Dietary and other risk factors in women having fibrocystic breast conditions

with and without concurrent breast cancer: A nested case-control study

in Shanghai, China

Wenjin Li1, Roberta M. Ray1, Johanna W. Lampe1,2, Ming-Gang Lin1, Dao Li Gao4, Chunyuan Wu1, Zakia C. Nelson1,E. Dawn Fitzgibbons

1, Neilann Horner

1, Yong Wei Hu

5, Jackilen Shannon

1,3, Jessie A. Satia

6, Ruth E. Patterson

1,2,

Helge Stalsberg7 and David B. Thomas1,2*

1Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA2Department of Epidemiology, University of Washington, Seattle, WA, USA3Portland Veterans Administration Medical Center, Portland, OR, USA4Department of Epidemiology, Zhong Shan Hospital Cancer Center, Shanghai, China5Shi Dong Hospital, Shanghai, China6University of North Carolina at Chapel Hill, Chapel Hill, NC, USA7Institute of Medical Biology, University of Tromsø, Tromsø, Norway

Risk of breast cancer is increased in women with proliferativebenign breast conditions. Most of these conditions, however, do notprogress to breast cancer. The purpose of our study was to identifyfactors possibly associated with this progression. Women withproliferative fibrocystic breast conditions alone (214), and womenwith proliferative fibrocystic breast conditions and concurrentbreast cancer (130), were compared to each other, and each of thesegroups of women were also compared to 1,070 controls; and 176women with non-proliferative benign breast conditions alone, and155 also with breast cancer, were similarly compared. All studysubjects were selected from a cohort of women enrolled in a trial ofbreast self-examination in Shanghai. Women were interviewed toascertain information on suspected risk factors for breast cancerand dietary habits. Conditional logistic regression was used to esti-mate adjusted odds ratios (OR) and 95% confidence intervals (CI).Increased risks of both proliferative fibrocystic breast conditionsalone, and with breast cancer, were associated with low parity, aprior benign breast lump and breast cancer in a first-degree rela-tive. Decreasing trends in the risk of both conditions with increasingintake of fruits and vegetables were observed. No factors were sig-nificantly associated with risk of breast cancer relative to risk ofproliferative changes. Similar, but in some instances weaker, associ-ations were observed for non-proliferative fibrocystic conditionswith and without breast cancer. The possible risk or protective fac-tors that were observed in our study most likely alter the risk ofbreast cancer at an early stage in the carcinogenic process, andprobably do not alter risk of progression from proliferative fibro-cystic breast conditions to breast cancer.' 2005 Wiley-Liss, Inc.

Key words: breast cancer; fibrocystic breast conditions; risk factors;diet; fruits; vegetables

Women who have undergone a breast biopsy for benign breastdisease are at increased risk of breast cancer.1 Although non-proliferative breast conditions do not seem to be associated withincreased risk of breast cancer, proliferative fibrocystic breast con-ditions without and with atypia have been associated with 2-foldand 4-fold increased risks of breast cancer, respectively.2–8 Mostwomen who are diagnosed with proliferative fibrocystic breastconditions do not develop breast cancer, however, suggesting thepresence of risk factors necessary for progression.

Breast cancer presumably results when a cell first undergoes aninitiating genetic alteration, and then either this cell or one of itsdaughter cells, which inherits that initiating genetic damage istransformed into a cell with malignant characteristics by under-going one or more subsequent events. In this scenario, prolifera-tive activity may play an important role by increasing theexpansion of initiated cells and the likelihood that one willundergo subsequent events ultimately leading to transformation toa malignant phenotype.9,10 The morphologic changes that resultfrom the genetic alterations vary from case to case and constitute

an apparently continuous spectrum from normal to invasive malig-nancy through various grades of proliferative changes and atypia.Risk factors for invasive breast cancer could operate either beforeor after the development of hyperplasia. Those acting before thedevelopment of hyperplasia would be observed in relation to bothproliferative benign conditions and breast cancer, whereas thoseacting to enhance the probability that proliferative breast diseasebecomes breast cancer would be observed only in relation tobreast cancer.

The purpose of our study was to identify and distinguish repro-ductive, dietary and other risk factors for proliferative fibrocysticbreast conditions and for progression from proliferative fibrocysticconditions to breast cancer. To identify risk factors for proliferativefibrocystic conditions, we compared women with these conditionsto control women not known to have these conditions; and in anattempt to identify possible risk factors for progression from prolif-erative fibrocystic conditions to breast cancer, we compared womenwith proliferative fibrocystic conditions and concurrent breast can-cer to women with proliferative fibrocystic conditions alone, as wellas to the control women. Women with non-proliferative benignbreast conditions with and without concurrent breast cancer weresimilarly compared to aid in the interpretation of the results.

Material and methods

Study population

The women in our study were selected from participants in arandomized trial of breast self-examination (BSE) in Shanghai,China.11,12 All currently working and retired female employees ofthe Shanghai Textile Industry Bureau (STIB), who were bornbetween January 1, 1925 and December 31, 1958, were eligible toparticipate in the trial. From October 1989 to October 1991,266,064 women were enrolled in the trial. Thirty-four formermedical workers, who were recruited and trained to be BSE trialfield workers, trained approximately 5,000 factory medical work-ers to administer a baseline questionnaire and to perform othertasks for the trial. When a woman developed a breast lump shewas evaluated by a medical worker in her factory. If indicated shewas referred to 1 of 3 hospitals operated by the STIB or to otherhospitals with contractual agreements with specific factories. All

Grant sponsor: National Cancer Institute; Grant number: 1 R01-CA75332; Grant sponsor: National Institutes of Health.*Correspondence to: Fred Hutchinson Cancer Research Center, 1100

Fairview Ave. N. M4-B874, Seattle, WA 98109. Fax: þ206-667-4787.E-mail: dbthomas@fhcrc.orgReceived 10 August 2004; Accepted after revision 15 November 2004DOI 10.1002/ijc.20964Published online 18 February 2005 in Wiley InterScience (www.

interscience.wiley.com).

Int. J. Cancer: 115, 981–993 (2005)' 2005 Wiley-Liss, Inc.

Publication of the International Union Against Cancer

new cases of breast cancer and benign breast disease wererecorded by medical workers at each factory. Breast self-examina-tion workers obtained histologic slides from each case for standar-dized review, and abstracted information on date of diagnosis,histologic diagnosis and stage from medical records and pathologyreports.

Cases

Women in the cohort who had a breast biopsy between Septem-ber 1995 and July 2000 in 1 of 3 hospitals operated by the STIBand who were diagnosed by the local pathologists as having breastcancer or fibrocystic breast conditions, with or without atypia,were provisionally recruited for the present study. Women withfibroadenoma and other benign conditions were not considered.Approximately two-thirds of the women in the cohort whoreceived a breast biopsy attended one of these 3 STIB hospitals. Atotal of 432 breast cancer patients were diagnosed in these clinicsduring the study period, and in-person interviews were completedfor 384 (89%). Six breast cancer patients were excluded from thestudy due to prior mastectomy reported on the baseline question-naire (4 cases) or a prior diagnosis of breast cancer after the base-line questionnaire but before the present study (2 cases). Of theremaining 378 breast cancer patients, 288 women had adequateextra-tumoral tissue for pathological review (5 or more scanningpower fields that contained epithelial breast tissue other than fromthe nipple area, not infiltrated or occupied by any neoplasm, andnot damaged by heavy inflammation, hemorrhage, or necrosis),and were included in the present study. A total of 622 women withfibrocystic breast conditions were identified during the studyperiod and in-person interviews were completed for 551 (89%) ofthem. Breast cancer patients and women with fibrocystic breastconditions in our study who were diagnosed before the end ofAugust, 1997, were also included in a previous immunocytochem-ical study of cell proliferation.

Controls

Controls were selected from women in the BSE trial cohort whohad not had a breast biopsy before our present study. For eachbenign and malignant case that was also in the previous study of cellproliferation, 20 potential controls of the same age were randomlyselected and listed on a form. The women were contacted in theorder listed, starting with the first 2 names, until 2 women with thesame age and menopausal status of their matched case wererecruited. A total of 367 controls were recruited in this manner(64% of the eligible women contacted). Controls for the cases whowere not also in the cell proliferation study were frequency-matchedto those cases and also to cases in a concurrent study of fibroade-noma by 5-year age groups (so that there would be a 1:1 case-to-control ratio for the largest benign or malignant case group in eachage stratum), and also by hospital affiliation of their factory at thebeginning of the BSE trial. In-person interviews were completed for704 (82%) of the 862 controls selected in this manner.

