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Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated., Objective: To characterize breast cancer risk in relation to recent childbirth., Design: Pooled analysis of individual-level data from 15 prospective cohort studies., Setting: The international Premenopausal Breast Cancer Collaborative Group., Participants: Women younger than 55 years., Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression., Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns., Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited., Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women., Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Importance: The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation., Objective: To investigate the association of BMI with premenopausal breast cancer risk, in particular by age at BMI, attained age, risk factors for breast cancer, and tumor characteristics., Design, Setting, and Participants: This multicenter analysis used pooled individual-level data from 758 592 premenopausal women from 19 prospective cohorts to estimate hazard ratios (HRs) of premenopausal breast cancer in association with BMI from ages 18 through 54 years using Cox proportional hazards regression analysis. Median follow-up was 9.3 years (interquartile range, 4.9-13.5 years) per participant, with 13 082 incident cases of breast cancer. Participants were recruited from January 1, 1963, through December 31, 2013, and data were analyzed from September 1, 2013, through December 31, 2017., Exposures: Body mass index at ages 18 to 24, 25 to 34, 35 to 44, and 45 to 54 years., Main Outcomes and Measures: Invasive or in situ premenopausal breast cancer., Results: Among the 758 592 premenopausal women (median age, 40.6 years; interquartile range, 35.2-45.5 years) included in the analysis, inverse linear associations of BMI with breast cancer risk were found that were stronger for BMI at ages 18 to 24 years (HR per 5 kg/m2 [5.0-U] difference, 0.77; 95% CI, 0.73-0.80) than for BMI at ages 45 to 54 years (HR per 5.0-U difference, 0.88; 95% CI, 0.86-0.91). The inverse associations were observed even among nonoverweight women. There was a 4.2-fold risk gradient between the highest and lowest BMI categories (BMI≥35.0 vs <17.0) at ages 18 to 24 years (HR, 0.24; 95% CI, 0.14-0.40). Hazard ratios did not appreciably vary by attained age or between strata of other breast cancer risk factors. Associations were stronger for estrogen receptor-positive and/or progesterone receptor-positive than for hormone receptor-negative breast cancer for BMI at every age group (eg, for BMI at age 18 to 24 years: HR per 5.0-U difference for estrogen receptor-positive and progesterone receptor-positive tumors, 0.76 [95% CI, 0.70-0.81] vs hormone receptor-negative tumors, 0.85 [95% CI: 0.76-0.95]); BMI at ages 25 to 54 years was not consistently associated with triple-negative or hormone receptor-negative breast cancer overall., Conclusions and Relevance: The results of this study suggest that increased adiposity is associated with a reduced risk of premenopausal breast cancer at a greater magnitude than previously shown and across the entire distribution of BMI. The strongest associations of risk were observed for BMI in early adulthood. Understanding the biological mechanisms underlying these associations could have important preventive potential.

Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individual-level data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations. Cancer Epidemiol Biomarkers Prev; 26(9); 1360-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The MDM4 protein plays an important part in the negative regulation of the tumor suppressor p53 through its interaction with MDM2. In line with this, MDM4 amplification has been observed in several tumor forms. A polymorphism (rs4245739 A>C; SNP34091) in the MDM4 3' untranslated region has been reported to create a target site for hsa-miR-191, resulting in decreased MDM4 mRNA levels. In this population-based case-control study, we examined the potential association between MDM4 SNP34091, alone and in combination with the MDM2 SNP309T>G (rs2279744), and the risk of breast-, colon-, lung-, and prostate cancer in Norway. SNP34091 was genotyped in 7,079 cancer patients as well as in 3,747 gender- and age-matched healthy controls. MDM4 SNP34091C was not associated with risk for any of the tumor forms examined, except for a marginally significant association with reduced risk for breast cancer in a recessive model (OR = 0.77: 95% CI = 0.59-0.99). Stratifying according to MDM2 SNP309 status, we observed a reduced risk for breast cancer related to MDM4 SNP34091CC among individuals harboring the MDM2 SNP309GG genotype (OR = 0.41; 95% CI = 0.21-0.82). We conclude, MDM4 SNP34091 status to be associated with reduced risk of breast cancer, in particular in individuals carrying the MDM2 SNP309GG genotype, but not to be associated with either lung-, colon- or prostate cancer., (© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

