Perinatal characteristics and breast cancer risk in daughters: a Scandinavian population-based study.

The in utero origins of breast cancer are an increasing focus of research. However, the long time period between exposure and disease diagnosis, and the lack of standardized perinatal data collection makes this research challenging. We assessed perinatal factors, as proxies for in utero exposures, and breast cancer risk using pooled, population-based birth and cancer registry data. Birth registries provided information on perinatal exposures. Cases were females born in Norway, Sweden or Denmark who were subsequently diagnosed with primary, invasive breast cancer (n = 1419). Ten controls for each case were selected from the birth registries matched on country and birth year (n = 14,190). Relative risks (RRs) and 95% confidence intervals (CIs) were estimated using unconditional regression models. Breast cancer risk rose 7% (95% CI 2-13%) with every 500 g (roughly 1 s.d.) increase in birth weight and 7% for every 1 s.d. increase in birth length (95% CI 1-14%). The association with birth length was attenuated after adjustment for birth weight, while the increase in risk with birth weight remained with adjustment for birth length. Ponderal index and small- and large-for-gestational-age status were not better predictors of risk than either weight or length alone. Risk was not associated with maternal education or age, gestational duration, delivery type or birth order, or with several pregnancy complications, including preeclampsia. These data confirm the positive association between birth weight and breast cancer risk. Other pregnancy characteristics, including complications such as preeclampsia, do not appear to be involved in later breast carcinogenesis in young women.

Exposures in early life: associations with DNA promoter methylation in breast tumors.

There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case-control study. Promoter methylation of E-cadherin, p16 and RAR-ß2 genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case-case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case-case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15-6.82, for ⩽2.5 v. 2.6-2.9 kg); higher adult height with RAR-ß2 methylation (OR = 3.34, 95% CI, 1.19-9.39, for ⩾1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14-6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ⩾1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk.

Agreement between self-reported birth weight and birth certificate weights.

Birth weight is emerging as a potentially important risk factor for several chronic diseases with adult onset, including breast cancer. Because participant recall is frequently used to gather data on early life exposures, it is essential that the accuracy of recall be assessed and validated. Self-reported birth weights and birth certificate weights were compared in women aged 35-51 years from the Western New York Exposures and Breast Cancer (WEB) Study, a population-based case-control study. A total of 180 participants had both birth certificate and interview data on birth weight. Participants reported birth weight to one of six categories (<5, 5-5.5, 5.6-7, 7.1-8.5, 8.6-10 and >10 lbs). The Spearman correlation for self-reported and birth certificate weights was 0.67. Sixty percent of participants reported weights with exact agreement with birth certificate; unweighted and weighted kappas (κ) were 0.39 and 0.68, respectively. Spearman correlations were similar for cases (0.67) and controls (0.68). Controls exhibited a significantly higher unweighted κ (0.51) than cases (0.27; P = 0.03), but weighted κ were not statistically different [controls, 0.73; cases, 0.64 (P = 0.32)]. Demographic and anthropometric characteristics were not different between participants who underreported, overreported, or correctly reported their birth weight for either cases or controls. Overall, the level of agreement for report of birth weight and actual birth weight was fair to moderate.

The utility of focus group interviews to capture dietary consumption data in the distant past: dairy consumption in Kazakhstan villages 50 years ago.

From 1949 to 1962, residents of several villages in Kazakhstan received substantial doses of radiation to the thyroid gland resulting from nuclear tests conducted at the Semipalatinsk Nuclear Test Site. The primary source of radiation was internal from an intake of radioactive iodine by consumption of contaminated dairy products. A previous research study of childhood exposure and thyroid disease in this region gathered limited data on study participants' dairy intake at the time of the fallout for the purpose of estimating past radiation doses. As many participants were too young at the time of the nuclear tests to recall dietary consumption and existing sources of archival data are limited, it was necessary to interview parents and other village residents who cared for children during this time - older adults ranging in age from 75 to 90 years. Results from 11 focus group interviews conducted in 2007 with 82 women from 4 villages in Kazakhstan yielded group-level estimates of age-, gender-, ethnicity- and village-specific dairy consumption patterns in rural Kazakhstan during the 1950s. Children typically consumed cow's milk with limited consumption of mare, goat and sheep milk; and consumed dairy products such as sour milk (airan), soft cottage cheese (tvorog) and fermented mare milk (koumiss) with the greatest amounts of koumiss reported at ages 15-21 years. The consumption patterns differed by age, and between Kazakh and Russian children, which should lead to different estimates of radiation exposure to the thyroid. This study showed the utility of focus groups to obtain quantitative estimates for dietary intake in the distant past.

