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Diet and breast cancer: The possible connection with sugar consumption
Medical Hypotheses
11:
DIET AND BREAST CANCER:
319 - 327, 1983
THE POSSIBLE CONNECTION WITH SUGAR CONSUMPTION
Stephen Seely, University of Manchester Medical School, Department of Bacteriology and Virology, Oxford Road, Manchester, Ml3 9PT, England David F Horrobin, Efamol Research Nova Scotia, Canada B4N 4H8
Institute,
PO Box 818, Kentville,
ABSTRACT The paper presents an epidemiological study of breast cancer mortality in relation to food consumption. It was found that younger and older women (possibly pre- and post-menopausal women) differ with respect to such correlations. In older women a strong correlation was found between breast cancer mortality and sugar consumption (correlation coefficient = 0.9), and a weaker correlation, possibly of marginal interest, with fat consumption (correlation coefficient = 0.7). In younger women the correlation with diet seems weak. A possible connecting link between sugar consumption and breast cancer is insulin. This is an absolute requirement for the proliferation of normal mammary tissue and experimental mammary tumours may regress in its absence. Insulin secretion occurs in response to blood glucose level and could be excessive if the regulatory mechanism is overtaxed by large sugar intake. The same mechanism might account for the increased risk of mammary cancer in diabetics.
INTRODUCTION Breast cancer may be a diet-related disease. This assumption is supported mainly by migrant studies. Immigrant groups sooner or later tend to adopt the diet of the host country and if that is relevant to the pathogenesis of a disease, they are assimilated by the host country in respect to vulnerabililty to that disease. Many studies have been made on immigrant populations with respect to breast cancer, notably on groups ofJapanese origin in Hawaii (1,2), with the finding that the low mortality rates of Japan begin to increase in the first generation born in the host country, and approximate to the level of the host country in the second generation.
319
Amongst foodstuffs suspected of influencing carcinogenesis, animal fats are thought to be of the greatest importance by Wynder (3). Other authors (4) suggest sugar. Some critics (5) find the evidence for the causative effect of the diet unconvincing. The main emphasis amongst possible aetiological factors of breast cancer has always been on hormonal effects (6,7). Other factors thought to influence mammary carcinogenesis are parity, lactation, obesity, age at the birth of the first child and oral contraceptives (15). A positive correlation exists between breast cancer and diabetes and/or glucose intolerance (8,9,10). We have attempted the identification of dietary factors which may influence the pathogenesis of breast cancer by an epidemiological survey of its geographical distribution as compared with that of various items of diet. The survey covers 21 countries belonging to the Organisation of Economic Cooperation and Development (OECD) for which both mortality and detailed food consumption statistics are available. SOURCES AND METHODS World Health Statistics Annuals (1966-1981), (11) giving mortality rates of decennial age groups per 100,000 of the same age group, were used as sources of mortality statistics. Only female breast cancer mortality was considered. The mortality rates apply to the latest year for which data were available at the time of writing, ranging from 1975 to 1979. The actual date for each country is shown in table I where the relevant statistics are reproduced. TABLE I
Country
Year of mortal. stat.
Average consumption 1965-1969 g/day
Mortality per 100,000 in age groups 35-44
45-54
55-64
65-74
Sugar Glucose Total
UK Holland Ireland Denmark Canada Switzerland US Belgium N Zealand Norway Sweden Germany France Austria Finland Italy Spain Greece Portugal Yugoslavia Japan
1979 1979 1977 1979 1977 1979 1978 1976 1978 1979 1979 1978 1977 1979 1977 1976 1977 1978 1975 1977 1979
23.0 20.7 19.3 17.7 18.9 19.4 16.9 21.8 21.3 11.3 13.4 15.9 13.4 17.4 11.3 17.2 14.4 14.2 14.8 13.4 6.8
64.7 56.5 69.0 49.0 50.6 48.2 51.0 50.7 67.8 40.6 33.9 44.1 39.5 41.7 35.6 42.6 33.5 36.2 34.6 30.4 14.6
96.9 94.2 72.2 96.9 90.4 88.1 83.0 75.1 69.3 68.9 66.2 70.1 64.1 69.7 52.8 64.6 45.2 46.2 44.1 39.7 18.2
122.2 117.6 112.5 109.0 104.9 103.9 98.9 97.0 96.7 95.1 94.0 92.9 85.6 80.2 77.7 77.5 51.0 50.2 46.0 44.0 17.0
131.8 125.1 126.8 135.0 137.1 121.1 133.7 100.0 123.4 120.4 117.4 89.9 92.2 101.3 114.4 71.4 66.4 51.9 57.6 67.0 57.4
13.5 13.8 11.3 --------6.4 4.1 --0.5 ------
145.3 138.9 138.1 135.0 137.1 121.1 133.7 100.0 123.4 120.4 117.4 96.3 96.3 101.3 114.4 71.9 66.4 51.9 57.6 67.0 57.4
Mean
1978
16.3
44.5
67.4
84.5
101.9
2.4
104.3
320
The sources of food consumption statistics were OECD publications (1956-1981) (12) which give the consumption of about 60 items for each country. The current membership of OECD for which such data are published, consists of 22 countries, but Australia and Turkey joined OECD only recently and had to be eliminated owing to lack of retrospective
information. It was, however, possible to include Greece, an OECD member until 1968. Hence the number of countries surveyed in this paper is 21.
