CancerLetters, 53 (1990) 81-90 Elsevier Scientific Publishers Ireland Ltd

81

Review Letter

Consumption of methylxanthine-containing the risk of breast cancer

beverages

and

F. Lubin and E. Ron 5600

Lone

Oak Drive, Bethesda,

(Received

23 May 1990)

(Accepted

4 June

MD 20814

(U.S.A.)

1990)

Summary The idea that caffeine might be inuolved in the etiology of breast disease was first proposed by Minton et al. in 1979. Since that time, numerous experimental and epidemiolevaluating the relationship ogic studies between methylxanthines and breast disease have been conducted. Results from studies on benign breast disease haue been inconsistent, with some inoestigators observing a positiue assocfation and others no association. However, all but one of the studies which have examined methylxanthine intake and malignant breast disease have concluded that methylxanthines do not play a role in the deoelopment of this cancer. Although various methodologies were employed and different populations were evaluated, results were consistently negative. Thus, there appears to be no evidence of an association between coffee and other methylxanthine-containing beverages and breast cancer. Keywords: mammary cancer; epidemiology; methylxanthines; coffee; tea; cocoa; colas. Introduction Breast cancer is the leading cancer among women in most western countries [36]. In the 0304-3835/90/$03.50 Published and Printed

0 1990 in Ireland

Elsevier Scientific Publishers

United States, 142,000 new cases and 43,000 deaths due to breast cancer are expected in 1989 [49]. Since it has been estimated that over 85% of the adult population drinks coffee [13,50], any increase, no matter how small, in breast cancer risk associated with methylxanthine consumption would have major ramifications for public health. People ingest relatively large quantities of methylxanthines in coffee, tea, cocoa, cola drinks, chocolate and various non-prescription analgesic and antihistamine medications, but 87% of the total caffeine consumed in the United States comes from coffee and tea [14]. Coffee, however, also contains hundreds of chemicals in addition to caffeine [lo]. Public anxiety about cancer causes any report of a putative carcinogenic agent to become news, but when a proposed risk factor affects over 85% of the population, the subject becomes a significant news event. The hypothesis that coffee consumption may be related to breast cancer was first raised after Minton et al. [34,35] reported that women with benign breast disease experienced resolution of the symptoms of breast disease when they abstained from methylxanthine intake more often than women who did not abstain. Because women with a history of benign breast disease have an elevated risk of developing breast cancer [Z-4,11,54] it was hypothesized that coffee may increase the incidence of breast cancer through its link with Ireland Ltd.

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benign breast disease. Since the publication of Minton and colleagues’ papers [34,35], several investigations evaluating the relationship between methylxanthines and benign breast disease have been conducted. Results from these studies have been inconsistent, with some investigators observing a positive association [6,7,22] and others no association [12,17,24,28,33,45]. Correlational studies Because of methodologic limitations, correlational studies are used customarily to generate hypotheses. This method of study is not reliable for testing hypotheses because the exposure data concern practices of a population and take no account of an individual’s situation; consumption data reflect food availability and not intake and control for potential confounding variables is rarely achieved. Age is one of the most important factors in cancer incidence and food and beverage intake, yet the age distribution of many countries differs substantially. The developing nations usually have a younger age distribution than the developed countries, so that they would be expected to have lower cancer incidence and lower methylxanthine consumption. Per capita food consumption is based on an entire country’s population, from infants to the elderly. Nevertheless, correlational studies can provide useful information, often highlighting important environmental factors to be studied. Prentice et al. [39] and Schatzkin et al. [47] compared the level of agreement between analytical studies (case-control and cohort) and correlation studies in respect to fat intake and breast cancer and concluded that there was a high level of agreement between the study types. The Mormons and Seventh-Day Adventists have been studied frequently because their diet and lifestyle differ substantially from the rest of the United States population. Lyon et al. [31] compared breast cancer incidence among Mormons and non-Mormons in Utah and found that it was significantly lower among