Maternal, prenatal and perinatal characteristics and first trimester maternal serum hormone concentrations.

In uncomplicated pregnancies, first trimester androgen, oestrogen and prolactin concentrations were higher in nulliparous (n=160) than parous (n=260) mothers. Androgens and estrogens were higher in younger than older mothers. These data are consistent with elevated hormone concentrations mediating the breast cancer protection from a first pregnancy and pregnancies occurring at younger ages.

OPEN about obesity: recovery biomarkers, dietary reporting errors and BMI.

OBJECTIVE: Obesity-related under-reporting of usual dietary intake is one of the most persistent sources of bias in nutrition research. The aim of this paper is to characterize obese and non-obese individuals with respect to reporting errors observed with two common dietary instruments, using energy and protein recovery biomarkers as reference measures. POPULATION AND METHODS: This report employs data from the Observing Protein and Energy Nutrition (OPEN) study. Analyses are based on stratified samples of 211 (57 obese) men and 179 (50 obese) women who completed 24-h recalls (24HR), food frequency questionnaires (FFQ), doubly labelled water (DLW) and urinary nitrogen (UN) assessments. RESULTS: In obese and non-obese subgroups, FFQ yielded lower energy and protein intake estimates than 24HR, although biomarker-based information indicated under-reporting with both dietary instruments. Gender differences in obesity-related bias were noted. Among women, the DLW-based energy requirement was 378 kcal greater in obese than in non-obese groups; the FFQ was able to detect a statistically significant portion of this extra energy, while the 24HR was not. Among men, the DLW-based energy requirement was 485 kcal greater in the obese group; however, neither FFQ nor 24HR detected this difference in energy requirement. Combining protein and energy estimates, obese men significantly over-reported the proportion of energy from protein using the 24HR, but not with the FFQ. In obese women, no significant reporting error for energy percent protein was observed by either method. At the individual level, correlations between energy expenditure and reported energy intake tended to be weaker in obese than non-obese groups, particularly with the 24HR. Correlations between true and reported protein density were consistently higher than for protein or energy alone, and did not vary significantly with obesity. CONCLUSION: This work adds to existing evidence that neither of these commonly used dietary reporting methods adequately measures energy or protein intake in obese groups. The 24HR, while capturing more realistic energy distributions for usual intake, may be particularly problematic in the obese.

Birth size and colorectal cancer risk: a prospective population based study.

OBJECTIVE: To study whether birth size influences colorectal cancer risk in adulthood. DESIGN: A cohort of Norwegian men and women identified from midwives' birth records with long term cancer follow up through the Norwegian Cancer Registry. SETTING: St Olav's University Hospital, Trondheim, Norway. PARTICIPANTS: 16,016 women and 19 681 men born between 1920 and 1958 and alive in 1960. OUTCOME MEASURES: Incidence rate ratios (RRs) for colorectal cancer with 95% confidence intervals (CIs) and two sided p values for trend across categories of birth dimensions. RESULTS: Men whose birth length was less than 51 cm had a nearly twofold higher risk of colorectal cancer (RR 1.9 (95% CI 1.0-3.7)) compared with men who were 53 cm or more, after adjustment for birth cohort, maternal age at childbearing, length of gestation, gestational hypertension or pre-eclampsia, birth order, maternal height, and indicators of maternal socioeconomic status. The association displayed a linear trend across categories of birth length (p(trend) = 0.03). Among men, similar associations were found for birth weight and head circumference, but for women there was no association between any of these birth dimensions and risk of colorectal cancer. CONCLUSION: The results suggest that among men, but not women, being relatively short at birth is associated with increased risk of colorectal cancer in adulthood, indicating that intrauterine growth could be important for colorectal carcinogenesis.

Characteristics of respondents and non-respondents from a case-control study of breast cancer in younger women.

