Lynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility caused by germline mutations in the DNA mismatch repair (MMR) genes. Mutation carriers have a substantial burden of increased risks of cancers of the colon, rectum, endometrium and several other organs which generally occur at younger ages than for the general population. The issue of whether breast cancer risk is increased for MMR gene mutation carriers has been debated with evidence for and against this association.Using the PUBMED, we identified all relevant studies of breast cancer associated with Lynch syndrome that were published by 15 December 2012. In the review, we included: (i) molecular studies that reported microsatellite instability and/or immunohistochemistry in breast cancer tumors of MMR gene mutation carriers; and (ii) risk studies that investigated risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families.We identified 15 molecular studies and, when combined, observed 62 of 122  breast cancers in MMR gene mutation carriers were MMR-deficient. Of the 21 risk studies identified, 13 did not observe statistical evidence for an association of breast cancer risk with Lynch syndrome while 8 studies found an increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers). There is only one prospective study demonstrating an elevated risk of breast cancer for MMR gene mutation carriers compared with the general population .Since breast cancer is a relatively common disease in the general population, more precise estimates of risk and gene-specific risks will need to utilize large prospective cohort studies with a long follow-up. While current data are inconclusive at a population level, individual tumor testing results suggest that MMR deficiency is involved with breast cancers in some individuals with Lynch syndrome. MLH1, MSH2, MSH6 and PMS2. The prevalence of individuals who carry a pathogenic germline mutation in one of these genes in the population is estimated to be, depending on various assumptions, from 1 in 370 to 1 in 3,000 [Lynch syndrome, formerly known as hereditary nonpolyposis colorectal cancer (HNPCC) , is an ain 3,000 . Though in 3,000 .Lynch syndrome-associated cancers typically exhibit DNA microsatellite instability (MSI) and loss of MMR protein expression. Instability of microsatellite DNA sequences characterized by the presence of random contractions or expansions in the length of simple sequence repeats, can be detected by polymerase chain reaction-based methods ,7. The lThese cancers include adrenocortical adenocarcinoma -11, thyrInitially raised by Henry Lynch and colleagues several decades ago , the issWe used PUBMED  to searcFor molecular studies, studies were eligible if they reported mismatch repair deficiency status (either by MSI and/or IHC) of breast cancer tumors of MMR gene mutation carriers. For risk studies, studies were eligible (i) if they were case-control or cohort studies, and (ii) if they investigated the risk of breast cancer for confirmed MMR gene mutation carriers or families or clinically and/or pathologically defined Lynch syndrome families compared with non-carriers or the general population. Studies were excluded if they were editorials or literature reviews.For molecular studies, we extracted the following data: first author's name, year of publication, country in which the study was performed, number of breast cancers observed in MMR gene mutation carriers, specific mutated MMR gene, age at diagnosis of breast cancer, and the MSI and/or IHC status of the breast tumor.For risk studies, we extracted the following data: first author's name, year of publication, country in which the study was performed, recruitment and ascertainment method of families or mutation carriers, definition of Lynch syndrome, numbers of MMR gene mutation carriers, specific mutated MMR gene, observed and expected numbers of breast cancers, estimates of breast cancer risk for mutation carriers compared with non-carriers or the general population  and absolute or cumulative risk of breast cancer for mutation carriers (expressed as lifetime risk or 10-year risk).For molecular studies, we defined a tumor with high level of microsatellite instability (≥ 30% of markers tested) or those with loss of normal expression of any of the four DNA MMR genes by IHC to be a MMR-deficient tumor. We divided the total number of MMR-deficient breast cancers by the total number of breast cancers in MMR gene mutation carriers to estimate the proportion of breast cancers in MMR gene mutation carriers that were MMR-deficient.For risk studies that did not provide the relative risk (or standardized incidence ratio), we calculated the estimated the standardized incidence ratio (SIR) by dividing the observed numbers of breast cancers by the reported expected numbers. When not provided by the study, we calculated the 95% CI assuming that the numbers of observed cases followed a Poisson distribution. All statistical analyses were conducted using Stata 11.2 .We identified 638 studies identified through the literature search, and retrieved 129 of these studies for full assessment for eligibility. A total of thirty-four studies were included in the systematic review including fifteen molecular studies and twenty-one risk studies (two studies were both molecular and risk studies)  or accelerate carcinogenesis in breast cancers that occur in MMR gene mutation carriers (as an accelerator). However, these observations are also consistent with MMR deficiency being a phenotype arising within breast cancer that was caused by another factor (as a passenger), rather than the phenotype driving or accelerating carcinogenesis.One method to overcome this problem of cause or consequence is to determine whether breast cancer is more likely to develop in carriers of MMR gene mutations compared with non-carriers , that is, empirical evidence of risk. Eight studies ,47-53 esOne retrospective study  comparedSix studies -60 estimTwo studies ,62 from Prospective studies avoid the ascertainment issue described above because the carriers used to estimate cancer risk are unaffected at the time of recruitment or first observation. To date, there is only one prospective study of MMR gene mutation carriers without prior diagnosis of cancer . An incrThe two other studies of the Colon Cancer Family Registry observed an approximately 2-fold increased risk of breast cancer for MMR gene mutation carrying women. These included those who had a previous diagnosis of colorectal cancer  or endomet al. [MLH1 c.C1528T mutation. In this study design, unaffected siblings of familial cases have the same familial risk profile  and therefore, share potential confounders that are correlated within siblings, in other words, it is an informative comparison within the same study base [Blokhius et al.  comparedudy base . The lacet al. [et al. [in situ were predominantly of higher nuclear grade, suggesting that aberrations in MMR function may lead to a more aggressive phenotype in breast cancer.The estimates of an increased risk of breast cancer in Lynch syndrome described in the previous studies are relatively small compared with the increased risks observed for colorectal and endometrial cancers . Howeveret al.  hypothes [et al.  who obseThe suggested small increased risk of breast cancer in Lynch syndrome is important to confirm, given that breast cancer is a common disease in women. The average lifetime risk of breast cancer in women is estimated to be 12.2% . The thret al. [MLH1 mutation-carrying families but not in MSH2 families  for the risk studies included in the review [e review -65,78-80Click here for file