MDM2 is a key regulator of the p53 tumor suppressor protein and is overexpressed in many human cancers. Two single nucleotide polymorphisms (SNPs) located in the MDM2 intronic promoter (P2) have been found to exert biological function. The G-allele of SNP309T>G; rs2279744 increases MDM2 transcription and has been linked to increased cancer risk. In contrast, the less frequent SNP285G>C; rs117039649, which is in complete linkage disequilibrium with SNP309 (generating a SNP285C/309G variant haplotype), has been related to reduced MDM2 transcription and to reduced risk of breast, endometrial and ovarian cancer. In this large population-based case-control study, we genotyped SNP309 and SNP285 in 10,830 individuals, including cases with cancer of the breast (n=1,717), colon (n=1,532), lung (n=1,331) and prostate (n=2,501), as well as 3,749 non-cancer controls. We found a slightly reduced risk for lung cancer among individuals harboring the SNP309TG/GG genotypes compared to the SNP309TT genotype (OR= 0.86; CI = 0.67-0.98), but this association was restricted to women (OR = 0.77; CI = 0.63-0.95) and was not present among men (OR = 0.91; CI = 0.77-1.08). Consistent with previous findings, we found a reduced risk for breast cancer among individuals carrying the SNP285GC/309GG genotype versus the SNP285GG/309GG genotype (OR = 0.55; CI = 0.33-0.93). In conclusion, our data support the hypothesis that the effects of both SNP285 and SNP309 status are tissue dependent., (© 2014 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.)

Aims: The clinical significance of TOP2A as a prognostic marker has not been clarified. The aims of this study were to investigate the frequency of TOP2A copy number change; to correlate TOP2A with HER2 status, hormone receptor (HR) status and molecular subtype, and further to explore differences in breast cancer-specific survival according to TOP2A and HER2., Methods: In this study, TOP2A, HER2 and chromosome 17 copy number were assessed in 670 cases of breast cancer using in situ hybridisation techniques. Gene to chromosome ratios ≥2 were classified as amplification. TOP2A deletion (gene to chromosome ratio ≤0.8) or monosomy (only one signal for both gene and chromosome in more than 75% of nuclei) were classified as gene loss., Results: A strong association between TOP2A change and HR and HER2 status was found. During the first 5 years after diagnosis, the risk of death from breast cancer was significantly higher for cases with HER2 amplification irrespective of TOP2A status., Conclusions: TOP2A copy number change was strongly associated with HR and HER2 status and as a prognostic marker TOP2A is probably of limited value.

Background: Adult weight gain is associated with increased risk of postmenopausal breast cancer. Most previous studies are limited by using recalled or self-reported data, and it is not known if age-specific weight changes are important for breast cancer risk., Methods: In a Norwegian cohort of 28,153 women (and 900 incident breast cancers) with longitudinal anthropometric measurements over up to 30 years, we studied both overall and age-related weight changes in adulthood and risk of postmenopausal breast cancer., Results: Overall, weight gain in adulthood was associated with increased breast cancer risk (hazard ratio (HR) per kg per year 1.31, 95% confidence interval (CI) 1.11-1.54). Weight gain before (HR per kg per year 1.38, 95% CI 1.09-1.75) or around menopause (1.69, 95% CI 1.32-2.16) was associated with increased risk, but there was no clear risk increase associated with later weight gain (HR per kg per year 0.92, 95% CI 0.73-1.18)., Conclusion: Weight gain in adulthood was associated with increased risk of breast cancer. Our results suggest that weight gain before and around menopausal age may be particularly important for breast cancer risk among postmenopausal women.

Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. However, its clinical significance remains to be established. In this study, the main aims were to discover whether reclassification of breast cancer into molecular subtypes provides more precise information regarding outcome compared to conventional histopathological grading and to study breast cancer-specific survival in the different molecular subtypes. Cases of breast cancer occurring in a cohort of women born between 1886 and 1928 with long-term follow-up were included in the study. Tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded tissue from 909 cases. Using immunohistochemistry and in situ hybridisation as surrogates for gene expression analyses, all cases were reclassified into the following molecular subtypes: Luminal A; Luminal B (HER2-); Luminal B (HER2+); HER2 subtype; Basal phenotype; and five negative phenotype. Kaplan-Meier survival curves and Cox proportional hazards models were used in the analyses. During the first 5 years after diagnosis, there were significant differences in prognosis according to molecular subtypes with the best survival for the Luminal A subtype and the worst for HER2 and five negative phenotype. In this historic cohort of women with breast cancer, differences in breast cancer-specific survival according to subtype occur almost exclusively amongst the histopathological grade 2 tumours. From 5 years after time of diagnosis until the end of follow-up, there appears to be no difference in survival according to molecular subtype or histopathological grade.

Background: Swedish women aged 40-69 years were gradually offered regular mammography screening since 1974, and nationwide coverage was achieved in 1997. We hypothesized that this gradual implementation of breast cancer screening would be reflected in county-specific mortality patterns during the last 20 years., Methods: Using data from the Swedish Board of Health and Welfare from 1960 to 2009, we used joinpoint regression to analyze breast cancer mortality trends in women aged 40 years and older (1,286,000 women in 1995-1996). Poisson regression models were used to compare observed mortality trends with expected trends if screening had resulted in breast cancer mortality reductions of 10%, 20%, or 30% among women screened during 18 years of follow-up after the introduction of screening. All statistical tests were two-sided., Results: From 1972 to 2009, breast cancer mortality rates in Swedish women aged 40 years and older declined by 0.98% annually, from 68.4 to 42.8 per 100,000, and it continuously declined in 14 of the 21 Swedish counties. In three counties, breast cancer mortality declined sharply during or soon after the implementation of screening; in two counties, a steep decline started at least 5 years after screening was introduced; and in two counties, breast cancer mortality increased after screening started. In counties in which screening started in 1974-1978, mortality trends during the next 18 years were similar to those before screening started, and in counties in which screening started in 1986-1987, mortality increased by approximately 12% (P = .007) after the introduction of screening compared with previous trends. In counties in which screening started in 1987-1988 and in 1989-1990, mortality declined by approximately 5% (P = .001) and 8% (P < .001), respectively, after the introduction of screening. Conclusion County-specific mortality statistics in Sweden are consistent with studies that have reported limited or no impact of screening on mortality from breast cancer.

