Dietary Fat and Risk of Breast Cancer According to Hormone Receptor Status1

Transcription

1 Vol., 11-,_January/February 9 Cancer Epidemiology, Biomarkers & Prevention 11 Dietary Fat and Risk of Breast Cancer According to Hormone Receptor Status1 Lawrence H. Kushi,2 John D. Potter, Roberd M. Bostick, Carol R. Drinkard, Thomas A. Sellers, Susan M. Gapstur, James R. Cerhan, and Aaron R. Folsom Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, Minnesota IL. H. K., C. R. D., T. A. S., A. R. Fl; Cancer Prevention Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington [J. D. P.1; Division of Public Health Sciences, The Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina lr. M. B.I; Department of Preventive Medicine, Northwestern University Medical School, Chicago, Illinois IS. M. G.I; and Department of Preventive Medicine, College of Medicine, University of Iowa, Iowa City, Iowa U. R. C.l Abstract The association of dietary fat with breast cancer in prospective cohort studies has generally been weak and not statistically significant. However, these studies have not considered whether the risk related to fat intake may differ according to estrogen or progesterone receptor status. Dietary habits and other breast cancer risk fadors were assessed by mailed questionnaire in January 1 98 in,88 postmenopausal Iowa women. Through 1 991, 72 incident breast cancer cases were ascertained in this cohort using the Iowa cancer registry. Joint estrogen and progesterone receptor status was determined for 79 (%) breast cancers. For tumors that were positive for both estrogen and progesterone receptors (ER+/PR+) (n = 29), age- and energy-adjusted relative risks for breast cancer adjusted from lowest to highest third of fat intake were 1.0, 1.0, and 1. (P trend = 0.1 ). Corresponding risks for ER+/PR- tumors (n = 7) were 1.0, 0.8, and 1.0 (P trend = 0.8) and for ER-/PR- tumors (n = 1 ) were 1.0, 1.0, and 0.7 (P trend = 0.8). Only 1 cases were classified as having ER-/PR+ tumors. Adjustment for other breast cancer risk fadors did not appreciably alter these findings. There was a suggestion that dietary fat may be associated with ER+/PR+ breast cancers and not other breast cancers. These results are also consistent with an interpretation of no association between dietary fat with breast cancer, regardless of hormone receptor status. It has been suggested that etiological studies of breast cancer should investigate associations according to receptor status. This study provides evidence of a subset of breast cancers that may be related to dietary fadors. Similar analyses in other studies would provide information as Received 2/i /9; revised 10/1 1/9; accepted 1 0/1 /9. 1 Supported by NIH grant R01-CA972. MG. and J.R.C. were supported by NIH Training Grant T2-CA To whom requests for reprints should be addressed, at Division of Epidemiology, University of Minnesota School of Public Health, 1 00 South Second Street, Suite 00, Minneapolis, MN to whether the associations suggested here are etiologically important or represent random fluduations in the patterns of disease occurrence. Introdudion It has long been suspected that dietary factors, in particular dietary fat intake, may be related to risk of breast cancer. Evidence supporting such an association came initially from animal studies in which rodents fed high fat diets had a greater incidence of breast cancer than those fed low fat diets (1, 2). The preponderance of evidence from such studies supports a tumor-enhancing effect of high fat diets (2). Epidemiological studies also noted large geographic variations in fat consumption that correlated positively with breast cancer incidence and mortality (-). The importance of environmental factors in determining breast cancer rates is demonstrated in studies of migrants from areas with low breast cancer rates to areas with high breast cancer rates; migrants inevitably acquire the disease pattern of their host country rather than of their country of origin (7). Despite these lines of evidence indicating that high fat diets are associated with increased breast cancer risk, analytic epidemiology studies have generally failed to provide strong evidence to support such an association. In particular, several prospective studies, in which dietary habits were ascertained before development of cancer, have not found that dietary fat is related to breast cancer (7-1). Numerous commentaries have been written suggesting that unavoidable and substantial dietary measurement error and the relatively homogeneous, high fat diets consumed in most of these study populations inhibit the ability of such studies to detect associations of diet with breast cancer, even if such associations exist (1-1 9). Other commentaries have indicated that the evidence