Mormons. Although the majority of Mormons do not drink coffee and tea, they also do not drink alcohol and have more children. Since both alcohol and multiparity, through its association with age at full first-term pregnancy, have been negatively associated with breast cancer [21], it is not possible to know what factor or factors are associated with the reduced risk. only 3 correlational To our knowledge, studies on caffeine ingestion and breast cancer have been conducted. Stocks [53] compared the age-adjusted death rates, in 1964-65, from cancers of different sites with the annual consumption of cigarettes, solid fuel, tea and coffee using trade statistics from 20 countries. In 6 of 10 countries with the highest breast cancer rates a strong correlation with tea intake was found, but not with coffee. Armstrong and Doll [l] used cancer incidence data from 1960 -1966 from 23 countries ,and mortality data from 1964-1965 from 32 countries and compared the truncated age-standardized incidence and mortality rates to per capita consumption of coffee, tea and other environmental variables. A positive non-significant association with coffee was noted (r = 0.42 for incidence and 0.37 for mortality). Phelps and Phelps [37] used multiple regression analyses to evaluate the correlation between coffee and tea consumption and breast cancer mortality, taking total fat intake into account. The correlation coefficient for breast cancer mortality rates and caffeine intake in 44 countries was extremely significant (P < 0.001)) particularly for Western Europe. However, there was also a strong positive correlation (0.68) between fat intake and breast cancer. When the authors evaluated breast cancer versus caffeine consumption controlling for the effects of fat intake, there was a complete reversal of the findings, resulting in a statistically significant (P < 0.05) negative association. In contrast, when fat intake was correlated with breast cancer rates, holding caffeine intake constant, the positive association with fat remained. The analysis was done in several ways, yet

83

the main conclusion of a negative or no correlation between breast cancer mortality and caffeine ingestion held. The 44 countries were analyzed as separate observations, but because the size of the nations varied markedly the analysis was also done weighting each country by the square root of its population. Since four countries had extremely low reported breast the analysis was done cancer mortality, excluding these outliers. That analysis did yield a positive correlation, but it was far from statistically significant. This study, like all correlational studies, has a number of limitations. Most potential confounding variables could not be studied, exposure data were limited and only mortality could be assessed. However, although the authors were unable to control for reproductive factors they did control for fat intake. Thus, the 3 ecologic studies present contrasting findings. In a study in Israel, 82% of total methylxanthine intake was from coffee, Lubin et al. [28]. It is, therefore, difficult to accept that methylxanthines are an etiologic factor in breast cancer when there is a positive correlation with tea, but not with coffee. Case control studies None of 11 case-control studies based on populations in Australia, New Zealand, Argentina, United States, Canada, United Kingdom, Italy, France, Greece and Israel found a statistically significant link between breast cancer incidence and methylxanthine or coffee intake (Table 1). Within the United States, several different ethnic and religious groups were studied, but breast cancer risk was not increased with caffeine usage. Lawson et al. [24] were one of the first groups of investigators to specifically evaluate coffee and tea consumption and breast cancer in a case-control study. Women with newly diagnosed breast cancer (241) and 723 hospital controls, from the United States, Scotland and New Zealand, were personally interviewed shortly after their hospital admission regarding recent coffee and tea consumption,