BACKGROUND: This study assessed the nature of potential biases by comparing respondents with non-respondents from a case-control study of breast cancer in younger women. METHODS: The case-control study was conducted in three regions in the US: Atlanta GA, Seattle/Puget Sound WA, and central New Jersey. An abbreviated interview or mailed questionnaire was completed by willing non-respondents, most of whom had refused participation in the main study. RESULTS: Respondents and non-respondents appeared similar with respect to age, race, relative weight, smoking, family history of breast cancer, number of births, age at first birth, and several dietary items. Compared to non-respondents, case and control respondents were of shorter stature, and reported less frequent consumption of doughnuts/pastries. Respondent cases, compared with non-respondent cases, were more highly educated and more likely to have consumed alcohol regularly; similar but not statistically significant tendencies were observed for controls. Respondent cases experienced menarche earlier than non-respondents. Respondent controls were more likely to have used oral contraceptives than non-respondents; a similar but not statistically significant tendency was observed in cases. Comparisons of crude and simulated relative risks using available non-respondents' data generally showed a low impact of non-response on relative risks in this study. CONCLUSIONS: Our results suggest that non-response would not greatly affect relative risk estimates in this study, except possibly regarding height. However, we were limited by the numbers of informative non-respondents and the amount of data collected. Collecting similar information in future studies would be useful, especially since varying methods used to encourage participation may lead to differences in respondents' characteristics.

Menstrual risk factors and early-onset breast cancer.

OBJECTIVES: Epidemiologic studies provide evidence for increased breast cancer risk among women with prolonged exposure to endogenous estrogens and progesterone. Menstrual cycle characteristics, such as early menarche, rapid initiation of regular ovulatory cycles, short cycle length, and more days of flow, all potentially contribute to higher cumulative ovarian hormone exposure. METHODS: We assessed the associations between these characteristics and breast cancer risk in a population-based, case-control study of 1505 controls and 1647 newly diagnosed cases, all younger than 45 years of age. RESULTS: Compared to women with menarche at > or =15 years, we observed some increase in risk for women with younger ages at menarche, although those with very early ages were not at particularly high risk [odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-1.9 for menarche at age 12 and OR = 1.2, 95% CI = 0.9-1.7 for menarche at age < or =10]. Women who reported having regular menstrual cycles within 2 years of menarche were at increased breast cancer risk (OR = 1.7, 95% CI = 1.2-2.3), compared to those never having regular cycles. Stratification by current body mass index revealed slightly stronger associations with menstrual characteristics among thinner women (< 22.0 kg/m2) compared to heavier women (> 28.8 kg/m2). CONCLUSIONS: These findings suggest that future studies should focus on clarifying how the interrelated effects of body size and menstrual factors, such as age at menarche and cycle regularity, contribute to breast cancer etiology.

Validation of the American Cancer Society Cancer Prevention Study II Nutrition Survey Cohort Food Frequency Questionnaire.

We assessed the validity and reproducibility of a self-administered 68-item food frequency questionnaire completed in 1992-1993 by approximately 185,000 adults. Four hundred forty-one participants completed four 24-hour dietary recall interviews over a 1-year period and a repeat administration of the food frequency questionnaire. For 20 nutrients and 10 food groups, measured nutrient intakes, but not food group intakes, were consistently lower by food frequency questionnaire than by recall. Energy-adjusted, attenuation-corrected Pearson validity correlations ranged from 0.12 to 0.80, with a median of 0.58. Reproducibility measures were generally high, with a median of 0.69. The food frequency questionnaire performed similarly to food frequency questionnaires used in other cohort studies, indicating similar ability to examine diet-disease relations.

Evaluation of 2 brief instruments and a food-frequency questionnaire to estimate daily number of servings of fruit and vegetables.

BACKGROUND: Measurement of fruit and vegetable intake is important in the surveillance of populations and in epidemiologic studies that examine the relations between diet and disease. Some situations require the use of brief dietary assessment tools. OBJECTIVE: Our objective was to evaluate the performance of 2 brief dietary assessment instruments, a 7-item standard screener and a new 16-item screener, and a complete food-frequency questionnaire (FFQ) in measuring total fruit and vegetable consumption. DESIGN: About 800 men and women from the National Institutes of Health-AARP Diet and Health Study completed an FFQ, 1 of the 2 screeners, and two 24-h dietary recalls. Fruit and vegetable intakes as measured by each screener and the FFQ were compared with estimated true usual intake by using a measurement-error model. RESULTS: Median daily servings of fruit and vegetables were underestimated by both screeners. The estimated agreement between true intake and the screener was higher for the new screener than for the standard screener and was higher for women than for men. The estimated agreement between true intake and the FFQ was higher than that for both screeners. Attenuation coefficients for the FFQ and screeners were comparable. CONCLUSIONS: For estimating median intakes of fruit and vegetables and the prevalence of recommended intakes being met, the use of screeners without appropriate adjustment is suboptimal. For estimating relative risks in the relations between fruit and vegetable intake and disease, screeners and this FFQ are similar in performance.