against a dietary fatbreast cancer association is increasing, and that criticisms of negative studies amount to wishful thinking (20). This view is reinforced by the observations that the same dietary methods in the same study populations are adequate to detect associations of fat and other dietary variables with colon cancer (21 ) and other disease outcomes (-2). While comments regarding the ability of analytic epidemiological studies to investigate the dietary fat-breast cancer association have focused on the limitations of dietary assessment, relatively little attention has been directed at whether the disease entity breast cancer has been adequately specified in such studies. It is known that preand postmenopausal breast cancers have differing etiologies; for example, measures of body fat appear to have differing associations with pre- versus postmenopausal breast cancers (2). International variations in breast cancer rates appear to be due largely to differences in rates of postmenopausal breast cancers (). It has also been suggested that dietary fat may be a risk factor for postmeno-

2 12 Diet, Breast Cancer Risk, and Receptor Status pausal, but not premenopausal, breast cancer (2). Thus, some investigations of diet and breast cancer have stratified analyses according to menopausal status (1 1, 1 2), or have confined the study population to postmenopausal women (1-1). Although menopausal status is one dimension along which breast cancers can be classified, categorization according to cellular receptors for estrogen and progesterone may also be informative. The status of these hormone receptors is important in predicting prognosis and the potential efficacy ofchemotherapy (-1). For example, women with breast carcinomas that are positive for ERs and PRs have longer disease-free and overall survival than women with tumors that are negative for ER and PR, while women with tumors that are discordant for ER and PR have intermediate survival (, 28). Similarly, certain therapies appear to be most effective for ER-positive and PR-positive breast cancers and least effective for ER-negative and PRnegative tumors (29, 0). While the clinical relevance of hormone receptor status appears clear, there have been few investigations of the dietary etiology of breast cancer according to hormone receptor status (). Given the possibility that hormone receptor status may describe etiologically distinct breast cancer types (2), analyses were undertaken to determine whether the risk of breast cancer associated with dietary factors differs according to hormone receptor status. Methods The methods for establishing the Iowa Women s Health Study cohort, and for exposure and case ascertainment have been published previously (1, ). In brief, in January 8, a 1-page questionnaire was mailed to 98,029 eligible women ages -9 years who resided in Iowa and who were selected randomly from the state of Iowa s drivers license list; 1,87 (response rate of 2.7%) women who returned the questionnaire form the cohort under study. The vast majority of women (n = 0,902, 97.8%) in this cohort classified themselves as non-hispanic whites. Analyses detailing the mortality and cancer experience of respondents compared with nonrespondents have been published (). The baseline questionnaire included questions on major breast cancer risk factors, including age at menarche and menopause, age at first live birth, number of pregnancies, family history of breast cancer, height, weight, and waist and hip circumferences. It also included a semiquantitative food frequency questionnaire that was virtually identical to that used in the 1 98 survey of the Nurses Health Study (12). The reliability and accuracy of the food frequency questionnaire among members of this cohort was found to be comparable to that seen in the Nurses Health Study (). Women were excluded from analyses of diet and breast cancer risk if they reported on the baseline questionnaire that they had a menstrual period within the previous 1 2 months (n = 9), had a prior mastectomy or partial breast removal (n = 1 870), or had any previous cancer other than skin cancer (n = 9). Women were also excluded if The abbreviations used are: ER, estrogen receptor; PR, progesterone receptor; ER+, ER positive; ER-, ER negative; PR+, PR positive; PR-, PR negative; RR, relative risk. their food frequency questionnaire was only partially completed (i.e., responses to 0 or more of 1 total food items were left blank; n = 22) or if their responses resulted in extreme total energy intake values (<00 or 000 kcal/ day; n = 28). A total of,88 women remained eligible for follow-up. Follow-up questionnaires were mailed in October 87 and August 89 to establish vital status and change of address. Deaths among nonrespondents to these