Validation of diagnosis and histologic classification

As part of the BSE trial,11,12 all malignant breast lesions wereread by a reference pathologist and classified by ICD-0 code. Forthe present study, slides of the extra-tumoral tissue from womenwith cancer, and slides from the lesions from women with benignfibrocystic conditions, were also reviewed, by a single study pathol-ogist, and classified according to the scheme developed by Stalsberget al.13 The pathologist first sorted out the slides from the womenwith malignancy that contained malignant tissue. The remainingslides from these women were then blind labeled, and reviewed atleast 2 weeks later, along with similarly labeled slides from womenwith only benign fibrocystic conditions. The pathologist, who wastrained by Stalsberg et al.13 to utilize this classification system,scored the following features on a scale of 0–3 (0 ¼ normal/notpresent, 1 ¼ mild, 2 ¼ moderate, 3 ¼ florid/predominate): adenosis,sclerosing adenosis, ductal hyperplasia, apocrine metaplasia, apoc-

rine hyperplasia, fibrosis, duct ectasia, inflammatory reaction andlactation change. For lobular atypia, ductal atypia and apocrine aty-pia, a different scoring system was used (0 ¼ none, 1 ¼ uncertain,2 ¼ atypical hyperplasia). Samples of the major types of benignbreast conditions and of extra-tumoral breast tissue from cancercases were read by Dr. Stalsberg. There was satisfactory agreementbetween readings by the 2 pathologists on assessing level of prolif-eration and presence of atypia (weighted k coefficient ¼ 0.4), butless agreement on the specific features of the lesions. Therefore,benign breast conditions and the non-cancerous breast tissue ofmalignant cases were categorized into one of the following 3 cate-gories for analyses: non-proliferative conditions (includes ductalhyperplasia, and sclerosing adenosis with a score of 0 or 1), prolif-erative conditions without atypia (ductal hyperplasia and sclerosingadenosis with a score of 2 or 3) and atypical hyperplasia (atypicalductal hyperplasia, atypical lobular hyperplasia and atypical apoc-rine epithelium with a score of 2). The resulting classification issimilar to Page’s classification for benign breast disease.6

Of 551 women with fibrocystic breast conditions and completedin-person interviews, 390 (70.8%) had satisfactory slides forreview (at least 5 scanning power fields), of whom 176 had non-proliferative conditions, 181 had proliferative conditions withoutatypia and 33 had proliferative conditions with atypia. Of285 breast cancer patients with adequate extra-tumoral tissue forpathological review, 155 had non-proliferative conditions, 112had proliferative conditions without atypia and 18 had prolifera-tive conditions with atypia. Because the number of women withatypia was small, proliferative conditions with or without atypiawere combined, giving 130 breast cancer patients with prolifera-tive conditions in surrounding breast tissue and 214 women withproliferative fibrocystic breast conditions alone for analyses.

Data collection

The cases were interviewed in person by trained interviewers,primarily at the time of biopsy, and before the histologic diagno-ses were known. If malignancy was strongly suspected at the timeof the breast lump evaluation, the woman was admitted directly tothe hospital, and an outpatient biopsy was not scheduled. Whenthis situation arose, the woman was interviewed after the surgerywhile the woman was still in the hospital. Thirty-nine (13.7%) ofthe 285 women with breast cancer and 28 (7.2%) of the390 women with fibrocystic breast conditions were thus inter-viewed after they knew their diagnoses. The control women wereinterviewed in their homes or factories by the same team of inter-viewers that interviewed the cases.

Information was obtained on the subject’s birth date, education,marital status, height and weight, known and suspected reproduc-tive risk factors for breast cancer, medical history, family historyof breast cancer, smoking habits, alcohol consumption and physi-cal activity. Because when reporting prior breast surgery, manywomen erroneously included the breast surgery for the present dis-ease, data on prior breast lumps collected at baseline for the BSEtrial was used for the present study.

A modified version of a food frequency questionnaire, whichhad been used in previous studies in Shanghai,14 was utilized toascertain information on 99 food items. For each item, womenwere asked ‘‘During most of your adult life how often did you usu-ally eat. . .?’’ For seasonal foods, the number of months the foodwas eaten was also ascertained. Women responded to number oftimes per day, week, month or year, or they indicated that they hadnever consumed the item. The original questionnaire had been pre-viously validated in 74 Chinese-American women by comparingresponses to those from a 24-hr recall questionnaire.15 Our ques-tionnaire also included 9 questions about fried foods commonlyconsumed in Shanghai and how many liangs (1 liang ¼ 50 g) ofdifferent types of cooking oils were consumed by the woman’sfamily per month.

Informed consent was obtained from each woman before inter-view. The study was approved by the Institutional Review Boards

982 LI ET AL.

of the Fred Hutchinson Cancer Research Center and the Stationfor Prevention and Treatment of Cancer of the Shanghai TextileIndustry Bureau, in accordance with an assurance filed with theOffice for Human Research Protections (OHRP) of the US Depart-ment of Health and Human Services.

Data analysis

Consumption of each individual food was converted to numberof times consumed per year. The yearly intake of the food itemsavailable only seasonally was calculated based on the number ofmonths in a year that women reported consuming the items. Relatedfood items were then combined into 20 food groups (Fig. 1). The

yearly intake of each food group was calculated by summing fre-quencies of intake of all of the food items in the group. Fruits andvegetables were further categorized according to their botanicalfamilies (Fig. 2). For each type of oil consumed by the woman’sfamily, we divided the family’s monthly consumption by the num-ber of people in her household, to estimate the woman’s intake.Level of consumption of specific micronutrients was also estimated.The amount of each micronutrient attributed to each food item onthe Food Frequency Questionnaire was derived from the 1991Chinese Food Composition Table16 and average serving sizes fromthe 1992 China Health and Nutrition Survey,17 and the values forall foods were then summed. The daily intake of energy foreach woman was estimated by summing energy consumed from

FIGURE 1 – List of foodsassessed within each food group.

983BREAST CANCER AND FIBROCYSTIC CONDITIONS

carbohydrate, protein, fat, alcohol and oil also using the 1991 Chi-nese Food Composition Table16 and average serving size from the1992 China Health and Nutrition Survey.17 One woman with a non-proliferative fibrocystic breast condition and one control womanwere excluded from our study because their calculated daily energyintake was more than 4,000 kcal, which was considered unreliable.

Women with proliferative fibrocystic breast conditions werecompared to the controls, and the breast cancer cases with concur-rent proliferative fibrocystic conditions were compared to thesame controls, and to the women with proliferative fibrocysticbreast conditions alone. Analyses were carried out using SAS stat-istical software (SAS Institute, Inc., Cary, NC). Odds ratios (OR)and their 95% confidence intervals (95% CI) were used as meas-ures of association. Age was included in each model as catego-rized in Table I. Quartile distributions among controls were usedto categorize most of the dietary-intake variables, including dailyenergy intake. Fewer strata were used for infrequently consumeditems. Age and energy intake were included in the adjusted mod-els for odds ratio estimates when considering food groups. Ageand total fruit and vegetable intake were included in the adjustedmodel for odds ratio estimates when considering botanic familiesand micronutrients. Dietary habits have changed rapidly over past2 decades in China.18,19 Because controls tended to have beeninterviewed at a later date than the cases, we used conditional mul-tiple logistic regression models stratified by year of interview cate-gories (1995–96, 1997, 1998–99, 2000–01) that providedsignificant numbers of cases and controls in each stratum to calcu-late all OR. Potential confounding factors were included in the

conditional logistic regression models as categorical variables.Factors evaluated as possible confounders include education, num-ber of live births, age at first live birth, menopause status, bodymass index and physical activity. Confounding was defined as achange of over 10% in estimates of OR in multivariate analysesincluding the factor of interest.20 Tests for trend were carried outby entering the categorical variable as a continuous parameter inthe regression models. A 2-sided probability of <0.05 was used asthe criterion for statistical significance. To aid in the interpretationof our results, we similarly compared women with non-prolifera-tive fibrocystic breast conditions alone to the controls, and wecompared the breast cancer cases with non-proliferative fibrocys-tic breast conditions in surrounding breast tissue to the same con-trols, and to the women with non-proliferative fibrocystic breastconditions alone.

Results

As shown in Table I, the controls were somewhat older than thewomen with fibrocystic breast conditions alone and younger thanthe women with fibrocystic breast conditions and concurrentbreast cancer.

