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Nutritional Epidemiology

Fruits and Vegetables Intake Differentially Affects Estrogen Receptor Negative and Positive Breast Cancer Incidence Rates

Anja Olsen², Anne Tjønneland, Birthe L. Thomsen, Steffen Loft^*, Connie Stripp, Kim Overvad, Susanne Møller^** and Jørgen H. Olsen

Institute of Cancer Epidemiology, The Danish Cancer Society, Denmark; ^* Institute of Public Health, University of Copenhagen, Denmark; Department of Clinical Epidemiology, Aalborg Hospital and Aarhus University Hospital, and Department of Epidemiology and Social Medicine, University of Aarhus, Denmark; and ^** Danish Breast Cancer Co-operative Group, Rigshospitalet, Denmark

²To whom correspondence should be addressed. E-mail: email: anja{at}cancer.dk.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Despite intensive research, the evidence for a protective effect of fruits and vegetables on breast cancer risk remains inconclusive. Other risk factors for breast cancer seem to vary with the estrogen receptor status of the breast tumor, and it is thus possible that the inconsistent results regarding a preventive effect of fruits and vegetables are due to lack of controlling for estrogen receptor status. The objective of this study was to investigate the effect of fruit and vegetable intake on postmenopausal breast cancer and explore whether the estrogen receptor status of the tumor modifies this relation. Postmenopausal women (n = 23,798; aged 50–64 y) provided information about diet and established risk factors for breast cancer in the cohort "Diet, Cancer and Health." During follow-up, 425 cases were diagnosed with breast cancer. Associations between intake of fruits and vegetables and the breast cancer rate were analyzed using Cox’s regression model. The association for all breast cancers was an incidence rate ratio (IRR) of 1.02 (95% CI, 0.98–1.06) per 100 g/d increment of total intake of fruits, vegetables and juice. For estrogen receptor–positive (ER⁺) breast cancer, a borderline significant increase in the rate was seen, IRR: 1.05 (95% CI, 1.00–1.10), whereas a preventive effect was seen for estrogen receptor–negative (ER^-) breast cancers, IRR: 0.90 (95% CI, 0.81–0.99). In conclusion, we did not find the overall breast cancer rate to be associated with the intake of fruits and vegetables, but there seemed to be different effects for ER⁺ and ER^- breast cancer.

KEY WORDS: • breast neoplasms • fruits • vegetables • estrogen receptors • cohort study

During the last decades, fruits and vegetables have been regarded as the primary dietary components for the prevention of cancer. The available literature was summarized by the World Cancer Research Fund (WCRF) in 1997 and it was stated that convincing evidence existed for a preventive effect on eight different cancers and a probable preventive effect on four additional cancer types, one of which was breast cancer (1). Since the review by WCRF, additional studies on the probable association between intake of fruits and vegetables and risk of breast cancer have been published, but the question whether a preventive effect actually exists remains open.

The literature published to date is dominated by case-control studies. We found 19 studies of this type (2–20), but only five prospective cohort studies (21–25). In the case-control studies, findings varied from significant preventive effects of fruits, vegetables or fruit and vegetable-related dietary micronutrients on breast cancer risk (10,13,16,20) to null results (2,4,5,9). Results from prospective studies have been more consistent. No significant preventive effects of fruits and vegetables were shown on risk of breast cancer in any of the five published prospective cohort studies, nor in a recent large pooled study including eight different cohorts (26). In conclusion, the epidemiologic evidence for a preventive role for fruits and vegetables on breast cancer risk has relied exclusively on case-control studies, whereas results from cohort studies have been negative.

The hypothesis that diet affects postmenopausal breast cancer risk originated primarily from observed differences in breast cancer incidence rates and lifestyle (including diet) between women from the Western part of the world and Asian women, as well as from the rising incidence of breast cancer observed among Japanese women emigrating to North America (27,28). Interestingly, breast cancers are more frequently estrogen receptor positive (ER⁺) (29), and normal breast tissue shows a higher estrogen receptor expression among Western women than among Asian women (30–32). Moreover, the observed increase in incidence of breast cancer among postmenopausal Western women has been shown to be dominated by ER⁺ tumors (33).

The effects of nondietary risk factors for breast cancer, i.e., parity and BMI, were shown previously to vary dependently with both estrogen and progesterone receptor status, indicating that the receptor status of tumors is an important issue to consider when potential risk or preventive factors for breast cancer are evaluated (34). To our knowledge, whether the possible preventive effects of fruits, vegetables or micronutrients from fruits and vegetables are directed toward breast cancer with a specific estrogen receptor status has been considered in only a few published studies showing inconsistent results (35–39).

