Affiliation of authors: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
Correspondence to: Sjoerd G. Elias, PhD, Julius Center for Health Sciences and Primary Care, Rm. Str. 6.119, University Medical Center Utrecht, P.O. Box 85060, 3508 AB Utrecht, The Netherlands (e-mail: s.elias{at}jc.azu.nl)
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ABSTRACT |
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INTRODUCTION |
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In the majority of animal models evaluating energy restriction and cancer risk, animals are subjected to lifelong dietary interventions (2). Animal data on short-term, transient caloric restriction and cancer risk are scarce and inconclusive (813). Few human studies on the relationship between substantial energy restriction and breast cancer risk have been performed, in part, because such a relationship is ethically difficult to investigate. However, in extreme situations such as war, opportunities arise to address the impact of short-term, transient energy restriction. Indeed, several studies have linked breast cancer risk to the experiences of women during World War II. For example, the average daily caloric intake in Norway declined from 3475 kilocalories in 1939 to a minimum of 2700 kilocalories in 19441945 (14,15). Results from four Norwegian studies (1619) suggest that a decreased risk of breast cancer is associated with such a decreased caloric intake.
Many people residing in the densely populated western parts of The Netherlands experienced a severe famine at the end of World War II. The famine was the result of an accumulation of several circumstances. By September 1944, the Allied forces had liberated the southern part of The Netherlands and tried to end the war quickly with an offensive aimed at capturing the Rhine bridge at Arnhem; a capture would facilitate an advance into the Ruhr area (20). To thwart the transport of German troops and ammunition, the exiled Dutch government ordered a railroad strike. German authorities responded to the strike with a food embargo that specifically affected the western parts of The Netherlands. The Allied offensive failed, and the abundance and availability of food deteriorated rapidly. Official daily adult per capita rations, which were roughly sufficient during the first 4 years of the war, decreased from approximately 1500 kilocalories in September 1944 to less than 700 kilocalories in January 1945. During this period, the relative amounts of protein, fat, and carbohydrate remained more or less balanced. Many residents of the large western Dutch cities undertook long and exhaustive journeys to the countryside in search of food. The famine situation began to improve on April 29, 1945, when food was airlifted and dropped over the region. Food again became abundant with the liberation of The Netherlands on May 5, 1945 (21,22).
In contrast to the Norwegian studies (1619), a Dutch study investigating the relation between the famine of 19441945 and subsequent breast cancer risk (23) found no decreased risk. However, that study used "place of residence" during the famine as a proxy for individual famine exposure. In this analysis, we have used individual exposure data from women participating in a large, population-based breast cancerscreening cohort to investigate the effect of the 19441945 Dutch famine on subsequent breast-cancer risk. We were able to examine this relation during different stages of female development, because the women in this cohort were aged 233 years during the Dutch famine that lasted for a relatively short period of time (i.e., 6 months).
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SUBJECTS AND METHODS |
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In 1974, a population-based prospective cohort study (24) for the early detection of breast cancer, the Diagnostisch Onderzoek Mammacarcinoom (DOM) project, started in Utrecht and surrounding municipalities in The Netherlands. Between 1974 and 1986, the DOM project recruited a total of 55 519 women who were born between 1911 and 1945. Participation in the project was voluntary. Depending on their year of birth, the women were offered mammographic screening at different intervals and at different ages, and formed four distinct cohorts: DOM-1, women born between 1911 and 1925 and recruited between 1974 and 1979; DOM-2, women born between 1926 and 1931 and recruited between 1981 and 1982; DOM-3, women born between 1932 and 1941 and recruited between 1982 and 1985; and DOM-4, women born between 1942 and 1945 and recruited between 1985 and 1986. The overall participation rate was 70% (range = 44%72%). During the screening examinations that took place between 1983 and 1986, the 19 732 women who were still participating in the DOM project were sent questionnaires seeking information on their personal experiences during the 19441945 Dutch famine. These women were aged 4173 years at the time they responded to the questionnaires and were born between 1911 and 1941. Women in the DOM-4 cohort did not receive this questionnaire because they were too young during the famine to remember their own experiences. Participants were asked about their place of residence during the famine and about their personal experience with hunger, cold, and weight loss during the famine. The participants were asked to grade their famine experiences as "absent," "moderate," or "severe." We combined the answers to the three personal experience questions into a new variable, which we called the famine score. Women who answered "severe" to at least two of the three questions were categorized as "severely exposed." Similarly, women who answered "absent" to at least two of the three questions were categorized as "unexposed." All other women were categorized as "moderately exposed" (25).
Of the 19 732 women who received the questionnaire, we excluded 2355 women who resided in the liberated region in the southern part of The Netherlands or abroad at the time of the famine. We thus included all women who resided in the occupied parts of The Netherlands during the winter of 19441945. A famine score could be computed for 15 396 women (89%).
