The Experience of Japan as a Clue to the Etiology of Breast and Ovarian Cancers: Milk and Dairy Products are Causatively Related to Both Malignancies


Adapted from:
Li D, Ganmaa D, Sato A.
The Experience of Japan as a Clue to the Etiology of Breast and Ovarian Cancers: Relationship between Death from Both Malignancies and Dietary Practices.
Medical Hypotheses 2003;60:268-75.

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Summary

Although breast and ovarian cancers are rare in Japan compared with other developed countries, the death rates for both are increasing. In Japan, dramatic lifestyle changes occurred after World War II. Over the past 50 years (1947-1997), the age-standardized death rates of breast and ovarian cancers increased about 2- and 4-fold, respectively, and the respective intake of milk, meat, and eggs increased 20-, 10-, and 7-fold. The increase in the annual death rates from breast and ovarian cancers might be due to the lifestyle changes (increased consumption of animal-derived food) that occurred after 1945. Among the food, milk and dairy products should receive particular attention since they contain considerable amounts of female sex hormones.

Introduction

Breast cancer is one of the most frequent malignancies in women (1). Despite the introduction of early detection methods and promising medical and surgical procedures, there has been no overall decrease in the age-standardized death rate in any large population; instead, the death rate is increasing in most countries (2). For example, approximately 796,000 new cases of breast cancer are estimated to occur annually worldwide (1). The highest incidence of breast cancer is found in the US, where the age-standardized incidence rate is now 80-100 per 100,000.

Ovarian cancer is a moderately infrequent malignancy that is a leading cause of death from gynecological cancers (1). In the US, ovarian cancer is the fourth most frequent cause of cancer death in women, following lung, breast, and colorectal cancers. Each year, approximately 26,000 women are diagnosed with ovarian cancer in the US, and 14,000 have a fatal outcome (3).

In our previous work (4), we correlated the incidence rates of breast and ovarian cancers in 42 countries with the dietary variables in these countries using the cancer rates provided by the International Agency for Research on Cancer (IARC) (5) and the food supply data provided by the Food and Agriculture Organization (FAO) (6). Among the food items examined, meat was most closely correlated with the incidence of breast cancer (r= 0.820), followed by milk + cheese (r= 0.790). The food that was most closely correlated with the incidence of ovarian cancer was fats + butter (r= 0.747), followed by milk + cheese (r= 0.745). Stepwise multiple regression analysis identified meat and milk + cheese as a factor contributing to the incidence of breast cancer (standardized regression coefficient [R] = 0.875) and ovarian cancer (R = 0.748), respectively. The results of this study suggested a role for animal-derived food in the development and growth of both malignancies.

Breast and ovarian cancers are rare in Japan compared with the US, but the numbers of patients are increasing. The death rates from both cancers have been rising since the end of World War II (7,8). Dramatic lifestyle changes occurred in Japan after the war, the most conspicuous change being a change in dietary practices. For example, as shown in Fig. 1, the respective consumption of milk and dairy products, meat, and eggs increased 20-, 10-, and 7-fold. The great changes in Japanese dietary practices after the war appear to have affected death from breast and ovarian cancers in Japanese women.


Fig. 1. Relative changes in the intake of selective nutrients and food in Japan from 1942-1952 (1950) to 1993-97 (1995).

The experience of Japan serves as an excellent model for the dietary hypothesis of cancer etiology, because an essentially no-milk/no-meat culture prevailed in this country until the end of World War II. In this study, we used the available demographic data to analyze the time trends of breast and ovarian cancers in relation to dietary practices.

Materials and Methods

Data collection and sorting
In Japan, there is a working cancer registration system in several regions (9). However, national data on the incidence of breast and ovarian cancers are available only for the periods of 1975-1996 (10). In contrast, the death certification system was established in Japan before World War II, and the mortality data for both malignancies are readily available from the governmental statistics.

The age-specific numbers of deaths from breast and ovarian cancers and the population of 5-year age groups were obtained from the Vital Statistics of Japan for 1947-1997 (11). The population confirmed by censuses (every 5 years, in calendar years ending in 0 or 5) was used as representative of the grouped years; for example, the population in 1955 represented the population for the 5 years between 1953 and 1957 or the 10 years between 1951 and 1960. Age adjustments were made to the standard world population (Segi). The world cancer mortality data (12) were used to compare between Japan and the US.

Since the age-specific death rates of both breast and ovarian cancers were found to increase sharply in women aged over 50 years old, the truncated age-standardized death rates for ages 0-49 (premenopausal) and 50-85+ years (postmenopausal) were used for analysis.

Birth cohort study
The age-specific death rates were arranged to show the experience of women who were grouped by year of birth. We grouped the data into 10-year birth cohorts (years of birth: 1876-1885, 1886-1895, 1896-1905, 1916-1925, 1926-1935, 1936-1945, and 1946-1955), and investigated which cohort was most affected by the marked social and economic changes that occurred in Japan after World War II (i.e., after 1945).