As shown in Table II, risk of proliferative fibrocystic breastconditions alone decreased significantly with increasing numberof live births. Similar trends in risk with increasing ages at firstlive birth and menarche did not reach statistical significance. Toofew women were nulliparous for meaningful analysis. Risk of

FIGURE 2 – List of foods assessedwithin each botanical family.

984 LI ET AL.

proliferative fibrocystic breast conditions alone was significantlyelevated in women with a prior breast lump and non-significantlyincreased in women with a history of a first-degree relative(mother, sister or daughter) with breast cancer.

In analyses in which cases of breast cancer with proliferativefibrocystic breast conditions and controls were compared, there isa decreasing trend in risk of breast cancer with increasing numberof live births, and risk is increased significantly in women with acollege education, a prior breast lump and a first-degree relativewith breast cancer.

Risk of proliferative fibrocystic breast conditions with breast can-cer, relative to the risk of proliferative fibrocystic breast conditionsalone, is associated with increased age at first live birth, althoughthis observation could have occurred by chance. None of the otherfactors shown in the table was more strongly associated with risk ofbreast cancer with concurrent benign proliferative conditions thanrisk of proliferative fibrocystic breast conditions alone. We alsoinvestigated other factors, including induced abortion, body massindex, physical activity and alcohol consumption, none of whichshowed significant associations with risk of proliferative fibrocys-tic breast conditions alone or with concurrent breast cancer.

Strong decreasing trends in risk of proliferative fibrocysticbreast conditions alone with increasing intakes of fruits and vege-tables are shown in Table III. Weaker, but similar, and also statis-tically significant, trends in risk were observed with intake of soyfoods and sesame oil.

When the breast cancer cases with concurrent proliferative fibro-cystic breast conditions were compared to the controls, statisticallysignificant decreasing trends in risk of breast cancer with increasingconsumption of both fruits and vegetables were observed. Adecreasing trend in risk of breast cancer with increasing consump-tion of soy foods was not observed, but such trends in risk wereseen in relation to other legumes, and sesame and soybean oils. Incomparisons of breast cancer with concurrent proliferative fibrocys-tic breast conditions to risk of proliferative fibrocystic breast condi-tions alone, a decreased risk of breast cancer was associated withincreasing intake of shellfish; no significant associations wereobserved with any of the other foods investigated.

We also examined each food group in relation to risks of prolif-erative fibrocystic breast conditions alone and in relation to breastcancer with concurrent proliferative fibrocystic breast conditionsin a Multiple Nutrient Density Model.21 We computed the nutri-tional density for each food group (food group intake/total dailycalories) and entered this, total daily energy, and age in a multiplelogistic regression model, conditioned on year of interview cate-gories. The results from the Multiple Nutrient Density Model weresimilar to the results presented (data not shown). The results inTable III were also not altered appreciably after controlling foreducation, age at first live birth, parity, first-degree relative withbreast cancer and physical activity in adult life. When food groupsthat were not highly correlated were included in the same model,the OR also did not change substantially.

Possible associations with botanical families of fruits and vegeta-bles are shown in Table IV. Increasing consumption of the Compo-sitae, Sapindaceae and Vitaceae was associated with decreasingtrends in risk of proliferative fibrocystic breast conditions alone, andincreasing consumption of the Umbellifereae and Zingiberaceaewas associated with an increased risk of proliferative fibrocysticbreast conditions alone, after adjusting for total fruit and vegetableintake. Similar trends were observed for proliferative fibrocysticbreast conditions with concurrent breast cancer when compared tothe controls so that, with the exception of a decreasing trend in riskwith increasing consumption of the Zingiberaceae, risk of breastcancer relative to risk of proliferative fibrocystic breast conditionswas not associated with any botanic family investigated.

Odds ratios associated with intake of selected micronutrientsand fiber are shown in Table V. After controlling for total fruitand vegetable intake, no significant trends in risk of either prolif-erative fibrocystic breast conditions alone or breast cancer withproliferative breast conditions were observed.

As shown in Table VI, there are decreasing trends in risk of non-proliferative conditions, with and without concurrent breast cancer,in relation to fruit intake, and increased risks associated with havinga first-degree relative with breast cancer, that are similar in magni-tude to those for proliferative conditions alone and with concurrentbreast cancer. Risks of the 2 conditions shown in Table VI de-creased slightly with increasing numbers of live births and withincreasing intake of vegetables, and were elevated in women with aprior benign breast biopsy, but these associations were weaker thanthose for the comparable proliferative fibrocystic conditions withoutand with breast cancer. Unlike the results for women with prolifera-tive conditions, intakes of soy foods and other legumes were notsignificantly associated with risk of either condition shown in TableVI. None of the risks of breast cancer with non-proliferative fibro-cystic breast conditions relative to risks of non-proliferative fibro-cystic breast conditions alone in Table VI were statisticallysignificantly different from unity. Analyses similarly to those shownin Table VI were also carried out for other variables in Tables II–IV(not shown). No other noteworthy associations were observed.

Discussion

We directly compared possible risk factors for breast disease inwomen who had breast cancer with proliferative conditions in themammary epithelium surrounding their malignancy to womenwho had comparable proliferative fibrocystic breast conditionswithout breast cancer. These analyses were conducted in anattempt to identify factors that might affect development of breastcancer from proliferative fibrocystic changes. To our knowledgethis is the first study of breast cancer of this design. Previous com-parisons of risk factors for benign and malignant breast diseasehave been restricted to examinations of results of separately con-ducted investigations of these 2 groups of conditions.

In interpreting our results, we acknowledge that the breast carci-nomas may not have arisen directly from the proliferative mam-

TABLE I – DISTRIBUTION OF CONTROLS, CASES WITH FIBROCYSTIC BREAST CONDITIONS ALONE AND CASES OF FIBROCYSTIC BREASTCONDITIONS WITH CONCURRENT BREAST CANCER

Controls PFCs alone1 PFCs with BrCa2 Non-PFCs alone3 Non-PFCs with BrCa4

No. (%) No. (%) No. (%) No. (%) No. (%)

Age35–39 12 (1.1) 20 (9.4) 5 (3.9) 25 (14.2) 4 (2.6)40–44 471 (44.0) 94 (43.9) 36 (27.7) 70 (39.8) 43 (27.7)45–49 218 (20.4) 58 (27.1) 33 (25.4) 48 (27.3) 31 (20.0)50–59 124 (11.6) 12 (5.6) 14 (10.8) 18 (10.2) 28 (18.1)60þ 245 (22.9) 30 (14.0) 42 (23.3) 15 (8.5) 49 (31.6)

Total 1,070 (100.0) 214 (100.0) 130 (100.0) 176 (100.0) 155 (100.0)

1PFCs alone, proliferative fibrocystic breast conditions alone.–2PFCs with BrCa, breast cancer with proliferative fibrocystic breast conditionsin surrounding tissue.–3Non-PFCs alone, non-proliferative fibrocystic breast conditions alone.–4Non-PFCs with BrCa, breast cancer with non-proliferative fibrocystic breast conditions in surrounding tissue.

985BREAST CANCER AND FIBROCYSTIC CONDITIONS

mary epithelium present at the time of the histologic diagnosis ofbreast cancer. In order for any observed differences betweenwomen with proliferative fibrocystic conditions and concurrentbreast cancer and women with fibrocystic conditions alone to rep-resent risk factors for progression to cancer, 2 assumptions mustbe valid. One is that the proliferative fibrocystic conditions in thewomen with breast cancer are not a response to the presence ofthe carcinoma. Although we do not know the distance from themalignant lesion to the extra-tumoral tissue that was evaluated,the slide sorting procedure tended to exclude tissue immediatelyadjacent to the carcinoma, suggesting that the benign breast tissuethat was evaluated probably represented the general status of thenormal tissue at the time of surgery, and was unlikely to have beeninfluenced by being proximal to the malignancy itself. The otherassumption is that the observed proliferative conditions are repre-sentative of earlier changes from which the carcinoma arose. We

have no proof of the validity of this assumption. Any associationsobserved in the comparisons of women with proliferative fibro-cystic conditions with and without concurrent breast cancershould therefore be interpreted as only possible risk factors forprogression, which should be evaluated further in prospectivestudies.