Background: Hypertensive diseases in pregnancy may be associated with a reduced risk of breast cancer. Most previous studies are small and have shown conflicting results., Methods: In a cohort of 919 712 women who gave their first birth between 1967 and 2008, with linkage of information from two national registries, we assessed whether women with pregnancy hypertensive diseases are at reduced breast cancer risk. We used Cox regression to estimate hazard ratios (HRs) with 95% confidence intervals (CI)., Results: Compared with women with a normotensive first pregnancy, women with hypertension or preeclampsia in their first pregnancy had a reduced breast cancer risk (HR 0.83, 95% CI 0.77, 0.90). A reduced risk was consistently observed for hypertensive disease in any pregnancy, for recurrent hypertensive disease in pregnancy, and before and after 50 years of age at breast cancer diagnosis. The association was strongest for women with hypertension in pregnancy, who delivered at term/post-term (HR 0.81, 95% CI 0.75, 0.88) or had a child of average birth weight (HR 0.77, 95% CI 0.69, 0.85)., Conclusion: Women with pregnancy hypertensive diseases are at reduced breast cancer risk. Whether this association can be attributed to pregnancy-specific events or to underlying biological traits remains unclear.

Background: Breast cancer is less common in China than in the United States and perinatal characteristics predict breast cancer risk in the offspring. We determined levels of pregnancy hormones in Boston and Shanghai to identify those possibly involved in the intrauterine origin of breast cancer., Participants and Methods: We compared maternal and cord blood levels of estradiol, estriol, testosterone, progesterone, prolactin, insulin-like growth factors (IGF) 1 and 2, insulin-like growth factor-binding protein 3, adiponectin and sex hormone-binding globulin (SHBG) in 241 Caucasian and 295 Chinese women., Results: In both centers, hormone levels at the 16th were predictive of those at the 27th gestational week, but there was little correlation between maternal and cord blood levels. In cord blood, we found significantly (P < 0.01) higher levels of estradiol (44.2%), testosterone (54.5%), IGF-2 (22.7%) and strikingly SHBG (104.6%) in Shanghai women, whereas the opposite was true for IGF-1 (-36.8%)., Conclusions: Taking into account the current understanding of the plausible biological role of the examined endocrine factors, those likely to be involved in the intrauterine origin of breast cancer are SHBG and IGF-2, with higher cord blood levels among Chinese, and IGF-1, with higher cord blood levels among Caucasian women.

MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To examine changes in temporal trends in breast cancer mortality in women living in 30 European countries., Design: Retrospective trend analysis. Data source WHO mortality database on causes of deaths Subjects reviewed Female deaths from breast cancer from 1989 to 2006, Main Outcome Measures: Changes in breast cancer mortality for all women and by age group (<50, 50-69, and >or=70 years) calculated from linear regressions of log transformed, age adjusted death rates. Joinpoint analysis was used to identify the year when trends in all age mortality began to change., Results: From 1989 to 2006, there was a median reduction in breast cancer mortality of 19%, ranging from a 45% reduction in Iceland to a 17% increase in Romania. Breast cancer mortality decreased by >or=20% in 15 countries, and the reduction tended to be greater in countries with higher mortality in 1987-9. England and Wales, Northern Ireland, and Scotland had the second, third, and fourth largest decreases of 35%, 29%, and 30%, respectively. In France, Finland, and Sweden, mortality decreased by 11%, 12%, and 16%, respectively. In central European countries mortality did not decline or even increased during the period. Downward mortality trends usually started between 1988 and 1996, and the persistent reduction from 1999 to 2006 indicates that these trends may continue. The median changes in the age groups were -37% (range -76% to -14%) in women aged <50, -21% (-40% to 14%) in 50-69 year olds, and -2% (-42% to 80%) in >or=70 year olds., Conclusions: Changes in breast cancer mortality after 1988 varied widely between European countries, and the UK is among the countries with the largest reductions. Women aged <50 years showed the greatest reductions in mortality, also in countries where screening at that age is uncommon. The increasing mortality in some central European countries reflects avoidable mortality.