RESULTS The first finding of a preliminary survey was that it was necessary to differentiate between mammary cancers of younger and older women, a strong association between mortality and diet existing only in the latter group. The dividing line may or may not be the menopause (15) since we find that dietary influences appear before it. Hence we show mortality rates in table I for four decennial age groups, 35-44, 45-54, 55-64, and 65-74, separately. The preliminary work consisted of examining a number of food items for a possible correlation with breast cancer, notably animal fats, saturated fats, animal proteins, milk, eggs and sugar, mostly with indifferent results. The best correlation in the 45-74 groups was obtained with sugar, a considerably weaker correlation with animal fats. The preliminary correlation coefficients calculated in the two cases were of the order of 0.9 and 0.7, leaving some doubt regarding the significance of the correlation with fats. The correlation is probably indirect, as fat consumption tends to be high or low in the same countries as sugar consumption. The usual procedure in such cases is multivariate analysis to examine the combined effect of the two independent variables, but in the present case such calculations produced an indecisive result. The combined correlation coefficient for sugar and fats was of the order of 0.92--a marginal improvement on 0.9 for sugar alone. We have finally decided that only sugar merited detailed investigation, noting however, that animal fats may have some effect on the carcinogenic process. Further preliminary work was needed to deal with the inevitable difficulty presented by the latent period of diseases like breast cancer, in consequence of which, for the best results, mortality rates have to be correlated with food consumption predating them by a number of years. The optimum period has to be found by trial and error. We have found good correlationbetweenthe latest available mortality rates and sugar consumption during the 1965-1969 period, predating the average date of mortality statistics by about 10 years. The average consumption of a five-year period was used to minimise the effect of year-to-year random variations. Sugar consumption is given in considerable detail in OECD statistics in terms of refined sugar, syrup, molasses, glucose, honey, maple sugar and This made it possible to evaluate whether other, unspecified sugars. breast cancer was associated only with the consumption of refined sugar Preliminary calculations gave or all items with high sucrose content.
321
the highest correlation coefficient when all substances with a high sucrose content were included in sugar consumption. These items were taken into account in proportion to their sucrose content, as given in OECD statistics. This is 80% for syrup, 60% for molasses, 64% for maple sugar, 75% for honey and 67% for other sugars. Glucose appears as a separate item in the OECD statistics of only six countries--the United Kingdom, the Netherlands, Ireland, Germany, France In the first two of these and Italy, in Ireland only from 1972 onward. countries glucose accounted for about 10% for the total sugar consumption by weight in the 1956-69 period, in Germany and France for about 5% and glucose consumption between 1972 in Italy for less than 1%. In Ireland and 1978 was 83% of the per caput consumption of glucose in the United Kingdome in the same period. Assuming that the same ratio was valid for preceding years, glucose consumption probably accounted for about 8% of the total sugar consumption in Ireland in the 1965-69 period. The fact that the three countries with the highest rate of mortality from breast cancer--the UK, Holland and Ireland--are also world leaders in glucose consumption calls attention to the possibility that the suspected carcinogenic effect of glucose is higher than that of sucrose. In order to evaluate the relative influence of glucose and sucrose, multivariate analysis of the available data was performed with glucose consumption and sucrose consumption as the independent variables and breast cancer mortality in the 65-74 age group as the dependent variable. This gave the result that lg glucose was equivalent to 1.929 sucrose. While this finding points to a potentially important possibility, in view of the fact that glucose consumption data were available for only 5 out of 21 countries (with estimated consumption for one In table I the conmore country), it must be regarded with caution. sumption of regined sugar and glucose (including estimated consumption in Ireland) are shown as separate items and in the total column the two are added on a l/l basis. Correlation coefficients were calculated on the basis of these totals, but some additional calculationswere also made using the weighted value of glucose consumption. The following correlation
coefficients
were obtained
by calculation:
r65-74 = 0.92 r55-64 = 0.859 r45-54 = 0.752 r35-44 - 0.571 Using weighted values for glucose consumption, the correlation coeffiThere was a small improvement cient for the 65-74 age group was 0.926. for the 55-64 group, in the other groups the change was negligible.
