually exclusive botanical families (Appendix 2). Total daily energy intake was calculated from all macronutrients, oils, and alcohol using 1991 Chinese food composition tables (32, 33) and estimated average serving sizes from the 1992 China Health and Nutrition Survey (34). Total daily dietary intakes of vitamin E (mg of {alpha}-tocopherol equivalents), carotenoids (µg), vitamin C (mg), and crude fiber (g) were also calculated from the same Chinese food composition tables (32, 33). One woman with a nonproliferative fibrocystic breast condition and one control were excluded because their calculated daily energy intakes were considered implausible at more than 4,000 kcal.

To assess potential trends in risk with level of consumption, we divided food groups, botanical families, and nutrients into quartiles according to the distribution of consumption among the controls. We created fewer categories for food groups with too little variation in intake to create meaningful quartiles. Because controls were interviewed after the corresponding cases, they tended to have been interviewed at a later date. Therefore, we stratified study subjects by year of interview (1995–1996, 1997, 1998–1999, 2000–2001) in all analyses. We computed odds ratios (as estimates of relative risk) and associated 95 percent confidence intervals using conditional logistic regression (35). For small sample sizes (<5), we used exact logistic regression to calculate odds ratios and confidence intervals. All odds ratios were adjusted for age using 5-year age categories. We assessed residual confounding by age by comparing selected results in these analyses with results of analyses in which age was modeled as a continuous variable; no residual confounding by age was detected. The odds ratios for food groups were further adjusted for total energy intake (36). Odds ratios for botanical groups and specific micronutrients were adjusted for age and total fruit and vegetable intake. We performed tests for trend by entering the categorical variables in regression models as ordinal variables. We evaluated potential confounding by adding variables independently to the appropriate model. Variables were considered as confounders if they changed the estimated ß coefficient of the main independent variable by 10 percent or more.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 
As expected, because the controls for this study were also selected for studies of breast cancer, they tended to be older than the cases without atypia in this study (table 1). Women with atypia were older than women with nonproliferative and proliferative conditions. Almost 80 percent of the women who developed fibrocystic breast conditions were younger than age 50 years at diagnosis.


View this table:
[in this window]
[in a new window]
 
TABLE 1. Age distribution of cases with fibrocystic breast conditions and controls, Shanghai Nutrition and Breast Disease Study, 1995–2000
 
Although results were based on small numbers of postmenopausal women and the findings were not statistically significant, the risk of all three types of conditions was lower for women who had gone through natural menopause than for women of the same age who had not (table 2). This finding was not observed for artificial menopause. Risks of all three conditions declined with increasing number of livebirths, although only strongly and significantly so for proliferative lesions with and without atypia. Risk of proliferative conditions declined with age at menarche. Because only three cases and 25 controls had ever smoked, no meaningful analyses by smoking status were possible. Having lived for more than 20 years with a spouse who smoked was associated with a reduced risk of proliferative conditions that was of borderline statistical significance and a similar but not statistically significant reduced risk of atypia. Few women in this population had a family history of breast cancer, and although risk of all three conditions was increased among women with such a history, none of the odds ratios reached statistical significance. The risk of all three conditions was also associated with having had a benign breast biopsy prior to formation of the trial cohort. Detection of nonproliferative and proliferative fibrocystic breast conditions was associated with frequency of breast self-examination and months since last breast self-examination (data not shown). No significant associations were observed with duration of lactation, age at first livebirth, use of oral contraceptives or an intrauterine device, or education. In addition, no significant associations were observed with body mass index or either occupational or leisure-time exercise in any decade of adult life (data not shown). Weak decreasing trends in risk of all three types of conditions with daily energy intake, though not statistically significant, were controlled for in the analysis of food groups. No associations with percentage of energy derived from fat, carbohydrate, or protein were observed (data not shown).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Risk of fibrocystic breast conditions in relation to general risk factors, stratified by year of interview, Shanghai Nutrition and Breast Disease Study, 1995–2000*
 
As table 3 demonstrates, there were decreasing trends in risk of all three conditions with increasing consumption of fruits and vegetables. The point estimates of the odds ratios for the highest quartiles of consumption of both fruits and vegetables were lowest for atypia, next lowest for proliferative conditions, and closest to unity for nonproliferative conditions. Decreasing trends in risk were also seen with preserved vegetables (not statistically significant for proliferative conditions and atypia) and possibly with legumes other than soy foods (trends not statistically significant). There were nonsignificant decreasing trends in risk of proliferative conditions and atypia with soy consumption, as well as a possible decrease in risk of atypia in relation to fermented bean curd.