By linking the total cohort of 15 396 women with the DOM project cancer registry (established in 1974) and the regional cancer registry (established in 1989), we identified all primary invasive breast cancers, excluding carcinoma in situ, that occurred in the cohort until January 1, 2000. Because assessing vital status at follow-up is costly and time-consuming, we chose the efficiency of a casecohort study design, in which a random sample of the total cohort is used to represent total person-years lived for the entire cohort (26). As in a prospective cohort analysis, all breast cancer cases occurring in the entire cohort contribute to the dataset, but only a sample of the total cohort is needed to estimate the number of person-years lived. We randomly selected a sample of approximately 15% of the total cohort (n = 2352) for which we ascertained vital status. This random sample of women was followed until January 1, 2000, by using regional municipality registries for mortality and movement out of the catchment area of the cancer registry.
Data on reproductive events, demographics, and breast cancer risk factors were available from questionnaires obtained during the screening examinations, at which time trained medical assistants also took anthropometric measures. Women gave oral informed consent, and the study was approved by the institute's ethical committee.
Statistical Analysis
Characteristics of the random sample of women at baseline (i.e., at the time the completed famine questionnaire was received) are presented according to famine exposure status. For continuous variables, means with standard deviations are presented. Continuous variables were also dichotomized on the basis of their median values within the total random sample, except for age at screening examination, which was categorized by quartiles. For categorical variables, we present the total number of random-sample participants in each category, the total number of cases that occurred in the entire cohort, and the estimated number of person-years lived for the entire cohort. The casecohort design allows assessment of absolute incidence rates, which we adjusted for age. For this adjustment, we used the direct standardization method, in which the age distribution of the random sample of women served as the standard.
To assess the relation between famine and breast cancer risk, we used weighted Cox proportional hazards regression analyses. The methods for these analyses are similar to the standard Cox proportional hazards regression analyses and have previously been described by Barlow et al. (26). Follow-up time started with the date the completed famine questionnaire (administered between 1983 and 1986) was received and ended with the date of a primary invasive breast cancer diagnosis (event). Women who remained free of breast cancer during the observation period were censored at the date of emigration from the catchment area, the date of death from any cause, or the end of follow-up (January 1, 2000), whichever occurred first.
Analyses were performed with SAS version 8.2 (SAS Institute, Cary, NC) by use of a weighted Cox regression macro [(26), available at http://lib.stat.cmu.edu/general/robphreg] that computes the weighted estimates together with a robust standard error. From these standard errors, we calculated 95% confidence intervals (CIs). The proportionality of the hazards over time was evaluated with log minus log plots in SPSS 11 (SPSS, Chicago, IL), and assumptions of proportionality were met. Trend tests were used to explore doseresponse relations, introducing the famine score as a continuous variable (1 for unexposed, 2 for moderately exposed, and 3 for severely exposed).
We considered the following variables as potential confounders: age at menarche, age at screening examination (i.e., when the completed famine questionnaire was received), body mass index at screening examination (weight in kilograms divided by height in meters squared), height at screening examination, parity (nulliparous or parous), age at first childbirth, socioeconomic status (derived from health insurance information, for which women who used the public service were considered to be of low socioeconomic status, civil servants were considered to be of intermediate socioeconomic status, and those who had private insurance were considered to be of high socioeconomic status), and family (first-degree relative [mother or sister]) history of breast cancer (yes or no). Age at menopause was also considered to be a confounder, but we could assess its potential confounding effects only for a subgroup of women for whom the information on age at menopause was available. Continuous variables were introduced as such in the different models, and categorical variables were introduced as dummy variables. We adjusted for age at screening examination and its square, because these two variables were found in preliminary analyses to best describe the relation between age and breast cancer risk. To include age at first childbirth and parity simultaneously in the models, we used the age at first childbirth centered around its mean multiplied by parity (27,28).
To assess whether differences in breast cancer risk were associated with developmental stage, we analyzed the relationship between famine exposure and breast cancer risk separately for women exposed in early and middle childhood (aged 29 years), later childhood and adolescence (aged 1018 years), and adulthood (aged 19 years). These age groups are based on distinct female developmental stages as described by Bogin (29). Age during the famine was determined relative to the date the famine started (October 1, 1944) and resulted in an age range during the famine that varied between 2 and 33 years.
Because pregnancy is known to alter the neuroendocrine milieu (30) and we have previously found that exposure to the famine was associated with increased levels of sex steroids in postmenopausal nulliparous women but not in parous women (31), we evaluated whether a relation between the famine exposure and breast cancer risk was modified by parity. Interaction terms were introduced into the models to test any observed associations.
