- Email: [email protected]
Breast cancer risk and nutrient intake among French Canadians in Montreal: a case-control study
The Breusr (1998) 7, 108-l 13 0 1998 Harcoun Brace & Co. Ltd
ORIGINAL ARTICLE
Breast cancer risk and nutrient intake among French Canadians in Montreal: a case-control study P. Ghadirian, A. Lacroix*, C. Perret, A. Robidoux’, M. Falardeau’, P. Maisonneuve” and P. Boyle” Epidemiology Research Unit, Research Centre, CHUM, Pavillion Hotel-Dieu, Department of Nutrition, Faculty of Medicine, University of Montreal, *Laboratory of Nutrition and Cancer, Research Centre, CHUM, Pavillion Hotel-Dieu, ‘CHUM, Pavillion Hotel-Dieu, $CHUM, Pavillion Notre-Dame, Montreal, Quebec, Canada, §Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy S U M M A R Y. The association between dietary patterns and breast cancer risk remains one of the most important unresolved questions in epidemiology at the present time. In order to contribute to this debate, a case-control study of breast cancer was conducted in members of the Francophone community in Montreal. In total, 414 cases and 429 population-based controls were interviewed in this study. There was no association found between breast cancer risk and total energy intake or energy-providing nutrients, fat, protein and carbohydrates in any form or from any source. There was also no association found between the risk of breast cancer and the intake of vitamins and minerals, including vitamin A, retinol, beta-carotene, vitamin C or vitamin E. These results provide further evidence against the association between adult dietary fat intake and breast cancer risk. Given the indirect evidence supporting such an association, it appears imperative that consideration be given to how to further approach the subject of dietary fat intake and breast cancer risk. The lack of association between vitamins and minerals and breast cancer risk also casts doubt on such associations, indicating the importance of developing new hypotheses and approaches to the nutritional study of breast cancer.
INTRODUCTION
cancers in women. In Quebec, this rate is 93.0 per 100 000 women, representing 28.4% of all female cancers.3 The change in risk of breast cancer in migrants from lowincidence to high-incidence areas, and in their descendants, argues strongly for environmental influences. The incidence among Hawaii and San Francisco Bay area Japanese is now double that in Japan, although the difference is less in Los Angeles (1.4-fold). A comparable phenomenon is observable for the Chinese: the incidence in Singapore and Hong Kong Chinese is about 50% higher than in Shanghai and Tianjin, but well below that in US Chinese. In Singapore, the incidence in Singapore-born Chinese in 1968-1982 was 29.5, while for those born elsewhere, mainly in China, it was 18.2: a significant difference for all dialect groups4 The incidence of breast cancer is increasing slowly in most countries. Mortality rates have also been increasing in, for example, Japan and Hong Kong, having a tendency to remain stationary in western countries. In the USA, mortality in white women less than 50 years of age has fallen, overall mortality being remarkably stable between 1950 and 1982.’ There are many risk factors for breast cancer that have been identified for a long time. The frequency of breast cancer is higher among women of higher socioeconomic
Breast cancer is a major health problem concerning quality of life in many of the more developed countries of the world. Globally, breast cancer is the most frequent malignancy found among women, with over 700 000 new cases diagnosed worldwide each year in the mid-1980s.’ The highest incidence rates of breast cancer in women are exclusively from the USA. Incidence rates exceeding 100 per 100 000 are reported from the white population of the San Francisco Bay area (104.2). Rates in western Europe are considerably lower, with the highest incidence recorded from Geneva in Switzerland (73.5 per 100 000). The highest incidence rate in central and eastern Europe was reported from the former German Democratic Republic (46.3). Low rates are reported from other central and eastern European countries, Asia and Africa.* Breast cancer is the most common cancer of women in Canada, with an age-standardized incidence of 103 per 100 000 women, or 30.0% of all Address correspondence to: P. Ghadirian, Epidemiology Research Research Centre, CHUM, HBtel-Dieu Pavilion, 3850 St Urbain, Montreal, Quebec H2W lT8, Canada
Unit,
108
Breast cancer risk and nutrient intake status,“’ in women who are nulliparous or have a long menstrual history (early menarche and late menopause), and in women who have a first pregnancy later in life.’ The incidence of breast cancer is higher in relatives of women with breast cancer” as well as after exposure to ionizing radiation.” Women with cancer of the colon,‘2 ovaryI and endometrium’“.” have also been reported to be at increased risk for breast cancer, suggesting a common cause. However, these risk factors are held to account for only 40-50% of breast cancer cases.16 Several epidemiological studies have postulated the association of diet, particularly dietary fat, with breast cancer. Animal studies have shown that dietary fats act as carcinogen promoters, with high-fat diets causing more mammary tumours than low-fat diets.” Ecological studies indicate a positive correlation between per capita fat consumption in different countries and breast cancer incidence rates.” Migrant studies demonstrate an increase in breast cancer incidence among groups migrating from low to high fatconsuming societies. However, these types of studies are unable to control for other important influencing variables such as socioeconomic status and total caloric intake.” Epidemiological studies of the relationship between dietary fat and breast cancer, both case-control and cohort, give odds ratios and relative risks that are sometimes slightly positive or frequently null. Problems hampering elucidation of the dietary fat effect on breast cancer are limitations of precision of dietary measurement tools and the high correlation between dietary fat with other diet and lifestyle variables. Advocates of the dietary fat-breast cancer hypothesis maintain that most studies do not include the low levels of dietary fat necessary to see a dose-response relationship between dietary fat and breast cancer risk.‘* Studies documenting a significant relationship between fat intake and breast cancer risk suggest a 30% reduction in breast cancer risk per 10% decrease in dietary fat.” The purpose of conducting a case-control study of breast cancer in the Francophone community of Montreal was to investigate a population subgroup whose lifestyle differs from that of the surrounding population of North America. We studied the food habits, food patterns and nutrient intakes of this unique population with its particular characteristics; dietary instruments were developed and tested in this population. Therefore, it was very important to investigate the possible role of nutrition and cancer in this homogenous population.
MATERIALS
AND METHODS
This case-control study was conducted among the Francophone community in Greater Montreal using an established network of hospitals that had conducted previous studies of
109
diet and cancer risk in that region. Each study subject was interviewed using a structured questionnaire and by trained interviewers: subsequently, subjects were asked to give a blood sample for biological analysis. This article reports the results of the interview data relating to dietary intake.
Case ascertainment During 1989-1993, all patients aged between 35 and 79 years with a histological diagnosis of breast cancer were identified through the admission offices of three major teaching hospitals of the RICUM (Reseau Inter-hospitalier de Cancerologie de 1’UniversitC de Montreal). When an eligible case was identified, the attending surgeon or physician was approached for permission to interview the patient. If permission was given, the patient was contacted by letter, followed by a telephone call to arrange an interview.