follow-up questionnaires were identified through the Iowa State Health Registry and the National Death Index. Outof-state relocation of nonrespondents was determined from mailing address corrections. Cancer incidence was ascertained through the State Health Registry of Iowa, a part of the National Cancer Institute s Surveillance, Epidemiology and End Results Program (). A computer match was performed annually between the list of cohort members and the record of Iowans with incident cancer in the Health Registry using combinations of first, last, and maiden names; zip code; birthdate; and Social Security number. Through December 1, 91, corresponding to approximately years of follow-up, 72 incident cases of breast cancer (International Classification of Diseases for Oncology Code 1 7) occurred among the members of this cohort. Assays of hormone receptors were conducted in laboratories serving the hospitals where cases were diagnosed. Whenever available, the status (positive, negative, or borderline) of estrogen and progesterone receptors as stated in the medical records was recorded by Surveillance, Epidemiology and End Results personnel. The specific laboratory value of receptor activity was not recorded consistently, and thus was not used for analysis. For analysis, carcinomas that were recorded as borderline were considered as receptor positive; less than 1 % were characterized as borderline for ER status, and less than 2% were characterized as borderline for PR status. Data Analysis. Length offollow-up was calculated for each individual in the study as the number of days elapsed since completion of the baseline questionnaire until date of diagnosis for women with breast cancer, or until December 1, for women without breast cancer. Because mcident breast cancers were detectable only for Iowa residents, different termination dates were used for the following circumstances: (a) date of death, for deaths occurring in Iowa; (b) date moved out of Iowa, if date of move was known; (c) midpoint between date of last contact in Iowa and first known date out of Iowa or end of follow-up period, if moved from Iowa at an unknown date; and (c midpoint between date of last contact in Iowa and date of death, for non-iowa deaths. The primary exposures of interest were related to dietary fat intake, including total, saturated, monounsaturated, polyunsaturated, animal, and vegetable fat intake. The associations of breast cancer incidence with total, animal, and vegetable protein; total carbohydrate; dietary cholesterol; and dietary fiber were also examined. Because total energy intake is highly correlated with other dietary factors, associations with dietary factors were adjusted for energy intake. We have described previously the effect of different energy adjustment methods on the association between categorical dietary exposures and breast cancer

3 Cancer Epidemiology, Biomarkers & Prevention 1 risk (1 ). Simulations run by us and by Brown et al. (7) indicate that estimates of risk that are closest to the null are provided by either the nutrient density method of energy adjustment or the residual method described by Willett and Stampfer (8). These methods also provide the greatest power to detect associations and the most stable estimates of RR. Thus, energy-adjusted associations are presented using either ofthese two methods. Other methods of energy adjustment were considered, and the results of those procedures generally were qualitatively consistent with those presented here. Details of these energy adjustment methods have been presented elsewhere (9). Four sets of breast cancer outcomes were considered. First, diet-breast cancer associations were examined without regard to receptor status. These -year associations were generally similar to those reported after years of follow-up (1 ). Second, associations of dietary factors with breast cancer defined according to estrogen receptor status alone was investigated. ER+, ER-, and ER unknown breast cancers were considered as three separate entities. Third, breast cancer outcomes were defined according to progesterone receptor status alone; PR#{}, PR-, and PR unknown tumors were considered separately. Finally, risk according to the joint distribution of ER and PR status was examined. In this case, five separate disease entities were considered: tumors that were ER+/PR+, ER+/PR-, ER-/PR+, ER-/PR-, and tumors that were unknown for either ER or PR status. The analyses based on joint ER/PR status appeared to be most informative in terms of defining distinct disease entities, and these therefore are the focus of the results presented here. In general, the results for ER+/PR+ tumors were mimicked by those for both ER+ and PR+ tumors. The comparison group for breast cancer outcomes were