UGT1A6_19_T>G (rs6759892) polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA). An independent validation study comprised four independent breast cancer case-control studies from Finland , Germany (BBCC), and Sweden (SASBAC). The pooled analysis included 7418 cases and 8720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections . The pooled study showed a similar effect . The risk effect on the basis of allele frequencies was highly significant, the pooled analysis showed an OR of 1.11 . We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.Validation of an association between the  BRCA1, BRCA2, TP53, ATM, CHEK2, BRIP1 and PALB2 which are causative for hereditary breast cancers  polymorphism rs2981582 as well as loci close to the cell cycle regulator Cyclin D1 (CCND1) at 11q13 are the most prominent risk loci  and UGT1A6_541_A>G (rs2070959) are located in exon 1 causing amino acid exchanges from serine to alanine at position 7 and threonine to alanine at position 181, respectively [GenBank: P19224]. The variant alleles have been associated with decreased activity of the UGT1A6 enzyme  as described previously . Four subgroup analyses were performed including the analysis of ER-positive cases vs. controls, ER-negative cases vs. controls, PR-positive cases versus controls, and PR-negative cases vs. controls. Risk estimates were calculated as odds ratios (OR) with 95% confidence interval (95% CI) and corresponding p-value. Power calculation was done by nQuery Advisor® 4.0.Associations between UGT1A6_19_T>G and UGT1A6_541_A>G polymorphisms, respectively . We observed no breast cancer risk association for the UGT1A6_541_A>G genotypes and none of the two variants showed an association with tumor ER and PR status (data not shown).Our validation study had 80% power to detect a minimum OR of 1.06 and 1.07 for the UGT1A6_19_T>G polymorphism, we confirmed an increased breast cancer risk for women carrying the homozygous variant GG genotype  in the previous pilot investigation (stage 1)  for the UGT1A6_19_GG genotype , 1.10 , and 1.11  in the pilot and validation study as well as pooled analysis, respectively.In addition to the genotype frequencies the risk effect of the UGT1A6_19_GG genotype as an overall breast cancer risk factor, first, in an independent validation study including breast cancer cases and controls from Finland, Germany and Sweden as well as in a pooled analysis of more than 15,000 study subjects following our initial report from a German pilot study  (Easton et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We describe a screening and prevention programme primarily targeting under-served minority women at high risk of breast and/or ovarian cancer. Women attending this Bellevue Hospital Center (BHC) Clinic were either self-referred from a variety of special outreach programmes or referred internally by medical professionals caring for relatives or friends. Our objective was to delineate referral sources and preliminary risk-assessment findings in relation to demographic features in this population.Following a detailed family and personal history intake and physical examination, each woman on her initial visit is categorized into a low (standard) risk, high-risk or indeterminate-risk group. Women found to be at high risk of developing breast and/or ovarian cancers are referred for further testing, additional screening measures, or participation in chemoprevention trials. All other women are counselled concerning follow-up and lifestyle issues.Between 2003 and 2007, 171 women for whom complete information was obtained were analysed. Thirty-four of the women were Caucasians (19.8%) and 137 (80.2%) were ethnically diverse minority women. Sixty-two (36.2%) were found to be at high risk with a median age of 42 years. The majority of the high-risk women were referred to the clinic by medical professionals (58%), most of whom were from within the BHC health care system. In fact, one-fourth of the referrals were women who carried a diagnosis of cancer, mostly arising in the breast, and who were concerned with risks to other family members. Trends in genetic testing results indicate fewer mutations among high-risk Asians than among other ethnicities.Accurate risk assessments and implementation of screening and prevention measures have been challenging during the first few years of operation. Nevertheless, the need for providing consultation from internal referrals and the potential for genetic and psychosocial research in an ethnically diverse population are powerful incentives for continuing to evolve these services. An estimated 5–10% of all breast cancer cases are attributed to inherited mutations in genes conferring breast cancer susceptibility as high as 80% life-time risk . Early iStudies have shown that the prevalence of these mutations vary greatly between populations and ethnicities; for example while certain founder mutations in BRCA1 are reported to be the most common in Ashkenazi Jews –8, a sinSince 2001, 398 women were registered free of charge in the Lynne Cohen High Risk Clinic as part of a research project designed to identify women at high risk of developing breast and/or ovarian cancer. The resources utilized originated at the NYU Cancer Center and the Lynne Cohen Foundation. Referrals were from BHC various specialties as well as Center for Immigrant Health of NYU. The High Risk Clinic Staff has attended departmental conferences and tumour boards in relevant units such as Internal Medicine, Geriatrics, Gynecology, Gynecology-Oncology, and Medical Oncology. The goals of the clinic, services offered and eligibility criteria were presented to increase awareness and promote referrals.Collaboration with outreach and community programmes was sought out to help promote access for immigrant and minority women. These included the YWCA, the American Cancer Society Eastern Division, Latina Share, Cancer Care and the Women’s Outreach Network. Relatives of women found at high risk were also encouraged to enrol.et al [http://www.cancer.gov/bcrisktool/. Based on the interview and risk assessment models, the woman’s risk profile is discussed, with recommendations for surveillance and follow-up.Upon arrival, women go through the following procedure: women meet a bilingual nurse who explains the sequence of the visit and assists in filling out a comprehensive clinical and research questionnaire, available in both English and Spanish. Ethnic and demographic data and an expanded personal and family history (modified from the Gynecologic Oncology Group Protocol 199) are included . Mammogret al ) and is Since 2004, women estimated to be at an increased risk of breast and ovarian cancer based on personal or family history are referred to a dedicated genetic counsellor for a formal consultation in order to asses risk and determine need for genetic testing based on the clinic’s guidelines . The inflow risk have no established risk factors and are referred for standard follow-up: mammograms every 1–2 years after age 40 and annual visits with a primary care physician. Women at high risk are those with genetic risk factors , clinical risk factors, or a known diagnosis on biopsy such as atypical hyperplasia or lobular carcinoma in situ. These women are followed up every six months with physical and pelvic examinations and are eligible to undergo genetic testing  and 137 (80.1%) were ethnically diverse minorities . AssignaThe majority of women both as a whole and in most ethnic groups were referred to the clinic by medical professionals, most from within the Bellevue health system itself . The secIn the group referred by medical professionals, a common reason in the high-risk cohort was a personal history of cancer. This was the referral reason for 30 of the women in the high-risk group. The breakdown of the specific cancer types is as follows: 23 of these 30 had a diagnosis of pre-menopausal breast cancer and three had ovarian cancer, two of which were serous papillary carcinomas and one of which is a tumour of