Control ascertainment Population-based controls matched for age (within 5 years in each age group) and place of residence were selected by a modified random digit dialling telephone directory method: they were selected from the telephone directory in which the corresponding case was listed (all patients studied had a listed telephone number and only 1% of families in Montreal regions do not have a telephone). One page from the telephone directory was randomly selected from the sampling frame and the names and addresses of 10 individuals with the same first 3 digits of the telephone number (of the 7-digit code) were selected for each case. These residences were then contacted by telephone (if there was no answer, the number, date and time of calling were recorded and the same number was called 7 more times during the day, the evening and on weekends before the number was rejected) to see if the household contained an individual who matched the index case for age and who agreed to be interviewed. If so, an interview was arranged at the control’s home. If not, the procedure was repeated. If more than one eligible control was reached at a given number, this information was kept in a databank for future use. All controls were interviewed no later than 3 months after the matching cases were interviewed. For cases without a telephone, random digit dialling would have been used to select a control, but all of our cases had a telephone number. This study was conducted in parallel with a similar study of colon cancer and prostate cancer, and a common control population was selected. A total of 2085 controls was selected, of whom only 1361 (65%) fulfilled the eligibility criteria for the study. A total of 171 (8%) gave no answer, 335 (16%) refused to participate before the study was
110
The Breast
explained to them, and a further 167 (8%) refused to participate after the study was explained. Thus, 688 subjects were interviewed in total: this represents 33% of all controls selected and 50% of all eligible subjects. Of the 688 controls interviewed, 429 were women. For both cases and controls, interviews were carried out in the respondent’s home using a structured questionnaire. If either the case or the control was hospitalized at the time of the scheduled interview and seemed unlikely to be available for home interview within 2 weeks, an in-hospital interview was arranged. If the patient was very ill, whether at home or in hospital, the interview was carried out in the presence and with the help of any family members or other persons who were available and likely to have relevant information. The matched control was interviewed no longer than 3 months after interview of the case, and no proxy interviews were performed. Questionnaires All information was obtained through questionnaires administered in a standardized manner to all cases and controls by trained interviewers. Core questionnaire This questionnaire was developed, evaluated and tested in our unit. It consisted of several questions concerning lifestyle, occupation, level of drinking and/or smoking, medical history, history of weight changes, information on supplementary vitamin and mineral intake, detailed information on changing food habits and food patterns before the diagnosis of cancer, family history of breast cancer, etc. Foodfrequency history questionnaire The food frequency questionnaire of the Epidemiology Unit of the National Cancer Institute of Canada (NCIC), which was devised for Canadian populations, served as the basis of the questionnaire used in this study. The French version used by our centre was adapted for cancers of the pancreas, bile duct and gallbladder. This instrument is designed to collect quantitative information based on ‘food models’ and qualitative data on food habits and dietary patterns. It includes questions on more than 200 different food items and beverages as well as frequency of consumption and amount consumed. The questionnaire covered 2 years prior to diagnosis for casesand a corresponding period for controls. This dietary questionnaire has been examined for validity and reliability,20~2’and a databank is available to permit collected data to be translated into a detailed dietary history. Statistical analysis Initially, the dataset was scanned using standard descriptive statistics. Crude odds ratios (ORs) and corresponding
Table 1 1989-1993 Age group
Distribution (years)
o-44 4549 S&54 55-59 60-64 65-69 XL74 75+
of cases and controls
by age in Montreal:
All subjects
Cases
Controls
158 136 128 99 97 102 73 50
79 69 66 41 50 51 27 25
79 61 62 52 41 51 46 25
confidence intervals (CIs) were calculated. ORs and corresponding 95% CIs were then estimated by unconditional logistic regression. The study subjects were stratified by age groups and all models included the corresponding indicator terms for age. All analyses were adjusted for age and energy intake using categories of residuals obtained by regression of the nutrient on total energy intake.22 Statistical analysis was conducted with SAS statistical software.
RESULTS The age distribution of cases and controls is fairly similar, with a slight excess of controls over the age of 70 years (Table 1). During 1989-1993, 935 cases of breast cancer were identified, of which 396 (42%) were ineligible for inclusion in the study for a variety of reasons: age (62,7%), place of residence (286, 30%), diagnosis (e.g. second primary cancer [37, 4%]) or death prior to interview (11, 1%). Thus, there were 539 eligible cases, representing 58% of all cases identified. Of these eligible patients, 72 refused to participate (13%), consent of doctor was not obtained (refused or no answer) for 45 cases (8%), a change of address resulted in lost contact on 6 occasions (l%), and the final diagnosis was changed in 2 after surgery and interview (~1%). Thus, 414 cases were interviewed, representing a response rate of 77% of eligible cases. After adjustment for age, parity, age at first full-term pregnancy, breast cancer in first-degree relatives and personal income (taken as a measure of socioeconomic status), there was no association found between breast cancer risk and total energy intake (relative risk [RR] = 1.14; P = 0.43); Table 2). When the major energy-providing nutrients were examined after adjustment as described above and additionally for intake of calories from other sources, there was no association found with either protein intake (RR = 0.97; P = 0.90), total fat intake (RR = 0.91; P = 0.38) or total carbohydrate intake (RR= 1.18; P = 0.27). In cases, the OR in the highest quarter was not significantly different from that of the referent category. When these data were examined in an alternative manner, as a percentage of calories, there
Breast cancer risk and nutrient intake Table 2 Relative risk of breast cancer in Montreal: 1989-1993 Nutrient
associated
with energy-providing
nutrients
among
2nd* quartile
3rd* quartile
4th* quartile
P value for trend
1.00 1.00 1.00 1.00
1.17 1.04 1.16 0.91
1.33 0.76 1.39 1.07
1.14 0.91 1.18 0.97
0.4330 0.3808 0.2789 0.8967
energy” fatb carbohydrate? protem’
*ORs “From degree bAlso
and 95% Cls. logistic regression, adjusted for age, parity, age at first full-term pregnancy, breast relatives, marital status, history of benign breast disease and personal income. adjusted for total energy using the nutrient residual method.
(0.78-1.75) (0.69-1.57) (0.77-1.74) (0.61-1.37)
Table 3 Relative risk of breast cancer associated among French Canadians in Montreal: 1989-1993 Nutrient fat carbohydrates protein
(0.89-1.99) (0.50-1.15) (0.93-2.08) (0.71-1.61)
(0.75-1.71) (0.61-1.37) (0.78-1.79) (0.65-1.46) cancer
in first-
min C (RR = 0.84; P = 0.14), retinol (RR = 0.80; P = 0. 15>, beta-carotene (RR = 1.08; P = 0.97) or vitamin E (RR = 0.75; P = 0.21). We carried out a separate analysis of pre- and postmenopausal women for all food items and observed no changes, except that among the postmenopausal group, fat from vegetable sources was inversely associated with risk [OR = 0.59; 95% CI (0.35-l.OO), P = 0.04941. Therefore, in this article, we present the results of the study of all subjects combined (data not shown).