Food Intake
The National Nutritional Survey has been conducted annually in Japan by the Ministry of Health and Welfare since 1946, and an annual report is published. Nutrient and food intake data (g/capita/day for both) were collected from the Health and Welfare Statistics Association of Japan (13) and other published tabulations (14). The intake of each selected food item (fats and oils, milk and dairy products, eggs, meat, fish and fishery products, cereals, pulses, and yellow and green vegetables) in addition to the intake of protein, fats, and carbohydrates were averaged every five years beginning from 1948-1952, and used as the intake in the middle year of the grouped years (1950, 1955, etc.).

Results

Breast cancer
The average number of deaths from breast cancer per year was 1374 in the period 1948-1952; it increased progressively and peaked at 7589 in 1993-1997 (a 5.5-fold increase). The number of deaths in premenopausal women increased from 505 in 1948-1952 to 1894 in 1993-1997 (a 3.8-fold increase), whereas the increase of the number of deaths in postmenopausal women during the same period was about 7-fold, from 869 to 5695.

While the age- standardized death rate of breast cancer was stable between 1948-1952 (represented by 1950) and 1963-1967 (1965), it started to increase almost linearly in the 1970s. Over the past 30 years, the death rate almost doubled, from 3.84 (per 100,000) in the years 1963-1967 to 7.37 in 1993-1997. The death rate was much higher in postmenopausal women than in premenopausal women (Fig. 2). Thus, most of the increase in the death rate in Japanese women was attributed to an increased number of deaths among postmenopausal women.


Fig. 2. Changes in the truncated age-standardized death rates of breast and ovarian cancers in premenopausal (0-49 years old) and postmenopausal (50-85+ years old) Japanese women from 1948-52 (1950) to 1993-1997 (1995).

In the years from 1948-1952 to 1993-1997, the patterns of the age-specific death rate curves differed substantially (Fig. 3). The death rate in women under the age of 74 years did not peak until 1968-1972. In recent years (1978-1982 and later), however, a distinct peak appeared in the death rate curves for the age range 55-59 years.


Fig.3. Changes in the age-specific death rates of breast and ovarian cancers in Japan from 1948-52 (1950) to 1993-97 (1995).

The age-specific death rate of breast cancer in Japan differed substantially from that in the US (Fig. 4; death data in 1990). Unlike the pattern in Japan, the death rate in the US increased almost linearly with increasing age; the increase in the death rate with age in postmenopausal women was only slight in Japan compared to the dramatic increase in the US. The age-standardized death rate of breast cancer in Japan was 6.75 (per 100,000), less than 1/3 that in the US (23.41).


Fig. 4. Comparison of the age-specific death rates of breast and ovarian cancers between Japan and the US.


Fig. 5. Age-specific death rates of breast cancer in Japan by birth cohort.

The cohort study showed that the later the year of birth, the higher the death rate from breast cancer in later life (Fig. 5). The age-death curves of women born in the period 1916-1925 or later differed from those of the cohorts born in 1906-1915 or earlier. The death rates of the later cohorts increased more sharply with increasing age than did those of the early cohorts.

Ovarian cancer
While the annual average number of deaths from ovarian cancer was as low as 316 per year in the period 1948-1952, it increased rapidly to 3918 (a 12.4-fold increase) in 1993-1997. The number of deaths in premenopausal women increased from 161 in 1948-1952 to 698 in 1993-1997 (roughly a 4-fold increase), whereas the increase in postmenopausal women during the same period was about 22-fold, from 145 to 3219. Accordingly, the percentage of cancer deaths among postmenopausal women to total deaths increased markedly, from 47.4% in 1948-1952 to 82.2% in 1993-1997. On the other hand, the deaths of young women (0-29 years old), which were 15.9% of the total deaths in 1948-1952, decreased to as low as 1.15% in 1993-1997, a decrease to less than 1/10 over the last 45 years studied.

From 1948-1952 to 1993-1997, the age-standardized death rate of ovarian cancer increased about 4-fold, from 0.83 (per 100,000) to 3.53. The death rate in premenoausal women increased about 2-fold, from 0.50 to 1.14 during the same period, whereas the rate in postmenopausal women increased about 6-fold, from 2.17 to 13.06 (Fig. 2). The pattern of death from ovarian cancer differed from that of breast cancer, in that the death rate of ovarian cancer increased more steadily with time throughout the observation period.

In the most recent five years (1993-1997), the death rate of ovarian cancer increased almost linearly with increasing age (Fig. 3), quite unlike the period 1968-1972 and before, when the death rate in women aged 50-74 years was essentially constant, irrespective of age.

