Vol. 107, No. 6
Copyright O 1978 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Printed in UJSA.
A STUDY OF DIET AND BREAST CANCER1 A. B. MILLER,' A. KELLY,1 N. W. CHOI,4 V. MATTHEWS,' R. W. MORGAN,' L. MUNAN,3 J. D. BURCH,1 J. FEATHER,' G. R. HOWE1 AND M. JAIN1 Miller, A. B. (NCIC Epidemiology Unit, U. of Toronto, Toronto, Ontario M5S 1A8, Canada), A. Kelly, N. W. Choi, V. Matthews, R. W. Morgan, L. Munan, J. D. Burch, J. Feather, G. R. Howe and M. Jain. A study of diet and breast cancer. Am J Epidemiol 107:499-509,1978. A case-control study has been conducted in four areas in Canada In which 400 cases of breast cancer matched by age and marital status with neighborhood controls were administered a medical and dietary history questionnaire, a 24-hour recall for dietary Information and a four-day diet record. The Study has produced evidence of an association between an Increased Intake of nutrients, especially total fat, in both pre-menopausal and post-menopausal women with breast cancer. Reasons why a weak association might have been anticipated are discussed, and It Is concluded that In reality the association Is stronger. Furthermore, Its consistency with other evidence, both experimental and International, suggests that it Is causal. breast neoplasms; cancer; diet; nutrition
International differences in breast cancer morbidity and mortality are substantial and suggestive of the influence of environmental factors (1). Although it is difficult to rule out a small contribution of genetic factors to such differences, studies of population migration (2) indicate that environmental factors predominate even though the changes that occur in the incidence of breast cancer from the rates in the original population to that in the host population seem to take more than one generation. This suggests either that the Received for publication May 2, 1977, and in final form January 3, 1978. 1 This study was supported by the National Cancer Institute of Canada and in part under National Health Research and Development Project No. 6131047-30 of the Department of National Health and Welfare of Canada. * Epidemiology Unit, National Cancer Institute of Canada. 1 University of Sherbrooke. 4 University of Manitoba. ' University of Saskatchewan. ' University of Toronto. Reprint requests to Dr. Miller, NCIC Epidemiology Unit, University of Toronto, McMurrich Building, Toronto, Ontario M6S 1A8, Canada. 499
relevant factors are only acquired in the migratory population from the host population after one or two generations, or that acculturation must be established early in life to have an important effect upon subsequent breast cancer risk (3). Although an analysis of the correlation between suspect environmental factors and international incidence and mortality data suggested the possible importance of temperature differences correlated with latitude (4), subsequent analyses have tended to concentrate on assessing the possible importance of dietary factors such as sugar (5), butter (5-7), cheese, liquid milk and green vegetable intake (8), and particularly total fat intake (5-7, 9-12), though it is known that total fat intake is highly correlated with other dietary factors (9-12). A disadvantage of these studies is that they tend to be based on data on national food practices, which relate to food disappearance rather than food consumption, and that they tend to correlate recent data of this type with recent incidence or mortality data, though the stud-
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ies of population migration suggest an interval of 30 or more years may be more appropriate. An alternative line of inquiry into the importance of dietary factors in breast cancer is the use of experimental animal models. Studies particularly in the rat support the hypothesis that dietary fat may be relevant to subsequent incidence of breast cancer (12). Thus the incidence of mammary cancer in rats that are on a carcinogen free, high fat diet is higher than in rats on a low fat diet (13) and this effect is enhanced when a carcinogen such as methylcholanthrene is incorporated in the diet (14). Studies in which anti-estrogen and anti-prolactin are combined with carcinogen feeding and different levels of fat intake appear to suggest an action through prolactin rather than estrogens (15). It has been suggested that the mechanism, whereby a high intake of dietary fat produces its effect on subsequent breast cancer risk, is that gut bacteria under certain circumstances may produce estrogens from biliary steroids present in the colon, it being known that such production is likely to be higher on a high than on a low fat diet (16). This hypothesis, which has not yet been delineated by detailed studies in man, provides an indirect link between the high dietary fat hypothesis and the estriol ratio hypothesis (17, 18). Indirect evidence from other studies also supports the importance of nutritional factors in the etiology of breast cancer. For example in Iceland, changes in cohort specific incidence rates for breast cancer have resulted in the cross-sectional age specific curve for breast cancer shifting from a Japanese type pattern in the 1920s to a western type pattern in the 1950s (19). This change has followed the substantial westernization that occurred in Iceland, an important aspect of this being the changes in diet from that of a largely fishing- and agriculture-based economy to an industrial economy. Further indirect