was again no indication of any association with fat, protein or carbohydrates expressed as a proportion of total energy intake (Table 3). When the different sources and types of fat were examined, there was no association found whether the breakdown was into type of fat, such as saturated fat (RR = 0.89; P = 0.84), monounsaturated fat (RR = 0.86; P = 0.32), polyunsaturated fat (RR = 0.87; P = 0.25) or cholesterol (RR = 1.08; P = 0.48), or the source of fat, namely animal (RR-1.16; P = 0.51) or vegetable (RR = 0.71; P = 0.22). Similarly, there was no association between subtypes of carbohydrate or protein intake and the risk of breast cancer. There was also no association found between total ethanol intake or fibre intake (Table 4). There was no significant association between breast cancer risk and vitamins, minerals or other nutrients in the diet. In particular, there was no association found between breast cancer risk and total vitamin A (RR = 0.94; P = 0.49) vita-
from from from
Canadians
1st quartile
Total Total Total Total
% calories % calories % calories
French
DISCUSSION Despite many detailed epidemiological studies, including a large number with biological measurements, the aetiology of breast cancer remains unclear.23~24The association between breast cancer risk and diet, particularly dietary fat
with the proportion
of energy
from
fat, carbohydrate
and protein
1st quartile
2nd* quartile
3rd* quartile
4th* quartile
P value for trend
1.00 1 .OO 1.00
0.98 (0.65-1.47) 1.05 (0.70-l .57) 0.86 (0.58-1.29)
0.94 (0.63-1.41) 1.06 (0.71-1.60) 0.95 (0.63-1.42)
0.98 (0.66-1.47) 1.10 (0.73-1.65) 0.90 (0.6Sl.36)
0.8896 0.6680 0.7561
*ORs and 95% CIs from logistic regression, adjusted for age, parity, age at first full-term pregnancy, breast cancer in first-degree relatives, marital status, history of benign breast disease and personal income. The cut-off points for quartiles are 12.0%, 13.6% and 15.3% for protein, 28.6%, 32.9% and 36.4% for fat and 49.5%, 54.2% and 58.9% for carbohydrates.
Table 4 Canadians
Relative risk of breast cancer in Montreal: 1989-1993
associated
with intake
of alcohol
and dietary
tibre
among
French
Nutrient
1st quartile
2nd* quartile
3rd* quartile
4th* quartile
P value for trend
Total ethanol Crude total fibre Dietary tibre Mixed fibre
1.00 1.00 1.00 1.00
1.02 0.77 1.05 0.91
0.78 1.10 0.83 0.81
0.90 0.81 0.82 0.77
0.454 1 0.6788 0.2156 0.1647
(0.65-1.61) (0.51-1.15) (0.70-1.58) (0.61-1.36)
111
(0.48-1.25) (0.73-1.64) (0.56-l .25) (0.54-1.20)
*ORs and 95 % CIs from logistic regression, adjusted for age, parity, age at first cancer in first-degree relatives, personal income, marital status, history of benign energy using the nutrient residual method.
(0.561.44) (0.54-1.22) (0.55-l .24) (0.51-1.15)
full-term pregnancy, breast breast disease and total
112
The Breast
intake, currently remains the subject of a great deal of controversy.25 Theoretical considerations of biological processes lead to the conclusion that an increased risk of breast cancer is plausible with increasing saturated fat intake in postmenopausal women.“j However, the evidence from investigations in human subjects with breast cancer is unclear. A meta-analysis of studies of dietary fat and breast cancer risk,*’ comparing highest to lowest level fat intakes, showed a summary RRof 1.12 [95% CI (1.04-1.21)]. When cohort studies alone were analysed, a non-significant risk of 1.01 was obtained, compared to case-control studies alone giving a significant RR of 1.2 1. This difference in risk estimates between study types has been attributed to a potential bias of case-control studies in recall of dietary information.** In the meta-analysis, European studies were more likely to show a positive correlation between dietary fat and breast cancer risk, irrespective of study type.27 This finding appears to be driven by the results from casecontrol studies, particularly those conducted in European populations where the authors have observed that the diet may be more varied than in North American populations. The large North American studies of dietary fat intake and breast cancer risk have been criticized as having too limited a range of intakes available in the population to detect the magnitude of risk being investigated. It is notable that in subsequent reports of two large, well-conducted casecontrol studies in low-risk populations with low intakes of saturated fat where an effect of fat could be investigated, no significant effect of any fat on breast cancer was seen in Spain,29 but the protective influence of olive oil on breast cancer was noted in Greece30%3’ as well as in Italy.32 It is still not altogether straightforward to interpret these findings. Meta-analysis is a technique that needs more thought when applied to observational studies than when applied to randomized trials, and many issues remain unresolved.33 It is also somewhat discomfiting that the positive association between breast cancer risk and fat intake is being driven by findings from case-control studies that represent a design perceived to be weaker than the prospective design of cohort studies for the analysis of dietary associations.34 Studies from Greece35 and Italy36 suggest that green vegetable consumption is an indicator of a low-risk dietary pattern. This may simply reflect low intake of fat or calories, or may suggest that some constituent of green vegetables may be protective. However, this has not been a consistent finding from studies of the association between fruit and vegetable consumption and cancer risk.37 In a prospective study of over 80 000 US nurses, no association was found between breast cancer risk and dietary intakes of vitamin C, vitamin E or beta-carotene. However, women in the lowest fifth of daily intake of vitamin A from dietary sources were found to have an increased risk of breast
cancer over other women in the cohort.36 Furthermore, when the effect of vitamin supplementation was investigated, there was a protective effect of vitamin A, but only among women in the lowest fifth of daily intake of this vitamin. This is a particularly interesting finding, the true significance of which will become apparent as the results of other ongoing epidemiological studies become available.38 Different studies have shown different dietary fat components to be risk factors for breast cancer. In their case-control study, Goodman et a139found significant associations between consumption of meat and dairy products and breast cancer risk, acting in conjunction with body size, but failed to establish an association with total or saturated fat consumption. A difference in effect patterns of dietary fat on breast cancer risk was observed in a Moscow casecontrol study, diet being more important in postmenopausal women40 and this was postulated to be a cohort effect in eating habits. The same study found polyunsaturated fatty acids to be protective against breast cancer and showed no effect for saturated fat or protein in the diet. Multivariate analysis of a case-control study in France revealed small but significant effects (OR = 2) of total, saturated and monounsaturated fat consumption on breast cancer risk.41 In contrast, a Dutch case-control study reporting a significant overall fat effect could show no influence of any specific fat category (saturated, mono- and polyunsaturated fats), but found a significant association between breast cancer risk and meat, cakes and snacks.”
Acknowledgements It is a pleasure to thank our collaborators in RICUM for their support. They include the following surgeons: Drs J. Cantin and C. Potvin (Hotel-Dieu de Montreal); A. Peloquin and M. Poljicak (Notre-Dame de Montreal); E. Nassif, P. Franchebois, S. Legault and R. Poisson (St-Luc Hospital). We also thank Florence Auclair, Lucie Gravel, Jacqueline Marchand and Johanne Theroux for interviewing the case and control subjects in this study. We are grateful to Mr Ovid Da Silva for his editorial work and MS Helene Hamois for typing this manuscript. It is a pleasure to acknowledge funding for this study from the Medical Research Council of Canada and the Cancer Research Society. This investigation was conducted within the framework of an international collaborative study of breast cancer coordinated by the European Institute of Oncology, with coordination funds being provided by the Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research).