cohort members who did not develop any breast cancer. Analyses of the association of dietary factors with breast cancer began with a comparison of mean age- and energy-adjusted nutrient intakes between women who developed breast cancer of various receptor types with women who did not. The dietary factors of interest were then categorized by tertiles, and the incidence rate of breast cancer in each category was calculated by dividing the number of events by the number of person-years of followup. The incidence rate in the lowest category of intake was the reference level in the calculation of relative risks for all analyses. Analyses were also done using other categorizations of the exposure variable (such as quintiles). These results generally provided similar estimates for trend tests, while providing less stable risk estimates for some of the breast cancer subtypes due to smaller numbers of cases within exposure categories. Age-adjusted relative risks were calculated by stratifying cases and person-years into four age categories, less than 0 years, between 0 and years, between and 9 years, and 70 years or older. The Mantel extension test (0) was used to identify trends in age-adjusted relative risks of breast cancer. Adjustment for multiple confounding variables was conducted using proportional hazards regression. The relative risk for a given category of dietary exposure was calculated by exponentiating the regression coefficient for the corresponding indicator variable. The test for trend after adjustment for covariates was calculated using the Wald Unpublished results. Table 1 Distribution of 72 incident breast cancer cases according to estrogen receptor and progesterone receptor status among postmenopausal Estrogen receptor status Positive Negative Unknown Iowa women, 8-91 Proges terone recept or status Positive Negative Unknown Total statistic across the vector of indicator variables for the exposure of interest. For all relative risks, 9% confidence limits were calculated. In order to compare whether the observed risk patterns differed according to the several breast cancer outcomes, multivariate polychotomous logistic regression was used. In these models, outcomes were classified as ER+/PR+ case, ER-t-/PR- case, ER-/PR- case, unknown receptor status, and noncase. ER-/PR+ cases were not included in these analyses due to small numbers (n = 1). This method allows estimation of subtype-specific risk parameters in comparison to noncase and direct statistical significance testing of differences between logistic regression coefficients. Risk estimates were similar to those provided by proportional hazards regression, and in no case was there evidence of statistically significant differences in risk estimates. Results As reported elsewhere (2, 1, 2), the established breast cancer risk factors were evident in this cohort. For example, higher values of body mass index, waist-to-hip ratio, alcohol, and age at first live birth were associated with higher risk of breast cancer, while older age at menarche and higher parity were associated with lower risk. Family history of breast cancer and history of benign breast disease were also associated with increased risk of breast cancer. Differences in risk factor profiles according to joint ER/PR status have also been reported in this cohort (); in general, risk factors hypothesized to operate through hormonal mechanisms (e.g., body mass index or age at menarche) were more strongly associated with risk of ER+/PR+ breast cancer than other receptor-stratified breast cancers. Table 1 presents the distribution of ER and PR status among the 72 women diagnosed with breast cancer. Estrogen receptor status was unknown for 208 (28.7% of) breast cancer cases. Among the women for whom ER status was known, 7 (8.7%) were diagnosed as having ER+ breast cancer, while 79 (1.%) had ER- breast cancer. Progesterone receptor status was unknown for 2 (.% of) breast cancer cases; of those with known PR status, (71.% of) women had PR+ breast cancer and 1 7 (28.%) had PR- breast cancer. Overall, ER or PR status was unknown in (.8% of) breast cancer cases. Among those with known joint receptor status, there were 29 (8.7%) ER+/PR+ breast cancers, 7 (1.7%) ER+/PR- breast cancers, 1 (2.9%) ER-/PR+ breast cancers, and 1 (12.7%) ER-/PR- breast cancers. Table 2 presents age- and energy-adjusted mean intakes of various dietary factors according to ER/PR status. Women who developed ER+/PR+ breast cancer had somewhat higher average daily fat intake than women who did Total