evidence is that of deWaard and Baandersvan Halewijn (20, 21) who showed an association with both height and weight acting independently in post-menopausal women, breast cancer being found to occur most frequently in post-menopausal women of greatest height and of greatest body weight. The association with height, which is associated with nutrition in adolescence, provides an indirect link with the association of breast cancer with age at menarche (22), a factor also related to the state of nutrition (23). Indeed, a possible explanation for the increase in breast cancer rates which have been occurring in recent years is decreasing age at menarche, due to improving nutritional status in adolescence. The fact that there is evidence, at least from Britain, that age at menarche may have been stable for the last decade (24) suggests that the increase in breast cancer incidence rates (25) that has been noted particularly in post-menopausal women (26, 27) may shortly come to an end if decreasing age at menarche was indeed the reason. Although we have failed to substantiate an effect of height as a risk factor for breast cancer (28), there is evidence of the importance of weight in post-menopausal women, another indirect pointer to the importance of dietary factors. T. Hirayama (personal communication, 1976) has pointed out that morbidity and mortality for breast cancer is increasing sharply in Japan. Hirayama examined the effect of diet and noted a high correlation coefficient between dietary fat intake and breast cancer age adjusted mortality rates in 12 districts in Japan. A similar correlation was observed with intake of pork but not with any other nutritional element. Among each nutritional element, dietary fat intake has shown the most striking increase in Japan in recent years. Population correlations and animal experimental studies can only point to a possible causal association in man and it
A STUDY OF DIET AND BREAST CANCER
is important before preventive action is based on them that direct confirmation should be attempted. It is, however, recognized that dietary studies are imprecise, particularly in homogeneous populations, (29) and thus it was important to ensure that the dietary methods used gave as much information as possible on relevant dietary factors, as we discussed in the preceding paper in this issue (30). An important assumption in the present study is that dietary habits are established in youth or adolescence and persist largely unchanged throughout adult life, so that long-term observation is not required to establish their relevance to breast cancer. To the extent that this assumption is untrue, it will be difficult to measure the effects of dietary factors, particularly if their main period of action is early in life.
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such treatment was completed. Wherever possible, allowance was made for only two months further delay (i.e., five months after surgery); this procedure was established to avoid collecting dietary information during periods when a major alteration in diet due to the operation or subsequent treatment might have occurred. For all areas we attempted to schedule the control's interview no later than two weeks after that of the corresponding case. All interviews were undertaken in the household of the respondent. The Dietary History used food models and household utensils and referred to the usual intake of all food items during the immediate past two months (time D and, if different the intake of food during the two-month period, six months prior to the time of interview (time II). The 24-Hour Recall was introduced mainly as a trainMETHODS ing method for the Four-Day Diet Record. Study hypotheses. The general dietary The subject was then asked to complete hypothesis investigated in this study is the Four-Day Record. that there is an association between breast Case and control selection. The study cancer and diet, most specifically between population consisted of 100 newly diagbreast cancer and high fat intake. nosed cases of breast cancer and an equal The study also investigated supplemen- number of matched controls from each of tary hypotheses that there are associations the areas, giving a total of 400 matched between breast cancer and 1) total caloric pairs. intake, 2) a high intake of saturated fat, 3) Subjects were reported to the centers a high intake of unsaturated fat. through hospitals, surgeons and physiStudy instruments. The instruments in- cians, clinics and cancer registries. Cases cluded dietary questionnaires comprising were limited to-women with newly diaga detailed dietary history, a 24-hour recall nosed malignant breast disease aged 35 to and a four-day diet record and a personal 74 inclusive. Cases with metastases were and medical history. The dietary question- excluded. Controls were matched to cases naires are described in the preceding paper on age (five years either way of the year of (30) while the results of the analysis of birth of the case), marital status, and non-dietary factors are presented in a residence. Cases and controls were matched on neighborhood in the expectathird paper published in this issue (28). Interview procedures. The study was tion that, this would lead to matching on introduced in all areas as a "Study of Diet socioeconomic status. Further details of and Health" and no mention was made of the selection of cases and controls are cancer to avoid motivation bias on the part given in the third paper (28). of the cases. Cases were interviewed no Methods of analysis. As indicated in the earlier than three months after surgery or preceding paper (30), the data on individif other treatment subsequent to the oper- ual food items were converted into estiation was given, at least one month after mated intakes of the six main nutrients