Birth size has been positively associated with age at menarche and height in adolescence and adulthood, but the relevant biological mechanisms remain unclear. Among 262 Norwegian term-born singleton girls, birth size measures (weight, length, ponderal index, head circumference and subscapular skin-fold thickness) were analysed in relation to adolescent hormone levels (oestradiol, prolactin, dehydroepiandrosterone sulphate, androstenedione and free testosterone index), age at menarche and adolescent (ages 12.7-15.5 years) and body size (height, weight, body mass index and waist-to-hip ratio) using survival analysis and general linear modelling. The results were adjusted for gestational age at birth, age and menarcheal status at measurement in adolescence and maternal age at menarche. Birth weight, birth length and head circumference were positively associated with adolescent weight and height, and small birth size was associated with earlier age at menarche. Subscapular skin-fold thickness at birth was not associated with adolescent body size, but low fold-thickness was associated with earlier age at menarche. Measures of birth size were inversely related to circulating levels of dehydroepiandrosterone sulphate in adolescence, but there was no clear association with other hormones. These results suggest that physical and sexual development in puberty and adolescence is influenced by prenatal factors, and in combination, these factors may influence health and disease later in life.

If the negative association between pre-eclampsia and subsequent breast cancer risk differs by gender, this would strengthen the hypothesis that factors intrinsic to the particular pregnancy may explain the association. The study included 701,006 parous Norwegian women with follow-up for breast cancer through the Cancer Registry of Norway. Breast cancer risk was lower in women with pre-eclampsia/hypertension in their first pregnancy, compared to other women (relative risk, 0.86, 95% CI, 0.78-0.94), after adjustment for age at first birth, maternal birth year, length of gestation, marital status, and parity. The risk reduction was slightly greater if the woman delivered a son as opposed to a daughter (relative risks of 0.79 vs 0.94, P-value for interaction, 0.06), and if pre-eclampsia/hypertension was combined with pre-term delivery, these differences were more pronounced (relative risks, 0.62 vs 1.07, P-value for interaction 0.03). A subanalysis among 176,036 primiparous women showed a substantial risk reduction if the mother delivered a son (relative risk, 0.62, 95% CI, 0.47-0.82), but essentially null if she delivered a daughter (relative risk, 0.92, 95% CI, 0.72-1.18; P-value for interaction, 0.05). These results suggest that the effect of pre-eclampsia/hypertension may be attributed to factors associated with the particular pregnancy rather than an underlying biological trait of the mother. The stronger risk reduction related to having a son suggests a role for sex-dependent hormones in pregnancy.

Women who experience pre-eclampsia or hypertension during pregnancy may have a reduced risk for breast cancer later in life. The evidence is based on case-control studies, and here we report the results of a cohort study exploring the link between pre-eclampsia and gestational hypertension diagnosed in the first pregnancy and subsequent risk for breast cancer. We combined information from the Medical Birth Registry and the Cancer Registry in Norway, which are both nation-wide. Between 1967, when the birth registry was established, and 1998, 694 657 women were recorded with a first birth, and classified according to whether pre-eclampsia and/or hypertension was diagnosed in the first pregnancy. Linkage to the Norwegian Cancer Registry identified 5474 new cases of breast cancer diagnosed subsequently to their first delivery. Compared to other parous women, women with pre-eclampsia and/or hypertension diagnosed in their first pregnancy had 19% lower risk (95% confidence interval, 9 to 29%) for breast cancer, after adjustment for attained age, calendar period of diagnosis, age at first birth, and parity. This result was similar for term and preterm deliveries, across the range of offspring birth weight, and for pre- and postmenopausal women. These results suggest that the pathophysiology surrounding pre-eclampsia and gestational hypertension plays an important role in breast cancer etiology. A better understanding of the underlying processes could provide an insight into the pathogenesis of breast cancer.

In a prospective study of 694 657 parous women in Norway, 5474 developed breast cancer after their first birth. If the first pregnancy lasted less than 32 weeks, the risk was 22% (95% confidence interval, -3% to 53%) less than after a pregnancy of 40 weeks or more, with a significant declining trend in risk (P for trend=0.02)., (Copyright 2002 Cancer Research UK)

Women born after pre-eclamptic pregnancies have been reported to be at reduced risk of breast cancer as adults, because of reduced intrauterine oestrogen influence on breast tissue; high levels of alpha-foetoprotein (a glycoprotein with anti-oestrogenic properties), however, could also be important. In severe pre-eclampsia, placental function and foetal growth are reduced, and umbilical cord plasma levels of alpha-foetoprotein could reflect the underlying processes. Umbilical cord blood was collected in 12804 consecutive deliveries. Among 307 pregnancies with clinical pre-eclampsia, 66 singleton pregnancies were identified as clinically severe, and 610 singleton pregnancies were selected as controls. Oestradiol and alpha-foetoprotein were measured from umbilical plasma, and birth weight was standardized as the ratio between the observed and expected birth weight, adjusted for differences in gestation length and offspring sex. Cord plasma levels of alpha-foetoprotein were significantly higher in severe pre-eclampsia than controls (P<0.01) after adjustment for gestational age and birth weight. For oestradiol, there was no difference in cord plasma levels between the severe pre-eclampsia group and controls, after adjustment for length of gestation and birth weight. These results suggest that an anti-oestrogenic effect associated with pre-eclampsia may be mediated through high levels of alpha-foetoprotein rather than low levels of oestradiol., (Copyright 2002 Cancer Research UK)