4 1 Diet, Breast Cancer Risk, and Receptor Status Table 2 Age- and energy-adjusted da ily mean intake of dietary factors, according to joint ER/PR status comparing brea,88 postmenopausal Iowa women, 8-91 St cancer cases and noncases among Dietary factor Breast Cancer ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- (n = 29) (n = 7) (n = 1) (n = 1) ER or PR unknown (n = ) No breast cancer (n =,) Total energy (kcal( ±. 00. ± ± ± ± ±. Total fat (g) Saturated fat (g) Monounsaturated fat (g) Polyunsaturated fat (g) Animal fat (g( Vegetable fat (g) 9.92 ± o. 9. ± ± ± ± ± 0..8 ± ± ± ± 0.9. ± 1.7. ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0..1 ± ±0. 9. ± ± ± ± ± ± ± ± 0.0 Total protein (g) Animal protein (g) Vegetable protein (g) 80. ± ± ± ± ± ± ± ± ± ± ± 1.. ± ± ± ± ± ± ± 0.0 Carbohydrate (g( 21.7 ± ± ± ± ± ± 0.20 Dietary cholesterol (mg) 01. ± ± ± ± ± ± 0.0 Dietary fiber (g) ± ± ± ± ± ± 0.0 As a percent of energy Total fat Saturated fat Monounsaturated Polyunsaturated Animal fat Vegetable fat fat fat.8 ± 0.1 a.8 ± 0.. ± ± ± ± ± ± ± ± ± ± ± ± ± 0.. ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.0 Total protein 17.9 ± ± ± ± ± ± 0.02 Total carbohydrate 7.9 ± ± ± ± ± ± 0.0 Dietary cholesterol (mg/i 000 kcal) ± ± ± ± ± ± 0.2 Dietary fiber (gil 000 kcal) 1 1. ± ± ± ± ± ± 0.02 a p < o. 10, compared to noncase. not develop any breast cancer (9.9 versus 8.7 g; P = 0.072). Average daily fat intake for women who developed other breast cancer types was less than that for those who developed ER+/PR+ breast cancer and not significantly different from that of women who did not develop breast cancer. The fat intake differences were mirrored by lower average total carbohydrate intake among women with ER+/ PR+ breast cancer compared with women who did not develop breast cancer (21.7 versus g/day; P = 0.09). Unlike dietary fat intake, average daily carbohydrate intake appeared to be lower for cases than for noncases, not just for those with ER+/PR+ breast cancer but also for those with ER+/PR- and ER-/PR- breast cancer. Table presents age- and energy-adjusted relative risks associated with various dietary factors for hormone receptor-specific breast cancers. As suggested by the comparison of mean intakes, fat intake was modestly associated with increased risk of ER+/PR+ breast cancer. From lowest to highest third of fat intake, RRs of ER+/PR+ breast cancer were 1.0, 1.0, and 1. (P trend = 0.1). There was suggestion of an inverse association of fat intake with ER-! PR+ breast cancer; however, there were only 1 cases with this receptor pattern. Carbohydrate intake was modestly associated with decreased risk of ER+/PR+ breast cancer; relative risks from lowest to highest third of intake were 1.0, 0.82, and 0.79 (Ptrend = 0.07). An inverse association was also suggested for ER-/PR- tumors (corresponding RRs of 1.0, 0.89, and 0.0; P trend = 0.1 2). Adjustment of diet-breast cancer associations for additional breast cancer risk factors did not alter appreciably the pattern or magnitude of relative risk estimates; detailed results are not presented. As before, dietary fat suggested a positive association with ER#{}/PR+breast cancers but not with other types of breast cancer. Relative risks of developing ER+/PR+ breast cancer were 1.0, 1.0, and 1.2 (P trend = 0.1 ) from lowest to highest third of fat intake. There was essentially no suggestion of an association of dietary fat with ER+/PR- or ER-/PR- breast cancers. There were suggestions of inverse associations of carbohydrate intake with both ER+/PR+ (RRs from lowest to highest third of intake were 1.0, 0.82, and 0.79; P trend = 0.1 0) and ER-/PRbreast cancers (RRs 1.0, 0.8, and 0.2; Ptrend = 0.1 ). As noted previously, in analyses comparing risk estimates from multivariate polychotomous logistic regression, there was no evidence of statistically significant differences in risk parameters among breast cancer subtypes. Discussion Estrogen and progesterone receptor status is recognized as having prognostic value in the clinical course of breast cancers. Women with tumors that are positive for estrogen and progesterone receptors tend to have longer disease-free survival than women with receptor-negative tumors (, 28). Yet, relatively little attention has been directed at investigation of whether risk factors differ for tumors with