References 1. Parkin D M, Pisani P, Ferlay J. Estimates of the world wide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. 2. Parkin D M, Muir C S, Whelan S et al, eds. Cancer incidence in five continents, vol VI. Lyon: IARC Scientific Publications, 1992: 120. 3. National Cancer Institute of Canada. Canadian Cancer Statistics, 1994. 4. Lee H P, Day N E, Shanmugaramam K, eds. Trends in cancer incidence in Singapore 1968-1982. Lyon: IARC Scientific Publications, 1988: 91.
Breast cancer risk and nutrient intake 5. Devesa S S, Silverman D T, Young J L et al. Cancer incidence and mortality among whites in the United States, 1974-1984. J Nat1 Cancer Inst 1987; 79: 701-770. 6. Paymaster .I C, Grangadharan P. Some observations on the epidemiology of cancer of the breast in women of western India. Int J Cancer 1972; 10: 443. 7. Wynder E L, Bross I J, Hirayama T. A study of the epidemiology of cancer of the breast. Cancer 1960; 13: 559. 8. Lancaster H 0. The mortality in Australia from cancers peculiar to the female. Med J Austr 1971; 7: l-7. 9. MacMahon B, Cole P, James B. Etiology of human breast cancer: a review. J Nat1 Cancer Inst 1973; 50: 2142. 10. Harris R E, Lynch H T, Guirgis H A. Familial breast cancer: risk to the contralateral breast. J Nat1 Cancer Inst 1978; 60: 955-960. 11. Boice J D, Stone B J. Interaction between radiation and other breast cancer risk factors. In: Late biological effects of ionising radiation, vol. 1. Vienna: IAEA, 1978: 231-249. 12. Schottenfeld D, Berg J, Vitsky B. Incidence of multiple primary cancer. II. Index cancers arising in the stomach and lower digestive system. J Nat1 Cancer Inst 1969; 43: 77-86. 13. Schoenberg B S, Greenberg R A, Eisenberg H. Occurrence of certain multiple primary cancers in females. J Nat1 Cancer Inst 1969: 43: 15-32. 14. MacMahon B, Austin J H. Association of carcinomas of the breast and corpus uteri. Cancer 1969; 23: 275-280. 15. Schottenfeld D, Berg J. Incidence of multiple primary cancers. IV. Cancer of the female breast and genital organs. J Nat1 Cancer Inst 1971; 46: 161-170. 16. Hankin J H. Role of nutrition in women’s health: diet and breast cancer. J Am Diet Assoc 1993; 93: 994-999. 17. Howe G R. High-fat diets and breast cancer risk: the epidemiologic evidence. JAMA 1992; 268: 2080-2081. 18. Wynder E L. Cohen L A, Rose D P et al. Dietary fat and breast cancer: where do we stand with the evidence? J Clin Epidemiol 1994; 47: 217-222. 19. Van’t Veer P, Kok E J, Brants H A M et al. Dietary fat and the risk of breast cancer. Int J Epidemiol 1990; 19: 12-18. 20. Jain M, Howe G R, Johnson K C et al. Evaluation of a diet history questionnaire for epidemiologic studies. Am J Epidemiol 1980; 111:212-219. 2 1. Jain M, Howe G R, Harisson L et al. A study of the repeatability of dietary data over a seven-year period. Am J Epidemiol 1989; 129: 422429. 22. Willett W C, Stampfer M J. Total energy intake: implications for epidemiologic analysis. Am J Epidemiol 1986; 124: 17-27. 23. Boyle P. The epidemiology of breast cancer. In: Veronesi U, ed. Bailliere’s clinical oncology, vol. 2. 1988: l-58
113
24. Boyle P, Maisonneuve P. Diet. In: Waxman J, ed. Hormonal carcinogenesis. Cambridge: Cambridge University Press, 1996. 25. Willett W C. Nutritional epidemiology. Oxford: Oxford University Press, 1989. 26. Boyle P, Leake R E. Progress in understanding breast cancer: epidemiologic and biologic interactions. Breast Cancer Res Treat 1988; 11:91-112. 27. Boyd N F, Martin L J, Noffel M et al. A meta-analysis of studies of dietary fat and breast cancer risk. Br J Cancer 1993; 68: 627-636. 28. Giovannuci E, Stampfer M J, Colditz G A et al. A comparison of prospective and retrospective assessments of diet in the study of breast cancer. Am J Epidemiol 1993; 137: 502-5 11. 29. Martin-Moreno J, Willett W C, Gorgojo L et al. Dietary fat, olive oil and breast cancer risk. Int J Cancer 1994; 58: 774-780. 30. Katsouyanni K, Trichopoulou A, Stuver S et al. The association of fat and other macronutrients with breast cancer: a case-control study from Greece. Br J Cancer 1994; 70: 537-541. 3 1. Trichopolou A, Katsouyani K, Stuver S et al. Consumption of olive oil and specific food groups in relation to breast cancer risk in Greece. J Nat1 Cancer Inst 1995; 87: 110-l 16. 32. La Vecchia C, Negri E, Franceschi S et al. Olive oil, other dietary fats and the risk of breast cancer. Cancer Causes Control 1995: 6: 545-550. 33. Spitzer W 0. Meta-analysis: unanswered questions about aggregating data. J Clin Epidemiol 1991; 44: 103-107. 34. Boyle P. Dietary factors in the aetiology of cancer (editorial). Oncol Haematol Literature Serv 1994: 1: 7-8. 35. Katwouyani K, Trichopoulos D, Boyle P et al. Diet and breast cancer: a case-control study in Greece. lnt J Cancer 1986: 38: 815-820. 36. La Vecchia C, Decarli A, Franceschi S et al. Dietary factors and the risk of breast cancer. Nutr Cancer 1987: 10: 205-214. 37. Steinmetz K A, Potter J D. Vegetables, fruits and cancer. Cancer Causes Control 1991: 2: 325-357. 38. Hunter D J, Manson J, Colditz G A et al. A prospective study of the intake of vitamins C, E and A and the risk of breast cancer. N Engl J Med 1993; 329: 234-240. 39. Goodman M T Y, Nomura A M Y, Wilkens L R et al. The association of diet, obesity and breast cancer in Hawaii. Cancer Epidemiol Biomarkers Prev 1992; 1: 269-275. 40. Zaridze D, Lifanova Y, Masimovitch D et al. Diet, alcohol consumption and reproductive factors in a case-control study of breast cancer in Moscow. Int J Cancer 1991; 48: 493-501. 41. Richardson S, Gerber M, Cenee S. The role of fat, animal protein and some vitamin consumption in breast cancer: a case control study in southern France. Int J Cancer 1991; 48: l-9.