Number of live births was inversely associated with risk of pro-liferative fibrocystic breast conditions, but also with risk of prolif-erative fibrocystic breast conditions with concurrent breast cancerwhen the breast cancer patients were compared to unaffected con-trols, so that no association was observed between this factor andrisk of breast cancer relative to that of proliferative fibrocysticbreast conditions. This observation suggests that the number oflive births may influence risk of breast cancer at an early stage inthe carcinogenic process by reducing the development of prolifer-ative fibrocystic breast conditions. This suggestion is strengthened

TABLE II – OR AND 95% CONFIDENCE INTERVAL 95% CI OF PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS ALONE AND OF BREAST CANCERWITH PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS IN SURROUNDING TISSUE IN RELATION TO GENERAL RISK FACTORS

Factor/CategoryNumber of women PFCs alone vs. controls

PFCs with BrCa vs.controls

PFCs with BrCa vs.PFCs alone

Controls PFCs alone PFCs with BrCa OR3 95% CI OR3 95% CI OR3 95% CI

Education�Elementary school 212 22 32 1.0 ref. 1.0 ref. 1.0 ref.Middle school 826 183 86 1.8 0.9, 3.9 1.4 0.7, 2.9 0.7 0.3, 1.7�college 31 9 12 1.0 0.3, 3.4 3.4 1.2, 10.0 1.6 0.5, 5.6Trend p 0.59 0.04 0.53

Number of livebirths1

1 712 167 78 1.04 ref. 1.04 ref. 1.04 ref.2 125 16 9 0.2 0.1, 0.5 0.2 0.1, 0.6 0.8 0.2, 2.83þ 188 20 35 0.2 0.1, 0.5 0.5 0.1, 1.6 1.8 0.4, 8.3Trend p 0.001 0.16 0.39

Age at first live birth1

�24 years old 273 37 36 1.05 ref. 1.05 ref. 1.05 ref.25–29 599 129 59 0.6 0.3, 1.2 0.9 0.5, 1.9 1.7 0.7, 3.930þ 153 37 27 0.6 0.2, 1.3 1.1 0.5, 2.6 2.3 0.8, 6.0Trend p 0.19 0.78 0.11

Total duration of lactation1

Never 190 48 19 1.06 ref. 1.06 ref. 1.06 ref.<6 Months 209 59 24 1.4 0.8, 2.7 1.0 0.5, 2.3 0.8 0.4, 1.87–12 Months 359 61 41 0.6 0.4, 1.2 0.8 0.4, 1.7 1.5 0.7, 3.013–24 Months 115 17 8 1.2 0.4, 3.7 0.5 0.1, 1.8 0.4 0.1, 1.4�25 Months 152 18 30 1.5 0.4, 5.7 1.1 0.3, 4.0 1.1 0.4, 3.3Trend p 2 0.19 0.36 0.55

Age at first menstrual period�13 171 35 19 1.0 ref. 1.0 ref. 1.0 ref.14 204 57 25 0.9 0.5, 1.7 0.9 0.4, 1.9 1.1 0.5, 2.415 214 41 30 0.7 0.3, 1.3 1.1 0.5, 2.3 1.5 0.7, 3.316 220 34 22 0.5 0.3, 1.0 0.6 0.3, 1.4 1.1 0.5, 2.5�17 259 47 34 0.7 0.4, 1.3 0.8 0.4, 1.7 1.3 0.6, 2.7Trend p 0.10 0.41 0.56

MenopauseNo 686 164 74 1.0 ref. 1.0 ref. 1.0 ref.Yes 384 50 56 0.8 0.4, 1.7 1.1 0.5, 2.8 0.9 0.4, 2.2

Age at menopause�50 176 20 28 1.0 ref. 1.0 ref. 1.0 ref.45–49 142 22 22 1.1 0.4, 2.6 0.9 0.5, 1.9 1.0 0.4, 2.4�44 66 8 6 0.5 0.1, 2.4 0.7 0.2, 2.0 1.5 0.3, 7.9Trend p 0.58 0.50 0.77

Years of oral contraceptive useNever 979 184 115 1.0 ref. 1.0 ref. 1.0 ref.< 1 year 34 8 8 0.7 0.2, 1.9 1.0 0.4, 2.4 1.8 0.6, 5.0� 1 year 56 12 7 1.2 0.5, 2.9 0.8 0.3, 2.2 0.5 0.2, 1.5

Prior breast lumpsNever 1,038 184 121 1.0 ref. 1.0 ref. 1.0 ref.Ever 32 30 9 6.0 2.8, 13.2 3.0 1.1, 8.0 0.5 0.2, 1.2

First degree relative with breast cancerNo 1,035 203 122 1.0 ref. 1.0 ref. 1.0 ref.Yes 17 6 6 2.6 0.6, 11.4 6.0 1.4, 25.5 1.4 0.4, 4.9

1Restricted to the parous women.–2Test for trend among exposed.–3Adjusted for age (as a categorical variable in Table I) and conditioned onyear of interview (1995–1996, 1997, 1998–1999, 2000–2001).–4Additionally adjusted for education (�elementary school, middle school,�college), age at first livebirth (�24, 25–29, 30þ).–5Additionally adjusted for education (as a categorical variable), number of live births(1,2,3þ).–

6Additionally adjusted for number of live births (as a categorical variable).

986 LI ET AL.

TABLE III – OR AND 95% CI OF PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS ALONE AND OF BREAST CANCER WITH PROLIFERATIVEFIBROCYSTIC BREAST CONDITIONS IN SURROUNDING TISSUE IN RELATION TO FOOD GROUPS

Exposure (times/year)Number of women PFCs alone vs. controls

PFCs with BrCa vs.controls

PFCs with BrCa vs.PFCs alone

Controls PFCs alone PFCs with BrCa OR5 95% CI OR5 95% CI OR5 95% CI

Dairy�12 283 62 45 1.0 ref. 1.0 ref. 1.0 ref.>12–134 252 51 33 0.8 0.4, 1.4 1.2 0.7, 2.1 1.4 0.7, 2.6>134–375 263 53 39 1.2 0.7, 2.2 1.6 0.8, 2.9 1.5 0.8, 2.8> 375 272 48 13 1.4 0.8, 2.7 0.9 0.4, 2.1 0.6 0.3, 1.3Trend p 0.17 0.61 0.44

Fruits<202 267 69 39 1.0 ref. 1.0 ref. 1.0 ref.202–306 268 57 26 0.5 0.3, 0.9 0.6 0.3, 1.1 1.0 0.5, 2.0>306–<435 268 45 42 0.3 0.2, 0.5 0.6 0.3, 1.2 2.2 1.1, 4.2�435 267 43 23 0.2 0.1, 0.4 0.3 0.1, 0.5 1.0 0.5, 2.2Trend p <0.001 <0.001 0.33

Vegetables1

�538 267 95 50 1.0 ref. 1.0 ref. 1.0 ref.>538–735 268 38 36 0.5 0.3, 0.8 0.8 0.4, 1.4 1.9 1.0, 3.6>735–956 267 33 17 0.5 0.3, 0.8 0.4 0.2, 0.8 1.0 0.5, 2.1>956 268 48 27 0.4 0.2, 0.7 0.4 0.2, 0.7 1.1 0.5, 2.2Trend p <0.001 <0.001 0.92

Preserved vegetables�5 252 42 23 1.0 ref. 1.0 ref. 1.0 ref.>5–16 284 50 30 0.9 0.5, 1.6 0.9 0.4, 1.7 1.0 0.5, 2.017–56 264 55 27 1.0 0.5, 1.7 0.9 0.4, 1.7 0.8 0.4, 1.7>56 270 67 50 0.7 0.4, 1.2 0.9 0.5, 1.7 1.2 0.6, 2.4Trend p 0.22 0.8 0.59

Soy food2

�121 266 69 30 1.0 ref. 1.0 ref. 1.0 ref.>121–219 269 60 32 0.8 0.5, 1.3 0.9 0.5, 1.8 1.6 0.8, 3.0>219–369 267 43 35 0.7 0.4, 1.2 1.2 0.6, 2.2 2.2 1.1, 4.3>369 268 42 33 0.6 0.3, 1.0 1.0 0.5, 1.9 1.7 0.8, 3.5Trend p 0.04 0.81 0.06

Fermented soyfoodYes 446 87 53 1.0 ref. 1.0 ref. 1.0 ref.No 624 127 77 0.8 0.5, 1.1 0.8 0.5, 1.2 1.0 0.6, 1.6

Other legumes<98 267 73 46 1.0 ref. 1.0 ref. 1.0 ref.98–138 268 41 31 0.5 0.3, 0.9 0.6 0.3, 1.1 1.2 0.6, 2.2>138–201 267 48 25 0.7 0.4, 1.2 0.5 0.3, 0.9 0.8 0.4, 1.5>201 268 52 28 0.6 0.3, 1.1 0.4 0.2, 0.8 0.7 0.3, 1.4Trend p 0.14 0.006 0.24