5 Cancer Epidemiology, Biomarkers & Prevention 1 - Table Age- and energy-adjusted RR of breast cancer stratified by joint ER/PR status, according to,88 postmenopausal Iowa women, 8-91 intake of dietary factors categorized by tertiles, in Breast cancer Dietary factor ER+/PR+ ER+/PR- ER-/PR+ ER-/PR- ER or PR unknown No. cases RR (9% CI) No. RR (9% Cl) No. RR (9% CI) cases cases No. cases RR (9% Cl) No. RR (9% CI) cases Total energy (kcal) < ( ) 1.0( ) 1.09 ( ) 1.18 ( ) ( ) 1.1 ( ) (0.9-1.) 0.87 ( ) ( ) 1.09 ( ) Total fat (g) < ( ) 0.8 ( ) 0.8 ( ) ( ) 9 1. ( ) ( ) 1.0 ( ) 0.7( ) ( ) 7 ( ) Saturated fat (g) < ( ) ( ) 1.0(0.2-.1) ( ) ( ) ( ) 0 1.8( ) 0.91 (0.2-.) 1 0.7( ) ( ) Monounsaturated fat (g) < ( ) ( ) 0.7(0.-2.8) ( ) ( ) ( ) 0.89 ( ) 0. ( ) 0.80(0.-1.) (0.-1.) Polyunsaturated fat (g) < ( ) 0.79 (0.-1.8) 0.8 (0.-2.7) ( ) (0.7-1.) ( ) 0.90(0.2-1.) 0.0( ) 1.2( ) ( ) P (trend) Animal fat (g) < ( ) 1.99 ( ) 2.2 ( ) ( ) ( ) (0.78-i.) (0.7-2.) 1. (0.-.) (0.2-1.) ( ) P (trend) Vegetable fat (g) < ( ) (0.1-1.) (0.29-.) 1.1 (0.-2.1) (0.8-1.) i (0.8-1.) (0.1-1.) 0.80 ( ) ( ) ( ) Total protein (g) < (0.7-1.) 1.29 ( ) 1.1 (0.-.) 1.9 ( ) 9 1. ( ) ( ) 1.1 ( ) 0.98 (0.2-.9) 1.1 ( ) ( ) P (trend) Total carbohydrate (g) < ( ) ( ) 2. ( ) 0.89 ( ) (0.8-1.) ( ) (0.-1.9) 7.82 (0.7-.) 1 0.0( ) ( ) Dietary cholesterol (mg) < (0.8-1.) ( ) 1. ( ) 1.1 ( ) 7 1.0(0.7-1.) (0.8-1.) (0.-1.9) 0.(0.1-2.) ( ) ( S) P (trend) Dietary fiber (g) < ( ) 0.92 ( ) ( ) 1.2 ( ) 7 2. (0.0-9.) 1.8 (0.-.) ( ) 0.98 ( ) ( ) 1.0 ( ) P (trend) a CI, confidence interval.

6 1 Diet, Breast Cancer Risk, and Receptor Status differing receptor status (2, ). In particular, only a handful of studies have examined whether the risk of breast cancer due to fat intake or other dietary variables differs for receptor-positive versus receptor-negative tumors. To our knowledge, this is the first prospective study to do so. In this study, there was suggestion of a positive association of dietary fat with ER+/PR+ breast cancer, although this was not statistically significant. Dietary fat appeared to be unrelated to development of hormone receptor-negative breast cancers. A suggestion of a positive association of fat intake with ER+ or PR+ tumors was also observed, reflecting the fact that tumors that are positive for ER also tend to be positive for PR. Analysis of the relationship of dietary fat with breast cancer without consideration of receptor status resulted in weak, positive, but not statistically significant associations. This latter observation was reported previously in this cohort (1 ), and is consistent with the results of several other prospective cohort studies (8-1 2, 1, 1 ). A somewhat stronger inverse association of carbohydrate intake with receptor-positive breast cancers was also observed. However, similar associations were seen for receptor negative tumors, suggesting that receptor status does not differentiate risk of breast cancer related to carbohydrate intake. An initial impetus for examination of the diet-breast cancer association according to receptor status came from other types of studies that are consistent with the hypothesis that dietary fat may be related to hormone receptor-positive breast cancers and not other breast cancers. It is generally accepted that the proportion of ER+ and PR+ breast cancers increases with age (). There appears to be a marked increase in the proportion of breast cancers that are hormone receptor-positive after menopause (). In one study, 29% of premenopausal women with breast cancer had ER+ tumors, compared to 1 % of postmenopausal women with breast cancer (). While this difference between pre- and postmenopausal breast cancers was more sizable than that seen in other studies (, 7), these studies confirm the greater prevalence of ER+ tumors among postmenopausal women. There is also evidence for international differences in the proportion of breast cancers that are ER+. Nomura et a!. (8) reported that among postmenopausal breast cancers, a greater proportion were ER+ in the United States than in Japan; no difference was detected among premenopausal breast cancers. Although the descriptive epidemiology of PR status of breast cancers is not well characterized, the presence of estrogen receptors plus estrogen induces production of the PR receptor (1); thus, age and geographic differences in ER status are likely to reflect differences in PR status as well. It has been noted that dietary fat may be more strongly related to postmenopausal breast cancer than premenopausal breast cancer (2). This difference may be a reflection of the greater proportion of breast cancers that are positive for ER and PR among postmenopausal breast cancers rather than a feature of postmenopausal status itself. Similarly, it has been noted that much of the international variation in breast cancer incidence may be attributable to differences in rates of postmenopausal breast cancer (); there is approximately a -fold difference in postmenopausal breast cancer rates between the United States and Japan, and only a -fold difference in rates of premenopausal breast cancer (9). It has also been suggested that differences in breast cancer rates between the United States and Japan may be attributed in part to differences in ER status of breast tumors (0). If high intake of dietary fat increases the risk of developing ER-i-/PR+ breast cancer, international differences in dietary fat intake may account for differences in both the total