The hypothesis that birth weight is positively associated with adult risk of breast cancer implies that factors related to intrauterine growth may be important for the development of this malignancy. Using stored birth records from the two main hospitals in Trondheim and Bergen, Norway, we collected information on birth weight, birth length and placenta weight among 373 women who developed breast cancer. From the same archives, we selected as controls 1150 women of identical age as the cases without a history of breast cancer. Information on age at first birth and parity were collected from the Central Person Registry in Norway. Based on conditional logistic regression analysis, breast cancer risk was positively associated with birth weight and with birth length (P for trend=0.02). Birth weights in the highest quartile (3730 g or more) were associated with 40% higher risk (odds ratio, 1.4, 95% confidence interval, 1.1-1.9) of breast cancer compared to birth weights in the lowest quartile (less than 3090 g). For birth length, the odds ratio for women who were 51.5 cm or more (highest quartile) was 1.3 (95% confidence interval, 1.0-1.8) compared to being less than 50 cm (lowest quartile) at birth. Adjustment for age at first birth and parity did not change these estimates. Placenta weight was not associated with breast cancer risk. This study provides strong evidence that intrauterine factors may influence future risk of breast cancer. A common feature of such factors would be their ability to stimulate foetal growth and, simultaneously, to influence intrauterine development of the mammary gland.

The relationship of breast cancer to early reproductive development and height suggests that fetal and childhood nutrition may be important in its aetiology. Caloric restriction sufficient to reduce adult height may reduce breast cancer risk. During World War II (WWII) there was a marked reduction in average caloric intake in Norway that resulted in greater nutritional diversity. We hypothesized that a positive association between height and risk of breast cancer would be stronger among women who were born during this period than among women born before or after the war. A total of 25 204 Norwegian women were followed up for approximately 11 years, and 215 incident cases of breast cancer were registered. We found the strongest positive association between height and breast cancer among women born during WWII: women in the tallest tertile (>167 cm) had a relative risk of 2.5 (95% confidence interval = 1.2-5.5) compared with the shortest (< or = 162 cm). Among women born before or after the war we found no clear association with height. The association with height in the WWII cohort may imply a role for early nutrition in breast cancer aetiology., (Copyright 2001 Cancer Research Campaign)

The incidence of breast cancer in women in increasing, partly due to changes in age distribution in the population, and partly due to a real increase in risk. Changes in family patterns may, to some extent, explain the increased risk since giving birth to a first child late in life and bearing few children both increase the risk of breast cancer. The influence of female sex steroids on the breast plays a central role, but the biological mechanism is not clearly understood. There is a certain amount of risk involved in using hormonal medication (oral contraceptives or postmenopausal hormone replacement), but on ceasing to take the medication, risk will revert to the expected rate within a few years. Future epidemiological research on breast cancer will concentrate on events occurring during hormonally potent phases of life, such as growth and development during the fetal period, and sexual and somatic maturation during adolescence. Until now only modest interest has been shown in researching these two particular phases, but both may be important for the natural course of breast cancer.

Epidemiological studies have suggested that moderate intake (1-2 drinks per day) of alcohol may increase the risk of breast cancer by more than 50%. A relatively large proportion of women in many countries consume alcohol at this level, and a precise assessment of the related breast cancer risk is therefore important. In this paper we have reviewed all published studies subsequent to a comprehensive meta-analysis on alcohol and breast cancer, published in 1988. Among four cohort studies, the relative risk of breast cancer associated with 1-2 drinks per day (compared with no drinking) varied between 1.0 and 1.3, and the null value of 1.0 was included in the 95% confidence interval for each of the studies. For consumption higher than two drinks per day, two of the four cohort studies indicated a significantly increased risk. Among 14 case-control studies, the point estimates showed increased breast cancer risk in 11, and five were statistically significant. Three studies indicated a negative association, but the confidence interval included 1.0 in two of them. Among case-control studies which provided information on intakes higher than two drinks, eight out of 13 studies showed a statistically significant positive association. Collectively these studies support a weak positive association between moderate consumption of alcohol and breast cancer risk. The tendency between studies is consistent, but the precision of the estimate of relative risk is low in most studies. Unless consumption is two drinks or higher per day, no recommendation to reduce drinking should be made based on the present evidence relating alcohol consumption to breast cancer risk.

Earlier onset of menarche and tallness in adult women are mainly confirmed as risk markers for breast cancer. Recent disparate case-control studies have reported abdominal-type obesity and higher circulating levels of insulin, testosterone and insulin-like growth factor 1, to be further risk markers for breast cancer. There is evidence that abdominal-type obesity is recognisable in girls even before puberty, and disparate studies have shown it to be correlated with earlier onset of menarche, insulin resistance leading to hyperinsulinaemia, and an abnormal sex steroid profile. The implications are that earlier onset of puberty in a subset of girls can lead to more prolonged exposure of developing breast tissue to an abnormal sex steroid profile and also to a higher circulating level of insulin. It is postulated that these metabolic/endocrine concomitants of abdominal-type obesity could play a role in promoting mammary carcinogenesis at a young age, particularly if genetic predisposition is present.