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considered in this study, that is, total calories, total fat, saturated fat, linoleic acid, oleic acid and cholesterol, using the modified data bank. In preliminary analyses, the resultant output was considered within individual areas. However, as there was no major discrepancy between the findings by area, results for all areas were subsequently combined. Results were initially analyzed for each method individually, that is, 24-hour re. call, four-day diet record and the diet history for the two separate time periods. However, as there was little difference between the diet histories, the results presented in this paper for this method are for time II. In a presentation summarizing the findings from this study (3), the results were reported as a mean of the findings from the four-day diary and the mean of the two time periods. In this report, the findings are presented as group means for each of the three methods independently, while the risk ratio analysis is presented only for the dietary history time II. Since in a few instances estimates of intake from any one of the three methods produced extreme values for some nutrients, it was decided to exclude from the analyses of nutrient intake presented in this paper any pairs in which either the case or control had estimates more extreme than three times the mean for the group and nutrient concerned. For this reason, the numbers of pairs analyzed vary, and the numbers used are indicated in the tables. The significance for the mean difference between cases and controls for the different nutrient variables was determined using the paired t test. Risk ratio estimates were calculated with the individual matching preserved; for dichotomous risk factors, methods were based on the binomial distribution (31, 32); for risk variables considered at more than two levels, the consistent risk estimation procedure of Pike et al. (33) was used.
Although./? values are quoted in the tables, caution has to be used in their interpretation. Since the nutrients are highly correlated, one cannot interpret a combined result for more than one nutrient as if the probabilities were independent. RESULTS
Nutrient intake. The nutrient intake for all respondents in terms of total calories, total fat, saturated fat, oleic acid, linoleic acid and cholesterol is set out by dietary method in table 1. As discussed in the preceding paper (30), the 24-hour recall provides the lowest estimate of nutrient intake, and the dietary history the highest estimate. The number of respondents for the four-day record is less than for the other methods. In general, for each nutrient, by each method, the mean nutrient intake was greater for cases then controls. The differences were greatest for the 24hour recall. For the pre-menopausal respondents (table 2) the mean nutrient intake was greater for cases than controls for all nutrients as estimated by the 24-hour recall method and by the history, except for linoleic acid by the 24-hour recall and cholesterol in the dietary history. In contrast, the intake for the controls exceeded that of the cases as estimated by the four-day record, except for saturated fat. This discrepancy seems due to a low estimate of intake for the cases by the four-day record, producing levels similar to those for the 24-hour recall, a somewhat surprising discrepancy in view of the estimate of greater intake by the four-day record for both cases and controls for all respondents as seen in table 1, and for the post-menopausal respondents as seen in table 3. The mean nutrient intake for post-menopausal respondents, irrespective of age (table 3) was greater in cases than controls for all nutrients by each method, except for cholesterol as estimated by the four-
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A STUDY OF DIET AND BREAST CANCER TABLB 1
Mean nutrient intake for all respondents of menopausal status Nutrient and series Total calories Cases Controls Difference*
nt Total fat (gm) Cases Controls Difference Saturated fat (gm) Cases Controls Difference
Oleic acid (gm) Cases Controls Difference
Linoleic acid (gm) Cases Controls Difference n Cholesterol (mg) Cases Controls Difference
irrespective
Dietary method 24-hour recall
1697 1587 109 396 ipt = 0.01) 73.2 69.4 3.7 386
4-day record
History
1805 1785 20 309
2280 2230 150 388
81.9 80.0 1.9 309
99.1 96.6 2.5 395
irrespective of age, and are not presented here. In contrast, for those aged 70 or more (table 4) the estimated intake of controls exceeded that of cases for all nutrients by the four-day record and the dietary history, except for cholesterol as estimated by the four-day record. Influence of response to four-day record on estimates of nutrient intake. There was a lower response rate to the four-day record than for the other methods because the TABLI 2
Mean nutrient intake for pre-menopausal respondents Nutrient and series
28.0 26.2 1.8 383 (p = 0.05)
32.0 30.3 1.7 306
38.3 37.1 1.2 397
29.5 27.5 2.0 384
2500 91-120 gm >120gm 31-45 gm >45gm 31-45 gm >45gm 10-15 gm >15gm 351^90 mg >490mg
1.3 1.1 1.6 1.6 1.2 1.4 1.0 1.2 0.9 1.2 1.8 1.3
* Estimated relative to a risk of 1.0 for women in the referent category.