number and the proportion of breast cancers that are ER+ among countries. There are biological bases for the hypothesis that diet may influence the expression of estrogen and progesterone receptors. Several studies have noted that differences in diet result in differences in estrogen metabolism; lower dietary fat levels appear to be associated with lower blood levels of free estradiol, decreased urinary excretion of estrogens, and increased fecal excretion of estrogens (1-). Effects of fat on estrogen metabolism have been noted both in descriptive comparisons of women following different dietary patterns, such as comparing vegetarians with nonvegetarians (1, 2) or women of different ethnic origins (), and in feeding studies in which the fat intake of individuals is altered (, ). These effects of dietary intake patterns on estrogen metabolism suggest that dietary factors may have greater effects on hormone-sensitive breast cancers, i.e., those that are positive for estrogen and progesterone receptors, than on hormone-resistant breast cancers. These observations are further supported by rodent studies that indicate feeding a high fat diet increases the incidence of ER+ mammary tumors (), although this effect has been of differing magnitude among the few studies to examine this issue (7). In addition, diets low in fat tend to be high in grains and other vegetable foods, a pattern characterized by high consumption of lignans and other phytoestrogens that may effectively compete to inhibit the cell-proliferating effects of endogenous estrogens (8). These ecological and experimental studies suggested the possibility that the somewhat differing results seen in other prospective epidemiological studies of dietary fat and breast cancer may, in part, be explained by differences in receptor status of cases. Because none of the other studies considered the influence of hormone receptor status when examining the diet-breast cancer association, there is the possibility of misclassification of the outcome of interest. If dietary fat is a risk factor only for hormone receptor-positive breast cancers, then inclusion of other breast cancer types would diminish the likelihood of detecting an association of fat with breast cancer. This effect is in addition to the known impact of limitations of dietary assessment methodology on the ability to detect associations between diet and disease (1-1 9). For example, those prospective studies that reported inverse, nonsignificant associations of fat intake with breast cancer included substantial proportions of premenopausal and younger postmenopausal breast cancers (8, 1 2), cases that are less likely to have hormone receptor-positive tumors. However, the observation of an equally strong inverse association of dietary fat with both postmenopausal and premenopausal breast cancer in one of these studies (1 2) argues against an important role for hormone receptor status. We are unaware of any other epidemiological studies of dietary factors and breast cancer that considered either progesterone receptor status or joint estrogen and progesterone receptor status. However, a few studies have exammed the diet-breast cancer association according to estrogen receptor status. These studies were either case-case studies comparing dietary habits of women with ER+ breast cancers with women with ER- breast cancers (9-1), or case-control studies comparing dietary habits of women with ER+ or ER- breast cancer with women who did not

7 Cancer Epidemiology, Biomarkers & Prevention 17 have breast cancer (2, ). Because the case-control studies compare women with ER status-specific breast cancer with women without breast cancer, such studies are more directly comparable to the present study than case-case studies that compare women with ER+ tumors to women with ER- tumors. In one case-control study, Cooper et al. () reported a somewhat stronger association of fat intake with ER+ breast cancer, with relative risk estimates from lowest to highest third of fat intake of 1.0, 1.21, and 1.1, than with ER- breast cancer, with corresponding relative risks of 1.0, 1.0, and 1.1. Hislop et al. (2) examined the association of various foods and food groups, rather than nutrients, with ER#{} and ER- breast cancer. While their analyses indicated an increased risk of breast cancer with increasing frequency of consumption of various animal foods and fat-related items, there was little differentiation in risk profiles according to ER status. One of their few such observations indicated that the risk due to beef intake was somewhat higher for ER+ breast cancer (odds ratio of 1.2 comparing daily consumption with less frequent consumption) than for ER- breast cancer (corresponding odds ratio of 1.2). This corresponds with our observations