View this table:
[in this window]
[in a new window]
 
TABLE 3. Risk of fibrocystic breast conditions in relation to absolute intake of foods in various food groups, stratified by year of interview, Shanghai Nutrition and Breast Disease Study, 1995–2000
 
There were increasing trends in risk of nonproliferative and proliferative conditions with consumption of dairy products, but only that for nonproliferative conditions was statistically significant. Possible increasing trends of all three conditions in relation to consumption of grain products other than corn and rice were also evident, but only that for proliferative conditions was of borderline statistical significance.

With the possible exception of atypia, no associations with red meat were observed. Unexpectedly, there were decreasing trends in risk of nonproliferative conditions with increasing intakes of cured meat and fish and fried foods. With these two exceptions, no associations were observed with fish, cured meat and fish, poultry, eggs, shellfish, sesame oil, soybean oil, fried foods, rice, or tea.

The significant odds ratios shown in table 3 were adjusted further for other food groups and for age at first livebirth, parity, family history of breast cancer, physical activity during the woman’s 20s–40s, intrauterine device use, oral contraceptive use, a prior breast lump, active and passive smoking, body mass index, and frequency of breast self-examination. Adjustment for any of these variables did not significantly alter the odds ratios for any of the food groups, nor did adjustment for these dietary factors appreciably alter the odds ratios in relation to any of the nondietary factors shown in table 2.

Table 4 shows odds ratios in relation to intake of mutually exclusive botanical groups, adjusted for age and total intake of fruits and vegetables. The Compositae, Rutaceae, Sapindaceae, and Vitaceae families were significantly associated with reduced risk of nonproliferative fibrocystic breast conditions. The Sapindaceae and Vitaceae families were similarly associated with proliferative fibrocystic breast conditions. Possible associations of Compositae and Rutaceae with proliferative fibrocystic breast conditions were not as strong as those with nonproliferative fibrocystic breast conditions and were not statistically significant. The Zingiberaceae family was significantly associated with increased risk of proliferative conditions and atypia. The Umbelliferae family was possibly associated with increased risk of all three histologic types of fibrocystic breast conditions, but the trends were not statistically significant.


View this table:
[in this window]
[in a new window]
 
TABLE 4. Risk of fibrocystic breast conditions in relation to intake of foods from various botanical families, stratified by year of interview, Shanghai Nutrition and Breast Disease Study, 1995–2000
 
After results were controlled for total fruit and vegetable intake, no significant associations with vitamins E and C, total carotenoids, or total crude fiber were observed (table 5). {alpha}-tocopherol, ß- and {gamma}-tocopherol, and {delta}-tocopherol are subcomponents of vitamin E and showed results similar to those for total vitamin E.


View this table:
[in this window]
[in a new window]
 
TABLE 5. Risk of fibrocystic breast conditions in relation to absolute intake of various nutrients, stratified by year of interview, Shanghai Nutrition and Breast Disease Study, 1995–2000
 
We also carried out analyses of both the food-group data and the botanical-group data using nutrient densities (intake divided by total energy intake). Total daily energy-adjusted multivariate nutrient density models (36) for both food groups and botanical groups yielded results that were not appreciably different from those presented.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 
In case-control studies, differential ascertainment of information from cases and controls can result in biased odds ratios. In this study, few case women were ill, and most were interviewed before their histologic diagnosis. Therefore, it can reasonably be assumed that the effect on observed odds ratios of this source of bias would not vary by histologic type of breast lesion and that the differences in the odds ratios for the three groups of cases would not be subject to this source of bias. Thus, in interpreting the results of this study, emphasis must be given to differences in results for proliferative and nonproliferative conditions. Where the results for atypia are consistent with or stronger than those for proliferative conditions, they can strengthen the evidence for an association indicating a possible causal link to breast cancer; but because the number of case women with atypia was low, such interpretations must be made with caution, and the absence of associations with atypia cannot be interpreted as evidence against a particular interpretation or hypothesis.