322
The regression line for the 56-74 age group is shown in figure 1. can be more accurately represented by the equation:
'55-64 - 0.577x
7.24
y45-54
q
0.319x
11.2
y35-44
q
0.074x
8.55
This
Lastly it was attempted to ascertain whether the worldwide increase in sugar consumption in the recent past was matched to a similar increase in mortality from breast cancer. OECO food consumption statistics are available from 1954, and WHO mortality statistics in their present form--with age-specific mortality rates replacing the previously published crude rates--from 1965. If food consumption statistics have to predate mortality statistics by 10 years, there is little room for the investigation of secular changes. However, an attempt was made to examine the relation between a lo-year change in sugar consumption (from the 1955-59 period to the 1956-69 period), compared with a loyear change in mortality rates over last decade for which data were available. These data are shown in table II. When this is compared with table I, it can be seen that the increase in total sugar consumption was 11.7%, while the mortality increases were 0.6, 2.5, 6.8 and 3.7% in the 35-44, 45-54, 55-64, and 65-74 age groups respectively. The correlation coefficients and regression equations calculated from the data in table II are:
= 0.788x
7.87
5 0.860,
y55-64 = 0.533x
13.30
r-45-54 = 0.845,
'45-54 = 0.321x
13.40
r35-44 = 0.675,
y35-44
10.90
r65-74 = 0.982, 'S-64
y65-74
1 0.089x
change in mortality corresponding to It may be noted that the expected a given change in sugar consumption has to be calculated with the aid Notably, 11.7% increase in sugar consumpof the regression equations. tion would correspond to 3.8, 6.2, 7.6 and 9.6% increase in mortality in the 35-44, 54-54, 55-65 and 65-74 age groups respectively, if the mortality increases would exactly correspond to the slope of their regression lines. The actual increases of 0.6, 2.5, 6.8 and 3.7;: are considerably lower than these expected increases with the exception of the 55-64 group.
323
TABLE II
Country
Year of mortal. stat.
Mortality per 100,000 in age groups
Average consumption 1955-1959 g/day
35-44
45-54
55-64
65-74
Sugar Glucose Total
59.0
UK Holland Ireland Denmark Canada Switzerland us Be1 gium New Zealand Norway Sweden Germany France Austria Finland Italy Spain Greece Portugal Yugoslavia Japan
1969 1967 1969 1967 1969 1968 1966 1968 1969 1969 1968 1967 1969 1967 1966 1967 1968 1965 1967 1969
23.6 22.8 21.5 21.8 18.9 17.2 21.0 21.8 18.0 14.6 13.0 15.9 13.5 13.4 11.3 16.3 11.2 11.7 14.8 13.4 5.4
61.0 67.0 58.4 50.6 48.0 52.9 50.7 51.2 42.1 44.8 44.1 36.4 41.5 38.3 39.1 24.1 25.4 34.6 30.4 11.0
94.0 91.2 65.8 86.8 90.4 77.3 77.9 75.1 75.7 73.9 65.4 70.1 57.9 67.0 42.9 52.4 33.1 32.0 44.1 39.7 12.2
111.4 111.9 96.4 112.3 104.9 112.4 97.9 97.0 128.9 82.5 88.3 92.2 79.7 87.4 72.0 68.7 34.1 30.8 46.0 44.0 11.5
124.9 114.6 113.1 129.2 132.0 114.1 126.3 88.2 126.6 110.7 121.4 81.7 81.0 94.0 109.9 49.5 41.2 54.0 44.6 34.5 35.0
Mean
1968
16.2
43.4
63.1
81.5
91.7
1969
0.3 __ __ -_ __ -_
134.3 124.7 121.0 129.2 132.0 114.1 126.3 88.2 126.6 110.7 121.4 85.3 85.1 94.0 109.9 49.8 41.2 54.0 44.6 34.5 35.0
1.7
93.4
9.4 10.1 7.9 __ __ -_ __ __ __ __ __ 3.6 4.1 __ __
DISCUSSION An often heard objection against epidemiological surveys based on published mortality and food consumption data is that statistics are unreliable. Breast cancer, however, is a comparatively easily diagnosed cause of mortality, hence death certification and national statistics are likely to be reliable. Similarly, sugar is normally produced in large factories, transported in bulk, and not vulnerable to spoilage by microorganisms, so that many of the circumstances which bedevil the consumption statistics of commodities like milk, eggs, meat, etc., like backyard production or wastage at the consumer level, are absent. We were, therefore, in the fortunate position of basing our survey on statistics which are likely to be at least comparatively accurate. The subdivision of the surveyed population into 4 decennial age groups and the rep tition of the survey at an interval of 10 years have provided a large volume of data and, at least in one respect, these tell a consistent story. This is that diet has little influence on the breast cancer mortality of younger women,but that the correlation with sugar consumption becomes more pronounced with every decade of age af-
324