Red meat3

�148 267 35 29 1.0 ref. 1.0 ref. 1.0 ref.>148–220 270 55 30 1.5 0.8, 2.8 1.2 0.6, 2.3 0.8 0.4, 1.5>220–302 269 53 31 2.0 1.0, 3.8 1.4 0.7, 2.7 0.8 0.4, 1.7>302 264 71 40 1.4 0.7, 2.6 1.3 0.7, 2.5 0.7 0.3, 1.5Trend p 0.37 0.41 0.41

Fish without cured fish4

�65 266 41 27 1.0 ref. 1.0 ref. 1.0 ref.>65–1148 244 55 34 1.6 0.9, 2.9 1.4 0.7, 2.7 1.2 0.6, 2.4>114–16 316 65 30 1.5 0.9, 2.8 1.1 0.5, 2.1 1.0 0.5, 2.0>168 244 53 39 1.1 0.6, 2.0 1.3 0.7, 2.6 1.6 0.8, 3.3Trend p 0.91 0.58 0.31

Preserved or cured meat�4 268 50 33 1.0 ref. 1.0 ref. 1.0 ref.>4–9 284 68 42 1.3 0.8, 2.2 1.1 0.6, 2.0 0.9 0.5, 1.7>9–16 254 43 20 1.4 0.7, 2.5 1.1 0.5, 2.1 0.7 0.3, 1.4>16 264 53 35 1.1 0.6, 2.0 1.2 0.6, 2.1 1.0 0.5, 2.0Trend p 0.72 0.67 0.91

Poultry<20 254 40 36 1.0 ref. 1.0 ref. 1.0 ref.20–<42 270 64 30 1.3 0.7, 2.2 0.9 0.5, 1.6 0.7 0.4, 1.542–64 288 59 34 1.3 0.8, 2.4 1.2 0.6, 2.1 0.8 0.4, 1.6>64 258 51 30 1.2 0.7, 2.3 1.0 0.5, 2.0 0.9 0.5, 1.9Trend p 0.47 0.70 0.96

Eggs�52 257 46 44 1.0 ref. 1.0 ref. 1.0 ref.>52–156 371 91 47 1.3 0.8, 2.2 0.8 0.4, 1.3 0.7 0.4, 1.3>156–312 174 37 14 1.0 0.5, 2.0 0.4 0.2, 0.9 0.7 0.3, 1.5>312 268 40 25 1.0 0.5, 1.9 0.7 0.4, 1.4 1.0 0.5, 2.1Trend p 0.81 0.18 0.96

987BREAST CANCER AND FIBROCYSTIC CONDITIONS

by the absence of a significant association between the number oflive births and non-proliferative fibrocystic breast conditions.

We observed a 6-fold increased risk of proliferative fibrocysticbreast conditions associated with a prior breast lump and a 3-foldincreased risk of breast cancer with concurrent benign proliferativechanges. The comparable increases in risks of non-proliferativebenign conditions alone and with breast cancer were lower, and notstatistically significant for the latter. In both incidences, the relativerisks are probably underestimated because prior breast lumps thatdeveloped after the baseline questionnaire was administered werenot included. These findings are consistent with the results fromprospective studies1–8 showing risk of breast cancer to be greaterand more consistently observed in women with proliferative thannon-proliferative benign breast conditions, and they are supportiveof the hypothesis that breast carcinomas may arise from benign pro-liferative epithelium. Conversely, we observed about a 3-foldincreased risk of fibrocystic breast conditions alone and about a 6-fold increased risk of breast cancer in women with a first-degree rel-ative with breast cancer; and these associations were observed bothin women with proliferative and non-proliferative benign breastconditions. This suggests that the mechanism by which a positivefamily history increases risk of breast cancer is not merely throughthe development of the common types of proliferative changes inthe mammary epithelium. Although the resulting increase in risk ofbreast cancer relative to that of fibrocystic breast conditions couldhave occurred by chance, it is also plausible that there are subtlegenetic differences between the fibrocystic breast conditions inwomen with and without a family history of breast cancer that ren-der those in the former more prone to progression to cancer. Alter-natively, other conditions under genetic control unrelated to benignproliferative changes, such as growth factors, could differ in womenwith and without a family history of breast cancer.

High intakes of fruits and vegetables have been associated withreduced risks of many cancers,22 including breast cancer,23–27 aswell as of benign breast disease26,28–30; but some studies26,31–33

have shown either only a moderate, or no reduction in risk of breastcancer in association with these foods. A meta-analysis of 14 case-control studies and 3 cohort studies showed a reduced risk of breastcancer in relation to vegetable consumption, but with significantheterogeneity among studies, and only a weak, non-significant,association with fruit intake.34 A subsequent pooled analysis of9 cohort studies35 found that neither fruit nor vegetable intake wassignificantly associated with breast cancer risk, suggesting that theassociations observed in case-control studies may have been due todifferential reporting of dietary intakes by cases and controls. Thecohort studies were conducted in North America and WesternEurope. A recent case-control study in Shanghai,30 where dietarypatterns are quite different from those of western countries, alsoshowed no associations between breast cancer risk and either totalfruit or total vegetable consumption, but associations wereobserved with most individual fruits considered, and with somedark green and dark yellow-orange vegetables. Our findings ofdecreasing trends in risk of both proliferative and non-proliferativefibrocystic breast conditions, and of breast cancer (largely irre-spective of the proliferative status of the non-cancerous breast tis-sue), in relation to increasing consumption of both fruits andvegetables are fairly consistent with these prior observations inShanghai. The average total daily intakes of fruits and vegetablesby the control women in both our study and in the prior study inShanghai are roughly similar to those of participants in the cohortstudies in Western countries. This suggests that differential recallmay be responsible for the results of both studies in Shanghai.Alternatively, there may be qualitative features of the fruits andvegetables in the Chinese diet that are less prevalent in the westerndiet, that exert an influence on the mammary epithelium. This pos-sibility could be addressed by others by analyses of botanical fami-lies similar to those presented in Table IV.

Although we have provided evidence that a Chinese diet rich infruits and vegetables may reduce risk of breast cancer, our findingssuggest that mechanisms other than, or in addition to, a reduction

TABLE III – OR AND 95% CI OF PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS ALONE AND OF BREAST CANCER WITH PROLIFERATIVEFIBROCYSTIC BREAST CONDITIONS IN SURROUNDING TISSUE IN RELATION TO FOOD GROUPS (CONTINUED)

Exposure (times/year)Number of women PFCs alone vs. controls

PFCs with BrCa vs.controls

PFCs with BrCa vs.PFCs alone

Controls PFCs alone PFCs with BrCa OR5 95% CI OR5 95% CI OR5 95% CI

Shellfish<12 153 26 32 1.0 ref. 1.0 ref. 1.0 ref.12–<24 261 45 33 1.0 0.5, 1.9 0.7 0.4, 1.3 0.8 0.4, 1.824–<52 234 57 23 1.7 0.9, 3.4 0.6 0.3, 1.2 0.4 0.2, 1.0�52 422 86 42 1.4 0.7, 2.6 0.8 0.4, 1.4 0.5 0.2, 1.0Trend p 0.17 0.50 0.02

Fried food�33 263 40 32 1.0 ref. 1.0 ref. 1.0 ref.>33–63 272 52 26 1.0 0.5, 1.8 0.5 0.3, 1.1 0.6 0.3, 1.2>63–122 270 59 34 1.0 0.5, 1.8 0.7 0.4, 1.4 0.8 0.4, 1.6>122 265 63 38 0.9 0.5, 1.6 0.8 0.4, 1.5 0.9 0.4, 1.8Trend p 0.64 0.69 0.99

Sesame oil (g/day)6

�0.55 327 93 68 1.0 ref. 1.0 ref. 1.0 ref.0.56–1.10 391 68 30 1.0 0.6, 1.6 0.7 0.4, 1.3 0.7 0.4, 1.31.11–1.65 186 25 9 0.4 0.2, 0.8 0.3 0.1, 0.6 0.6 0.3, 1.5>1.65 166 28 23 0.7 0.4, 1.3 0.7 0.3, 1.2 1.0 0.5, 2.1Trend p 0.03 0.01 0.97

Soybean oil (g/day)6

>28.8 268 62 45 1.0 ref. 1.0 ref. 1.0 ref.28.8–38.4 295 64 36 1.0 0.6, 1.8 0.8 0.5, 1.4 0.7 0.4, 1.338.5–49.4 265 49 28 1.1 0.7, 2.0 0.6 0.3, 1.2 0.6 0.3, 1.2>49.5 242 39 21 1.0 0.5, 1.8 0.6 0.3, 1.2 0.5 0.2, 1.1Trend p 0.97 0.08 0.07

Tea7

Never 556 88 61 1.0 ref. 1.0 ref. 1.0 ref.Ever 514 126 69 0.8 0.5, 1.2 0.8 0.5, 1.3 0.9 0.6, 1.5

1Excluding soy, legumes, powders, favorings, extracts and salted vegetables.–2Excluding fermented bean curd.–3Excluding cured meat.–4Ex-cluding cured fish.–5Individual models, adjusted for age (as a categorical variable in Table I) and energy (<1647, 1647–1868, 1869–2128,>2,128) and conditioned on year of interview (1995–1996, 1997, 1998–1999, 2000–2001).–6Additionally adjusted for fresh vegetable intake (asa categorical variable in table I).–

7Including black tea and greeen tea, and adjusted for age (as a categorical variable in Table I).