A topic of general interest is whether important life changes may play a role in the onset of cancer. The hypothesis of this study was that death of a husband or marital divorce, is associated with an increased risk of breast cancer. The study included 4491 incident breast cancer cases and 44,910 controls, matched on age, in a population-based nested case-control study, among Norwegian women born between 1935 and 1954. The risk of breast cancer among widowed compared to married women showed an odds ratio (OR) of 1.13 [95% confidence interval (CI) 0.94-1.36], after adjusting for age at first birth and parity. For divorced women the analogous OR was 0.83 (95% CI 0.75-0.92), after adjusting for age at first birth, parity and place of residence. Thus, the results did not show any clear evidence that death of a husband or marital divorce was associated with an increased risk of breast cancer.

We have tested the hypothesis that specific polyunsaturated fatty acids (PUFA) of the n-3 and n-6 families, as measured in serum phospholipids, are negatively associated with the risk of breast cancer. The study is based on serum samples from women who have donated blood to the Janus serum bank at the University Hospital in Oslo, Norway. It consists of sera from 87 women who developed breast cancer (cases) subsequent to blood donation and 235 women who were free of any diagnosed cancer (controls), but were of similar age and had similar blood storage time as the cases. We measured fatty acids (monounsaturated, polyunsaturated and saturated) in serum phospholipids, and made comparisons between cases and controls. The results showed that there was an inverse relation between the n-6 PUFA linoleic acid (18:2n-6) and risk of breast cancer, but this association was restricted to women who were 55 years and younger. In this age group, the relative risk (odds ratio) of women in the highest quartile of linoleic acid was 0.4 (95% confidence limits, 0.2 and 1.0) compared with women in the lowest quartile, and there was a negative trend over quartiles of linoleic acid (Mantel's chi for trend = -2.49, P < 0.02). No association was noted between the n-3 PUFA of marine oil origin and breast cancer risk. If the measured concentration of linoleic acid in serum phospholipids reliably reflects dietary intake, these data suggest that linoleic acid in the diet may decrease breast cancer risk among women at premenopausal and perimenopausal age. No similar association with n-3 unsaturated fatty acids was observed. It is noteworthy that none of the measured fatty acids (saturated or unsaturated) showed a positive association with breast cancer risk.

It has been suggested that pregnancy is associated with a short-term increased risk of breast cancer followed by a life-long protection. We studied 340 incident cases of breast cancer in relation to parity, age at first full term birth, and time since last child birth during 14 years follow-up in a prospective cohort of 29,981 Norwegian women. We found no evidence for a transient increase in risk of breast cancer subsequent to pregnancy followed by a reduction in risk of long lasting duration. However, our results indicate that up to an approximate age of 45 years, the nulliparous have a lower breast cancer risk than everparous women. Among parous women, there was an increasingly protective effect on breast cancer risk at a young age (less than 50 years) with increasing number of child births, independent of age at first birth, whereas the protection associated with an early age at first full term pregnancy may increase in importance with increasing age. This finding may reconcile conflicting reports related to these two factors. This study confirms the results of previous investigations suggesting that a "cross-over" in breast cancer incidence between nulliparous and ever-parous women appears to take place some time during the fifth decade of life.

The associations of breast cancer risk with height and body mass index have been examined in 291 cases of breast cancer that occurred among 25,967 Norwegian women during a mean follow-up of approximately 14 years (range 12-16 years). There was an overall increased risk of breast cancer with increasing body height, and the relative risk of women in the fourth quartile of height (mean = 170 cm) was 1.43 (95% confidence limits, 1.18-1.73) compared to women in the lowest quartile (mean = 155 cm), after adjusting for age, parity, age at first birth, and county of residence. Simultaneously, there was an overall inverse relation between body mass index (BMI) and breast cancer risk, which, however, was confined to women 50 years or younger. After adjustment for age, parity, age at first birth, and county of residence, the relative risk of women (less than or equal to 50 years) in the highest quartile of BMI (mean Quetelet = 30) was 0.63 (95% confidence limits, 0.48-0.82), compared to women in the lowest (mean Quetelet = 21). We propose that the lower breast cancer risk in shorter women may reflect caloric restriction during the pre- and peripubertal period, which may affect hyperplastic growth, and lead to a reduced number of breast tissue cells. The negative association with BMI may be related to a lower rate of cell division of breast tissue among obese premenopausal women.

The nutritional component during childhood and adolescence that contributes to variation in adult height may be associated with the subsequent risk of breast cancer in women. Municipalities in three Norwegian counties were ranked and divided in three categories according to resident women's height, where variation in height is assumed to reflect variation in nutritional living conditions during childhood and adolescence. For each county observed number of incident cases (1975-1984) and deaths (1966-1987) of breast cancer in "short", "medium" and "tall" municipalities were compared with the expected number computed from the national rates. An analogous analysis was done, comparing incidence and mortality between 18 Norwegian counties, but using county-specific infant mortality for the period 1921-1935 as an alternative indicator of living conditions. There was a consistent positive association between height in municipalities and breast cancer incidence (overall P trend = 0.02) and mortality (overall P trend = 0.05). For infant mortality between counties, there was no association with breast cancer. In populations where variation in height reflects variation in nutritional living conditions during childhood and adolescence, there may be a positive association between height and risk and mortality of breast cancer.