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RESULTS |
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A total of 32 357 person-years were accrued in the random sample, with a median time of follow-up of 184 months (15.3 years). By extrapolation, 215 714 person-years were accrued in the total cohort, during which 585 women were diagnosed with primary invasive breast cancer. By using this number of diagnoses, we calculated an overall breast cancer incidence rate of 2.71 per 1000 person-years. According to data from the Netherlands Cancer Registry (32), the breast cancer incidence rate in 1997 among similar aged women from the general Dutch population was 2.75 per 1000 person-years. Thus, follow-up of the breast cancer cases in our cohort was largely complete.
The median age at diagnosis among all women with breast cancer was 64 years. A total of 487 women were postmenopausal when diagnosed with breast cancer, whereas seven women were premenopausal when diagnosed with breast cancer. The menopausal status of an additional 91 women diagnosed with breast cancer was unknown. The median age at diagnosis of the 91 women with unknown menopausal status was 52 years. Thus, the majority of the breast cancer cases in our study were diagnosed in postmenopausal women.
Baseline characteristics of the random sample of women according to famine exposure are presented in Table 1. Among this sample of women, 10% reported severe exposure and 39% reported moderate exposure to the famine. The women who reported severe exposure were, on average, older during the famine and at the screening examination, had a higher body mass index, reached menopause at a younger age, gave birth to their first child at an earlier age, and had a lower socioeconomic status than the women in the other exposure groups.
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We next determined whether there was an association between age during the famine, breast cancer risk, and famine exposure (Table 3). The association between famine exposure and breast cancer risk, although not statistically significant, was in the same direction for all age groups. The largest impact of famine exposure on breast cancer risk was seen for women who were exposed at a young age. Compared with the risk of breast cancer in women who were not exposed to the famine, the risk in women who were severely exposed to the famine between the ages of 2 to 9 years was doubled (HR = 2.01, 95% CI = 0.92 to 4.41). The risk of breast cancer was also increased in women who were severely exposed to the famine at later ages (HR = 1.55, 95% CI = 0.89 to 2.73 for women aged 1018 years during the famine, and HR = 1.18, 95% CI = 0.77 to 1.80 for women aged 19 years during the famine). Among women who were aged 29 years during the famine, the association between severe exposure and breast cancer risk was not statistically significantly different from that among women aged 19 years or older during the famine (test for interaction: P = .06).
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DISCUSSION |
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Although the 19441945 famine is a black page in Dutch history, it provides a unique situation in which to study the long-term consequences of a short but severe famine in humans. We explored the relation between famine exposure and breast cancer risk in a cohort of approximately 15 000 women, with approximately 200 000 person-years of follow-up and 585 primary invasive breast cancers. We analyzed individual famine-exposure data, which may be more accurate than area-exposure data, in which all women in a specific area are assigned to the same exposure status. However, the individual exposure scores in our study were derived from subjective information and were based on individual recall, and thus may be subject to misclassification. Because the women reported their famine experiences years before any breast cancers were diagnosed, it is unlikely that recall would be related to subsequent breast cancer risk. Random misclassification would have resulted in an underestimation of the true effects; such underestimates may be greatest in those women who were the youngest during the famine because their recall of famine experiences is likely to be the least accurate.
Severe famine exposure was reported more frequently by women who lived in urban areas during the famine than by women who lived in rural areas (25). This result was expected on the basis of historical information reporting that the famine was worse in large cities (21). Furthermore, women who were severely exposed to the famine were, on average, older during the famine than women who were not exposed. During the entire war period and during the famine, rations were provided on the basis of age and were aimed at providing relative protection to the young (22). From these circumstantial data, we conclude that the individual famine score is quite accurate in measuring true famine exposure status.
A methodologic shortcoming of our study is that the results are conditional on the women surviving until the screening examinations that were conducted between 1983 and 1986, approximately 40 years after the famine. We can only speculate what effects this could have had on our findings. Although an estimated 22 000 people died of starvation during the famine, mortality data from Amsterdam, a large city that was severely struck by the famine, showed that 75% of all deaths were male and 79% of all deaths were either babies (aged 1 year) or the elderly (aged
65 years) (21). A direct increase in mortality resulting from the famine in the source population for our study was therefore minimal (female cohort, aged 233 years during the famine). Furthermore, the overall life expectancy of women born between 1930 and 1942 (aged between 2 and 14 years during the famine) did not deviate substantially from what was expected, based on the trend of increased life expectancy during the last century (33). Even if the famine did decrease survival until the screening examination, it is unlikely that this was related to the risk of developing breast cancer. Therefore, we believe that conditional survival was not related to famine experiences or to subsequent breast cancer risk and therefore could not have influenced the results.