988 LI ET AL.

TABLE IV – OR AND 95% CI OF PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS ALONE AND OF BREAST CANCER WITH PROLIFERATIVEFIBROCYSTIC BREAST CONDITIONS IN SURROUNDING TISSUE IN RELATION TO BOTANICAL FAMILIES

Exposure (times/year)2Number of women PFCs alone vs. controls

PFCs with BrCa vs.controls

PFCs with BrCa vs.PFCs alone

Controls PFCs alone PFCs with BrCa OR1 95% CI OR1 95% CI OR1 95% CI

AraliaceaeNever 861 173 112 1.0 ref. 1.0 ref. 1.0 ref.Ever 209 41 18 1.5 0.9, 2.5 0.9 0.5, 1.7 0.5 0.3, 1.0

Compositae�8 276 59 34 1.0 ref. 1.0 ref. 1.0 ref9–21 254 45 46 0.5 0.3, 1.0 1.1 0.6, 2.1 2.1 1.1, 3.922–56 280 70 30 0.9 0.5, 1.5 0.8 0.4, 1.5 0.9 0.5, 1.7>56 260 40 20 0.4 0.2, 0.8 0.6 0.3, 1.2 0.9 0.4, 1.9Trend p 0.05 0.07 0.36

Convolvulacea/Dio.Never 305 70 35 1.0 ref. 1.0 ref. 1.0 ref.Ever 765 144 95 0.7 0.4, 1.0 0.8 0.5, 1.3 1.5 0.9, 2.5

Cruciferae<162 265 79 39 1.0 ref. 1.0 ref. 1.0 ref.162–251 271 54 44 0.9 0.5, 1.6 1.3 0.7, 2.4 1.5 0.8, 2.8>251–377 266 44 25 0.7 0.4, 1.4 0.8 0.4, 1.6 1.2 0.5, 2.5> 377 268 37 22 0.8 0.4, 1.8 0.9 0.4, 1.9 1.1 0.5, 2.9

Trend p 0.52 0.48 0.73Cucurbitaceae

� 143 267 80 41 1.0 ref. 1.0 ref. 1.0 ref.>143–188 268 56 46 0.9 0.5, 1.6 1.4 0.8, 2.8 1.4 0.8, 2.6>188–243 267 40 26 0.9 0.5, 1.8 0.9 0.4, 1.9 0.8 0.4, 1.8>243 268 38 17 1.0 0.5, 2.0 0.5 0.2, 1.2 0.6 0.2, 1.5Trend p 0.97 0.08 0.24

EbenaceaeNever 259 59 45 1.0 ref. 1.0 ref. 1.0 ref.�3 370 68 37 0.9 0.5, 1.5 0.9 0.5, 1.6 0.9 0.5, 1.7>3 441 87 48 0.6 0.4, 1.1 0.6 0.4, 1.1 0.9 0.5, 1.6Trend p 0.09 0.10 0.75

Laminariaceae�1 263 52 34 1.0 ref. 1.0 ref. 1.0 ref.2–6 341 84 45 1.1 0.6, 1.9 1.3 0.7, 2.4 1.0 0.6, 1.97–13 243 45 27 0.9 0.5, 1.7 1.1 0.5, 2.1 1.0 0.5, 1.9>13 223 33 24 0.9 0.5, 1.7 1.4 0.7, 2.9 1.5 0.7, 3.4Trend p 0.64 0.49 0.45

Leguminosae<257 267 72 40 1.0 ref. 1.0 ref. 1.0 ref.257–381 268 58 26 1.1 0.6, 1.9 0.5 0.3, 1.0 0.8 0.4, 1.5382–554 267 43 34 0.8 0.5, 1.5 1.0 0.5, 1.8 1.6 0.9, 3.2>554 268 41 30 0.7 0.4, 1.3 0.7 0.4, 1.3 0.9 0.5, 1.8Trend p 0.18 0.47 0.64

Liliaceae�38 267 73 52 1.0 ref. 1.0 ref. 1.0 ref.39–156 272 70 37 0.9 0.5, 1.4 0.6 0.3, 1.2 0.7 0.4, 1.3157–371 273 36 30 1.1 0.6, 2.1 1.3 0.7, 2.4 1.1 0.6, 2.3>371 258 35 11 1.1 0.6, 2.1 0.5 0.2, 1.1 0.5 0.2, 1.1Trend p 0.63 0.47 0.26

Rosaceae�49 268 61 33 1.0 ref. 1.0 ref. 1.0 ref.>49–99 267 54 30 1.1 0.6, 1.9 1.0 0.5, 2.1 1.1 0.6, 2.2100–191 270 51 35 0.6 0.3, 1.1 1.0 0.5, 1.9 1.4 0.7, 2.8>191 265 48 32 0.6 0.3, 1.3 1.1 0.5, 2.4 1.4 0.7, 3.2Trend p 0.10 0.90 0.33

Rutacceae�13 282 60 34 1.0 ref. 1.0 ref. 1.0 ref.14–35 348 68 38 0.9 0.5, 1.6 0.8 0.4, 1.5 1.1 0.6, 2.136–52 175 29 20 0.7 0.4, 1.5 0.8 0.4, 1.8 1.2 0.6, 2.6>52 265 57 38 0.9 0.5, 1.6 0.9 0.4, 1.6 1.4 0.7, 2.7Trend p 0.56 0.72 0.37

SapindaceaeNever 138 38 34 1.0 ref. 1.0 ref. 1.0 ref.�3 427 120 69 0.7 0.4, 1.3 0.9 0.5, 1.6 0.9 0.5, 1.6>3 505 56 27 0.5 0.3, 1.0 0.5 0.2, 0.9 0.8 0.4, 1.7Trend p 0.03 0.03 0.61

Solanaceae�80 268 72 47 1.0 ref. 1.0 ref. 1.0 ref.>80–127 265 59 32 1.4 0.8, 2.5 1.0 0.5, 1.8 1.0 0.5, 1.9>127–182 272 46 30 1.5 0.8, 2.8 1.4 0.8, 2.7 1.0 0.5, 1.9>182 265 37 21 1.1 0.6, 2.1 1.0 0.5, 2.0 0.8 0.4, 1.7Trend p 0.64 0.76 0.63

989BREAST CANCER AND FIBROCYSTIC CONDITIONS

in mammary epithelial proliferation may be involved. Risks ofboth fibrocystic breast changes, and of breast cancer, were reducedin relation to fruit and vegetable intake whether or not prolifera-tive elements were observed in the non-neoplastic epithelium.Vegetables and fruits are rich sources of micronutrients, includingvitamins, minerals, dietary fibers and many other classes of bio-logically active compounds. Free radicals formed endogenously asa result of normal oxidative metabolic reactions can form DNAadducts, which can accumulate and result in gene mutations36;and antioxidants present in fruits and vegetables could reduceDNA damage by quenching exogenous or endogenously producedfree radicals. In addition, fruits and vegetables contain substancesthat can modulate enzymes that both activate and detoxify chemi-cal carcinogens.37 Fruits and vegetables also contain substancesthat can lower circulating levels of biologically active steroid sexhormones by increasing their enzymatically controlled inactiva-tion and excretion, and by influencing the activity of enzymes thatconvert them to metabolites of lesser potency.37

Results from several studies have provided inconsistent resultsfor an association of cruciferous vegetables and breast cancer risk,and a previous study in Shanghai found no association betweenbreast cancer and these foods.30,38 We did not find an associationof cruciferous vegetables with risk of either proliferative fibrocys-tic breast conditions or breast cancer after controlling for totalintake of fruits and vegetables. Inclusion of total fruits and vegeta-bles in the statistical model that we used to examine associationsof individual botanic families to risk is analogous to inclusion oftotal energy intake in models used to examine the effect of indi-vidual food groups, nutrients or macronutrients on risk.39 Ourresults suggest that any protective effect that cruciferous vegeta-bles may have on breast diseases is due to their contributions tototal vegetable intake.