ORIGINAL ARTICLE
Breast cancer risk and nutrient intake among French Canadians in Montreal: a case-control study P. Ghadirian, A. Lacroix*, C. Perret, A. Robidoux’, M. Falardeau’, P. Maisonneuve” and P. Boyle” Epidemiology Research Unit, Research Centre, CHUM, Pavillion Hotel-Dieu, Department of Nutrition, Faculty of Medicine, University of Montreal, *Laboratory of Nutrition and Cancer, Research Centre, CHUM, Pavillion Hotel-Dieu, ‘CHUM, Pavillion Hotel-Dieu, $CHUM, Pavillion Notre-Dame, Montreal, Quebec, Canada, §Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy S U M M A R Y. The association between dietary patterns and breast cancer risk remains one of the most important unresolved questions in epidemiology at the present time. In order to contribute to this debate, a case-control study of breast cancer was conducted in members of the Francophone community in Montreal. In total, 414 cases and 429 population-based controls were interviewed in this study. There was no association found between breast cancer risk and total energy intake or energy-providing nutrients, fat, protein and carbohydrates in any form or from any source. There was also no association found between the risk of breast cancer and the intake of vitamins and minerals, including vitamin A, retinol, beta-carotene, vitamin C or vitamin E. These results provide further evidence against the association between adult dietary fat intake and breast cancer risk. Given the indirect evidence supporting such an association, it appears imperative that consideration be given to how to further approach the subject of dietary fat intake and breast cancer risk. The lack of association between vitamins and minerals and breast cancer risk also casts doubt on such associations, indicating the importance of developing new hypotheses and approaches to the nutritional study of breast cancer.
INTRODUCTION
cancers in women. In Quebec, this rate is 93.0 per 100 000 women, representing 28.4% of all female cancers.3 The change in risk of breast cancer in migrants from lowincidence to high-incidence areas, and in their descendants, argues strongly for environmental influences. The incidence among Hawaii and San Francisco Bay area Japanese is now double that in Japan, although the difference is less in Los Angeles (1.4-fold). A comparable phenomenon is observable for the Chinese: the incidence in Singapore and Hong Kong Chinese is about 50% higher than in Shanghai and Tianjin, but well below that in US Chinese. In Singapore, the incidence in Singapore-born Chinese in 1968-1982 was 29.5, while for those born elsewhere, mainly in China, it was 18.2: a significant difference for all dialect groups4 The incidence of breast cancer is increasing slowly in most countries. Mortality rates have also been increasing in, for example, Japan and Hong Kong, having a tendency to remain stationary in western countries. In the USA, mortality in white women less than 50 years of age has fallen, overall mortality being remarkably stable between 1950 and 1982.’ There are many risk factors for breast cancer that have been identified for a long time. The frequency of breast cancer is higher among women of higher socioeconomic
Breast cancer is a major health problem concerning quality of life in many of the more developed countries of the world. Globally, breast cancer is the most frequent malignancy found among women, with over 700 000 new cases diagnosed worldwide each year in the mid-1980s.’ The highest incidence rates of breast cancer in women are exclusively from the USA. Incidence rates exceeding 100 per 100 000 are reported from the white population of the San Francisco Bay area (104.2). Rates in western Europe are considerably lower, with the highest incidence recorded from Geneva in Switzerland (73.5 per 100 000). The highest incidence rate in central and eastern Europe was reported from the former German Democratic Republic (46.3). Low rates are reported from other central and eastern European countries, Asia and Africa.* Breast cancer is the most common cancer of women in Canada, with an age-standardized incidence of 103 per 100 000 women, or 30.0% of all Address correspondence to: P. Ghadirian, Epidemiology Research Research Centre, CHUM, HBtel-Dieu Pavilion, 3850 St Urbain, Montreal, Quebec H2W lT8, Canada
Unit,
108
Breast cancer risk and nutrient intake status,“’ in women who are nulliparous or have a long menstrual history (early menarche and late menopause), and in women who have a first pregnancy later in life.’ The incidence of breast cancer is higher in relatives of women with breast cancer” as well as after exposure to ionizing radiation.” Women with cancer of the colon,‘2 ovaryI and endometrium’“.” have also been reported to be at increased risk for breast cancer, suggesting a common cause. However, these risk factors are held to account for only 40-50% of breast cancer cases.16 Several epidemiological studies have postulated the association of diet, particularly dietary fat, with breast cancer. Animal studies have shown that dietary fats act as carcinogen promoters, with high-fat diets causing more mammary tumours than low-fat diets.” Ecological studies indicate a positive correlation between per capita fat consumption in different countries and breast cancer incidence rates.” Migrant studies demonstrate an increase in breast cancer incidence among groups migrating from low to high fatconsuming societies. However, these types of studies are unable to control for other important influencing variables such as socioeconomic status and total caloric intake.” Epidemiological studies of the relationship between dietary fat and breast cancer, both case-control and cohort, give odds ratios and relative risks that are sometimes slightly positive or frequently null. Problems hampering elucidation of the dietary fat effect on breast cancer are limitations of precision of dietary measurement tools and the high correlation between dietary fat with other diet and lifestyle variables. Advocates of the dietary fat-breast cancer hypothesis maintain that most studies do not include the low levels of dietary fat necessary to see a dose-response relationship between dietary fat and breast cancer risk.‘* Studies documenting a significant relationship between fat intake and breast cancer risk suggest a 30% reduction in breast cancer risk per 10% decrease in dietary fat.” The purpose of conducting a case-control study of breast cancer in the Francophone community of Montreal was to investigate a population subgroup whose lifestyle differs from that of the surrounding population of North America. We studied the food habits, food patterns and nutrient intakes of this unique population with its particular characteristics; dietary instruments were developed and tested in this population. Therefore, it was very important to investigate the possible role of nutrition and cancer in this homogenous population.
MATERIALS
AND METHODS
This case-control study was conducted among the Francophone community in Greater Montreal using an established network of hospitals that had conducted previous studies of
109
diet and cancer risk in that region. Each study subject was interviewed using a structured questionnaire and by trained interviewers: subsequently, subjects were asked to give a blood sample for biological analysis. This article reports the results of the interview data relating to dietary intake.
Case ascertainment During 1989-1993, all patients aged between 35 and 79 years with a histological diagnosis of breast cancer were identified through the admission offices of three major teaching hospitals of the RICUM (Reseau Inter-hospitalier de Cancerologie de 1’UniversitC de Montreal). When an eligible case was identified, the attending surgeon or physician was approached for permission to interview the patient. If permission was given, the patient was contacted by letter, followed by a telephone call to arrange an interview.