low malignant potential (LMP). Three women had been diagnosed with other primary cancers, including stomach cancer, endometrial carcinoma and vulvar melanoma. Three women with early onset breast cancer developed bilateral disease, and a fourth was later diagnosed with endometrial cancer . In the Twenty per cent of all the women who registered in our clinic, and mostly among the high-risk group, belonged to ten families with two to five members (median 2) being screened; only two families were of Caucasian ethnicity. A diagnosis of breast cancer in first-degree relatives prompted referral in seven , whereas a diagnosis of ovarian cancer in a first-degree family member was the major impetus for referral in three families. Mother--daughter referrals outnumbered sister–sister referrals.Genetic testing for BRCA mutations has been carried out since 2003 and more than half of these since 2007 when special funding was obtained from an institutional grant (see acknowledgement). The ethnicities of all women seen in the clinic from 2003 to 2007 is illustrated in Providing minority women risk-guided screening and prevention opportunities remains challenging. While some women may be highly motivated by self-perceived increased risk due to multiple cases of cancer in the family, many barriers exist preventing their enrolment into clinics and trials. Our clinic set out to provide specialized care at no cost thereby eliminating the possible lack of insurance as a major obstacle to care. Language barrier problems were dealt with by the presence of bilingual nurse and patient navigators; however, the difficulty of reaching the target population to inform them of the clinic’s services, remained an issue. Over the course of the first six years, the clinic staff has dedicated much of its activity to educational initiatives for the medical community, and to the formation of bonds with community and outreach programmes. The specific organizations approached were chosen for their work with particular populations and their agenda of promoting health education, screening and prevention. The most highly represented ethnic group, which also comprises the largest group of women at high risk, is the Latina. Although Ashkenazi Jewish and Asian women were referred less frequently to our clinic, the relative percentage of high-risk women was the highest in these groups.et al described a similar dual approach for both in- and outreach [A similar approach of mapping high-risk populations and forming partnerships with trusted community institutions in order to maximize penetration to these populations was described by Barry and Britt, in their paper describing efforts to promote cervical and breast cancer screening in impoverished minority women . While toutreach . It is ioutreach –23.In conclusion, our clinic has been a valuable resource for internal referral of affected patients and family members of patients with breast cancer to discuss their risk. It also relies on external referrals that depend on awareness in communities within BHC catchment area. Classification into risk based on sometimes inadequate family information and challenges in obtaining genetic testing have been our major obstacles. On the other hand, the Lynne Cohen Foundation for Ovarian Cancer Research has sponsored research symposia activities and the formation of a consortium with four institutions including our own. This Lynne Cohen Foundation Consortium includes the MD Anderson Cancer Centers, the University of Alabama, the University of Southern California as well as our own, and the creation of a common registry represents an opportunity for subsequent collaborative research that may include prospective clinical trials.


The purpose of this paper is to identify risk factors for cardiovascular disease in women with breast cancer and review healthy lifestyle behaviors as essential risk reduction strategies.Women with breast cancer account for 22% of the 12 million cancer survivors. Women diagnosed with breast cancer often present with modifiable and non-modifiable cardiovascular risk factors and/or pre-existing co-morbid illness. Any one or a combination of these factors may increase the risk of cardiovascular disease. There is strong evidence that healthy eating and routine physical activity can reduce cardiovascular disease. Exercise improves cardiovascular fitness, body composition and quality of life in breast cancer survivors and observational studies suggest a survival benefit.Lifestyle interventions including a healthy diet, regular physical activity, weight management and smoking cessation should be integrated into a survivorship care plan to reduce cardiovascular disease risk and promote better health for women with breast cancer.  Among women of all ages in the United States, cardiovascular disease is the leading cause of death . When coOverweight, obesity, abdominal adiposity, cigarette smoking, sedentary behavior, hypertension, impaired glucose tolerance, and abnormal cholesterol are known modifiable risk factors for cardiovascular disease (CVD) in women , 10. The1). Pre-existing diabetes in breast cancer survivors has been associated with increased treatment toxicity and reduced survival [Women diagnosed with breast cancer may be at risk for cardiac disease unrelated to cancer treatment. Forty percent of women by 50 years of age in the US population have at least one cardiac risk factor and 17% have 2 or more risk factors, increasing their lifetime risk of developing cardiovascular disease. As the majority of women are diagnosed with breast cancer after the age of 45 years, a cardiovascular risk assessment is indicated even if women are asymptomatic . Women wsurvival -28. Hypesurvival , 30, hassurvival , 24, a rsurvival , is assosurvival  and has survival , 32, 33.survival  which susurvival , 24, 25 survival , 20. Comsurvival , 35. Redsurvival .1).While some data exist on co-morbid conditions in newly diagnosed women with breast cancer , 36, theAdjuvant breast treatment includes chemotherapy, endocrine therapy and targeted agents. There is a wide variety of symptoms, many of which persist once the treatment ends . FatigueWeight gain during and after breast cancer treatment is common , 62 and Elevation in the systemic inflammatory marker, hsCRP, and central obesity have been associated with the development of metabolic syndrome in breast cancer survivors  both of The contribution of menopause to cardiovascular risk is a complex blend of chronological aging and ovarian aging . While tCardiotoxicity associated with agents used in adjuvant breast cancer therapy has been well described , 79, 80.2, no cigarette smoking, healthy diet, and regular physical activity of ≥ 150 minutes a week of moderate intensity or ≥ 75 minutes//week of vigorous intensity or a combination of intensities [Ideal cardiovascular health includes total cholesterol <200 mg/dL, blood pressure < 120/80, fasting blood glucose < 100 mg/dL, body mass index <25 kg/mensities . Dietaryensities , 88. Theensities , improveensities , 91 and ensities . This leensities . To achiensities . improved cardiovascular fitness, body composition, quality of life, psychological adjustment, aerobic capacity, muscle strength and a decrease in fatigue, depression, anxiety, and sleeping disturbance [et al. [Data from six observational studies concluded that moderate exercise (3-5 hours/week) improved all cause mortality in breast cancer survivors -99. Multturbance -109. Jonturbance  reviewedturbance  and highturbance , 26, 112turbance . Waist c [et al.  reportedMore than half of women diagnosed with breast cancer who have participated in exercise trials have been overweight and some obese, reflecting a similar pattern of weight to women without breast cancer in the US. Only a few trials have investigated diet and exercise as an intervention for weight loss in breast cancer survivors -117. Dat1). Physical activity recommendations by the American College of Sports Medicine for cancer survivors [Lifestyle interventions are strongly recommended for breast cancer survivors , 45, 120urvivors  are consurvivors , 16 and urvivors . For resurvivors . Persisturvivors , arthralurvivors , decreasurvivors  and fatiurvivors  are commurvivors , 125. Li