We observed a strong inverse association between intake offood rich in Vitaceae, i.e., grapes, and risk of proliferative fibro-cystic breast conditions and breast cancer. Several reports havedemonstrated that resveratrol, a natural phytoalexin found in highconcentrations in grape skin, has strong anti-carcinogenetic effectsin in vitro systems and animal models.40,41 Multiple potentialmechanisms involving initiation, promotion and progression havebeen identified.42,43 Although our observations support an anti-neoplastic role of resveratrol as reported by Savouret et al.,44

grape intake even among the highest quartiles was very low. It isnot known whether intakes at this level could impart protection orwhether grape intake is a marker of other dietary behavior.

Unexpectedly we observed 2-fold and 3-fold increased risks ofproliferative fibrocystic breast conditions only and of breast cancerwith proliferative fibrocystic conditions in surrounding breast tis-sue, respectively, in relation to intake of foods rich in umbelli-ferea. This increasing trend was not observed for women who hadnon-proliferative fibrocystic breast conditions with or withoutbreast cancer. We also observed an inverse association betweenintake of foods rich in Compositae and Sapindaceae, and a posi-tive association between intake of foods rich in Zingiberaceae andUmbellifereae, and risk of proliferative fibrocystic breast condi-tions. To our knowledge, these associations have not beenobserved previously. With the large number of botanical familiesconsidered, we believe that these results should be replicated byothers before hypothesizing mechanisms for their possible effectson mammary epithelial proliferation.

No significant associations between risk of either proliferativefibrocystic breast conditions alone or of breast cancer with prolif-erative fibrocystic breast conditions and intake of total vitamin E,total carotenoids, total vitamin C or total crude fiber were observedafter adjusting for total fruit and vegetable intake. This observationprovides further evidence that intake of various fruits and vegeta-bles, rather than these individual constituents, plays a role in pre-vention of mammary epithelial proliferation and breast cancer.

Studies of breast cancer and soy food intake have yielded incon-sistent results. Early studies in Shanghai and Tianjin33 and inJapan,45,46 showed no significant associations between soy intakeand risk of breast cancer. A weak, non-significant decreasing trendin risk with increasing soy consumption was, however, observedin a more recent study in Shanghai.47 The observed associationsmay reflect more sensitive estimates of soy intake in the recentstudies. Alternatively this possible emergence of an association ina recent study in China could be due to greater variability in soyconsumption in recent years as more people adopt a less tradi-tional diet, with some reducing their soy intake below a thresholdlevel needed to provide protection against breast cancer. Thishypothesis is consistent with results from studies of Asians livingin the United States,48,49 and of Chinese in Singapore,50,51 where amixture of traditional and western diets predominates, that showedevidence for a protective effect of soy against breast cancer. Theresults of our study are also supportive of this hypothesis.Although we found no association between soy intake and risk ofbreast cancer when breast cancer cases were compared to controls,we did find a decreasing trend in risk of proliferative (but not non-proliferative) benign breast conditions with increasing soy con-

TABLE IV – OR AND 95% CI OF PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS ALONE AND OF BREAST CANCER WITH PROLIFERATIVEFIBROCYSTIC BREAST CONDITIONS IN SURROUNDING TISSUE IN RELATION TO BOTANICAL FAMILIES (CONTINUED)

Exposure (times/year)2Number of women PFCs alone vs. controls

PFCs with BrCa vs.controls

PFCs with BrCa vs.PFCs alone

Controls PFCs alone PFCs with BrCa OR1 95% CI OR1 95% CI OR1 95% CI

Umbelliferea<13 256 51 27 1.0 ref. 1.0 ref. 1.0 ref.13–23 273 60 32 1.3 0.7, 2.4 1.5 0.7, 2.9 1.2 0.6, 2.324–39 274 57 27 1.9 1.0, 3.4 1.9 0.9, 3.7 0.8 0.4, 1.7>39 267 46 44 1.9 1.0, 3.6 3.1 1.5, 6.1 1.9 0.9, 4.1Trend p 0.03 0.001 0.17

Vitaceae�4 287 80 41 1.0 ref. 1.0 ref. 1.0 ref.5–13 379 61 49 0.7 0.4, 1.2 1.1 0.6, 1.9 1.6 0.9, 2.814–26 209 45 24 0.7 0.4, 1.2 1.0 0.5, 2.0 1.1 0.6, 2.3>26 195 28 16 0.4 0.2, 0.8 0.6 0.3, 1.2 1.1 0.5, 2.6Trend p 0.02 0.19 0.79

Zingiberaceae<208 264 67 53 1.0 ref. 1.0 ref. 1.0 ref.208–260 219 36 20 1.3 0.7, 2.5 0.9 0.4, 1.8 0.9 0.4, 1.7261–365 156 19 13 2.5 1.1, 5.5 2.0 0.9, 4.6 0.8 0.3, 1.9�365 431 92 44 2.4 1.5, 4.1 1.3 0.8, 2.3 0.5 0.3, 0.9Trend p <0.001 0.19 0.03

1Individual models, adjusted for age, total fruits and vegetables and conditioned on year of interview.–2See Figure 1 for fruits and vegetablesincluded in each botanical family.

990 LI ET AL.

TABLE VI – ORs AND 95% CIs OF NON-PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS ALONE AND OF BREAST CANCER WITHNON-PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS IN SURROUNDING TISSUE IN RELATION TO SELECTED FACTORS

Factor/CategoryNumber of women

Non-PFCs alone vs.controls

Non-PFCs with BrCa vs.controls

Non-PFCs with BrCavs. Non-PFCs alone

Controls Non-PFCs alone Non-PFCs with BrCa OR3 95% CI OR3 95% CI OR3 95% CI

Total 1070 175 155Number of live births

1 712 136 72 1.0e ref. 1.0e ref. 1.0e ref.2 125 14 40 0.4 0.2, 0.9 1.5 0.7, 3.1 2.9 0.1, 7.53þ 188 17 34 0.8 0.2, 2.9 0.7 0.3, 2.1 0.4 0.1, 2.5Trend p 0.22 0.79 0.76

Prior breast lumpsNever 1036 159 148 1.0 ref. 1.0 ref. 1.0 ref.Ever 32 16 7 2.9 1.2, 7.0 1.9 0.7, 5.2 0.6 0.2, 1.7

First degree relative with breast cancerNo 1035 169 139 1.0 ref. 1.0 ref. 1.0 ref.Yes 1 6 9 3.9 0.9, 16.8 6.4 2.0, 20.0 2.6 0.8, 8.0

Fruits (times/year)<202 267 47 52 1.0 ref. 1.0 ref. 1.0 ref.202–306 268 49 29 0.8 0.4, 1.4 0.5 0.3, 0.9 0.6 0.3, 1.1>306–<435 267 37 34 0.4 0.2, 0.8 0.3 0.2, 0.6 1.0 0.5, 1.9�435 268 42 40 0.3 0.2, 0.6 0.3 0.1, 0.5 1.0 0.5, 2.0Trend p <0.001 <0.001 0.91

Vegetables (times/year)1

�538 267 56 50 1.0 ref. 1.0 ref. 1.0 ref.>538–735 268 29 35 0.6 0.4, 1.2 0.8 0.5, 1.5 1.5 0.8, 3.0>735–956 267 41 28 0.7 0.4, 1.3 0.7 0.4, 1.3 0.8 0.4, 1.6>956 268 49 42 0.6 0.3, 1.1 0.5 0.3, 1.0 1.1 0.5, 2.1Trend p 0.15 0.03 0.82

Soyfood (times/year)2

�121 266 39 34 1.0 ref. 1.0 ref. 1.0 ref.>121–219 269 45 40 1.0 0.6, 1.9 1.1 0.6, 2.1 1.3 0.6, 2.6>219–369 267 41 31 1.1 0.6, 2.1 1.0 0.5, 1.9 1.1 0.5, 2.2>369 268 50 50 1.3 0.7, 2.4 1.4 0.8, 2.5 1.0 0.5, 2.1Trend p 0.36 0.29 0.84

Other legumes (times/year)<98 267 47 38 1.0 ref. 1.0 ref. 1.0 ref.98–138 268 44 28 0.9 0.5, 1.5 0.8 0.4, 1.5 0.8 0.4, 1.7>138–201 267 46 42 1.1 0.6, 1.9 1.3 0.7, 2.3 1.3 0.7, 2.7>201 268 38 47 0.6 0.3, 1.2 1.0 0.5, 1.8 1.3 0.6, 2.7Trend p 0.24 0.74 0.35

1Excluding soy, legumes, powders, favorings, extracts and salted vegetables.–2Excluding fermented bean curd.–3Individual models, adjustedfor age (as a categorical variable in Table I) and energy (as a categorical variable in Table II) and conditioned on year of interview.