Control ascertainment Population-based controls matched for age (within 5 years in each age group) and place of residence were selected by a modified random digit dialling telephone directory method: they were selected from the telephone directory in which the corresponding case was listed (all patients studied had a listed telephone number and only 1% of families in Montreal regions do not have a telephone). One page from the telephone directory was randomly selected from the sampling frame and the names and addresses of 10 individuals with the same first 3 digits of the telephone number (of the 7-digit code) were selected for each case. These residences were then contacted by telephone (if there was no answer, the number, date and time of calling were recorded and the same number was called 7 more times during the day, the evening and on weekends before the number was rejected) to see if the household contained an individual who matched the index case for age and who agreed to be interviewed. If so, an interview was arranged at the control’s home. If not, the procedure was repeated. If more than one eligible control was reached at a given number, this information was kept in a databank for future use. All controls were interviewed no later than 3 months after the matching cases were interviewed. For cases without a telephone, random digit dialling would have been used to select a control, but all of our cases had a telephone number. This study was conducted in parallel with a similar study of colon cancer and prostate cancer, and a common control population was selected. A total of 2085 controls was selected, of whom only 1361 (65%) fulfilled the eligibility criteria for the study. A total of 171 (8%) gave no answer, 335 (16%) refused to participate before the study was
110
The Breast
explained to them, and a further 167 (8%) refused to participate after the study was explained. Thus, 688 subjects were interviewed in total: this represents 33% of all controls selected and 50% of all eligible subjects. Of the 688 controls interviewed, 429 were women. For both cases and controls, interviews were carried out in the respondent’s home using a structured questionnaire. If either the case or the control was hospitalized at the time of the scheduled interview and seemed unlikely to be available for home interview within 2 weeks, an in-hospital interview was arranged. If the patient was very ill, whether at home or in hospital, the interview was carried out in the presence and with the help of any family members or other persons who were available and likely to have relevant information. The matched control was interviewed no longer than 3 months after interview of the case, and no proxy interviews were performed. Questionnaires All information was obtained through questionnaires administered in a standardized manner to all cases and controls by trained interviewers. Core questionnaire This questionnaire was developed, evaluated and tested in our unit. It consisted of several questions concerning lifestyle, occupation, level of drinking and/or smoking, medical history, history of weight changes, information on supplementary vitamin and mineral intake, detailed information on changing food habits and food patterns before the diagnosis of cancer, family history of breast cancer, etc. Foodfrequency history questionnaire The food frequency questionnaire of the Epidemiology Unit of the National Cancer Institute of Canada (NCIC), which was devised for Canadian populations, served as the basis of the questionnaire used in this study. The French version used by our centre was adapted for cancers of the pancreas, bile duct and gallbladder. This instrument is designed to collect quantitative information based on ‘food models’ and qualitative data on food habits and dietary patterns. It includes questions on more than 200 different food items and beverages as well as frequency of consumption and amount consumed. The questionnaire covered 2 years prior to diagnosis for casesand a corresponding period for controls. This dietary questionnaire has been examined for validity and reliability,20~2’and a databank is available to permit collected data to be translated into a detailed dietary history. Statistical analysis Initially, the dataset was scanned using standard descriptive statistics. Crude odds ratios (ORs) and corresponding
Table 1 1989-1993 Age group
Distribution (years)
o-44 4549 S&54 55-59 60-64 65-69 XL74 75+
of cases and controls
by age in Montreal:
All subjects
Cases
Controls
158 136 128 99 97 102 73 50
79 69 66 41 50 51 27 25
79 61 62 52 41 51 46 25
confidence intervals (CIs) were calculated. ORs and corresponding 95% CIs were then estimated by unconditional logistic regression. The study subjects were stratified by age groups and all models included the corresponding indicator terms for age. All analyses were adjusted for age and energy intake using categories of residuals obtained by regression of the nutrient on total energy intake.22 Statistical analysis was conducted with SAS statistical software.
RESULTS The age distribution of cases and controls is fairly similar, with a slight excess of controls over the age of 70 years (Table 1). During 1989-1993, 935 cases of breast cancer were identified, of which 396 (42%) were ineligible for inclusion in the study for a variety of reasons: age (62,7%), place of residence (286, 30%), diagnosis (e.g. second primary cancer [37, 4%]) or death prior to interview (11, 1%). Thus, there were 539 eligible cases, representing 58% of all cases identified. Of these eligible patients, 72 refused to participate (13%), consent of doctor was not obtained (refused or no answer) for 45 cases (8%), a change of address resulted in lost contact on 6 occasions (l%), and the final diagnosis was changed in 2 after surgery and interview (~1%). Thus, 414 cases were interviewed, representing a response rate of 77% of eligible cases. After adjustment for age, parity, age at first full-term pregnancy, breast cancer in first-degree relatives and personal income (taken as a measure of socioeconomic status), there was no association found between breast cancer risk and total energy intake (relative risk [RR] = 1.14; P = 0.43); Table 2). When the major energy-providing nutrients were examined after adjustment as described above and additionally for intake of calories from other sources, there was no association found with either protein intake (RR = 0.97; P = 0.90), total fat intake (RR = 0.91; P = 0.38) or total carbohydrate intake (RR= 1.18; P = 0.27). In cases, the OR in the highest quarter was not significantly different from that of the referent category. When these data were examined in an alternative manner, as a percentage of calories, there
Breast cancer risk and nutrient intake Table 2 Relative risk of breast cancer in Montreal: 1989-1993 Nutrient
associated
with energy-providing
nutrients
among
2nd* quartile
3rd* quartile
4th* quartile
P value for trend
1.00 1.00 1.00 1.00
1.17 1.04 1.16 0.91
1.33 0.76 1.39 1.07
1.14 0.91 1.18 0.97
0.4330 0.3808 0.2789 0.8967
energy” fatb carbohydrate? protem’
*ORs “From degree bAlso
and 95% Cls. logistic regression, adjusted for age, parity, age at first full-term pregnancy, breast relatives, marital status, history of benign breast disease and personal income. adjusted for total energy using the nutrient residual method.
(0.78-1.75) (0.69-1.57) (0.77-1.74) (0.61-1.37)
Table 3 Relative risk of breast cancer associated among French Canadians in Montreal: 1989-1993 Nutrient fat carbohydrates protein
(0.89-1.99) (0.50-1.15) (0.93-2.08) (0.71-1.61)
(0.75-1.71) (0.61-1.37) (0.78-1.79) (0.65-1.46) cancer
in first-
min C (RR = 0.84; P = 0.14), retinol (RR = 0.80; P = 0. 15>, beta-carotene (RR = 1.08; P = 0.97) or vitamin E (RR = 0.75; P = 0.21). We carried out a separate analysis of pre- and postmenopausal women for all food items and observed no changes, except that among the postmenopausal group, fat from vegetable sources was inversely associated with risk [OR = 0.59; 95% CI (0.35-l.OO), P = 0.04941. Therefore, in this article, we present the results of the study of all subjects combined (data not shown).