The characteristics of established risk factors for breast cancer may vary among countries. A better understanding of local characteristics of risk factors may help in devising effective prevention strategies for breast cancer.2 test. Crude associations between the selected factors and breast cancer were estimated using the cases in the present study and a representative control population, which was selected from qualified published studies.Information on exposures to risk factors was collected from the medical charts of 4211 women with breast cancer diagnosed during 1999–2008. The distributions of these exposures among regions, and by menopausal status and birth period, were compared with the χP < 0.05), and were less likely to have breastfed (P = 0.08). As compared with premenopausal cases, postmenopausal cases were more likely to be overweight and to have breastfed and had more childbirths (P < 0.05). The number of live births and rate of breastfeeding decreased in relation to birth period (P for trends <0.001). Overweight, late menopause, and family history of breast cancer were significantly associated with breast cancer among Chinese women.As compared with cases from less developed regions, those from more developed regions were significantly more likely to be nulliparous, had fewer childbirths (Breast cancer incidence was associated with nulliparity and history of breastfeeding. Population attributable risks should be assessed, especially for more developed areas and young women. The effects of body mass index, age at menopause, and family history of breast cancer should be given priority during assessment of breast cancer risk among Chinese women. However, a number of risk factors for breast cancer are supported by strong evidence, especially in Western countries. Population-based studies have shown that reproductive factors, including early menarche, late menopause, nulliparity, and absence of a history of breastfeeding, increase the risk of breast cancer.2 Several lifestyle-related risk factors have also been shown to contribute to breast cancer development, including lack of physical activity, overweight, smoking, alcohol drinking, oral contraceptive use, hormone replacement therapy, poor dietary intake, and radiation exposure.3 In addition, studies of families with high breast cancer incidence have shown that about 5% to 7% of all breast carcinomas are hereditary.4According to global cancer statistics for the year 2008, breast cancer was the most frequently diagnosed malignancy among women worldwide  and resulted in 46 million deaths.5 In addition, using nationally representative information on risk factors for breast cancer, a method of identifying women at high risk for breast cancer (the Gail model) has been used in clinical counseling and breast cancer prevention studies in North America and Europe.6Although the mechanisms underlying breast cancer risk require further clarification, experience in Western countries has highlighted the benefits of awareness and understanding of modifiable factors. The publication of the Women’s Health Initiative randomized trial in the United States led to a rapid decrease in the number of women receiving postmenopausal women hormone replacement, which might partly explain the sharp decline in breast cancer incidence in the United States and other Western countries.7 Average age at breast cancer onset is approximately 10 years earlier among Chinese women as compared with Western women. Thus, the disease burden in China has substantially increased. Because most established risk factors are related to lifestyle, which is influenced by culture and economic development, disparities may exist between China and Western countries in population distribution and the effects of risk factors. To date, primary prevention has received little attention in China, partly because of insufficient knowledge of risk factors for breast cancer among Chinese women. In relation to secondary prevention, it has been suggested that implementing mammography screening programs in populations at high risk for breast cancer would be more cost-effective in low-income countries.8 Therefore understanding the characteristics of risk factors in China might help identify high-risk groups and improve secondary prevention.Although Chinese women are at relatively low risk for breast cancer, age-standardized breast cancer incidence and mortality rates have risen rapidly in China during the past 2 to 3 decades, making it the leading cancer among women.Currently, there are few national monitoring data on risk factors among the Chinese general population. High-quality epidemiologic studies of breast cancer risk factors in China have predominately been conducted in regions with greater development and higher economic status, and the results may thus not represent the entire country. In this 10-year (1999–2008) nationwide multicenter retrospective clinical epidemiologic study of female breast cancer in China, we examined the distribution of risk factors among Chinese women with breast cancer. Because exposure to most risk factors in a population is influenced by local culture, policy, and economic status, disparities in distributions among cancer cases may indicate possible differences in distribution in their source population. In addition, we estimated associations between selected risk factors and breast cancer by retrospectively reviewing representative national data on cases and comparing those findings with information on controls reported in previous studies. We hope our results provide clues for further study of the Chinese population and contribute to the development of appropriate prevention strategies in China.We conducted a 10-year (1999–2008) nationwide multicenter retrospective clinical epidemiology study of female breast cancer in China. The study protocols were approved by the Institutional Review Board of the Cancer Foundation of China.7 In brief, to ensure that our sample was geographically representative of China, 1 tertiary hospital was selected in each of 7 geographic regions of China, ie, north, northeast, northwest, central, east, south, and southwest. These regions encompass most of the country and represent different levels of breast cancer burden. We selected leading regional public cancer hospitals and referral centers that provide pathologic diagnosis, surgery, radiotherapy, medical oncology, and routine follow-up care for women with breast cancer. Patients visiting the selected hospitals were from different parts of the region. Another criterion for sampling was that the patients of a selected hospital must reside throughout the respective study region.Hospital selection and case sampling methods have been previously described.The selected hospitals provided the medical records of patients with breast cancer diagnosed during 1999–2008. One month was randomly selected for each year for each hospital, and all pathologically diagnosed inpatient cases for that month were reviewed. January and February were excluded from the random selection to decrease any confounding effects of the Chinese New Year holiday (the longest holiday period of the year). If the number of qualifying cases was less than 50 in a selected month, the cases from the 1 month immediately before and the 1 month immediately after the selected month would be included until the total number in that year reached 50. If the