TABLE 6
Summary of risk ratio analysis of individual nutrient intake for post-menopausal women based on the diet history Nutrient
Referent category
Total calories
£1500
Total fat
£ 5 0 gm
Saturated fat
£ 2 0 gm
Oleic acid
£25 gm
Linoleic acid
Cholesterol
£ 6 gin
£210 mg
Comparison level
Risk ratio*
1501-2000 2001-2500 >2500 51-80 gm 81-110 gm >110gm 21-30 gm 31-40 gm >40gm 26-35 gm 36-45 gm >45 gm 7-9 gm 10-12 gm >12gm 211-350 mg 351-490 mg >490mg
1.0 0.8 1.2 1.7 1.2 1.8 1.2 1.1 1.2 1.2 1.5 1.1 1.1 1.2 1.2 1.3 1.3 1.2
* Estimated relative to a risk of 1.0 for women in the referent category.
Attempts to distinguish between the effects of the different nutrients in pre-menopausal women are made difficult by the high correlation that exists between them (30), which results in small numbers of discordant pairs when one nutrient is examined while controlling for the effect of the other. Bearing this limitation in mind, when total fat is controlled for saturated fat and vice versa (table 7), the risk ratio for total fat becomes 2.0, while that for saturated fat becomes 0.4, while the risk ratio for cholesterol is reduced when controlled for total fat and saturated fat. All estimates have wide confidence limits, but these results are suggestive of the importance of the role of total fat in pre-menopausal women. Since in pre-menopausal women, the cases tended to be lighter than the controls, the ratio of caloric intake to weight six months before interview was also examined. The mean values for cases and controls were 7.8 and 7.2 calories/kg, respectively (p = 0.13, two sided). However,
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MILLER ET AL. TABLB 7
Nutrient intake based on dietary history in pre-menopausal women controlled for other nutrients Level ofriskfactor Risk factor
Total fat (gin)
Saturated fat (gm)
Cholesterol (mg)
Referent category S90
a30
S350
Comparison level
Controlled for*
>90
No. of discordant pairet
Risk ratio (with 90% confidence limits)
Saturated fat Cholesterol
22/14 8/4 10/5
1.6 (0.9-3.0) 2.0 (0.6-7.2) 2.0(0.7-6.1)
Total fat Cholesterol
21/16 3/7 10/4
1.3 (0.7-2.4) 0.4(0.1-1.5) 2.5 (0.8-S.7)
Total fat Saturated fat
21/14 8/6 9/7
1.5 (0.8-2.8) 1.3 (0.5-3.9) 1.3 (0.5-3.4)
>30
>350
* Stratified by two levels of control factor. t Number of pairs; Case + Control - /Case - Control +.
the risk ratio estimate for calories controlled for weight remains 1.0, though based on small numbers. DISCUSSION
The findings on nutrient intake in the present study are in general supportive of the hypothesis that breast cancer in both pre- and post-menopausal women is related to an increased dietary intake of fat. Although the three basic methods used produced different quantitative estimates of intake (30), in general the methods complemented each other in producing a similar order of difference between cases and controls apart from the discrepancy between the four-day record and the other measures in pre-menopausal women and the 24-hour recall and other measures in women age 70 or more. Nevertheless, there is a high correlation between intake of total calories, total fat and saturated fat and some correlation with oleic, and linoleic acid and cholesterol intake (30) and this is reflected in the results. Both in the quantitative analysis and in the risk ratio analysis, the association seems strongest for total fat. In post-menopausal women considered by age, the quantitative analysis appears
to have identified a small group of women aged 70 or more with breast cancer where the estimated intake of total fat, calories and other nutrients is exactly the reverse of that anticipated from the prior hypothesis. It was this group of individuals who had a significant association with increased weight at the time of the menopause and up to six months before diagnosis (28). There are three possible explanations for the discrepancy: first, obese women may be more inclined than normal women to systematically under-report their food intake; second, older women may not be as able to handle the demands of the long questionnaire as younger women, so that in those age 70 or more the 24-hour recall may be more reliable because it does not take so long to complete; and third, this could be a sub-group of individuals with a reduced metabolic turnover, thus accounting for a combination of increased weight and reduced dietary consumption. The latter would seem to fit with the suggestion that patients with breast cancer may have a level of thyroid function which is lower than that found in women with conditions unrelated to the breast, and that this lowered function is of primary thyroid origin (34).