Because of the focal distribution of fibrocystic conditions in the breast, there was probably some misclassification of the lesions into the three histologic types. This would have tended to obscure true differences in odds ratios for the three histologic types, and observed differences in odds ratios may reflect larger actual differences.

Decreasing trends in risk with increasing numbers of livebirths were stronger for atypia and proliferative conditions than for nonproliferative conditions, suggesting that high parity may protect against breast cancer by reducing mammary epithelial cell proliferation and atypical changes. A similar interpretation could be argued for the effect of age at menarche on risk, but the differences in the odds ratios among the three groups in relation to this factor were less striking than those for parity and could readily have been due to chance.

Smoking is known to reduce endogenous estrogen levels, and the weak decreasing trend in risk of proliferative (but not nonproliferative) conditions with years of having lived with a spouse who smoked suggests that environmental tobacco smoke could reduce cell proliferation in the mammary epithelium through its effect on estrogen levels. However, this observation could also be due to chance.

A history of benign breast lesions was associated with increased risk of fibrocystic breast conditions. It was not possible to determine whether the prior lumps were fibrocystic breast conditions or other benign breast conditions, so risks related to specific types of benign breast conditions could not be estimated. However, multiple occurrence and recurrence of fibrocystic breast conditions has been well established (2, 3). Our findings suggest that this phenomenon may be more common for proliferative conditions than for nonproliferative conditions.

Previous studies have found a positive family history of breast cancer or benign breast disease to be related to fibrocystic breast conditions (4, 69, 12). In this study, after adjustment for multiple variables, family history of breast cancer was no more strongly associated with proliferative fibrocystic breast conditions than with nonproliferative fibrocystic breast conditions. However, few women reported a family history of breast cancer, and the power of this study to distinguish differences in risk in relation to this factor was low.

The increased relative risks associated with history of breast self-examination clearly indicate increased detection of fibrocystic breast conditions among women who practice breast self-examination. If breast self-examination were associated with any of the other factors considered, this confounding could explain observed relations of risk to these factors. However, no confounding by breast self-examination practice was observed.

The main finding from this study is that consumption of fruits and vegetables was associated with a reduced risk of all three types of fibrocystic breast conditions and that the associations were stronger for atypia and proliferative conditions than for nonproliferative conditions. Thus, it seems reasonable to conclude that fruits and vegetables contain substances that exert an antiproliferative or proapoptotic effect on the mammary epithelium. However, of the 16 botanical families considered individually, none was appreciably more strongly associated with proliferative conditions than with nonproliferative conditions after results were controlled for total fruit and vegetable intake. Similarly, specific micronutrients derived from fruits and vegetables (i.e., vitamins C and E and carotenoids) were also not associated with these conditions after controlling for total fruit and vegetable intake. These observations suggest that the apparent inhibitory effect of fruits and vegetables on the development of proliferative changes in the breast is not due to consumption of any single specific nutrient or food but rather is a result of total fruit and vegetable consumption or of following an overall dietary pattern rich in fruits and vegetables.

Vegetables and fruits are rich sources of a variety of nutrients, including vitamins, trace minerals, and fiber, and numerous bioactive and potentially anticarcinogenic compounds (3739). These phytochemicals can have complementary and overlapping potential mechanisms of action, including quenching free radicals and inhibiting DNA adduct formation, altering hormone and carcinogen metabolism, and directly affecting cell proliferation, differentiation, and apoptosis. If the net result of these effects were to enhance the ratio of the rate of cell proliferation to cell differentiation or death, proliferative changes would result.

Many in vitro and in vivo studies have provided experimental evidence for a protective effect of soy isoflavones against certain hormone-dependent cancers, including breast cancer (40). Case-control studies of soy food intake and risk of breast cancer in Asian women have yielded weak associations and inconsistent results (4143). Furthermore, one prospective study carried out in Japan showed no association between breast cancer risk and soy foods (44), which suggests that associations based on retrospectively collected data may be due to differential recall of intake by cases and controls. In the present study, decreasing trends in risk with increasing intake of soy foods were strongest for fibrocystic conditions with atypia, weaker for proliferative conditions without atypia, and absent for nonproliferative conditions. Although these differences could be due to chance, they are also consistent with the hypothesis that isoflavones in soy could reduce risk of breast cancer by inhibiting mammary epithelial cell proliferation. This effect would be exerted early in the carcinogenic process, which is consistent with results from two studies that show reduced risk of breast cancer to be associated particularly with soy intake during adolescence (42, 45). Possible mechanisms for this include a reduction in the level of endogenously produced estrogens in response to soy intake (46, 47) and competitive binding at estrogen receptor sites (37).