The purpose of this prospective cohort study was to provide evidence concerning the putative preventive effect of fruits and vegetables on breast cancer risk. In particular, we wanted to investigate possible preventive effects of fruits and vegetables with respect to estrogen receptor expression of breast cancer.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The study "Diet, Cancer and Health" is a prospective cohort study, established with the primary aim of studying the etiological role of diet on cancer risk. From December 1993 through May 1997, women (n = 79,729; aged 50 to 64 y) were invited to participate in the study and 29,875 accepted the invitation. Cohort members were identified by a unique, 10-digit identification number composed of date of birth and a four digit running number, which is allocated to every Danish citizen by the Central Population Registry. Women eligible for invitation were born in Denmark, lived in the Copenhagen or Aarhus areas and were not registered with a previous diagnosis of cancer in the Danish Cancer Registry at the time of invitation.

"Diet, Cancer and Health" and the present substudy were approved by the regional Ethical Committees on Human Studies in Copenhagen and Aarhus, and by the Danish Data Protection Agency.

All participants attended one of two established health centers. Each participant filled in a 192-item food-frequency questionnaire (FFQ), which they received by mail before a visit to one of the two study clinics. Forty-four of the items exclusively concerned intake of fruits, vegetables or fruit/vegetable juice. In addition, information about vegetable intake was derived from other questions as parts of recipes. Development and validation of the FFQ was described previously (40–43). Briefly, the participants were asked to report their average intake of different food and beverage items over the past 12 mo within 12 possible categories ranging from never to ≥8 times/d. To adjust for a possible overestimation, the questions on frequency of intake of several specific types of fruits and vegetables were complemented by three additional questions on the overall intake of fruits, raw vegetables/salad and cooked vegetables. The intake of each type of fruit and vegetable was weighted in accordance with the answers to these additional questions. Daily intakes of specific foods and nutrients were calculated for each participant using the software program Food Calc (44), using specially developed standardized recipes and portion sizes.

During the visit to the study clinic, participants completed a lifestyle questionnaire, which included questions about reproductive factors, health status, social factors and lifestyle habits. From this questionnaire, we obtained information about years of school education (short: ≤7 y, medium: 8–10 y, or long: >10 y), parity, age at first birth, history of benign breast tumor surgery (yes/no), use of hormone replacement therapy (HRT; never, past, current) and duration of HRT. Anthropometrical measurements were obtained by professional staff members. BMI was calculated as weight (kg) per height (m) squared.

During the visit to the study clinic, the two self-administered questionnaires were processed by optical scanning and checked for missing information, so that unclear information could be clarified with the participant, preferably before she left the study clinic. A few missing values were accepted in the lifestyle questionnaire but not in the dietary questionnaire.

A total of 326 women who later were reported to the Danish Cancer Registry with a cancer diagnosed before the visit to the study clinic were excluded from the study. In addition, eight women were excluded from the study because they did not fill in the lifestyle questionnaire. Because the present analysis aimed at the subgroup of women who were postmenopausal at study entry, we further excluded 4844 who failed to meet this criterion, comprising 4798 women who had reported at least one menstruation no more than 12 mo before entry and no use of HRT, nine women who gave a lifetime history of no menstruations and 37 women who did not answer the questions about current or previous use of HRT. From the resulting group of 24,697 postmenopausal women, we finally excluded 899 individuals due to missing information on reproductive events (number and ages at births), use or duration of HRT, length of school education, history of benign breast tumor surgery, alcohol intake or BMI, leaving 23,798 postmenopausal women for this study. Included in this group were 5232 women who gave a history of oophorectomy, hysterectomy or both.

All 23,798 postmenopausal cohort members were linked to The Central Population Registry for information on vital status and emigration. Information on cancer occurrence among cohort members was obtained through record linkage to the Danish Cancer Registry, which collects information on all inhabitants with cancer in Denmark (45). Linkage was performed by use of the personal identification number. Each cohort member was followed up for breast cancer occurrence from date of entry, i.e., date of visit to the study center until the date of diagnosis of any cancer (except for nonmelanoma skin cancer), date of death, date of emigration or 31 December 2000, whichever came first.