Workshop to identify critical windows of exposure for children's health: cancer work group summary.

We considered whether there are discrete windows of vulnerability in the development of cancer and which time periods may be of the greatest importance. Cancer was considered broadly, including cancers in childhood as well as adult cancers that may have an in utero or childhood origin. We concluded that there was evidence from animal and epidemiologic studies for causal relationships for preconceptional, in utero, and childhood exposures and cancer occurrence in children and adults. However, the evidence is incomplete and all relevant critical windows may not have been identified. The comprehensive evaluation of the relative importance of specific time windows of exposure is limited. Improvements in the design of epidemiologic studies and additional animal studies of mechanisms are warranted.

Characteristics associated with recent recreational exercise among women 20 to 44 years of age.

Data on 1,501 control women from a multi-center, population-based, case-control study of breast cancer were used to examine characteristics associated with recreational exercise during the year prior to the interview among women 20 to 44 years of age. In a univariate analysis, higher levels of recreational exercise were associated with: higher education; higher family income; white race; previous participation in recreational exercise above the median level at ages 12 to 13 and at age 20; being nulliparous; ever lactating; being a never or past smoker; having a low current Quetelet's index (QI: weight in kilograms divided by height in meters squared); and living in Atlanta or Seattle (compared to New Jersey). In a multiple linear regression model, independent predictors of higher levels of recreational exercise were: participation in higher levels of exercise at 20 years of age; having a low current QI; and never having smoked. Though all women should be encouraged to participate in exercise, these findings identity subgroups of women that may need targeting when developing exercise intervention programs.

Breast cancer risk in young women and history of selected medical conditions.

BACKGROUND: Several common medical conditions are associated with altered hormone levels, and may thus plausibly influence breast cancer risk. Few studies have examined such relationships, and we utilized a population-based case-control study of young women in the US to examine breast cancer risk following a history of various medical conditions. Relationships between breast cancer and each medical condition examined are biologically plausible, and relevant in terms of public health. METHODS: The study included 2173 breast cancer cases and 1990 population-based controls from three areas of the US, under 55 years, who were administered a questionnaire including details of physician-diagnosed medical conditions. RESULTS: No significantly increased or decreased breast cancer risk was associated with a history of thyroid disease, gallbladder disease, colorectal polyps, diabetes, high blood pressure, high cholesterol or surgery for endometriosis. There was some evidence of an increased breast cancer risk associated with ovarian cysts among women who did not receive an oophorectomy (relative risk [RR] = 1.94, 95% CI: 1.0-3.9). Non-significant increases in breast cancer risk were observed following diagnoses of several other cancers, including thyroid cancer, basal cell carcinoma, Hodgkin's disease and malignant melanoma. CONCLUSIONS: To conclude, our generally null results from this large, population-based study support results from previous studies in providing reassurance that women with a history of several common medical conditions do not appear to be at an increased risk of breast cancer at a young age.

Risk of breast cancer in young women in relation to body size and weight gain in adolescence and early adulthood.

Findings have been inconsistent on effects of adolescent body size and adult weight gain on risk of breast cancer in young women. These relations were examined in a population-based case control study of 1590 women less than 45 years of age newly diagnosed with breast cancer during 1990-1992 in three areas of the US and an age-matched control group of 1390 women. Height and weight were measured at interview and participants asked to recall information about earlier body size. Logistic regression was used to estimate the relative risk of breast cancer adjusted for other risk factors. Women who were either much heavier or lighter than average in adolescence or at age 20 were at reduced risk. Weight gain after age 20 resulted in reduced risk, but the effect was confined to early-stage and, more specifically, lower grade breast cancer. Neither the risk reduction nor the variation by breast cancer stage or grade was explained by the method of cancer detection or by prior mammography history. These findings suggest that relations between breast cancer risk in young women and body weight at different ages is complex and that the risk reduction with adult weight gain is confined to less aggressive cancers.

Comparison of the 60- and 100-item NCI-block questionnaires with validation data.