Some previous studies have found that saturated fats but not mono- or polyunsaturated fats are directly, although moderately, associated with breast cancer risk (3, 19, 25, 26). High-fat diets have been associated with higher circulating estrogen levels (21). However, we did not find any association between consumption of fried foods or percentage of energy derived from fat and risk of proliferative fibrocystic breast conditions. We did observe a possible association of atypia with consumption of red meat, which might suggest a role of animal fats in the development of atypical changes.

Other associations between specific food groups and botanical families and one or more of the three histologic categories of fibrocystic conditions were observed, but many possible relations were considered, and biologic interpretations are not warranted unless the observations are confirmed by others. The absence of associations with the Cruciferae does not support the a-priori hypothesis that substances in these foods can protect against breast diseases.

One limitation of this study is that almost 30 percent of the cases had breast lesions that could not be classified because insufficient material was available for review. However, these women did not differ significantly from those included in the analyses by age, parity, body mass index, total energy intake, or fruit or vegetable consumption (data not shown), so the exclusion of these cases is unlikely to have influenced the results.

Another limitation of this study is that average serving size was used to calculate intake for all food groups. This could have resulted in imprecise estimates of intake but would only have biased odds ratio estimates toward the null. This effect is probably small because most variability in food consumption is due to frequency of intake, not portion size (36).

Although our food frequency questionnaire was not validated for intake of all foods, Frankenfeld et al. (48) compared soy intake estimated from the food frequency questionnaire and Chinese food tables to isoflavone concentration in plasma samples collected within 1 week of food frequency questionnaire completion. A significant linear trend was observed in serum daidzein and genistein concentrations across increasing categories of soy intake. These results suggest that the food frequency questionnaire provided a reasonably good assessment of soy food consumption.

A strength of this study is the variety in and wide range of consumption of fruits and vegetables in the study population, which enhanced our chances of discovering variations in risk with consumption levels. Another strength is the standardized histologic classification of fibrocystic breast conditions by a single pathologist. The final histologic classification of each case was based on the most advanced change in any of the scanning power fields reviewed. Therefore, the chance of recording high scores might be associated with the number of scanning power fields examined, and, if this was associated with a variable of interest, a spurious association with that variable could have resulted. However, the numbers of scanning power fields examined were similar for the three histologic types of fibrocystic breast conditions (data not shown), providing evidence that a high score was not a function of the number of fields examined.

In summary, a diet rich in fruits and vegetables was associated with a reduced risk of proliferative fibrocystic breast conditions. Reduction of mammary epithelial cell proliferative changes may be one mechanism by which fruits and vegetables reduce risk of breast cancer.


    ACKNOWLEDGMENTS
 
This research was supported by grant I R01-CA 75332 from the US National Cancer Institute. Participants with fibrocystic breast conditions diagnosed between September 1995 and August 1997 were simultaneously enrolled in an ongoing immunocytochemical study of mammary cell proliferation supported by National Cancer Institute grant R01 CA 56791.

The authors thank Wenwan Wang and the medical workers, breast self-examination workers, and interviewers of the Shanghai Textile Industry Bureau for their efforts in collecting data; Drs. Fan Liang Chen, Guan Lin Zhao, and Lei Da Pan for their support of all of the studies carried out in Shanghai; and Judith Calman, Georgia Green, Ted Grichuhin, Jan Kikuchi, Mary Molyneaux, Karen Wernli, and Shirley Zhang for their technical and administrative assistance.