ter 35. The correlation coefficients of the order of 0.9, obtained twice for the 65-74 gorup, and 0.86 obtained twice of the 55-64 group, denote strong association which is unlikely to be due to coincidence. Other pointers in the same direction are the regression equations, particularly the varying magnitude of the intercepts on on the y axis. A positive intercept of the regression line on the y axis denotes mortality that would remain if sugar consumption were reduced to zero, provided that the assumption of causal connection between sugar consumption and breast cancer mortality is correct. A negative intercept denotes the small consumption that would be tolerated without causing mortality. In the case of the oldest group the intercept on the y axis is small. In the youngest group the positive intercept is 8.6 in one case, 10.9 in the other, representing 53 and 67% of the average mortality in these groups. This is the residual mortality independent of sugar consumption presumably caused by non-dietary pathogenic agents. These are probably hormonal, their effect gradually decreasing after the menopause. In contrast to the generally good agreement between the geographical distribution of breast cancer and sugar consumption, the correlation between secular changes in them is weak. During the 10 year period investigated in this survey the increase in mortality from breast cancer was considerably less than would have been expected if the increase in sugar consumption had been the only relevant change. Time, however, may bring more than one relevant change simultaneously. In the givencase a clue is provided, once more, by the study of the intercepts of the regression lines, all of which decreased during the 10 years of the study. Thus in the earlier survey the intercepts were 10.9, 13.4, 13.3 and 7.87 in the four decennial age groups between 35 and 74. In the later survey the corresponding figures were 8.55, 11.2, 7.24 and -1.84. The intercepts indicate mortality independent of sugar consumption. Their decrease means that some extraneous factor has changed for the better during the 10 years in question, partly counteracting the effect of increased sugar consumption. Such extraneous factors could have been, for example, earlier diagnosis and more effective treatment of breast cancer, decreasting oestrogen content of oral contraceptives, a more judicious application of hormone replacement therapy in postmenopausal women. Associations are, of course, not causations, and even high correlation coefficients provide no proof that sugar causes breast cancer. However, associations are more likely to be taken seriously if a plausible causative mechanism exists. The connecting link between sugar and breast cancer may be insulin, the secretion of which occurs in response to rising blood glucose level. Insulin is an absolute requirement for the proliferation of normal mammary tissue (13), and 70% of experimental mammary tumours may regress after destruction of the insulinsecreting capacity of the pancreas by streptozotocin (14). The effect of insulin on normal mammary tissue is similar to oestrogens and prolactin. All three hormones are necessary for the growth of the breast as a whole or some of its constituent tissues. Many mammary cancer cells are, at least initially, dependent on these substances, as demonstrated by temporary regression following oophorectomy or other en325
docrine manipulation, or by the great increase in the growth of experimental cancers after the administration of oestrogen or prolactin. The normal pathway for the utilisation of all dietary polysaccharides and disaccharides includes conversion into glucose, but there is no statistical correlation between breast cancer and the consumption of starches or disaccharides other than sucrose. Stimulation of insulin secretion following ingestion of complex carbohydrates is much less than after sucrose or glucose. The possibility that the pathogenic property of sucrose is due to the insulin stimulation it causes, is supported by the even higher apparent carcinogenicity of glucose. In that case the digestive system has not work whatever to perform, so that its absorption and appearance in the portal circulation is even more rapid than that of sucrose. There is good evidence that maturity onset diabetes mellitus is associated with a high intake of sucrose and this may account for the correlation between diabetes and breast cancer.
In conclusion we suggest that aetiologically breast cancer falls into two categories, one related to dietary influences, particularly sugar consumption, and the other to unknown factors which may be hormonal. The latter is probably more malignant, with a shorter latent period, and predominates in younger women. The diet-related form has a long latent period and predominates in older women. REFERENCES
1.
Wynder EL, Hiayama T. Comparative epidemiology of cancers of United states and Japan. Prev Med 6: 567, 1977.
2.
Modan B. Role of migrant studies in understanding of cancer. Am J Epidemiol 112: 289, 1980.
3.
Wynder EL. Dietary factors related to breast cancer. (Suppl 4) 46: 899, 1980.
4.
Maruchi N, Aoki S, Tsuda K et al. Relation of food consumption to cancer mortality in Japan with special reference to international figures. Gann 68: 1, 1977.
5.
Miller AB, Bulbrook RD. The epidemiology cancer. N Engl J Med 303: 1246, 1980.
6.
Cambrell RD. The role of hormones in the etiology of breast and Acta Obstet Bynecol Stand (Suppl) 88: 73, 1979. endometrial cancer.
7.
Korenman SG. Oestrogen window hypothesis breast cancer. Lancet 1: 700, 1980.
8.
Lender M, Lawrence AM, Paloyan E. Diabetes autoimmune disease and breast cancer. Lancer 1: 1110, 1977.