More than six-fold variation in incidence between countries, an increasing incidence among immigrants to high incidence areas, and a general increase in the incidence of breast cancer within countries, are factors which suggest a potential for prevention. Reproductive factors such as early menarche, late age at first full term birth, nulliparity, and late age at menopause increase risk of breast cancer, but manipulation of any one of these factors does not seem to be a realistic preventive tool. Nevertheless, the future possibility of using tamoxifen as a chemopreventive agent against breast cancer is discussed, particularly in relation to women at increased risk due to familial clustering. Alcohol consumption by young women, and overweight among postmenopausal women may also increase the incidence of breast cancer. Consequently, reduced alcohol intake by young women, and weight reduction among overweight women after menopause may reduce the risk of breast cancer.

Mean overall 5-year survival related to preclinically determined total serum cholesterol, body mass index (BMI), height and cigarette smoking has been analysed among 242 incident cases of breast cancer aged 36-63 years that developed in a population of 24,329 Norwegian women during a mean follow-up of 12 years (range 11-14). The study factors were ascertained at least 1 year prior to diagnosis (mean = 8 years), and the cases have been followed up with respect to death for a mean time of approximately 5 years after diagnosis. Patients whose preclinical total serum cholesterol values were within the highest quartile (greater than or equal to 7.52 mmol/l, mean = 8.58 mmol/l) of the underlying population had a hazard ratio of dying of 2.0 (95% confidence limits, 1.1 and 3.7) compared to cases with cholesterol values in the lowest quartile (mean = 5.28 mmol/l), after adjustment for age at diagnosis, clinical stage, and body mass index. In relation to BMI (Quetelet's index: weight/height2) patients who were obese prior to diagnosis were at higher risk of dying than those who were lean. Compared to patients in the lowest quartile of BMI (mean Quetelet = 21), the hazard ratio was 2.1 (95% confidence limits, 1.2 and 3.8) for patients in the highest quartile (mean Quetelet = 30), after adjustment for age at diagnosis, clinical stage, and total serum cholesterol. For height and for cigarette smoking, no relation with survival was observed. A potential problem of this study might be insufficient information about other well known prognostic factors, but the results suggest that preclinical total serum cholesterol and BMI are positively associated with the risk of dying among women who develop breast cancer.

The association between coffee consumption and the incidence rate of breast cancer has been analysed in 152 incident cases of breast cancer that developed among 14,593 Norwegian women during a mean follow-up of 12 years. At the time of inquiry they were between 35 and 51 years of age, and at the end of follow-up between 46 and 63. There was an overall weak negative association between daily intake of coffee and risk of breast cancer, which was not statistically significant. However, the association with coffee varied, depending on the body mass index (BMI) of the women. In the lean (Quetelet less than 24; population mean) there was an inverse relation between coffee intake and risk of breast cancer (chi 2 trend = 5.07, P = 0.02). In this group, women who reported drinking 5 cups or more per day had an age-adjusted IRR of 0.5 (95% confidence intervals, 0.3 and 0.9) compared to women who had 2 cups or less. In women with Quetelet's index equal to or greater than 24 there was a positive relation between coffee intake and breast cancer risk (chi 2 trend = 2.33, P = 0.13), where the corresponding age-adjusted IRR was 2.1 (95% confidence intervals, 0.8 and 5.2). This interaction effect between coffee intake and BMI was statistically significant (chi 2 interaction = 10.2, 3 d.f., P = 0.02). In summary, the results of this study suggest that coffee consumption reduces the risk of breast cancer in lean women, whereas coffee might have the opposite effect in relatively obese women.

The association between the frequency of meat and fish intake and the incidence rate of breast cancer has been analyzed in 152 incident cases that developed among 14,500 Norwegian women during 11 to 14 years of follow-up. At the time of dietary inquiry they were between 35 and 51 years of age. A positive association was observed between the frequency of overall meat intake and breast cancer risk. There was an age-adjusted incidence rate ratio (IRR) of 1.8 (95% confidence limits, 1.1 and 3.1) for women who had a main meal with meat 5 times or more per week compared to women who had 2 meat dinners or less per week, and this association displayed a linear trend (chi 2 trend = 4.30, p = 0.04). No association was detected between the overall frequency of fish for dinner and breast cancer risk (chi 2 trend = 1.39, p = 0.24), but there was an inverse relation with the frequency of main meals containing fish in poached form. The age-adjusted IRR was 0.7 (95% confidence limits, 0.4 and 1.0) for women who had poached fish for dinner at least 5 times per month compared to women who had fish in this form twice monthly or less often (chi 2 trend = 3.56, p = 0.06). The positive association with meat may be in accordance with the hypothesis that dietary fat increases the risk of breast cancer. Although there was no association with overall fish intake, the inverse relation with poached fish might deserve further investigation.