    APPENDIX 1
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 

Foods Assessed within Each Food Group, Shanghai Nutrition and Breast Disease Study, 1995–2000
Fruits

Apples

Pears

Oranges or tangerines

Litchis

Bananas

Peaches

Persimmons

Pineapples

Grapes

Apricots

Watermelon

Vegetables

Bok choy

Spinach

Cabbage

Chinese cabbage

Watercress

Broccoli

Chinese broccoli

Green asparagus

Cauliflower

Celery

Eggplant

Wild rice stem

Winter squash

Lettuce

Yellow sweet potatoes or yams

Other potatoes

Wax gourd

Gherkin (cucumber)

Carrots

Pumpkin

Mushrooms

Red or green pepper

Tomato

Bamboo shoots

Radishes or turnips

Lotus rhizomes

Taro root

Corn

Onions and chives

Garlic stalk

Seaweed

Preserved vegetables

Salted mustard greens

Other salted vegetables

Soy foods

Soybeans

Soybean milk

Fried bean curd puff

Fresh bean curd

Other soybean foods

Fermented bean curd

Other legumes

Dried

Red pea or green bean soup

Peanuts

Peanut butter

Mung beans

Other dried beans

Fresh

Mung bean sprouts

String beans

Hyacinth beans

Peas or cowpeas

Green or kidney beans

Fresh fava beans

Red meat

Pork

Pork chops

Spareribs

Pig trotters

Fresh pork, fat and lean

Ham

Pork liver

Beef

Other red meat

Organ meat (except liver)

Lamb or mutton

Fish

Saltwater fish

Hair tail or yellow crooker

Freshwater fish

Carp

Rice-field or Japanese eel

Canned fish

Cured meat and fish

Chinese sausage

Salted pork

Salted fish

Poultry

Chicken

Duck or goose

Eggs

Shellfish

Shrimp

Crab

Snail

Conch

Squid

Sea cucumber

Oysters

Mussels

Clams

Dairy foods

Fresh whole milk

Fresh nonfat milk

Ice cream

Powdered milk

Rice

Other grains

Steamed bread, unfilled

Cakes or pastries

Cookies

Wheat gluten

Noodles

Sesame oil

Soybean oil

Fried foods

Fried bean curd puff

Fried chicken

Breaded fried vegetables

Breaded fried fish

Breaded fried pork chop

Deep-fried egg rolls

Deep-fried dumplings

Deep-fried dough sticks

Pan-fried pizza


    APPENDIX 2
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 

Foods Assessed within Each Botanical Family, Shanghai Nutrition and Breast Disease Study, 1995–2000
Araliaceae

Fresh ginseng

White ginseng powder or extract

Red ginseng powder or extract

Compositae

Sunflower seeds

Lettuce

Convolvulaceae/Dioscoreaceae

Yellow sweet potatoes

Yams

Cruciferae

Bok choy

Cabbage

Chinese cabbage

Watercress

Broccoli

Chinese broccoli

Cauliflower

Radishes or turnips

Cucurbitaceae

Winter squash

Wax gourd

Gherkin (cucumber)

Pumpkin

Watermelon

Laminariaceae

Seaweed

Leguminosae

Peanuts

Peanut butter

Soybean milk

Fried bean curd puff

Fresh bean curd

String beans

Soybeans

Mung beans

Green or kidney beans

Fresh fava beans

Hyacinth beans

Peas or cowpeas

Other dried beans

Mung bean sprouts

Red pea or green bean soup

Other soybean foods

Liliaceae

Asparagus

Garlic

Garlic stalk

Onions

Chives

Scallions

Chinese chives

Nymphaceae

Lotus rhizomes

Rosaceae

Apples

Pears

Peaches

Apricots

Rutaceae

Oranges

Tangerines

Sapindaceae

Litchis

Solanaceae

Eggplant

Other potato

Tomato

Hot pepper

Red or green pepper

Umbelliferae

Celery

Carrots

Vitaceae

Grapes

Zingiberaceae

Ginger root


    NOTES
 
Correspondence to Dr. David B. Thomas, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, MP-474, Seattle, WA 98109 (e-mail: dbthomas{at}fhcrc.org). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX 1
 APPENDIX 2
 REFERENCES
 