326
the etiology
and etiology
Cancer
of breast
of the aetiology
of
thyroid
9.
De Waard F, Banders van Halevijn B. A prospective study in general practice on breast cancer in postmenopausal women. Int J Cancer 14: 153, 1974.
10.
Carter AC, Lefkon BW, Farlin M et al. women with metastatic breast disease. 1975.
11.
World Health Statistics Annuals, tion, Geneva, 1966-1982.
12.
Food Consumption Statistics, 1954-1978. Organisation of Economic Cooperation and Development (OECD), Paris, 1956-1981.
13.
Forsyth IA, Myres RP, Human prolactin. Evidence obtained by the bio-assay of human plasma. J Endocr 51: 157, 1971.
14.
Shafie SM, Cho-Chung YS, Gullino PM. Cyclic adenosine monophosphate and protein kinase activity in insulin-dependent and independent mammary tumours. Cancer Res 39: 2501, 1979.
15.
Frank1 G. Risk factors in breast cancer: are they important and are they the same in pre- and post-menopausal breast cancer patients? Oncology 37: 37, 1980.
327
Metabolic parameters in J Clin Endoc Metab 40: 260,
1965-1981.
World Health Organisa-
11:
DIET AND BREAST CANCER:
319 - 327, 1983
THE POSSIBLE CONNECTION WITH SUGAR CONSUMPTION
Stephen Seely, University of Manchester Medical School, Department of Bacteriology and Virology, Oxford Road, Manchester, Ml3 9PT, England David F Horrobin, Efamol Research Nova Scotia, Canada B4N 4H8
Institute,
PO Box 818, Kentville,
ABSTRACT The paper presents an epidemiological study of breast cancer mortality in relation to food consumption. It was found that younger and older women (possibly pre- and post-menopausal women) differ with respect to such correlations. In older women a strong correlation was found between breast cancer mortality and sugar consumption (correlation coefficient = 0.9), and a weaker correlation, possibly of marginal interest, with fat consumption (correlation coefficient = 0.7). In younger women the correlation with diet seems weak. A possible connecting link between sugar consumption and breast cancer is insulin. This is an absolute requirement for the proliferation of normal mammary tissue and experimental mammary tumours may regress in its absence. Insulin secretion occurs in response to blood glucose level and could be excessive if the regulatory mechanism is overtaxed by large sugar intake. The same mechanism might account for the increased risk of mammary cancer in diabetics.
INTRODUCTION Breast cancer may be a diet-related disease. This assumption is supported mainly by migrant studies. Immigrant groups sooner or later tend to adopt the diet of the host country and if that is relevant to the pathogenesis of a disease, they are assimilated by the host country in respect to vulnerabililty to that disease. Many studies have been made on immigrant populations with respect to breast cancer, notably on groups ofJapanese origin in Hawaii (1,2), with the finding that the low mortality rates of Japan begin to increase in the first generation born in the host country, and approximate to the level of the host country in the second generation.
319
Amongst foodstuffs suspected of influencing carcinogenesis, animal fats are thought to be of the greatest importance by Wynder (3). Other authors (4) suggest sugar. Some critics (5) find the evidence for the causative effect of the diet unconvincing. The main emphasis amongst possible aetiological factors of breast cancer has always been on hormonal effects (6,7). Other factors thought to influence mammary carcinogenesis are parity, lactation, obesity, age at the birth of the first child and oral contraceptives (15). A positive correlation exists between breast cancer and diabetes and/or glucose intolerance (8,9,10). We have attempted the identification of dietary factors which may influence the pathogenesis of breast cancer by an epidemiological survey of its geographical distribution as compared with that of various items of diet. The survey covers 21 countries belonging to the Organisation of Economic Cooperation and Development (OECD) for which both mortality and detailed food consumption statistics are available. SOURCES AND METHODS World Health Statistics Annuals (1966-1981), (11) giving mortality rates of decennial age groups per 100,000 of the same age group, were used as sources of mortality statistics. Only female breast cancer mortality was considered. The mortality rates apply to the latest year for which data were available at the time of writing, ranging from 1975 to 1979. The actual date for each country is shown in table I where the relevant statistics are reproduced. TABLE I
Country
Year of mortal. stat.