number of inpatients in the selected month exceeded 50, all cases were reviewed.7A designed case report form was used to collect information on the enrolled patients, including general information, demographic characteristics, risk factors for breast cancer, results of clinical breast examination, diagnostic imaging, treatment process, and pathologic characteristics. All information was collected during a review of medical charts. The risk factors recorded were age at menarche, age at menopause, age at first delivery, number of live births, breastfeeding history, family history of breast cancer , body mass index (BMI), use of oral contraceptives, and histories of regular smoking and regular alcohol drinking. The details of the data collection process have been described previously.To assess the effects of selected risk factors on breast cancer among Chinese women, nationally representative population data were selected from national behavioral survey reports and the published literature and used as control data. Frequencies of behavior-related factors, including BMI, smoking, and alcohol drinking, were collected from Chinese national surveys of women in the general population. Due to the lack of national survey data on reproductive factors in the Chinese general population, we attempted to pool the reported exposure frequencies of selected factors among women without breast cancer from studies of risk factors for breast cancer in Chinese women. To ensure the representativeness of pooled controls, we used the following inclusion criteria. First, the recruitment periods of published studies had to coincide with that of the present study. Second, to ensure that the included controls would encompass the above-mentioned 7 geographic regions of China, studies conducted in the provinces and regions of the present study were preferentially selected. If there were no high-quality studies from 1 of the above provinces, data from studies conducted in neighboring provinces were collected. Finally, if multiple papers reported the same or overlapping data, the largest or most recent publication was selected.We searched for studies published between 1995 and 2011 on the relationship between selected risk factors and breast cancer among Chinese women, using combinations of the following keywords: “breast cancer,” “risk factors,” and “Chinese women.” The databases searched were PubMed, Ovid, the Chinese Biomedical Literature Analysis and Retrieval System, and the Chinese medical databases, namely, National Knowledge Infrastructure and WanFang. All the subjects of the selected studies had to be recruited in 1995 or later. All included studies reported frequencies of cases and controls for the selected risk factors.t test and χ2 test were used to compare the distributions of selected risk factors for breast cancer, stratified by regional economic development level .9 We also compared women by menopausal status. After stratification by menopausal status, the trend χ2 test was used to identify trends in selected risk factors among women born in 4 birth periods: before 1950, 1950–1959, 1960–1969, and 1970 or later. To estimate the effect of selected risk factors for breast cancer among Chinese women, crude odds ratios (ORs) and their 95% CIs were calculated based on the frequencies of cases included in the retrospective studies and controls reported in included articles.The P values were 2-tailed. SPSS 17.0 was used to perform χ2 tests, t tests, and trend χ2 tests and to calculate crude ORs and 95% CIs.All 7 Because the rates of missing data for some risk factors  were greater than 50%, we did not include those factors in the final analysis. For the included risk factors, the distributions for age at diagnosis and menopausal status were comparable between women with and without missing data.A total of 4211 cases were identified during the 10-year period 1999–2008. Mean (SD) age at diagnosis was 48.7 (10.5) years.P < 0.05). Age at menopause, history of breastfeeding, and family history of breast cancer did not vary significantly by regional development level.The 7 regions were divided into less developed  and more developed  areas Table . There wP < 0.05; Table Among the breast cancer cases, 2649 were premenopausal (average [SD] age 43.1 [7.2] years) and 1562 were postmenopausal (average age 58.2 [7.9] years). As compared with premenopausal cases, postmenopausal cases had more live births and were more likely to be overweight and to have breastfed . The distributions of smoking, alcohol drinking, and family history of breast cancer did not vary significantly among by birth period. Among postmenopausal cases, the numbers of cases in the birth periods 1960–1969 and post-1970 were too small, so we combined all women born after 1950 into 1 subgroup for analysis. As compared with cases born in 1950 or earlier, cases born after 1950 had lower proportions of overweight and late menopause but higher proportions of nulliparity and family history of breast cancer (P < 0.001).Among premenopausal cases, the proportion of overweight women declined from the pre-1950 to the post-1970 birth period , 20 qualified studies were included, and covered the 7 regions of China included in the present study14–33 . However, there was no significant risk associated with nulliparity, absence of a history of breastfeeding, or history of smoking and drinking Table .This is the first nationally representative epidemiologic study of breast cancer risk factors in China. We found that the distribution of risk factors among patients differed by region, birth period, and menopausal status. These disparities could be due to differences in economic status and changing domestic policies.34–36 In the current analysis, we found that cases from more developed areas had fewer average births and larger proportions of nulliparous women and women who had not breastfed. Comparison with the control data in the present study showed that, among cases in more developed regions, the proportions of nulliparous women and women who had not breastfed were 2.41 and 3.55 times, respectively, those of the general population . These findings indicate that the disparities in the distributions of childbirth and breastfeeding among cases may be due to the characteristics of the general population.Studies in Western countries revealed that socioeconomic inequality may be associated with the distributions of some breast cancer risk factors, including reproductive control and habits such as smoking and drinking.37 The 2001 National Family Planning and Reproductive Health Survey reported that the total fertility rate was 1.3 in urban areas and slightly less than 2.0 in rural areas.37One explanation for our findings is that, as in many other low-income countries with increasing economic prosperity, urbanization and modernization in more developed areas of China lead local women to adopt different lifestyles, including reproductive control. Another possible explanatory factor is that the 1-child policy in China is much more strictly enforced for families in more developed areas, which have largely urban populations.According to a current report on the Chinese Cancer Registry, the incidences of breast cancer in economically developed provinces were higher than those in developing areas. Thus, it is necessary to assess the population attributable risks of these reproductive factors for Chinese women, as this may help in understanding regional disparities in breast cancer incidence and devising proper prevention strategies in China.During the past half-century, China has experienced dramatic social changes and rapid economic development. We therefore explored birth period trends in breast cancer risk factors. Because risk factors differ between pre- and postmenopausal women, we conducted the analysis of birth period