as part of a short list of items also inciuding and alcohol. smoking habits, medications Information about coffee was obtained before Minton et al. [34,35] published their papers suggesting a link between benign breast disease and caffeine. Patients admitted for cancer or gynecologic, cardiovascular, or respiratory disorders were excluded as controls because these diseases might be related to breast cancer or methylxanthine intake. No information on response rate was provided. The effect of caffeine was assessed using conditional multiple logistic regression analyses, taking account of smoking, age (same decade) and hospital. Odds ratios of 1.0; 1.3; 1.5; and 1.1 were calculated for 0; l-3; 4-6; and 7 + cups of coffee or tea per day. None of these risks were significant even when 90% confidence intervals were used. Lubin et al. [30] studied 577 Canadian women with breast cancer and 826 population controls who were interviewed under different circumstances. Cases were questioned by nurses at a referral clinic during the years 1976 -77, while trained interviewers administered questionnaires to controls in their homes, in 1978. Successful interviews were obtained from 95% of the cases and 72% of the potential controls. The amount of tea or coffee consumed recently was elicited as one of 9 questions on diet. Women drinking more than 5 cups of coffee or tea per day had a risk ratio of 1.2 (95% confidence interval 0.9-1.5) compared to women drinking 5 or less cups per day. When the analysis was adjusted for beef and pork consumption, the risk was reduced slightly. A group of investigators [32] from the United Kingdom reported a positive relationship of borderline statistical significance for coffee drinkers compared to non-drinkers (relative risk = 1.26; 95% CI 0.99-1.60), but there was no evidence for a doseresponse. Information about coffee and tea intake for patients with a histological diagnosis of breast cancer and matched non-breast disease controls was abstracted from a computer database of 20,000 patients in the United

241 Cases 723 Surgical Controls 577 Cases 826 Population Controls ? Cases ? Hospital Controls 2651 Cases 1501 Hospital Controls 385 Cancer Controls 818 Cases 724 Surgical Controls 802 Neighborhood Controls 500 Cases 945 Hospital Controls

Case Control Case Control Case Control Case Control

Case Control

Case Control

Case Control Case Control

Case Control

Lawson et al. 1981 Lubin et al. 1981 Manse1 et al. 1982 Rosenberg et al., 1985

Lubin et al.

Le 1986

Katsouyanni et al., 1986 La Vecchia et al., 1986

Schairer et al., 1987

Rohan & McMichael 1988

N.A.

Hormonal, BBD, BMI family history Fat, BBD, hormonal, BMI Hormonal BBD, BMI family history No

Recent

I.A.

No

Past Past

Current

No. cups coffee No. cups coffee

Cohort mortality Cohort incidence/ mortality Correlation mortality

Snowdon & Philips, 1984 Jacobsen et al., 1986

N.A.

N.A.

N.A.

N.A., no statistically significant association; I.A., inverse association; P.A., positive association; BBD, benign breast disease; BMI, body mass index.

44 Countries per capita

Coffee/tea consumption

Recent

No. cups coffee

150 Cases 150 Hospital Controls 150 Neighborhood Controls 23,912 SDA (males & females) 2891 Norwegians

Case Control

lscovich et al., 1989

Phelps 8c Phelps, 1988

N.A.

Meat, smoking No

Recent

Quantified Coffee/tea/cola

451 Cases 451 Population control

Case Control

LA.?

N.A.

Past Recent

Hormonal, alcohol, smoking Hormonal, Smoking, BBD family history Hormonal, Smoking, BBD family history No

Quantified coffee/tea/cola

Cases Hospital Controls Cases Orthopedic Controls

1510 Cases 1882 Screened Controls

120 120 616 616 Recent

N.A.

1.A

No. cups coffee

Recent

N.A.

P.A.?

No

Past

Past, Recent

N.A.

Beef, pork

Recent

Quantified coffee/tea chocolate/cola No. cups coffee

N.A.

Results

No

No. cups coffee/tea No. cups coffee/tea No. cups coffee/tea No. cups coffee No. cups tea

Adjust confounding

Last 3 months Recent

Time of exposure

Exposure measure

Coffee/cola

1985

Study population

Type of study

Descriptive summary table of human studies.