Compared with the age-standardized death rate of ovarian cancer in the US (6.51/100,000), the death rate in Japan was low (3.55) (Fig. 4). At younger ages (15-44 years), however, the death rate in Japan (1.33) was slightly higher than that in the US (1.04). The age-related increase in cancer deaths was much less noticeable in Japan than in the US. Accordingly, the difference in the death rate between the two countries became proportionately larger with increasing age.


Fig. 6. Age-specific death rates of ovarian cancer in Japan by birth cohort.

As with deaths from breast cancer (Fig. 5), the later the year of birth, the higher the death rate from ovarian cancer in later life (Fig. 6). The curve for the age-related death rate in the cohorts born in 1896-1905 or later differed from that of earlier cohorts; the age-related increase in the death rate was much greater in the later cohorts than in the early cohorts.

Food consumption
Between 1948-1952 and 1993-1997, total energy intake changed only slightly (Fig. 1), from 2090 kcal in 1948-1952 and 2021 kcal in 1993-1997. While the increase in total protein intake (animal and plant) during the same period was small (67.1-80.3 g/day), the intake of animal protein more than doubled, from 17.5 to 43.2 g/day. Total fat intake was 17.4 g/day in 1948-1952; this started to increase rapidly around 1958-1963, and peaked at 58-59 g in the 1990s (roughly a 3-fold increase). The increase in animal fat intake was particularly marked; it increased about 5-fold, from 6.1 to 29.1 g/day. In contrast, carbohydrate intake decreased by 33%, from 416.2 to 278.8 g/day.

In terms of food items, the consumption of animal-derived food increased conspicuously between 1948-1952 and 1993-1997 (Fig. 1); consumption of milk and dairy products, meat, and eggs increased about 20- (6.6-135.3 g/day), 10- (7.6-77.78/day), and 7-fold (5.8-42.1 g/day), respectively, during this period. By contrast, cereal consumption, which was 472.7 g/day in 1948-1952, decreased to 268.6 g/day in 1993-1997. Among cereals, the consumption of rice, the principal food of Japanese, decreased to almost half during the same period, from 333.9 to 177.5 g/day. The consumption of pulses, including soybeans, increased slightly from 55.8 g/day in 1948-1952 to 69.2 g/day in 1993-1997.

Discussion

The age-standardized death rates from breast and ovarian cancers in Japan increased about 2- and 4-fold, respectively, in the 50 years between 1947 and 1997. Since the time trend in the death rate of any cancer involves the diagnosis, recording, and fatality rate of the cancer, a study like ours using data from death certificates may be criticized. However, if the yearly changes in the numbers of deaths from breast and ovarian cancers were due solely to changes in diagnosis, certification or recording, there must have been a large loss of fatal cases from the recording system in the 1960s or earlier, when the recorded rates of both malignancies were low. This is unlikely in Japan, where both health care and death certification systems were well established before World War II. We believe that environmental factors played an important role in the increased numbers of breast and ovarian cancer deaths.

Diet is widely recognized as an important cause of cancer, causing approximately 35% of cancer deaths (15). According to the ecological study of Rose et al. (16), there is a strong positive correlation between deaths from breast and ovarian cancers and the consumption of animal-derived food, like meat, milk, and dairy products. Therefore, it is likely that Westernized dietary practices affected the development of breast and ovarian cancers in Japan, where an essentially no-milk/no-meat culture prevailed until the end of World War II (1945).

Breast cancer
For breast cancer, the increase in the death rate was not very great until the 1916-1925 birth cohort (Fig. 5). The women belonging to this cohort were 20-29 years old in 1945, when the Japanese lifestyle started to change. They arrived at a full-scale cancer age of 50-59 years in 1975, when the economic growth of Japan accelerated, and the Westernization of Japanese dietary practices (more meat, eggs, and milk and dairy products) was realized (Fig. 1). We suggest that the increase in breast cancer deaths in these women was related to some features of Japanese life after World War II, specifically the Westernization of dietary habits. The breast cancer death rate started to increase 15 years after the start of the increase in the consumption of milk, meat, and eggs (Fig. 1 vs. Fig. 2). This suggests that it took around 15 years for the dietary change to have a significant effect on the death rate of this malignancy.

Many epidemiological studies have indicated a positive correlation between the consumption of meat/milk/dairy products and breast cancer risk (16-26). According to La Vecchia and Pampallona (20), who found a significantly positive correlation between breast cancer mortality and meat/milk consumption, milk and cheese were the only dietary variables to remain significantly positive after the correlation was adjusted for women's age at the birth of their first child and economic variables.