Large epidemiological studies often require short food frequency questionnaires (FFQ) to minimize the respondent burden or to control for confounding from dietary factors. In this analysis, we compared the extensively used National Cancer Institute-Block 60- and 100-item FFQs with one another and with usual intake as estimated from 12 days of validation data. The analysis focused on nutrients from different aspects of the diet, including energy, fat, saturated fat, beta-carotene, dietary fiber, and vitamin C. By use of an errors-in-variables analysis, the correlations of usual intake with the two types of FFQs for these nutrients were not different. Attenuation coefficients, a measure of misclassification error, for both FFQs were of similar magnitude and indicated that substantial attenuation of logistic regression coefficients would result from either FFQ. Our results confirm previous analyses describing the validity and utility of the 60-item FFQ (Epidemiology 1, 58-64, 1990) and indicate that it is essentially equivalent to the 100-item FFQ for epidemiological analyses of major nutrients.

Intake of food groups and associated micronutrients in relation to risk of early-stage breast cancer.

Epidemiologic studies have evaluated the risk of breast cancer related to dietary fat intake, but only recently have other dietary factors received attention. Frequent intakes of fruit, vegetables and fiber have been associated with low risk of the disease in some studies but results are inconsistent. In a large case-control study of early-onset breast cancer, we evaluated risk related to a variety of food groups, associated micronutrients and non-nutritive constituents. Cases treated with chemotherapy appeared to have altered reporting of food intake and were excluded. Analyses were restricted to 568 cases with in situ and localized disease and 1,451 population-based controls. Reduced risks were observed for high intake of cereals and grains [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.6-1.1 for highest compared with lowest quartile], vegetables (OR = 0.86, 95% CI = 0.6-1.1), beans (OR = 0.87, 95% CI = 0.7-1.2) and fiber from beans (OR = 0.88, 95% CI = 0.7-1.2). However, no trends of decreasing risk across quartiles of increasing intake were observed. Risk was not associated with dietary constituents related to these food groups including dietary fiber, carotenoids, vitamins A, C and E and folate. Incorporation of information from vitamin supplements did not alter the results for micronutrients. Our data suggest that intakes of cereals and grains, vegetables and beans are associated with minimal, if any, reduction in risk of early-stage breast cancer among young women.

Causal criteria in nutritional epidemiology.

Making nutrition recommendations involves complex judgments about the balance between benefits and risks associated with a nutrient or food. Causal criteria are central features of such judgments but are not sufficient. Other scientific considerations include study designs, statistical tests, bias, confounding, and measurement issues. At a minimum, the set of criteria includes consistency, strength of association, dose response, plausibility, and temporality. The current practice, methods, and theory of causal inference permit flexibility in the choice of criteria, their relative priority, and the rules of inference assigned to them. Our approach is as follows. Consistency across study designs is compelling when the studies are of high quality and are not subject to biases. A statistically significant risk estimate with a > 20% increase or decrease in risk is considered a positive finding. A statistically significant linear or otherwise regularly increasing trend reinforces the judgment in favor of a recommendation. A plausible hypothesis likewise reinforces a recommendation, although the rules of inference for biological evidence are highly variable and depend on the situation. Temporality is, for nutrition recommendations, more a consideration of the extent to which a dietary factor affects disease onset or progression. Evidence supporting these criteria provides a strong basis for making a nutrition recommendation, given due consideration of the balance between presumed benefits and presumed harms. Recommendations should make clear their breadth of application; a narrow recommendation involves a single disease or condition whereas a broad recommendation involves all relevant diseases or conditions.

Stage of breast cancer in relation to body mass index and bra cup size.

Most studies on women with breast cancer indicate that obesity is positively associated with late-stage disease. Some results have shown a similar relationship between breast size and stage. A recent study found that the association between body mass index (BMI) and stage was limited to cancers that were self-detected, suggesting that the BMI-stage relation may be due to delayed symptom recognition. We examined the relationships between stage and both BMI and breast (bra cup) size, stratified by method of detection, using data from a population-based case-control study of 1,361 women (ages 20-44 years) diagnosed with breast cancer during 1990-1992. Height and weight measurements and information on bra cup size, method of cancer detection and other factors predictive of stage at diagnosis were collected during in-person interviews. A case-case comparison was conducted using logistic regression to estimate odds of regional or distant stage rather than local stage in relation to BMI and bra size. Odds of late-stage disease were increased with higher BMI [adjusted odds ratio (OR) for highest to lowest tertile = 1.46, 95% confidence interval (CI) 1.10-1.93] and larger bra cup size (OR for cup D vs. cup A = 1.61, 95% CI 1.04-2.48). These relationships were not modified by the method of detection. Differences in etiologic effects, rather than differences in detection methods, may explain the relations observed between stage and both BMI and breast size.