In addition to the general Danish Cancer Registry, a registry exclusively concerning breast cancer has been established in Denmark. The Danish Breast Cancer Co-operative Group holds records on a range of details for 90% of breast cancers diagnosed in Denmark, including estrogen receptor status (46). Linkage to the Danish Breast Cancer Co-operative Group registry was performed by use of the personal identification number as well.

Statistical methods.

The analyses of the relation between the breast cancer rate and the exposure variables were based on the Cox proportional hazard models (including time-dependent variables) using age as the time axis to ensure that the estimation procedure was based on comparisons of individuals at the same age, which allowed for age adjustment to prevent confounding by age. The other time variable, time under study, was included as a time-dependent variable modeled by a linear spline with a boundary at 1 y after entry into the study cohort to allow for a possible "healthy-participants" effect. A linear spline was used because this allows a steady increase in the rate during y 1 (47). In the analyses considering estrogen receptor status, the two types of breast cancer defined by the receptor status were treated as competing causes of failure, that is, in separate analyses in which breast cancers of the opposite type were censored at the age at the cancer diagnosis. Breast cancers with unknown receptor status were censored at the cancer diagnosis in both analyses. All models were adjusted for baseline values of established risk factors for breast cancer such as parity (entered as two variables; the categorical variable parous/nulliparous and the quantitative variable number of births), age at first birth, previous benign breast tumor surgery (yes/no), length of school education (low, medium, high), use of HRT (never, former, current), duration of HRT, BMI and alcohol intake. The only exceptions were the ER-specific analyses categorized according to intakes of fruits and vegetables divided into quartiles among cases; these analyses were adjusted only for age and time under study due to limited power. Two-sided 95% CI for the incidence rate ratio (IRR) were calculated on the basis of Wald’s test of the Cox regression parameter, that is, on the log rate ratio scale. The procedure PHREG in SAS (release 6.12; SAS Institute, Cary, NC) on a Unix platform was used for statistical analyses.

All quantitative variables were entered linearly in the Cox model because this is biologically more reasonable than the step functions corresponding to categorization and, furthermore, increases the power of the analyses (48). The linearity of the associations was evaluated graphically by linear splines with three boundaries placed at the quartiles among cases (see Table 1 for placement of boundaries) (47). None of the associations showed signs of deflection or threshold values.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The median age at entry into the cohort of the 23,798 postmenopausal women was 57 y (range 50–65 y). The average length of follow-up was 4.7 (1.1–6.8) y (1st to 99th percentiles). Cohort members accrued a total of 112,712 person years during which time 425 cases of a primary breast cancer were diagnosed. Information about estrogen receptor status of the tumors was obtained for 394 (93%) cases of breast cancer, with 303 of the observed tumors reported to be ER⁺ and 91 tumors estrogen receptor negative (ER^-). Information about estrogen receptor status was not obtained for the remaining 31 women. Of these, it was not possibly to determine estrogen receptor status on 10 in situ tumors, whereas the remaining 21 could not be located in the registry. Baseline characteristics of the study population and the subgroup of women diagnosed with breast cancer are presented in Table 1. The associations between the potential confounding variables and the breast cancer incidence were all in the expected directions, i.e., the incidence rates decreased with number of children, but increased with increasing values of age at first birth, length of education, use of HRT, duration of HRT use, intake of alcohol and history of benign breast tumor surgery.

Reported intakes of each of the three food item groups, fruits, vegetables and juice (both fruit and vegetable) were not associated with the incidence rate of breast cancer, when analyzed as crude variables or mutually adjusted as well as adjusted for the established risk factors presented in Table 1. The total intake of fruits, vegetables and juice also did not affect the incidence rate ratio IRR = 1.02 (95% CI, 0.98–1.06) (per 100-g increment in intake/d) (Table 2). To study whether the combining into food item groups masked a preventive effect of one or more specific types of fruits and/or vegetables, we divided total intake of fruits, juice and vegetables into 20 subgroups. Classification of vegetables was done according to their botanical characteristics. The type of vegetable within each group with the highest consumption is presented in parenthesis; leafy vegetables (salad), fruiting vegetables (tomato), root vegetables (other than potatoes) (carrot), cabbages (cauliflower), mushrooms, onion/garlic, stalk vegetables (leek), citrus fruits, apples, pears, bananas, peaches, strawberries, kiwi fruits, water melon, other melons, fruit porridge, preserved fruit, fruit juice and vegetable juice. The 20 groups of fruits and vegetables were analyzed as quantitative variables mutually adjusted (results not shown). This detailed model did not provide additional information compared with the simple model presented in Table 2, indicating that no single subgroup of fruits and/or vegetables was strongly associated with the incidence rate of breast cancer in this study. The result should, however, be considered carefully due to limited power to evaluate this large number of variables in a single model.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

It has been hypothesized in a study by Potter and colleagues (34), that risk factors may differ between breast cancers according to their estrogen and progesterone receptor status. Due to lack of information about progesterone receptor status we had to restrict our analyses to estrogen receptor status. The division into ER⁺ and ER^- breast cancer cases weakened the power of the analyses because only 91 of the breast cancer cases were found to be ER^-. Therefore, our results must be considered primarily as serving to generate hypotheses.