Author and year

Table 1. $

85

Kingdom. Since this investigation was published as an abstract, few details regarding the study methods were presented. No information on number of cases, response rate, completeness of ascertainment, type of control, type of questionnaire, or potential confounders was reported. In a large case-control study conducted in the United States [43], trained nurses interviewed 2,650 breast cancer cases, 1501 noncancer hospital controls and 385 newly diagnosed cancer controls to elicit information on recent coffee and tea intake, as well as demographic, medical and reproductive histories. The non-cancer control group included patients admitted for trauma or infections. Interviews were conducted between 1975 and 1982 and the overall response rate was about 95%. Age-adjusted and multiple logistic regression analyses allowing for all potential confounding factors yielded essentially the same results. For the consumption of l-2, 3-4, and 5 + cups daily, the odds ratios ranged from 1 .O to 1.2. Because of the large size of this study, the confidence intervals were narrow and the highest upper bound was 1.6. No association between breast cancer and decaffeinated coffee was found. The similar findings obtained using two different control groups lends additional weight to this result. In Israel, Lubin et al. [29] conducted a dietary case-control study of breast cancer between 1975 and 1979. Histologically confirmed cases of breast cancer (818) were individually matched for age, country of origin and length of residence in Israel to 743 surgical controls and 813 neighborhood controls. All hospitalized patients were interviewed in the hospital, while the neighborhood controls were interviewed at home. Ninety-six percent of the cases and surgical controls and 72% of the neighborhood controls were interviewed. Questions regarding methylxanthines (coffee, tea, cocoa, cola and chocolate) and other dietary items referred to consumption 1 year prior to interview and up to 11 years prior to interview. A non-significant negative association was found between consumption of cof-

fee, tea and total methylxanthines. This inverse association was observed in different ethnic groups, but only among women over age 50. For women younger than 50 years, there was no association. To test whether caffeine promotes breast carcinogenesis in the presence of fat intake, analysis restricted to subjects with high fat intake, adjusting for hormonal factors, was also done. The risk of breast cancer among the high-fat consumers tended to decrease as methylxanthine consumption increased. The results of this study were similar when the cases were compared to hospital and neighborhood controls, as well as to patients with benign breast disease, making it unlikely that there was a bias stemming from an illness-related reduction in coffee consumption. In a French matched case-control study [25,26] of 500 cases and 945 surgical controls recent coffee consumption was significantly inversely associated with histologically confirmed breast cancer. Patients completed a self-administered questionnaire between 1976 and 1980 [26]. Adjusting for potential confounding variables, women drinking l-2 or 3 or more cups of coffee per day had a risk ratios of 0.8 and 0.6, respectively compared to women who never drank coffee. This pattern of decreased risk was also seen among patients with a history of benign breast disease. A small case-control study of diet and breast cancer in Greece found no evidence to suggest that caffeine may be an etiologic factor in breast cancer [20]. The distribution of 120 cases and 120 controls by the 3 levels of coffee and cola beverage frequency was virtually the same. Interpretation of results from this investigation has to be tempered by its low statistical power. In Northern Italy, La Vecchia and colleagues [23] examined the relationship of recent coffee consumption to breast cancer in 616 cases and an equal number of hospital controls. Cases and controls were selected from different hospitals serving the same catchment areas and the response rate was over 95%. Structured questionnaires administered

86

by trained interviewers elicited information about coffee, decaffeinated coffee, tea and cola. Using multiple regression analyses, controlling for hormonal variables, cigarette smoking and alcohol consumption, the authors found that coffee drinkers of 1-3 cups per day had significantly elevated risks compared to non-drinkers, but women who drank four or more cups had a risk ratio of unity. Duration of coffee drinking was not related to breast cancer. There was a small increased risk associated with tea (1.2)) but agaIn there was no evidence for increasing risk with increasing consumption. The investigators conclude that coffee consumption does not enhance the risk of breast cancer. The Breast Cancer Detection Demonstration Project (BCDDP) has been the source of a large amount of data on breast cancer risk factors. Past and recent information on methylxanthine including consumption, coffee (brewed, instant and non-caffeinated), tea, cocoa, chocolate milk, cola and diet cola was collected [46]. The study population included 1510 cases (73% of those eligible) and 1882 screened controls (90% of those eligible). In the total study population, the risk of breast cancer did not vary in association with methylxanthine or caffeine intake and among older women the data provided some evidence of a negative association. People coming to screening programs are often health conscious and may follow particularly healthy diets. However, since the controls were also selected from the screening program, no bias inherent to this study population would be expected. A case-control study of 451 matched pairs was conducted in Australia between 1982 and 1984 [42]. Both the cases and the population controls were interviewed at home. The response rate was 82% for cases and 70% for controls. Information regarding medical and reproductive history was obtained by trained interviewers, however methylxanthine and other diet information was collected using a self-administered quantitative food frequency questionnaire. Neither methylxanthine nor caffeine intake was associated with an increased