was again no indication of any association with fat, protein or carbohydrates expressed as a proportion of total energy intake (Table 3). When the different sources and types of fat were examined, there was no association found whether the breakdown was into type of fat, such as saturated fat (RR = 0.89; P = 0.84), monounsaturated fat (RR = 0.86; P = 0.32), polyunsaturated fat (RR = 0.87; P = 0.25) or cholesterol (RR = 1.08; P = 0.48), or the source of fat, namely animal (RR-1.16; P = 0.51) or vegetable (RR = 0.71; P = 0.22). Similarly, there was no association between subtypes of carbohydrate or protein intake and the risk of breast cancer. There was also no association found between total ethanol intake or fibre intake (Table 4). There was no significant association between breast cancer risk and vitamins, minerals or other nutrients in the diet. In particular, there was no association found between breast cancer risk and total vitamin A (RR = 0.94; P = 0.49) vita-
from from from
Canadians
1st quartile
Total Total Total Total
% calories % calories % calories
French
DISCUSSION Despite many detailed epidemiological studies, including a large number with biological measurements, the aetiology of breast cancer remains unclear.23~24The association between breast cancer risk and diet, particularly dietary fat
with the proportion
of energy
from
fat, carbohydrate
and protein
1st quartile
2nd* quartile
3rd* quartile
4th* quartile
P value for trend
1.00 1 .OO 1.00
0.98 (0.65-1.47) 1.05 (0.70-l .57) 0.86 (0.58-1.29)
0.94 (0.63-1.41) 1.06 (0.71-1.60) 0.95 (0.63-1.42)
0.98 (0.66-1.47) 1.10 (0.73-1.65) 0.90 (0.6Sl.36)
0.8896 0.6680 0.7561
*ORs and 95% CIs from logistic regression, adjusted for age, parity, age at first full-term pregnancy, breast cancer in first-degree relatives, marital status, history of benign breast disease and personal income. The cut-off points for quartiles are 12.0%, 13.6% and 15.3% for protein, 28.6%, 32.9% and 36.4% for fat and 49.5%, 54.2% and 58.9% for carbohydrates.
Table 4 Canadians
Relative risk of breast cancer in Montreal: 1989-1993
associated
with intake
of alcohol
and dietary
tibre
among
French
Nutrient
1st quartile
2nd* quartile
3rd* quartile
4th* quartile
P value for trend
Total ethanol Crude total fibre Dietary tibre Mixed fibre
1.00 1.00 1.00 1.00
1.02 0.77 1.05 0.91
0.78 1.10 0.83 0.81
0.90 0.81 0.82 0.77
0.454 1 0.6788 0.2156 0.1647
(0.65-1.61) (0.51-1.15) (0.70-1.58) (0.61-1.36)
111
(0.48-1.25) (0.73-1.64) (0.56-l .25) (0.54-1.20)
*ORs and 95 % CIs from logistic regression, adjusted for age, parity, age at first cancer in first-degree relatives, personal income, marital status, history of benign energy using the nutrient residual method.
(0.561.44) (0.54-1.22) (0.55-l .24) (0.51-1.15)
full-term pregnancy, breast breast disease and total
112
The Breast
intake, currently remains the subject of a great deal of controversy.25 Theoretical considerations of biological processes lead to the conclusion that an increased risk of breast cancer is plausible with increasing saturated fat intake in postmenopausal women.“j However, the evidence from investigations in human subjects with breast cancer is unclear. A meta-analysis of studies of dietary fat and breast cancer risk,*’ comparing highest to lowest level fat intakes, showed a summary RRof 1.12 [95% CI (1.04-1.21)]. When cohort studies alone were analysed, a non-significant risk of 1.01 was obtained, compared to case-control studies alone giving a significant RR of 1.2 1. This difference in risk estimates between study types has been attributed to a potential bias of case-control studies in recall of dietary information.** In the meta-analysis, European studies were more likely to show a positive correlation between dietary fat and breast cancer risk, irrespective of study type.27 This finding appears to be driven by the results from casecontrol studies, particularly those conducted in European populations where the authors have observed that the diet may be more varied than in North American populations. The large North American studies of dietary fat intake and breast cancer risk have been criticized as having too limited a range of intakes available in the population to detect the magnitude of risk being investigated. It is notable that in subsequent reports of two large, well-conducted casecontrol studies in low-risk populations with low intakes of saturated fat where an effect of fat could be investigated, no significant effect of any fat on breast cancer was seen in Spain,29 but the protective influence of olive oil on breast cancer was noted in Greece30%3’ as well as in Italy.32 It is still not altogether straightforward to interpret these findings. Meta-analysis is a technique that needs more thought when applied to observational studies than when applied to randomized trials, and many issues remain unresolved.33 It is also somewhat discomfiting that the positive association between breast cancer risk and fat intake is being driven by findings from case-control studies that represent a design perceived to be weaker than the prospective design of cohort studies for the analysis of dietary associations.34 Studies from Greece35 and Italy36 suggest that green vegetable consumption is an indicator of a low-risk dietary pattern. This may simply reflect low intake of fat or calories, or may suggest that some constituent of green vegetables may be protective. However, this has not been a consistent finding from studies of the association between fruit and vegetable consumption and cancer risk.37 In a prospective study of over 80 000 US nurses, no association was found between breast cancer risk and dietary intakes of vitamin C, vitamin E or beta-carotene. However, women in the lowest fifth of daily intake of vitamin A from dietary sources were found to have an increased risk of breast
cancer over other women in the cohort.36 Furthermore, when the effect of vitamin supplementation was investigated, there was a protective effect of vitamin A, but only among women in the lowest fifth of daily intake of this vitamin. This is a particularly interesting finding, the true significance of which will become apparent as the results of other ongoing epidemiological studies become available.38 Different studies have shown different dietary fat components to be risk factors for breast cancer. In their case-control study, Goodman et a139found significant associations between consumption of meat and dairy products and breast cancer risk, acting in conjunction with body size, but failed to establish an association with total or saturated fat consumption. A difference in effect patterns of dietary fat on breast cancer risk was observed in a Moscow casecontrol study, diet being more important in postmenopausal women40 and this was postulated to be a cohort effect in eating habits. The same study found polyunsaturated fatty acids to be protective against breast cancer and showed no effect for saturated fat or protein in the diet. Multivariate analysis of a case-control study in France revealed small but significant effects (OR = 2) of total, saturated and monounsaturated fat consumption on breast cancer risk.41 In contrast, a Dutch case-control study reporting a significant overall fat effect could show no influence of any specific fat category (saturated, mono- and polyunsaturated fats), but found a significant association between breast cancer risk and meat, cakes and snacks.”
Acknowledgements It is a pleasure to thank our collaborators in RICUM for their support. They include the following surgeons: Drs J. Cantin and C. Potvin (Hotel-Dieu de Montreal); A. Peloquin and M. Poljicak (Notre-Dame de Montreal); E. Nassif, P. Franchebois, S. Legault and R. Poisson (St-Luc Hospital). We also thank Florence Auclair, Lucie Gravel, Jacqueline Marchand and Johanne Theroux for interviewing the case and control subjects in this study. We are grateful to Mr Ovid Da Silva for his editorial work and MS Helene Hamois for typing this manuscript. It is a pleasure to acknowledge funding for this study from the Medical Research Council of Canada and the Cancer Research Society. This investigation was conducted within the framework of an international collaborative study of breast cancer coordinated by the European Institute of Oncology, with coordination funds being provided by the Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research).