  1. Love SM, Gelman RS, Silen W. Sounding board. Fibrocystic "disease" of the breast—a nondisease? N Engl J Med 1982;307:1010–14.[ISI][Medline]
  2. Bland KI, Copeland EM III, eds. The breast: the comprehensive management of benign and malignant disease. Vol 1. Philadelphia, PA: W B Saunders Company, 1998.
  3. Goehring C, Morabia A. Epidemiology of benign breast disease, with special attention to histologic types. Epidemiol Rev 1997;19:310–27.[ISI][Medline]
  4. Ernster VL. The epidemiology of benign breast disease. Epidemiol Rev 1981;3:184–202.[ISI][Medline]
  5. Bodian CA. Benign breast diseases, carcinoma in situ, and breast cancer risk. Epidemiol Rev 1993;15:177–87.[ISI][Medline]
  6. Didsbury W. Aetiological factors in benign breast disease. Br J Surg 1994;81:788–9.[ISI][Medline]
  7. Wang DY, Fentiman IS. Epidemiology and endocrinology of benign breast disease. Breast Cancer Res Treat 1985;6:5–36.[ISI][Medline]
  8. Berkowitz GS, Kelsey JL, Holford TR, et al. Risk factors for fibrocystic breast disease and its histopathologic components. J Natl Cancer Inst 1985;75:43–50.[ISI][Medline]
  9. Parazzini F, La Vecchia C, et al. Risk factors for pathologically confirmed benign breast disease. Am J Epidemiol 1984;120:115–22.[Abstract]
  10. Hislop TG, Elwood JM. Risk factors for benign breast disease: a 30-year cohort study. Can Med Assoc J 1981;124:283–91.[Abstract]
  11. Ingram D, Nottage E, Ng S, et al. Obesity and breast disease: the role of the female sex hormones. Cancer 1989;64:1049–53.[ISI][Medline]
  12. Webb PM, Byrne C, Schnitt SJ, et al. Family history of breast cancer, age and benign breast disease. Int J Cancer 2002;100:375–8.[CrossRef][ISI][Medline]
  13. Rohan TE, Miller AB. A cohort study of oral contraceptive use and risk of benign breast disease. Int J Cancer 1999;82:191–6.[CrossRef][ISI][Medline]
  14. Friedenreich CM, Rohan TE. Recreational physical activity and risk of benign proliferative epithelial disorders of the breast in women. Eur J Cancer Prev 1994;3:465–71.[Medline]
  15. Wyshak G, Frisch RE, Albright NL, et al. Lower prevalence of benign diseases of the breast and benign tumors of the reproductive system among former college athletes compared to non- athletes. Br J Cancer 1986;54:841–5.[ISI][Medline]
  16. Hsieh CC, Walker AM, Trapido EJ, et al. Age at first birth and breast atypia. Int J Cancer 1984;33:309–12.[ISI][Medline]
  17. Galvan-Portillo M, Torres-Sanchex L, Lopez-Carrillo L. Dietary and reproductive factors associated with benign breast disease in Mexican women. Nutr Cancer 2002;43:133–40.[CrossRef][ISI][Medline]
  18. Hislop GT, Band PR, Deschamps ME, et al. Diet and histologic types of benign breast disease defined by subsequent risk of breast cancer. Am J Epidemiol 1990;131:263–70.[Abstract]
  19. Vobecky J, Simard A, Vobecky JS, et al. Nutritional profile of women with fibrocystic breast disease. Int J Epidemiol 1993;63:481–5.
  20. Ingram DM, Nottage E, Roberts T. The role of diet in the development of breast cancer: a case-control study of patients with breast cancer, benign epithelial hyperplasia and fibrocystic disease of the breast. Br J Cancer 1991;64:187–91.[ISI][Medline]
  21. Horner NK, Lampe J. Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness. J Am Diet Assoc 2000;100:1368–80.[CrossRef][ISI][Medline]
  22. Rohan TE, Cook MG, Potter JD, et al. A case-control study of diet and benign proliferative epithelial disorders of the breast. Cancer Res 1990;50:3176–81.[Abstract]
  23. Baghurts PA, Rohan TE. Dietary fiber and risk of benign proliferative epithelial disorders of the breast. Int J Cancer 1995;63: 481–5.[ISI][Medline]
  24. McMichael-Phillips DF, Harding C, Morton M, et al. Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast. Am J Clin Nutr 1998;68(suppl):1431s–6s.
  25. Lubin F, Wax Y, Ron E, et al. Nutritional factors associated with benign breast disease etiology: a case-control study. Am J Clin Nutr 1989;50:551–6.[Abstract]
  26. London SJ, Sacks FM, Stampfer MJ, et al. Fatty acid composition of the subcutaneous adipose tissue and risk of proliferative benign breast disease and breast cancer. J Natl Cancer Inst 1993;85:785–93.[Abstract]