Average consumption 1965-1969 g/day
Mortality per 100,000 in age groups 35-44
45-54
55-64
65-74
Sugar Glucose Total
UK Holland Ireland Denmark Canada Switzerland US Belgium N Zealand Norway Sweden Germany France Austria Finland Italy Spain Greece Portugal Yugoslavia Japan
1979 1979 1977 1979 1977 1979 1978 1976 1978 1979 1979 1978 1977 1979 1977 1976 1977 1978 1975 1977 1979
23.0 20.7 19.3 17.7 18.9 19.4 16.9 21.8 21.3 11.3 13.4 15.9 13.4 17.4 11.3 17.2 14.4 14.2 14.8 13.4 6.8
64.7 56.5 69.0 49.0 50.6 48.2 51.0 50.7 67.8 40.6 33.9 44.1 39.5 41.7 35.6 42.6 33.5 36.2 34.6 30.4 14.6
96.9 94.2 72.2 96.9 90.4 88.1 83.0 75.1 69.3 68.9 66.2 70.1 64.1 69.7 52.8 64.6 45.2 46.2 44.1 39.7 18.2
122.2 117.6 112.5 109.0 104.9 103.9 98.9 97.0 96.7 95.1 94.0 92.9 85.6 80.2 77.7 77.5 51.0 50.2 46.0 44.0 17.0
131.8 125.1 126.8 135.0 137.1 121.1 133.7 100.0 123.4 120.4 117.4 89.9 92.2 101.3 114.4 71.4 66.4 51.9 57.6 67.0 57.4
13.5 13.8 11.3 --------6.4 4.1 --0.5 ------
145.3 138.9 138.1 135.0 137.1 121.1 133.7 100.0 123.4 120.4 117.4 96.3 96.3 101.3 114.4 71.9 66.4 51.9 57.6 67.0 57.4
Mean
1978
16.3
44.5
67.4
84.5
101.9
2.4
104.3
320
The sources of food consumption statistics were OECD publications (1956-1981) (12) which give the consumption of about 60 items for each country. The current membership of OECD for which such data are published, consists of 22 countries, but Australia and Turkey joined OECD only recently and had to be eliminated owing to lack of retrospective
information. It was, however, possible to include Greece, an OECD member until 1968. Hence the number of countries surveyed in this paper is 21.
RESULTS The first finding of a preliminary survey was that it was necessary to differentiate between mammary cancers of younger and older women, a strong association between mortality and diet existing only in the latter group. The dividing line may or may not be the menopause (15) since we find that dietary influences appear before it. Hence we show mortality rates in table I for four decennial age groups, 35-44, 45-54, 55-64, and 65-74, separately. The preliminary work consisted of examining a number of food items for a possible correlation with breast cancer, notably animal fats, saturated fats, animal proteins, milk, eggs and sugar, mostly with indifferent results. The best correlation in the 45-74 groups was obtained with sugar, a considerably weaker correlation with animal fats. The preliminary correlation coefficients calculated in the two cases were of the order of 0.9 and 0.7, leaving some doubt regarding the significance of the correlation with fats. The correlation is probably indirect, as fat consumption tends to be high or low in the same countries as sugar consumption. The usual procedure in such cases is multivariate analysis to examine the combined effect of the two independent variables, but in the present case such calculations produced an indecisive result. The combined correlation coefficient for sugar and fats was of the order of 0.92--a marginal improvement on 0.9 for sugar alone. We have finally decided that only sugar merited detailed investigation, noting however, that animal fats may have some effect on the carcinogenic process. Further preliminary work was needed to deal with the inevitable difficulty presented by the latent period of diseases like breast cancer, in consequence of which, for the best results, mortality rates have to be correlated with food consumption predating them by a number of years. The optimum period has to be found by trial and error. We have found good correlationbetweenthe latest available mortality rates and sugar consumption during the 1965-1969 period, predating the average date of mortality statistics by about 10 years. The average consumption of a five-year period was used to minimise the effect of year-to-year random variations. Sugar consumption is given in considerable detail in OECD statistics in terms of refined sugar, syrup, molasses, glucose, honey, maple sugar and This made it possible to evaluate whether other, unspecified sugars. breast cancer was associated only with the consumption of refined sugar Preliminary calculations gave or all items with high sucrose content.
321
the highest correlation coefficient when all substances with a high sucrose content were included in sugar consumption. These items were taken into account in proportion to their sucrose content, as given in OECD statistics. This is 80% for syrup, 60% for molasses, 64% for maple sugar, 75% for honey and 67% for other sugars. Glucose appears as a separate item in the OECD statistics of only six countries--the United Kingdom, the Netherlands, Ireland, Germany, France In the first two of these and Italy, in Ireland only from 1972 onward. countries glucose accounted for about 10% for the total sugar consumption by weight in the 1956-69 period, in Germany and France for about 5% and glucose consumption between 1972 in Italy for less than 1%. In Ireland and 1978 was 83% of the per caput consumption of glucose in the United Kingdome in the same period. Assuming that the same ratio was valid for preceding years, glucose consumption probably accounted for about 8% of the total sugar consumption in Ireland in the 1965-69 period. The fact that the three countries with the highest rate of mortality from breast cancer--the UK, Holland and Ireland--are also world leaders in glucose consumption calls attention to the possibility that the suspected carcinogenic effect of glucose is higher than that of sucrose. In order to evaluate the relative influence of glucose and sucrose, multivariate analysis of the available data was performed with glucose consumption and sucrose consumption as the independent variables and breast cancer mortality in the 65-74 age group as the dependent variable. This gave the result that lg glucose was equivalent to 1.929 sucrose. While this finding points to a potentially important possibility, in view of the fact that glucose consumption data were available for only 5 out of 21 countries (with estimated consumption for one In table I the conmore country), it must be regarded with caution. sumption of regined sugar and glucose (including estimated consumption in Ireland) are shown as separate items and in the total column the two are added on a l/l basis. Correlation coefficients were calculated on the basis of these totals, but some additional calculationswere also made using the weighted value of glucose consumption. The following correlation
coefficients
were obtained
by calculation:
r65-74 = 0.92 r55-64 = 0.859 r45-54 = 0.752 r35-44 - 0.571 Using weighted values for glucose consumption, the correlation coeffiThere was a small improvement cient for the 65-74 age group was 0.926. for the 55-64 group, in the other groups the change was negligible.