References 1. Parkin D M, Pisani P, Ferlay J. Estimates of the world wide incidence of eighteen major cancers in 1985. Int J Cancer 1993; 54: 594-606. 2. Parkin D M, Muir C S, Whelan S et al, eds. Cancer incidence in five continents, vol VI. Lyon: IARC Scientific Publications, 1992: 120. 3. National Cancer Institute of Canada. Canadian Cancer Statistics, 1994. 4. Lee H P, Day N E, Shanmugaramam K, eds. Trends in cancer incidence in Singapore 1968-1982. Lyon: IARC Scientific Publications, 1988: 91.
Breast cancer risk and nutrient intake 5. Devesa S S, Silverman D T, Young J L et al. Cancer incidence and mortality among whites in the United States, 1974-1984. J Nat1 Cancer Inst 1987; 79: 701-770. 6. Paymaster .I C, Grangadharan P. Some observations on the epidemiology of cancer of the breast in women of western India. Int J Cancer 1972; 10: 443. 7. Wynder E L, Bross I J, Hirayama T. A study of the epidemiology of cancer of the breast. Cancer 1960; 13: 559. 8. Lancaster H 0. The mortality in Australia from cancers peculiar to the female. Med J Austr 1971; 7: l-7. 9. MacMahon B, Cole P, James B. Etiology of human breast cancer: a review. J Nat1 Cancer Inst 1973; 50: 2142. 10. Harris R E, Lynch H T, Guirgis H A. Familial breast cancer: risk to the contralateral breast. J Nat1 Cancer Inst 1978; 60: 955-960. 11. Boice J D, Stone B J. Interaction between radiation and other breast cancer risk factors. In: Late biological effects of ionising radiation, vol. 1. Vienna: IAEA, 1978: 231-249. 12. Schottenfeld D, Berg J, Vitsky B. Incidence of multiple primary cancer. II. Index cancers arising in the stomach and lower digestive system. J Nat1 Cancer Inst 1969; 43: 77-86. 13. Schoenberg B S, Greenberg R A, Eisenberg H. Occurrence of certain multiple primary cancers in females. J Nat1 Cancer Inst 1969: 43: 15-32. 14. MacMahon B, Austin J H. Association of carcinomas of the breast and corpus uteri. Cancer 1969; 23: 275-280. 15. Schottenfeld D, Berg J. Incidence of multiple primary cancers. IV. Cancer of the female breast and genital organs. J Nat1 Cancer Inst 1971; 46: 161-170. 16. Hankin J H. Role of nutrition in women’s health: diet and breast cancer. J Am Diet Assoc 1993; 93: 994-999. 17. Howe G R. High-fat diets and breast cancer risk: the epidemiologic evidence. JAMA 1992; 268: 2080-2081. 18. Wynder E L. Cohen L A, Rose D P et al. Dietary fat and breast cancer: where do we stand with the evidence? J Clin Epidemiol 1994; 47: 217-222. 19. Van’t Veer P, Kok E J, Brants H A M et al. Dietary fat and the risk of breast cancer. Int J Epidemiol 1990; 19: 12-18. 20. Jain M, Howe G R, Johnson K C et al. Evaluation of a diet history questionnaire for epidemiologic studies. Am J Epidemiol 1980; 111:212-219. 2 1. Jain M, Howe G R, Harisson L et al. A study of the repeatability of dietary data over a seven-year period. Am J Epidemiol 1989; 129: 422429. 22. Willett W C, Stampfer M J. Total energy intake: implications for epidemiologic analysis. Am J Epidemiol 1986; 124: 17-27. 23. Boyle P. The epidemiology of breast cancer. In: Veronesi U, ed. Bailliere’s clinical oncology, vol. 2. 1988: l-58
113
24. Boyle P, Maisonneuve P. Diet. In: Waxman J, ed. Hormonal carcinogenesis. Cambridge: Cambridge University Press, 1996. 25. Willett W C. Nutritional epidemiology. Oxford: Oxford University Press, 1989. 26. Boyle P, Leake R E. Progress in understanding breast cancer: epidemiologic and biologic interactions. Breast Cancer Res Treat 1988; 11:91-112. 27. Boyd N F, Martin L J, Noffel M et al. A meta-analysis of studies of dietary fat and breast cancer risk. Br J Cancer 1993; 68: 627-636. 28. Giovannuci E, Stampfer M J, Colditz G A et al. A comparison of prospective and retrospective assessments of diet in the study of breast cancer. Am J Epidemiol 1993; 137: 502-5 11. 29. Martin-Moreno J, Willett W C, Gorgojo L et al. Dietary fat, olive oil and breast cancer risk. Int J Cancer 1994; 58: 774-780. 30. Katsouyanni K, Trichopoulou A, Stuver S et al. The association of fat and other macronutrients with breast cancer: a case-control study from Greece. Br J Cancer 1994; 70: 537-541. 3 1. Trichopolou A, Katsouyani K, Stuver S et al. Consumption of olive oil and specific food groups in relation to breast cancer risk in Greece. J Nat1 Cancer Inst 1995; 87: 110-l 16. 32. La Vecchia C, Negri E, Franceschi S et al. Olive oil, other dietary fats and the risk of breast cancer. Cancer Causes Control 1995: 6: 545-550. 33. Spitzer W 0. Meta-analysis: unanswered questions about aggregating data. J Clin Epidemiol 1991; 44: 103-107. 34. Boyle P. Dietary factors in the aetiology of cancer (editorial). Oncol Haematol Literature Serv 1994: 1: 7-8. 35. Katwouyani K, Trichopoulos D, Boyle P et al. Diet and breast cancer: a case-control study in Greece. lnt J Cancer 1986: 38: 815-820. 36. La Vecchia C, Decarli A, Franceschi S et al. Dietary factors and the risk of breast cancer. Nutr Cancer 1987: 10: 205-214. 37. Steinmetz K A, Potter J D. Vegetables, fruits and cancer. Cancer Causes Control 1991: 2: 325-357. 38. Hunter D J, Manson J, Colditz G A et al. A prospective study of the intake of vitamins C, E and A and the risk of breast cancer. N Engl J Med 1993; 329: 234-240. 39. Goodman M T Y, Nomura A M Y, Wilkens L R et al. The association of diet, obesity and breast cancer in Hawaii. Cancer Epidemiol Biomarkers Prev 1992; 1: 269-275. 40. Zaridze D, Lifanova Y, Masimovitch D et al. Diet, alcohol consumption and reproductive factors in a case-control study of breast cancer in Moscow. Int J Cancer 1991; 48: 493-501. 41. Richardson S, Gerber M, Cenee S. The role of fat, animal protein and some vitamin consumption in breast cancer: a case control study in southern France. Int J Cancer 1991; 48: l-9.