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The only other study reported to date (35) which directly examined the possible association between dietary fat intake and breast cancer, used a method which did not permit quantification of dietary fat intake, but examined the frequency of consumption of fat-containing foods. This was conducted in Seventh Day Adventists and other than a minor difference in the expected direction in relation to milk intake, was negative. Two other studies, one in Israel and one in Hawaii, are currently in progress in communities where dietary differences may be larger than might be anticipated in North America, and this may facilitate the demonstration of a dietary relationship. It has been noted before that it may be extremely difficult to confirm differences due to dietary factors when dealing with a relatively homogeneous population (29) or a chronic disease with a long latent period (36). This may go some way to explaining how a causal association could seem to be as weak as in this study. Such a finding might be anticipated in a circumstance where the majority of the population, both cases and controls, eat substantially more dietary fat than is required in order to act as a promoting agent in carcinogenesis, and are thus substantially above the threshold level of dietary fat required. If this, together with a partial failure of the methods accurately to quantify dietary intake, is valid explanation for a weak association, the finding of a weak association with total fat may indicate that the actual causal association is substantially stronger than has been demonstrated in the present study. Another explanation for finding a weaker association than may in fact exist is the use of neighborhood as distinct from random population controls. Neighborhood controls are in general preferable to hospital controls (37) and were specifically used in this study to match indirectly for socioeconomic status. However, neighbor-
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hood controls are also likely to consume a similar diet to the cases, and thus make it more difficult to demonstrate a relationship. It is of course possible that neither a dietary history directed to the period of six months before interview nor the other methods estimating current dietary intake may sufficiently reflect lifetime dietary experience to be relevant in relation to the etiology of breast cancer. However, emphasis on lifetime dietary intake may be misplaced if over-nutrition can operate as a promoting factor for breast cancer at any age. De Waard et al. (38) hypothesized that in the majority of patients with breast cancer occurring after the menopause, altered hormonal homeostasis related to over-nutrition is the major determinant, whereas most cases of breast cancer occurring in pre-menopausal women are connected with an endocrine imbalance, in which ovarian hormones are involved. Recently, however de Waard (21) has modified his own hypothesis, suggesting that more attention be given to hormones in relation to lean body mass. He pointed out that height correlates well with lean body mass, and that several endocrine and metabolic functions seem to correlate better with body surface area than with body weight. Indeed, because in de Waard's recent studies weight appeared to have no independent effect if there was an adjustment for its correlation with height, MacMahon (39) suggested that nutritional factors must operate in infancy and childhood, rather than in adult life. Our studies however, do not support a role for height, either in pre- or post-menopausal women (28). Nevertheless, a role for weight in post-menopausal women is indeed supported, though this appears to be maximally operative in women over the age of 70 related to weight at the time of menopause. This, therefore, puts the emphasis on nutritional factors related to
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body weight which obviously can be influenced by nutrition at any time in adult life. In order to facilitate clarification of these conflicting relationships it is desirable that every opportunity should be taken to collect dietary information on women who are likely to be observed prospectively for the development of breast cancer to overcome some of the difficulties with dietary assessment after a diagnosis of breast cancer is made. Until such confirmatory observations are forthcoming, recommendations of major dietary modification as a possible preventive measure for breast cancer are clearly premature. REFERENCES
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A STUDY OF DIET AND BREAST CANCER 34. Mittra I, Hayward JL: Hypothalamic pituitarythyroid axis in breast cancer. Lancet 1:886-889, 1974 35. Phillips RL: Role of life-style and dietary habits in risk of cancer among Seventh-Day Adventists. Cancer Res 35:3513-3522, 1975 36. Lilienfeld DE, Garagliano CF, Iilienfeld AM: Gastric cancer. (Letter to the Editor). J Natl Cancer Inst 57:9, 1976 37. Miller AB: Epidemiology: Problems in the study
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