322
The regression line for the 56-74 age group is shown in figure 1. can be more accurately represented by the equation:
'55-64 - 0.577x
7.24
y45-54
q
0.319x
11.2
y35-44
q
0.074x
8.55
This
Lastly it was attempted to ascertain whether the worldwide increase in sugar consumption in the recent past was matched to a similar increase in mortality from breast cancer. OECO food consumption statistics are available from 1954, and WHO mortality statistics in their present form--with age-specific mortality rates replacing the previously published crude rates--from 1965. If food consumption statistics have to predate mortality statistics by 10 years, there is little room for the investigation of secular changes. However, an attempt was made to examine the relation between a lo-year change in sugar consumption (from the 1955-59 period to the 1956-69 period), compared with a loyear change in mortality rates over last decade for which data were available. These data are shown in table II. When this is compared with table I, it can be seen that the increase in total sugar consumption was 11.7%, while the mortality increases were 0.6, 2.5, 6.8 and 3.7% in the 35-44, 45-54, 55-64, and 65-74 age groups respectively. The correlation coefficients and regression equations calculated from the data in table II are:
= 0.788x
7.87
5 0.860,
y55-64 = 0.533x
13.30
r-45-54 = 0.845,
'45-54 = 0.321x
13.40
r35-44 = 0.675,
y35-44
10.90
r65-74 = 0.982, 'S-64
y65-74
1 0.089x
change in mortality corresponding to It may be noted that the expected a given change in sugar consumption has to be calculated with the aid Notably, 11.7% increase in sugar consumpof the regression equations. tion would correspond to 3.8, 6.2, 7.6 and 9.6% increase in mortality in the 35-44, 54-54, 55-65 and 65-74 age groups respectively, if the mortality increases would exactly correspond to the slope of their regression lines. The actual increases of 0.6, 2.5, 6.8 and 3.7;: are considerably lower than these expected increases with the exception of the 55-64 group.
323
TABLE II
Country
Year of mortal. stat.
Mortality per 100,000 in age groups
Average consumption 1955-1959 g/day
35-44
45-54
55-64
65-74
Sugar Glucose Total
59.0
UK Holland Ireland Denmark Canada Switzerland us Be1 gium New Zealand Norway Sweden Germany France Austria Finland Italy Spain Greece Portugal Yugoslavia Japan
1969 1967 1969 1967 1969 1968 1966 1968 1969 1969 1968 1967 1969 1967 1966 1967 1968 1965 1967 1969
23.6 22.8 21.5 21.8 18.9 17.2 21.0 21.8 18.0 14.6 13.0 15.9 13.5 13.4 11.3 16.3 11.2 11.7 14.8 13.4 5.4
61.0 67.0 58.4 50.6 48.0 52.9 50.7 51.2 42.1 44.8 44.1 36.4 41.5 38.3 39.1 24.1 25.4 34.6 30.4 11.0
94.0 91.2 65.8 86.8 90.4 77.3 77.9 75.1 75.7 73.9 65.4 70.1 57.9 67.0 42.9 52.4 33.1 32.0 44.1 39.7 12.2
111.4 111.9 96.4 112.3 104.9 112.4 97.9 97.0 128.9 82.5 88.3 92.2 79.7 87.4 72.0 68.7 34.1 30.8 46.0 44.0 11.5
124.9 114.6 113.1 129.2 132.0 114.1 126.3 88.2 126.6 110.7 121.4 81.7 81.0 94.0 109.9 49.5 41.2 54.0 44.6 34.5 35.0
Mean
1968
16.2
43.4
63.1
81.5
91.7
1969
0.3 __ __ -_ __ -_
134.3 124.7 121.0 129.2 132.0 114.1 126.3 88.2 126.6 110.7 121.4 85.3 85.1 94.0 109.9 49.8 41.2 54.0 44.6 34.5 35.0
1.7
93.4
9.4 10.1 7.9 __ __ -_ __ __ __ __ __ 3.6 4.1 __ __
DISCUSSION An often heard objection against epidemiological surveys based on published mortality and food consumption data is that statistics are unreliable. Breast cancer, however, is a comparatively easily diagnosed cause of mortality, hence death certification and national statistics are likely to be reliable. Similarly, sugar is normally produced in large factories, transported in bulk, and not vulnerable to spoilage by microorganisms, so that many of the circumstances which bedevil the consumption statistics of commodities like milk, eggs, meat, etc., like backyard production or wastage at the consumer level, are absent. We were, therefore, in the fortunate position of basing our survey on statistics which are likely to be at least comparatively accurate. The subdivision of the surveyed population into 4 decennial age groups and the rep tition of the survey at an interval of 10 years have provided a large volume of data and, at least in one respect, these tell a consistent story. This is that diet has little influence on the breast cancer mortality of younger women,but that the correlation with sugar consumption becomes more pronounced with every decade of age af-
324