The association between body height and the incidence rate of breast cancer has been examined in 236 cases of breast cancer that occurred among 23,831 Norwegian women during 11-14 years of follow-up. At the time of height measurement they were 35-51 years of age. The age-adjusted incidence rate ratio (IRR) of breast cancer was 2.03 (95% of confidence limits 1.36 and 3.01) for women taller than or equal to 167 cm (mean = 170 cm) compared to women who were less than 159 cm (mean = 155 cm). The positive association with height was stronger among women who were diagnosed before the age of 51 (IRR = 2.63; 95% confidence limits 1.48 and 4.68), than among women diagnosed after this age. Moreover, the association appeared to be confined to women who had lived through their peripubertal growth during a period (1940-45) of nationally increased nutritional variability with reduction in dietary fat and restricted caloric intake. Among women born between 1929 and 1936, the relation with height displayed a strong positive linear trend (chi 2 trend = 13.4, P less than 0.001), which was not present among women born between 1925 and 1928 (chi 2 trend = 0.7, P = 0.40), nor among women born in 1937 or later (chi 2 trend = 1.5, P = 0.20). We hypothesise that a time-dependent diversity in nourishment, which may be of particular importance for women in their peri-menarcheal development, may explain the different association between body height and breast cancer risk that was observed for women in different birth cohorts.

The association between total serum cholesterol and triglycerides and the incidence rate of breast cancer has been examined in 242 incident cases of breast cancer that developed among 24,329 Norwegian women during 11-14 years of follow-up. At the time of lipid measurement they were between 35 and 51 years of age. There was an inverse relation between serum cholesterol and risk of breast cancer which was confined to women diagnosed before the age of 51. The incidence rate ratio was 0.53 (95% confidence limits, 0.32 and 0.88) for women in the highest quartile of serum cholesterol (mean = 8.52 mM = 329 mg/100 ml) compared to women in the lowest quartile (mean = 5.28 mM = 204 mg/100 ml), and the relation displayed a negative trend over quartiles of cholesterol (chi 2 for trend = 3.94, P = 0.05). No association with cholesterol was found among cases diagnosed during the initial 2 years of follow-up, whereas a strong inverse relation was observed among cases that were diagnosed during the following 4 years (chi 2 trend = 12.6, P less than 0.001). For serum triglycerides there was an overall negative, but not statistically significant, association with breast cancer incidence, which was weakened after further adjustment for body mass index and serum cholesterol. The lack of information on reproductive factors associated with breast cancer risk is a limitation of this study, since potential confounding with the results cannot be excluded. We conclude that there is an inverse relation between serum cholesterol and breast cancer risk among women diagnosed before the age of 51 years. The findings indicate that the negative association cannot easily be attributed to a preclinical effect of the cancer.

The association between body mass index (BMI) and the incidence rate of breast cancer has been examined in 236 cases of breast cancer that developed among 23,826 Norwegian women during 11 to 14 years of follow-up. At the time of height and weight measurement they were 35 to 51 years of age, and at the end of follow-up their age was between 46 and 63 years. There was an overall age-adjusted incidence rate ratio (IRR) of 0.52 (95% confidence limits, 0.34 and 0.77) for women in the highest quartile of BMI compared to women in the lowest quartile, which was confined to an effect observed among women who were diagnosed at age 50 or earlier (IRR = 0.36). The association with BMI displayed an inverse dose-related trend (chi 2 for trend = 14.22, p less than 0.001). The negative trend was particularly pronounced among non-smoking women (chi 2 = 14.63), and no clear trend associate with BMI was observed among women who smoked 10 or more cigarettes per day (chi 2 = 0.41), indicating an interaction between BMI and cigarette smoking (chi 2 interaction = 3.86, p = 0.05). We thus suggest that there is a negative association between body mass index and risk of breast cancer among premenopausal women.

The association between cigarette smoking and incidence of breast cancer has been analyzed in 242 cases of breast cancer that developed among 24,329 Norwegian women over 11-14 years of follow-up. At baseline they were aged 35-51. There was no overall association between cigarette smoking and the risk of breast cancer. The age-adjusted incidence rate ratio (IRR) was unity (IRR = 1.04, 95% CI 0.76-1.42) for regular smokers (10 or more cigarettes daily) compared with non-smoking women. In women who reported smoking between 1 and 9 cigarettes per day there was an age-adjusted IRR of 1.28 (95% CI 0.95-1.73). The lack of association with cigarette smoking was replicated in subgroup analyses of women diagnosed before age 51 ("premenopausal") and among women diagnosed after this age ("postmenopausal"). However, there was a significant interaction between cigarette smoking, body mass index and age at diagnosis (P = 0.01), which might indicate that an interaction between cigarette smoking and body mass exerts differential effects on breast cancer risk in premenopausal and postmenopausal women.