The beneficial associations found for ER^- breast cancer were seen when the separate intakes of fruits, vegetables and juice were analyzed mutually adjusted, as well as when the intakes were summed to a total intake. However, only the total intake was significant. The adverse associations for ER⁺ breast cancer were also seen in all categories, and were barely significant for the total intake. The association was identical for fruits, vegetables and juice within each receptor type, even though mutually adjusted, which reduced the probability that the results were due simply to chance.

It has not yet been fully established whether ER^- breast cancer is a progressed form of ER⁺ breast cancer or whether ER⁺ and ER^- breast cancer are two biologically different diseases with different risk factors (49). The prognosis of survival of ER^- breast cancer is known to be poorer than that of ER⁺ breast cancer, and tumors are known to lose their estrogen dependence while progressing, indicating that ER^- breast cancer may represent a more progressed state of ER⁺ breast cancer. Investigation conducted within this field, however, has shown inconsistent results, and no final conclusion has been stated (49).

Two different biologic mechanisms could explain our findings, according to the theories concerning estrogen receptors. First, if ER^- breast cancer is a progressed form of ER⁺ breast cancer, then the progression from ER⁺ to ER^- breast cancer may be inhibited by a high intake of fruits and vegetables. This indicates that fruits and vegetables do not prevent breast cancer, but that a high intake of fruits and vegetables might delay breast cancer progression, thereby improving survival after breast cancer. The effect of intake of fruits and vegetables or their related micronutrients on breast cancer recurrence and survival has been studied. Some studies indicate a better prognosis with high intakes of fruits, vegetables and/or related micronutrients (50–52), whereas other studies do not (53–55). Second, breast cancers may be either ER^- or ER⁺ from the origin of the tumor. Micronutrients from fruits and vegetables may prevent both types of breast cancer, but in ER⁺ cancer, the estrogen level is probably the most important factor and may therefore override the preventive effect of the micronutrients. In ER^- breast cancer, which has a lower dependence on estrogen level, the risk-reducing effect of fruits and vegetables may be fully expressed. It is not possible to evaluate the correctness of any of these theories using our current data.

The finding of a direct association between intake of fruits and vegetables and ER⁺ breast cancer could be due to residual confounding in our analyses, caused by insufficient controlling for education and social class, known to be linked to both increased risk for breast cancer and a high intake of fruits and vegetables in the Danish population (56,57). In that case, the preventive association seen for ER^- breast cancer is most likely to be even stronger than observed in this study.

The present findings confirm that the intake of fruits and vegetables does not have a preventive effect on the occurrence of postmenopausal breast cancer when studied in a prospective cohort design. However, increasing intake of fruits and vegetables was associated with a lower incidence of ER^- breast cancer, suggesting that fruits and vegetables either impose a delayed progression from ER⁺ to ER^- tumors, or that the development of ER⁺ and ER^- cancers responds differentially to the intake of fruits and vegetables. These findings require confirmation, preferably in larger studies due to the relatively small fraction of ER^- breast cancers. Prospective studies of measures of tumor progression in breast cancer are required to evaluate the effect of fruits and vegetables on cancer progression.

	ACKNOWLEDGMENTS

 
The authors acknowledge the contribution of Katja Boll and Jytte Fogh Larsen in the collection of the data, and Marianne Ewertz for valuable comments.

	FOOTNOTES

 
¹ Supported by grants from The Danish Cancer Society and "Europe against cancer": European Prospective Investigation into Cancer and Nutrition (EPIC).

³ Abbreviations used: ER⁺, estrogen receptor positive; ER^-, estrogen receptor negative; FFQ, food-frequency questionnaire; HRT, hormone replacement therapy; IRR, incidence rate ratio; WCRF, World Cancer Research Fund.

Manuscript received 6 February 2003. Initial review completed 3 March 2003. Revision accepted 28 March 2003.

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