  27. Thomas DB, Gao DL, Self SG, et al. Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst 1997;89:355–65.[Abstract/Free Full Text]
  28. Thomas DB, Gao DL, Ray RM, et al. Randomized trial of breast self-examination in Shanghai: final results. J Natl Cancer Inst 2002;94:1445–57.[Abstract/Free Full Text]
  29. Whittemore AS, Wu-Williams AH, Lee M, et al. Diet, physical activity, and colorectal cancer among Chinese in North America and China. J Natl Cancer Inst 1990;82:915–26.[Abstract]
  30. Lee MM, Lee F, Ladenla SW, et al. A semiquantitative dietary history questionnaire for Chinese Americans. Ann Epidemiol 1994;4:188–97.[Medline]
  31. Aaman TB, Stalsberg H, Thomas DB. Extratumoral breast tissue in breast cancer patients: a multinational study of variations with age and country of residence in low- and high-risk countries. WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Int J Cancer 1997;71:333–9.[ISI][Medline]
  32. Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine. Chinese food composition tables. 1st ed. Beijing, People’s Republic of China: New China Press, 1980.
  33. Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine. Chinese food composition tables. 2nd ed. Beijing, People’s Republic of China: New China Press, 1991.
  34. Carolina Population Center, University of North Carolina at Chapel Hill. The China Health and Nutrition Survey. Chapel Hill, NC: University of North Carolina at Chapel Hill, 1999. (World Wide Web URL: http://www.cpc.unc.edu/projects/china/china_home.html). (Last accessed September 9, 2003).
  35. Breslow NE, Day NE, eds. Statistical methods in cancer research. Vol. 1. The analysis of case-control studies. Lyon, France: International Agency for Research on Cancer, 1980. (IARC scientific publication no. 32).
  36. Willett WA. Nutritional epidemiology. New York, NY: Oxford University Press, 1990:92–126, 245–71.
  37. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 1991;2:427–42.[ISI][Medline]
  38. Lampe JW. Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies. Am J Clin Nutr 1999;70(suppl):475s–90s.
  39. Weisburger JH. Mechanisms of action of antioxidants as exemplified in vegetables, tomatoes and tea. Food Chem Toxicol 1999;37:943–8.[CrossRef][ISI][Medline]
  40. Fournier DB, Erdman JW Jr, Gordon GB. Soy, its components, and cancer prevention: a review of the in vitro, animal, and human data. Cancer Epidemiol Biomarkers Prev 1998;7:1055–65.[ISI][Medline]
  41. Dai Q, Shu XO, Jin F, et al. Population-based case-control study of soyfood intake and breast cancer risk in Shanghai. Br J Cancer 2001;85:372–8.[CrossRef][ISI][Medline]
  42. Shu XO, Jin F, Dai Q, et al. Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev 2001;10:483–8.[Abstract/Free Full Text]
  43. Wu AH, Ziegler RG, Nomura A, et al. Soy intake and risk of breast cancer in Asians and Asian Americans. Am J Clin Nutr 1998;68(suppl):1437s–43s.
  44. Key TJ, Sharp GB, Appleby PN, et al. Soya foods and breast cancer risk: a prospective study in Hiroshima and Nagasaki, Japan. Br J Cancer 1999;81:1248–56.[CrossRef][ISI][Medline]
  45. Wu AH, Wan P, Hankin J, et al. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis 2002;23:1491–6.[Abstract/Free Full Text]
  46. Wu AH, Stanczyk FZ, Seow A, et al. Soy intake and other lifestyle determinants of serum estrogen levels among postmenopausal Chinese women in Singapore. Cancer Epidemiol Biomarkers Prev 2002;11:844–51.[Abstract/Free Full Text]
  47. Kumar N, Cantor A, Allen K, et al. The specific role of isoflavones on estrogen metabolism in premenopausal women. Cancer 2002;94:1166–74.[CrossRef][ISI][Medline]
  48. Frankenfeld CL, Lampe JW, Shannon J, et al. Frequency of soy food consumption and serum isoflavone concentrations among Chinese women in Shanghai. Public Health Nutr 2004;7:765–72.[CrossRef][ISI][Medline]




This Article
Abstract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Wu, C.
Articles by Thomas, D. B.
PubMed
PubMed Citation
Articles by Wu, C.
Articles by Thomas, D. B.