ter 35. The correlation coefficients of the order of 0.9, obtained twice for the 65-74 gorup, and 0.86 obtained twice of the 55-64 group, denote strong association which is unlikely to be due to coincidence. Other pointers in the same direction are the regression equations, particularly the varying magnitude of the intercepts on on the y axis. A positive intercept of the regression line on the y axis denotes mortality that would remain if sugar consumption were reduced to zero, provided that the assumption of causal connection between sugar consumption and breast cancer mortality is correct. A negative intercept denotes the small consumption that would be tolerated without causing mortality. In the case of the oldest group the intercept on the y axis is small. In the youngest group the positive intercept is 8.6 in one case, 10.9 in the other, representing 53 and 67% of the average mortality in these groups. This is the residual mortality independent of sugar consumption presumably caused by non-dietary pathogenic agents. These are probably hormonal, their effect gradually decreasing after the menopause. In contrast to the generally good agreement between the geographical distribution of breast cancer and sugar consumption, the correlation between secular changes in them is weak. During the 10 year period investigated in this survey the increase in mortality from breast cancer was considerably less than would have been expected if the increase in sugar consumption had been the only relevant change. Time, however, may bring more than one relevant change simultaneously. In the givencase a clue is provided, once more, by the study of the intercepts of the regression lines, all of which decreased during the 10 years of the study. Thus in the earlier survey the intercepts were 10.9, 13.4, 13.3 and 7.87 in the four decennial age groups between 35 and 74. In the later survey the corresponding figures were 8.55, 11.2, 7.24 and -1.84. The intercepts indicate mortality independent of sugar consumption. Their decrease means that some extraneous factor has changed for the better during the 10 years in question, partly counteracting the effect of increased sugar consumption. Such extraneous factors could have been, for example, earlier diagnosis and more effective treatment of breast cancer, decreasting oestrogen content of oral contraceptives, a more judicious application of hormone replacement therapy in postmenopausal women. Associations are, of course, not causations, and even high correlation coefficients provide no proof that sugar causes breast cancer. However, associations are more likely to be taken seriously if a plausible causative mechanism exists. The connecting link between sugar and breast cancer may be insulin, the secretion of which occurs in response to rising blood glucose level. Insulin is an absolute requirement for the proliferation of normal mammary tissue (13), and 70% of experimental mammary tumours may regress after destruction of the insulinsecreting capacity of the pancreas by streptozotocin (14). The effect of insulin on normal mammary tissue is similar to oestrogens and prolactin. All three hormones are necessary for the growth of the breast as a whole or some of its constituent tissues. Many mammary cancer cells are, at least initially, dependent on these substances, as demonstrated by temporary regression following oophorectomy or other en325
docrine manipulation, or by the great increase in the growth of experimental cancers after the administration of oestrogen or prolactin. The normal pathway for the utilisation of all dietary polysaccharides and disaccharides includes conversion into glucose, but there is no statistical correlation between breast cancer and the consumption of starches or disaccharides other than sucrose. Stimulation of insulin secretion following ingestion of complex carbohydrates is much less than after sucrose or glucose. The possibility that the pathogenic property of sucrose is due to the insulin stimulation it causes, is supported by the even higher apparent carcinogenicity of glucose. In that case the digestive system has not work whatever to perform, so that its absorption and appearance in the portal circulation is even more rapid than that of sucrose. There is good evidence that maturity onset diabetes mellitus is associated with a high intake of sucrose and this may account for the correlation between diabetes and breast cancer.
In conclusion we suggest that aetiologically breast cancer falls into two categories, one related to dietary influences, particularly sugar consumption, and the other to unknown factors which may be hormonal. The latter is probably more malignant, with a shorter latent period, and predominates in younger women. The diet-related form has a long latent period and predominates in older women. REFERENCES
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