after stratifying by menopausal status. The analysis identified several generational trends in breast cancer risk factors.38,39 Thus, their effects on breast cancer risk among Chinese women merit future study.First, number of live births decreased significantly with time both in premenopausal and postmenopausal cases. This is probably due in large part to the 1-child policy that began in the 1970s. Second, the rate of breastfeeding declined among premenopausal cases, which may be the result of reform and liberalization policies that China adopted in the 1980s. Chinese women increasingly work outside the home and exert more reproductive control. The increase in breast cancer incidence during the past 2 decades indicates that the population attributable risks of these factors should be assessed, especially among younger women. Moreover, in conjunction with the decrease in child births, Chinese women might increasingly rely on oral contraceptives and induced abortions, both of which are suspected risk factors for breast cancer.40 This may be due to improvements in childhood nutritional status during that period. Our findings appear to be inconsistent with the increase in breast cancer incidence in China. However, among East Asian women breast cancer was more likely to be diagnosed before menopause, and about two-thirds of the cases in our study were premenopausal, so the contribution of late menopause to overall breast cancer incidence in China may be small.2Among postmenopausal cases, we found age at menopause was earlier among women born after 1950 than among those born in 1950 or earlier. Earlier age at menopause may be related to the decline in average age at menarche among Chinese females. A previous study revealed that age at menarche among Chinese females declined to 14.6 years in 1957–1961 birth cohorts from 15.7 years in 1927–1940 birth cohorts.12 This could be due to the decline in average age at diagnosis from the pre-1950 subgroup to the post-1970 subgroup in this cross-sectional study. Studies have shown that serum lipid and low-density lipoprotein levels, which are positively associated with BMI, increase with age among women.41We found that BMI decreased with time both in premenopausal and postmenopausal cases, despite the fact that BMI has increased among the general population in recent decades.42–44 and American white women45 in large-scale population-based cohort studies . We found no associations between other selected factors and breast cancer among Chinese women. However, significant associations were reported among both Japanese women and American white women. However, the strength of these associations was low, as the relative risks ranged between 0.8 and 2.0.43,45–49In the present study, BMI, age at menopause, and family history of breast cancer were associated with breast cancer risk among Chinese women. Similar findings were reported for Japanese women2 Such exposures could be influenced by traditional culture and the extent of modernization. Genetic background may also explain disparities in exposures. Studies showed that women of Asian ancestry had lower proportions of mutation alleles of BRCA1 and DNA repair genes, which are associated with breast cancer susceptibility.2,50 Our results indicate that, among Chinese women, BMI, age at menopause, and family history of breast cancer should be given priority as environmental factors in the assessment of breast cancer risk. These factors differ from those used in the Gail model, which was developed for use among white women.51Our results suggest that the magnitude of the effects of risk factors may contribute slightly to differences in breast cancer incidence among countries. It was reported that disparities in exposure to risk factors may partly explain variation in breast cancer incidence among countries.t = 1.44, P > 0.05; alcohol drinking: t = 1.55, P > 0.05). Similar results were observed for menopausal status . In addition, because exposures to the 2 factors were extremely low among Chinese women,10,11 their distributions are not likely to substantially differ between cases with and without missing information. Thus, the impact of missing data on the estimated effects of smoking and alcohol drinking is expected to be limited.About 40% of subjects had missing data on smoking and alcohol drinking. There was no significant difference in age between cases with and without information on either smoking or alcohol drinking . Thus, differences in age distribution are not likely to influence the estimated effect of family history of breast cancer.We verified the ages of controls, as age is the most important confounder. In present study, the age range of cases was 21 to 85 years, and average age was 48.7 years. For cultural reasons, the exposure of Chinese women to smoking and alcohol drinking has been very low.2 = 11.50, P > 0.05); thus, our results are likely to be reliable.With regard to age at menopause, the age range of controls was 41 to 60 years; 66% of cases in the retrospective study were in this age group. Due to the potential confounding effects of age, we recruited patients aged 41 to 60 years and calculated ORs. This group of patients was evenly distributed among the 7 regions . Use of a pooled odds ratio was thus deemed acceptable.As for BMI, the proportion of controls younger than 45 years was about 1.4 times that of cases in our retrospective study. Because overweight is more likely among perimenopausal women, we conducted an analysis stratified by age. According to data from the national survey,38 age range and average age were similar to that of the present patients, so the impact of age on the associations of childbirth and breastfeeding history with breast cancer is likely to be slight.With regard to number of live births and breastfeeding, most previous studies were case-control studies of breast cancer. In previous research, cases were consecutively recruited from hospitals or randomly selected from communities, so the age distribution of those studies might be similar to that of the cases in the present study. Because most earlier studies matched controls and original cases by age, the age distribution of those studies probably does not vary greatly from that of the cases in the present study. As shown in Table This study has 2 limitations. First, it was hospital-based rather than community-based, so the cases may not be entirely representative of Chinese women with breast cancer. However, population-based disease surveillance systems are deficient in China, as the population is large and spread over a vast area. There is as yet no large-scale, geographically representative study of breast cancer risk factors among the general population. Second, we were unable to control for all potential confounders in the association of risk factors with breast cancer.As compared with cases from less developed regions, those from more developed regions were significantly more likely to be nulliparous, had fewer childbirths, and were less likely to have breastfed. These reproductive factors became more common in later birth periods. Because breast cancer incidence has recently increased and is higher in more developed regions, it will be necessary to evaluate the population attributable risks of these factors among Chinese women, especially in more developed areas and among young women. Our findings indicate that primary prevention strategies, including health education and policy modification, might prove useful. In addition, overweight, late menopause, and a family history of breast cancer were associated with elevated risk of breast cancer among Chinese women. Future studies should carefully evaluate the effects of BMI, age at menopause, and family history of breast cancer as predictive factors in breast cancer risk assessment for Chinese women.