risk of breast cancer in the total population. Among pre-menopausal women the risk was non-significantly elevated, but there was no dose-response. No interaction between methylxanthines and high fat intake was seen. Iscovich et al. [18] studied 150 cases and an equal number of matched hospital and neighborhood controls in Argentina. Information on caffeine intake was collected as one of approximately 150 food items. A comparison of cases and controls, in terms of quartiles of caffeinecontaining beverages indicated no influence of caffeine on breast cancer. In fact, there was a borderline significant negative trend in the case-neighborhood control analysis. This study, however, suffers from its small size and its limited power to detect an association. Methodologic

limitations

of case-control

stud-

ies

As in most dietary case-control studies, the ones evaluating caffeine are subject to several potential problems. Some of the more important ones are discussed below. Timing of caffeine intake in relation to breast cancer diagnosis may be critical, yet the majority of studies only obtained information ahout recent caffeine consumption. Since the interval between exposure and cancer development is long, recent habits may not be appropriate to assess etiology. This problem is a particular concern in relation to dietary factors because people frequently reduce their coffee, as well as other food intake, as they grow older. The method of obtaining data on methylxanthine consumption is important. When subjects are asked about coffee in conjunction with alcohol and cigarettes, they may understate their intake because of the implied negative health effects. On the other hand, if subjects are asked a long list of food items they may answer automatically, especially for food items eaten with irregular frequency or in varying quantities. This seems to be less of a problem for caffeine because people can answer questions easily that refer to more standard habits. A major limitation of case-control studies is that of recall bias. If patients think that some-

87

thing is bad or harmful, they may not be willing to admit their use of the substance, if they think something is healthy they may overestimate usage. In the case of coffee and breast disease this is a real concern. After Minton et al. [34,35] published their original papers, the public became very aware of the hypothesis of an association between methylxanthines and breast disease. Thus, data gathered after 1979 have a high probability of a recall bias. Persons admitted to hospital with diet-associated diseases, such as diabetes or gastrointestinal disorders, etc., are often excluded from the control series. However, cases who have these diseases in addition to the disease under study are not always excluded from the case series. Depleting patients with diseases restricting caffeine intake from the control series, but not the case series would increase the probability of finding a negative association with coffee. In contrast, some investigators have shown that selected hospital controls have a wide variety of diseases for which coffee reduction is advised [44,50]. This bias would have the opposite effect as that discussed previously. Finally, there is always a concern about potential confounding factors. Coffee consumption is known to be associated with cigarette smoking, oral contraceptive use and fat consumption [8,9,15,16,27,48]. If any of these variables substantially affect the risk of breast cancer, then any effect ascribed to caffeine may actually be the result of its link to the other variables. Cohort studies Phillips and Snowdon [38,52] investigated breast cancer, as well as other cancer mortality among 23,912 white male and female Seventh-Day Adventists in California. The observation period was from 1960 to 1980. Coffee exposure was ascertained in 1967 by a selfadministered questionnaire which included information on demographic and medical data and frequency of coffee and a few selected foods and beverages. Deaths were ascertained by computer matching the members of the