In contrast, some investigators have reported a negative correlation between breast cancer and the consumption of milk/dairy products (27,28). The most notable is the prospective study reported by Knekt et al. (28), who reported that the age-adjusted relative risk of breast cancer was 0.42 (95% confidence interval = 0.24-0.74) between the highest and lowest tertiles of milk consumption. In fact, milk consumption differed between those who developed breast cancer and those who did not: meanSD was 432313 g/day in the former (n=88) and 531319 g/day in the latter (n=4609) (p<0.05). However, the consumption of cereals, potatoes, dairy products, meat and meat products, fish, and eggs was also significantly lower in women assigned to the lowest tertile of milk consumption (<370 g/day) than that in women assigned to the highest tertile (620 g/day) (p< 0.001). Accordingly, the mean total energy intake of women belonging to the lowest and highest tertiles was 1789 and 2588kcal/day (p<0.001), respectively. This means that a woman who eats less is more susceptible to breast cancer than a woman who eats much more, a conclusion that contradicts the epidemiological findings that an increased calorie intake is a risk factor for the malignancy (29-31).

There is substantial evidence that hormones, particularly estrogens, are involved in the development of breast cancer in postmenopausal women (32). Animal-derived foods, like meat, eggs and milk, contain considerable amounts of estrogens (33). According to Hartmann et al. (33), the major sources of estrogens in the human diet are milk and dairy products, which account for 60-70% of the estrogens. Present-day cows' milk differs from milk consumed 100 years ago, in that milk is now produced from cows in late pregnancy, when estrogen levels are markedly elevated (34).

In addition to estrogens, milk normally contains insulin-like growth factor-1 (IGF-1), which stimulates the proliferation of human breast cancer cell line MCF-7 at nanomolar concentrations (35). IGF-1, a peptide, is not deactivated by pasteurization (36) and can survive digestion in the gastrointestinal tract (37,38).

The risk of breast cancer is higher in nulliparous women than in parous women (1). Increased age of first childbirth is also associated with an increased relative risk of this malignancy (39). Another change in the Japanese lifestyle that occurred in the course of economic growth is the increase in the number of nulliparous women and the average age of the mother at the birth of the first child (7). These lifestyle changes might have had some impact on the death of Japanese women from breast cancer.

Ovarian cancer
The age-related death pattern of ovarian cancer differed from that of breast cancer, in that the older the women, the higher the death rate from ovarian cancer, whereas the breast cancer death rate had a distinct peak at ages 55-59 years (Fig. 3). The ovarian cancer death rate started to increase in women belonging to the 1896-1905 birth cohort (Fig. 6). The women born in this period reached ages 40-54 years in 1945 and 70-84 years in 1975. The dietary change in Japan that occurred after 1945 seems likely to have played a role in the development of ovarian cancer in women born in 1896-1905 or later. The increase in the ovarian cancer death rate roughly parallels that of animal-derived food consumption (Fig. 1 vs. Fig. 2). This suggests that the dietary change affects ovarian cancer mainly in its promotional stage.

The etiology of ovarian cancer is multifactorial, and the roles of many factors remain inconclusive. Ecological studies invariably indicate that mortality from ovarian cancer is associated with milk consumption (16,40,41). Several case-control studies (42-45) and a prospective study (46) have also suggested that milk consumption elevates the relative risk for ovarian cancer, while another negates the relationship (47).

The increase in deaths from ovarian cancer in Japan after World War II was particularly marked in postmenopausal women (Fig. 2). Serum gonadotropins (FSH and LH) reach maximal values in the perimenopausal years as estrogen levels decline (48). In this regard, gonadotropins are proposed to increase ovarian cancer risk by directly stimulating cell proliferation and inhibiting apoptosis in ovarian surface epithelium (49). In addition, hormonal factors have received increasing attention recently, since the use of oral contraceptives (decreasing risk) or non-contraceptive estrogens (increasing risk) is related to the risk of ovarian cancer development (50-53). It is not unreasonable to presume that milk, which contains both estrogens (33) and gonadotropin-releasing hormones (54-56) is associated with the development of ovarian cancer by changing the hormonal environment in the ovaries.

The death rates of breast and ovarian cancer in Japan are much lower than those in the US (Fig. 4). According to the data provided by the FAO (6,57), the average consumption (g/capita/day) of milk, meat, and eggs in the US over 1961-1990 was 666 (5.1-fold that in Japan), 289 (4.2-fold) and 44 (1.0-fold), respectively. If the dietary hypothesis of cancer development holds true, the difference in the death rates of both malignancies between Japan and the US might have resulted from the difference in the intake of milk and meat in both countries. Considering the recent changes in dietary practices in Japan, the death rates of breast and ovarian cancers in Japanese women should rise significantly in the future. Nevertheless, the rates will never become as high as those in the US, because the consumption of meat and milk in Japan is now reaching a plateau (Fig. 1).

In conclusion, dietary changes, in Japan after World War II may be related to the recent increase in deaths from breast and ovarian cancers. The increased consumption of milk should receive particular attention as a factor causing or promoting these malignancies.

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