Pregnancy may reduce breast cancer risk through induction of persistent changes of the mammary gland that make the breast less susceptible to carcinogenic factors. It is not known to what extent the effects of parity are independent of other breast cancer risk factors.In a Norwegian cohort of 58 191 women (2890 breast cancers), we assessed whether the effects of parity on postmenopausal breast cancer risk may be modified by menstrual and anthropometric factors. We calculated attributable proportions due to interaction as a measure of synergism.Parity, height, body mass index (BMI), age at menarche and menopause were all associated with breast cancer risk in the expected directions. For BMI, follow-up was stratified into two age groups because of non-proportional hazards. We found that nulliparity and overweight may amplify each other's effect on breast cancer risk among women after 70 years of age . There was some indication that parity and age at menopause may antagonise each other's effect. Effects of parity were largely unaffected by age at menarche and height.Nulliparity and overweight may have a synergistic effect on breast cancer risk in elderly women. If confirmed by others, the findings may help disentangle the interplay of different causes of breast cancer. The protective effect of pregnancies against breast cancer was first described as early as 1926 , and wasIf the breast undergoes permanent changes during pregnancy, it is possible that the mammary gland's susceptibility to other important exposures could also be altered by pregnancy-related factors  who were born between 1886 and 1928. They were invited to a breast cancer screening organised by the Norwegian Cancer Society between 1956 and 1959. The study has been described in detail elsewhere . Among 84 981 invited women who were alive at the census in 1960, 63 041 (74.2%) women had participated at the screening. Among 50 061 (79.4%) of the participating women, anthropometric information was also available.We started breast cancer follow-up from the age of 55 years. After exclusion of women who died or emigrated before 55 years of age, 62 108 women were eligible for follow-up. Participants were followed from 1 January 1961, or from the age of 55 years, and in analyses that included anthropometric measures, women were followed from the year after the height and weight measurements, or from 55 years of age. End of follow-up was set to the date of breast cancer diagnosis, emigration, death, or to the end of follow-up on 31 December 2008, whichever occurred first.Among eligible women, we excluded 759 women with a previous breast cancer diagnosis and 3158 women with missing information on the main study factors. A total of 58 191 women were therefore followed up for breast cancer occurrence. Among these women, 20 748 were postmenopausal at the time of the interview and had reported age at menopause. A total of 451 women who reported a surgical menopause  were excluded from the analyses related to age at menopause. Thus, the analyses of age at menopause were restricted to 20 297 women with a natural menopause. Information on anthropometric factors was not available for all participants, and among 49 624 eligible women with height and weight measurements, we similarly excluded women with prevalent breast cancer, women with missing information on parity or potentially confounding factors, and women with unreliable height measurements . Analyses that included anthropometric measures were therefore based on follow-up of 44 952 women. The number of exclusions and the number of women included in the analyses are summarised in −2. When evaluating synergism, menstrual and anthropometric exposures were dichotomised at the median value . Among parous women, number of full-term pregnancies was categorised as 1, 2, 3, ⩾4 and age at first full-term pregnancy as <20, 20–24, 25–29, 30–34, ⩾35 years.We categorised parity as nulliparous (no full-term pregnancy) or parous (one or more full-term pregnancies). In analyses of trend, age at menarche was categorised as ⩽13, 14, 15, ⩾16 years, age at natural menopause as <45, 45–49, 50–54, ⩾55 years, height as <155, 155–159, 160–164, 165–169, ⩾170 cm, and BMI as <25, 25–29, ⩾30 kg mP-values for trend across exposure categories were calculated by treating the categories as a continuous variable. We assessed heterogeneity of the HRs across strata of parity by likelihood ratio tests by comparing models with and without product terms between parity and each exposure variable (where exposure categories were treated as a continuous variable).We used Cox proportional hazards models to compute hazard ratios (HRs) with 95% confidence intervals (CIs). The associations of menstrual and anthropometric factors with breast cancer risk were assessed both overall and within the two strata of parity. For each exposure, the category with the largest number of person years was chosen as the reference category. The Statistical interaction in multiplicative models has no direct causal interpretation, whereas departure from additivity of risks may imply causal interaction , marital status (ever or never), county, urban or rural place of residence, and the participant's own or her husband's occupation . Age at menarche was considered a potentially confounding factor in analyses of age at natural menopause, height, and BMI, and these analyses were therefore also adjusted for age at menarche. In a separate analysis restricted to parous women, we controlled for potential confounding by number of full-term pregnancies and age at first full-term pregnancy, in the trend analyses of age at menarche, age at natural menopause, height and BMI.Proportionality between hazards was checked by comparing log minus log plots of survival and by performing tests based on Schoenfeld residuals. Assumptions were met for all exposures except BMI, for which the log minus log survival curves were non-parallel from 70 years and onwards. Others have also found that the positive association of BMI among postmenopausal women may be more pronounced among older women .The study was approved by the regional committee for medical research ethics and by the Norwegian Data Inspectorate.A total of 58 191 women without breast cancer at baseline were followed for 1 400 436 person years with a mean follow-up of 24.1 years . During follow-up, 2890 women were diagnosed with invasive breast cancer. Mean age at diagnosis was 72.9 years (s.d. 9.4), and overall, 48 945 (84.1%) women died during follow-up. Characteristics of the participants at baseline are shown in The HRs for menstrual and anthropometric risk factors stratified by parity are presented in Among both nulliparous and parous women, breast cancer risk increased with decreasing age at menarche. Breast cancer risk increased with increasing height among parous women, whereas the trend was less clear among nulliparous women.For age at menopause, there was a strong positive association with breast cancer risk among parous women, but no clear trend among nulliparous women.Using the entire follow-up period, there was a positive association of BMI with breast cancer risk in both strata of parity (results