We were not able to adjust for alcohol use in our analyses because this information was not available. A recent meta-analysis (34) reported that the relative risk of breast cancer increased by 7.1% for every 10 g of alcohol consumed per day. Thus, to fully explain our findings that severe famine exposure is associated with twice the risk of breast cancer in women aged 29 years during the famine, women who were severely exposed to the famine would, on average, have to consume approximately 100 g of alcohol or 10 drinks per day more than the amount of alcohol consumed by women who were not exposed to the famine. Women in western countries drink an average of 6.0 g of alcohol per day, and only 1.3% of women drink more than 45 g of alcohol per day (34). Thus, it seems unlikely that alcohol use could have confounded our results to any great extent.
Although considerable evidence showed that prolonged caloric restriction reduced mammary tumor risk in rodents (3,4), the short but severe caloric restriction imposed by the 19441945 Dutch famine was associated with an increased risk of breast cancer in humans. The only other report on the Dutch famine and its association with breast cancer risk by Dirx et al. (23) used place of residence as a proxy for famine exposure rather than individual recall of famine exposure, and it showed equivocal effects. Compared with women who lived in a non-western area during the famine, women who lived in a western rural area had a 1.5-fold (95% CI = 1.1-fold to 1.9-fold) increased risk for breast cancer, and women who lived in a western city had a 1.1-fold (95% CI = 0.9-fold to 1.4-fold) increased risk for breast cancer. Because the women in the study by Dirx et al. (23) were already aged 13 years or older during the famine, the authors were not able to explore the impact of famine during childhood on breast cancer risk.
Four studies (1619) have indirectly associated breast cancer risk with the 19401945 wartime conditions in Norway, when caloric intake was substantially reduced. Two studies (18,19) showed that women who were peripubertal during the war had a lower than expected incidence of breast cancer. Two other studies described the relation between adult height and breast cancer risk and showed that a positive relation was more pronounced in women who were born during the war years (17) or who were peripubertal during this period (16). These observations have led to the conclusion that dietary factors early in life that subsequently affect adult height may play a role in the etiology of breast cancer.
The association between caloric intake and subsequent breast cancer risk has been investigated in women with extremely low (anorexia nervosa) or high (obesity) body mass indices. Although the risk of breast cancer was 20% lower than expected in patients with anorexia nervosa, the observation was based on only seven breast cancer cases and was consequently not statistically significant. Furthermore, because patients with anorexia nervosa form a highly selective group, it is difficult to generalize these results (35). By contrast, obesity in adulthood, which is the result of high energy intake relative to low energy expenditure, is associated with increased breast cancer risk in postmenopausal women and probably with decreased breast cancer risk in premenopausal women (36). All of these human studies suggest an important role of energy balance in breast cancer etiology, although such a role is not straightforward.
Data on short-term, transient caloric restriction, in which animals were allowed to eat freely after the restriction, are limited (813). However, in one report (8), rats were calorie restricted for a short period of time after they were weaned and were then fed ad libitum for the rest of their lives. Compared with rats that were fed ad libitum throughout life, rats that were subjected to short-term caloric restriction had an increased risk of malignant cancer later in life. An absence of a decreased risk of cancer or an actual increased risk of cancer by short-term, transient caloric restriction was also reported in other rodent studies (913), of which two (10,13) refer to induced mammary tumors and caloric restriction during tumor initiation and promotion.
We hypothesize that several endocrine systems may adapt to adverse circumstances existent during the maturation of the hypothalamicpituitary axis and show an inadequate response to the period of abundance thereafter, ultimately leading to increased risk of breast cancer. We have shown that levels of circulating insulin-like growth factor-I are increased in postmenopausal women who were severely exposed to the 19441945 Dutch famine before age 20 years (37). Levels of sex steroids in the urine also seemed to be increased in postmenopausal women who were exposed to the 19441945 Dutch famine in young adulthood, although these associations were seen only in nulliparous women (31). High levels of insulin-like growth factor-I and sex steroids are both associated with increased breast cancer risk (38,39).
In conclusion, our data do not support the hypothesis that short-term, transient caloric restrictionsuch as during the 19441945 Dutch faminedecreases subsequent breast cancer risk. Our data suggest that the risk of breast cancer is increased in women severely exposed to the Dutch famine at a young age.
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NOTES |
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We thank Bernard Slotboom and Bep Verkerk for processing and handling of data. We also gratefully acknowledge the support of the regional population-based screening organization Stichting Preventicon and of the various municipalities within the region that provided us with the vital status information from the random sample as well as the support of the Comprehensive Cancer Centre Middle Netherlands in the record linkage.
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Manuscript received September 22, 2003; revised February 3, 2004; accepted February 10, 2004.
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