TABLE V – OR AND 95% CI OF PROLIFERATIVE FIBROCYSTIC BREAST CONDITIONS ALONE AND OF BREAST CANCER WITH PROLIFERATIVEFIBROCYSTIC BREAST CONDITIONS IN SURROUNDING TISSUE IN RELATION TO MICRONUTRIENTS AND FIBER

ExposureNumber of women

PFCs alone vs.controls

PFCs with BrCa vs.controls

PFCs with BrCa vs.PFCs alone

Controls PFCs alone PFCs with BrCa OR1 95% CI OR1 95% CI OR1 95% CI

Total 1070 214 130Total vitamin E (mg_ATE)

<13.9 268 71 46 1.0 ref. 1.0 ref. 1.0 ref.13.9–17.5 267 54 35 1.0 0.6, 1.8 0.9 0.5, 1.7 1.1 0.6, 2.117.6–22.9 267 50 30 0.8 0.4, 1.4 0.9 0.5, 1.7 1.0 0.5, 1.9>22.9 268 39 19 0.9 0.5, 1.6 0.6 0.3, 1.3 0.5 0.2, 1.0Trend p 0.51 0.23 0.1

Total carotenoids (mcg)<874.0 267 66 39 1.0 ref. 1.0 ref. 1.0 ref.874.0–1138.9 268 70 34 1.4 0.7, 2.6 1.0 0.5, 2.1 0.8 0.4, 1.71139.0–1450.5 267 40 32 0.9 0.4, 1.9 1.1 0.5, 2.5 1.5 0.6, 3.7>1450.5 268 38 25 0.6 0.3, 1.5 0.7 0.3, 1.9 1.4 0.5, 3.8Trend p 0.2 0.56 0.4

Total vitamin C (mg)<55.0 268 80 45 1.0 ref. 1.0 ref. 1.0 ref.55.0–73.4 267 52 38 1.1 0.5, 2.3 1.1 0.5, 2.4 1.0 0.5, 2.373.5–96.7 268 38 21 1.1 0.4, 2.7 0.8 0.3, 2.1 0.8 0.3, 2.4>96.7 267 44 26 0.9 0.3, 2.7 0.8 0.2, 2.6 0.7 0.2, 3.1Trend p 0.81 0.6 0.64

Total crude fiber (g)<7.59 267 73 42 1.0 ref. 1.0 ref. 1.0 ref.7.59–9.64 268 52 35 0.9 0.5, 1.6 1.0 0.5, 2.0 1.1 0.5, 2.19.65–11.81 268 49 21 1.1 0.5, 2.2 0.7 0.3, 1.8 0.6 0.2, 1.5>11.81 267 40 32 0.9 0.4, 2.2 1.3 0.5, 3.3 0.9 0.3, 2.6Trend p 0.96 0.69 0.66

1Individual models, adjusted for age (as a categorical variable) and total fruits and vegtable intakes (as a categorical variable) and conditionedon year of interview (1995–1996, 1997, 1998–1999, 2000–2001).

991BREAST CANCER AND FIBROCYSTIC CONDITIONS

sumption. Because we found no evidence that soy reduced thelikelihood that women with fibrocystic changes would progress tobreast cancer, any effect of soy consumption to reduce risk of breastcancer risk would seem to be an early effect on cell proliferation,and this would be observed before a reduction in breast cancerrisk would be evident. This hypothesized mechanism is supportedby results from 2 recent studies in Asian Americans52 and inShanghai53 that showed reduced risk of breast cancer to be particu-larly strongly associated with exposure to soy foods early in life.

There are certain limitations that must be considered wheninterpreting our results. First, our study included only breast can-cer cases with sufficient extra-tumoral tissue for evaluation. Thesewomen were compared to all other breast cancer cases in thecohort who were diagnosed during the same time period, onselected risk factors for breast cancer as ascertained from the base-line questionnaire for the BSE trial. We found that women in thestudy were younger at diagnoses than those not included. Becauseof the rapid change in childbearing practices during the past 3 dec-ades in China, these younger women also tended to have fewerlive births, to be older at first live birth, and to be younger atmenarche, than older women. This is unlikely to have influencedour results, however, because all of the OR estimates wereadjusted for age. Women with fibrocystic breast conditionsincluded in our study were similarly compared to women diag-nosed with fibrocystic breast conditions during the period of ourpresent study who were not included. No differences were found.

Another limitation of our study is that analysis of risk factorsfor different types of proliferative fibrocystic breast conditionswas not possible. The number of women with different types ofhyperplasia without atypia was too small for meaningful analysis,and the different types were not distinguished by the pathologistswith a high degree of reliability.

Detection of fibrocystic breast conditions requires access tomedical care that may be associated with socioeconomic statusand therefore associated with dietary habits. In contrast, breastcancer is likely to be diagnosed regardless of social status. Thispossible detection bias for the benign conditions could potentiallycause spurious odds ratios for different nutritional risk factorswhen comparing benign conditions to either breast cancer cases orto control women. This detection bias, however, is not of concernin our study. All women in the study cohort had ready access tomedical care through their factories, regardless of their position.

Recall and reporting biases could also have occurred. Effortswere made to interview women before they knew the outcome oftheir biopsies. Some analyses were repeated excluding the casesinterviewed after their diagnosis (results not presented) and theresults were not different from those presented in this report. Fur-thermore, the effect of any reporting bias was eliminated in thecomparisons of women with breast cancer to women with fibro-cystic breast conditions.

Another possible limitation is that we did not collect informa-tion on dietary serving size. Most of the variation in intake of spe-cific foods comes from differences in frequency of consumption,however, not from differences in serving size.21 Furthermore,although excluding serving size would reduce somewhat theobserved variability in intake, this would only bias observed ORtoward unity; it would not result in spurious associations. Even inthe absence of information on serving size, a significant lineartrend was observed in serum isoflavone concentrations acrossincreasing categories of soy intake,54 suggesting that the FoodFrequency Questionnaires provided a reasonably good assessmentof soy consumption.

Finally, there is epidemiological evidence suggesting that theinfluence on breast cancer risk of some reproductive and dietaryfactors may differ according to menopausal status. The size of ourstudy did not permit the detection of significant interactionsbetween menopausal status and other risk factors.

A major strength of our study is the comparable detailed histo-logical information on benign breast lesions and on the extra-tumoral tissue from women with breast cancer. The scores basedon the benign histological features of each case were based on themost advanced change in any of the scanning power fieldsreviewed. The chance of recording a high score was therefore pre-sumably associated with the number of scanning power fieldsexamined. The number of scanning power fields examined wassimilar for benign breast lesions and the extra-tumoral tissue frommalignant cases (data not presented) providing reassurance thatthere was an equal chance of finding high-score conditions in the2 groups of women.

Our findings support a role for foods high in fruits and veg-etables in reducing risk of fibrocystic breast conditions and ofbreast cancer. These results are supportive of the general publichealth recommendation to increase fruit and vegetable intake.The apparent protective effect of these foods against breastcancer probably is an early anti-carcinogenic effect. No factorswere identified that were clearly and strongly implicated aspromoters to breast cancer in women with proliferative fibro-cystic breast conditions. Large cohort studies will be requiredto more clearly identify factors that promote the developmentof breast cancer in women with benign mammary epithelialconditions.

Acknowledgements

We thank W.W. Wan, the BSE workers and interviewers fortheir effort in collecting data; Drs. F.L. Chen, G.L. Zhao andL.D. Pan for their ongoing support of this project; G. Green,K. Wernli, S. Zhang, R. Gandolfo, T. Grichuhin, J. Calman,M. Molyneaux and J. Kikuchi for their technical and administra-tive support.

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