of a possible positive association of fat intake with hormone receptorpositive tumors, but not with hormone receptor-negative tumors. However, this contrasts with observations by Hislop et al. (2) of a possible increased risk of ERbreast cancer associated with dairy fats (odds ratio of 1.1 comparing most frequent consumption with least frequent consumption) that was not evident for ER+ breast cancer (corresponding odds ratio of 0.90). Neither of these case-control studies reported results related to intake of carbohydrate or associated factors. Studies that compare dietary patterns of women with ER+ breast cancer to women with ER- breast cancer also provide conflicting evidence of the effect of differences in nutrient intake. A study by Harlan et al. (9) indicated that women with ER+ tumors were more likely to report diets with a high percentage of energy from fat (odds ratio of 2.8 comparing extreme quintiles of intake) and a low percentage of energy from carbohydrate (odds ratio of 0.0) than women with ER- tumors. However, HoIm et al. (0) reported opposite findings; women with ER- breast cancer had higher average fat (8.% energy) and lower average carbohydrate (.9% energy) intakes than women with ER+ breast cancer (.% energy as fat,.% energy as carbohydrate). A third study by Verreault et al. (1 ) found no relationship between fat intake and ER status; they did not report associations with carbohydrate intake. In the broader context of other risk factors for receptorspecific breast cancer, analyses from this cohort indicate that there may be differences in risk according to receptor status (). For example, hormone-related risk factors such as age at menarche, age at first birth, and body mass index appear to be associated with the incidence of PR#{} breast cancer but not other breast cancer types (). However, considering other studies, the evidence supporting such findings is inconsistent (2). Similarly, the conflicting results of the case-control and case-case studies may simply mdicate that there is no underlying systematic difference in the effect of fat intake or other dietary variables on risk of receptor status-specific breast cancer. Thus, the suggestion in this study of possible dietary fat associations with hormone receptor-positive breast cancer, but not with hormone receptor-negative breast cancer, may be a chance observation. Indeed, the observations reported here are substantially less striking than those suggested by preliminary analyses in the same cohort conducted after years of follow-up (). Commentaries on the ability of cohort studies to detect associations between diet and breast cancer have invariably focused on limitations of the dietary assessment method (1-20). In most such studies, nutrient intake was assessed by food frequency questionnaire (9, 11-1). It has been noted that due to both the relatively narrow range of fat intake in such within-country cohorts compared with the variation in fat intake across countries, and to the misclassification inherent in all dietary assessment methods, that the detectable relative risk between extreme categories of fat intake is substantially attenuated. Thus, in this cohort, any ability to detect true associations of nutrient intake with breast cancer is limited. It is in part for this reason that it was of interest to examine the association of dietary factors with breast cancer subtypes. If, for example, dietary fat is related only to hormone receptor-positive breast cancers, the outcome variable would also be misclassified, hence further compromising the ability to detect true associations. However, the analyses presented here provide little evidence that risk differs for breast cancer subtypes. Overall, the results presented here suggest either of two interpretations. On the one hand, there is some indication, admittedly weak, that better specification of the disease entity, i.e., classification of breast cancer according to receptor status, may point to breast cancer types that are etiologically distinct. The somewhat stronger associations of dietary fat with risk of ER+/PR+ or ER+ breast cancer than with other breast cancers suggest this may be the case. 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10 Dietary fat and risk of breast cancer according to hormone receptor status. L H Kushi, J D Potter, R M Bostick, et al. Cancer Epidemiol Biomarkers Prev 9;:11-. Updated version Access the most recent version of this article at: alerts Sign up to receive free -alerts related to this article or journal. Reprints and Subscriptions Permissions To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at pubs@aacr.org. To request permission to re-use all or part of this article, use this link Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.