study cohort with the California death certificate file. It is thought that a small proportion of deaths were missed by the record linkage procedures, but that there was no systematic bias because the probability of missing a death was not related to coffee use. No significant associations with coffee were observed. One problem with this study is the limited range of coffee use. Since the Adventist church discourages the use of caffeine-containing drinks, only about 30% of its members drink coffee and the highest consumption level was only 2 + cups per day. In addition, although 23,000 persons appears to be a large cohort, it included males and females. The authors do not state how many females were actually studied for the breast cancer analyses, In Norway, a prospective study of 2891 women who were spouses or siblings of patients interviewed in a case-control study of gastrointestinal cancer was conducted [ 191. These women completed a questionnaire concerning cardiorespiratory symptoms, dietary habits and coffee consumption. Cancer incidence and mortality was determined by computer linking the study cohort to the Norwegian Cancer Registry and the Central Bureau of Statistics. This cohort included a high proportion of heavy coffee drinkers: 28% of the cohort drank 5 or more cups per day, and the referent group was composed of women who drank 2 or less cups of coffee per day. With 32 b reast cancers, there was no indication that coffee drinking increases the risk. Pozner et al. [40] took a different approach and evaluated the relationship between cell differentiation in women with breast cancer and caffeine intake. They studied 101 women who underwent mastectomy and axillary dissection. Caffeine consumption was determined by questioning subjects about their diet history, including coffee, instant coffee, decaffeinated coffee, tea, cola and cocoa. Tumors were classified, according to surgical pathology reports, as poorly, moderately, or well differentiated. Taking various hormonal and dietary variables into account, women with poorly differentiated tumors reported lower caffeine and lower cof-

fee intake than patients differentiated tumors.

with moderate

or well

Conclusions To date, although coffee and other methylxanthine-containing beverages have been studied extensively as possible risk factors for breast cancer, they do not appear to contribute to an increased risk of this neoplasm [21,41,51]. Experimental studies have demonstrated varied results. Some studies have provided suggestive evidence for a promoting effect of caffeine, others have found no carcinogenic effect and still others have noted that caffeine inhibits the development of mammary carcinoma. Correlational studies have shown no or an inverse association between coffee and breast cancer and only one has found a link with tea. In the aggregate, analytic case-control and cohort studies have also been negative, although one provided some indication of an increased risk with high intake of coffee and tea and a few suggested a protective effect of coffee or methylxanthines. The one study reporting a positive association cannot be given the same weight as the others because it was published as an abstract with almost no description of the methods. An assessment of the analytic studies indicates that the majority were reasonably well done, had a large number of subjects and had the statistical power to distinguish an effect if one existed. In fact, several of the negative studies did find associations with other food items, so that it is reasonable to assume that if there was an effect it could have been detected. Non-differential misclassification of either caffeine intake or breast cancer diagnosis would tend to decrease the statistical power of a study, shift risk estimates toward unity [5] and narrow the confidence interval around the point estimate [8]. As a result, the potential of misclassification bias is a concern in negative studies. However, both breast cancer and caffeine are somewhat less subject to this limitation than many other diseases or exposures. Breast cancer is a disease which generally comes to medical attention and is diagnosed

fairly easily. Although some controls may have had minimal or early breast cancer, this would not occur frequently. Caffeine exposure is also easier to categorize than most other dietary variables because it is found in a limited and well defined number of foods and because people tend to have regular coffee drinking habits and can describe them in terms of cups per day. In fact, Jacobsen et al. [ 191 reported a correlation coefficient of 0.77 when 193 study subjects responded twice, 3-4 months apart, to questions regarding coffee drinking habits. The same authors also found a strong association between reported coffee drinking and concentrations of potassium, cholesterol, creatinine and uric acid in serum. Furthermore, most products containing methylxanthine are processed according to international standards, assuring a rather consistent composition of products consumed around the world. What is most apparent about studies on breast cancer and methylxanthines, is that although various methodologies were employed and different populations were evaluated, the results were consistently negative. Indeed, it is remarkable that the findings are so compatible. This is in contrast to many other nutritional factors, where the lack of agreement among studies is the norm, e.g., fat and breast cancer. It is also notable that several of the case-control studies reporting no association with coffee were able to demonstrate associations with other nutritional factors. Thus, it is unlikely that there is an association between the consumption of coffee and other methylxanthine-containing beverages and breast cancer. Acknowledgement Preparation of this review has been supported by the International Life Sciences Institute-Nutrition Foundation. References 1

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Consumption of methylxanthine-containing beverages and the risk of breast cancer.

The idea that caffeine might be involved in the etiology of breast disease was first proposed by Minton et al. in 1979. Since that time, numerous expe...
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