not shown). After stratification by age, BMI was not associated with breast cancer risk in the age group 55–69 years. However, for women 70 years and older, there was a clear positive association of BMI with breast cancer risk.The HRs for age at menarche, height and BMI were homogenous across the two strata of parity, whereas the trend of increasing risk with increasing age at menopause was more pronounced among parous women.The assessments of synergism between parity and age at menarche, age at natural menopause, height, and BMI are presented in Adjustments for potentially confounding factors had no material influence on the results. Among parous women, controlling for number of full-term pregnancies and age at first full-term pregnancy did not influence the associations of age at menarche, age at natural menopause, height, or BMI with breast cancer risk (results not shown).In this prospective cohort study, we found that overweight may enhance the effect of nulliparity on breast cancer risk in elderly women. The results suggest that one out of five breast cancer cases among nulliparous and overweight women may be attributed to a synergistic effect of these factors.Although there has been extensive research on the association of menstrual and anthropometric factors on breast cancer risk , most stThe interaction that we observed may advance our understanding of how different risk factors can act together. If confirmed by others, the finding might also be relevant for preventive strategies , as our A possible synergism between nulliparity and obesity suggests that there might be pathways where both factors are necessary for the development of breast cancer , all of which could have potentially confounded the results. However, given the birth year of the youngest women, the use of oral contraceptives in the cohort is likely to be negligible, and hormone replacement therapy may be relevant only for a small proportion of the youngest participants . AlthougIn the evaluation of synergism, we carried out five tests of interactions. Although these tests were dependant, caution is needed when interpreting our findings. In general, considerably higher statistical power is required to detect interactions than to detect single exposure–disease associations. Our study included a large number of elderly nulliparous women and an exceptionally long follow-up. Nevertheless, the statistical power to detect interactions was limited.In conclusion, our findings suggest a possible synergistic effect of nulliparity and BMI in elderly women on breast cancer risk. If confirmed by others, this finding may advance our understanding of breast cancer, and might eventually lead to better preventive strategies.


Incidence of breast cancer is increasing around the world and it is still the leading cause of cancer mortality in low- and middle-income countries. We utilized Swedish nationwide registers to study breast cancer incidence and case fatality to disentangle the effect of socioeconomic position (SEP) and immigration from the trends in native Swedes.A nation-wide cohort of women in Sweden was followed between 1961 and 2007 and incidence rate ratio (IRR) and hazard ratio (HR) with 95% confidence intervals (CIs) were estimated using Poisson and Cox proportional regression models, respectively.Incidence continued to increase; however, it remained lower among immigrants  but not among immigrants' daughters  compared to native Swedes. Case fatality decreased over the last decades and was similar in native Swedes and immigrants. However, case fatality was significantly 14% higher if cancer was diagnosed after age 50 and 20% higher if cancer was diagnosed in the most recent years among immigrants compared with native Swedes. Women with the highest SEP had significantly 20% to 30% higher incidence but had 30% to 40% lower case fatality compared with women with the lowest SEP irrespective of country of birth. Age at immigration and duration of residence significantly modified the incidence and case fatality.Disparities found in case fatality among immigrants by age, duration of residence, age at immigration and country of birth emphasize the importance of targeting interventions on women that are not likely to attend screenings or are not likely to adhere to the therapy suggested by physicians. The lower risk of breast cancer among immigrant women calls for more knowledge about how the lifestyle factors in these women differ from those with high risk, so that preventative measures may be implemented. Breast cancer is the most common tumor among women worldwide. However, there is large geographical variation in its incidence; with the exception for Japan, the incidence ranks highest in high-income countries . More thDespite the substantial improvement in breast cancer prognosis and survival, it is still the leading cause of cancer mortality in low- and middle-income countries and more than half of the breast cancer mortality is reported from low- and middle-income countries .Migrant studies are classical tools for exploring the importance of environmental, social and genetic factors in the etiology of diseases and has been particularly important for disentangling the etiology of cancer . MigrantIn this large, nationwide cohort study, we utilized Sweden's established system of demographic and medical population-based registers to explore the impact of country of birth and social position on breast cancer incidence and case fatality among large and growing immigrant populations and their daughters in Sweden and among native Swedes.The cohort was built through linkages between Swedish national registers using personal identity numbers (PIN). PIN is a 10-digit number which is maintained by the National Tax Board office for all individuals who have resided longer than one year in Sweden since 1947 . The linFor the purpose of this study, we used: 1) The Swedish Cancer Registry, which was founded in 1958 and covers the whole population of Sweden. It is compulsory for every health care provider to report newly detected cancer cases diagnosed at clinical, pathological or other laboratory examinations, as well as cases diagnosed at autopsy to the registry. The overall completeness of the registry is high and close to 100% . We obtaWe classified foreign-born individuals into six groups by the continents. We further subdivided continents into world regions, as defined by the United Nations Population Division. We report pooled data for countries and regions when we did not have enough power. For detailed information about the final classification, please refer to Tables Highest attained level of education was used as a surrogate indicator for socio-economic position and categorized into four levels .We stratified our analysis by age at exit (< 50 and 50+ years), calendar period of follow-up with respect to incidence rate  and calendar period of diagnosis with respect to case fatality  and geographical region of diagnosis  where each of the six Swedish national Oncologic Centrum is placed. In an attempt to study the possible influence of lifestyle and environmental exposures, we stratified the immigrants by age at immigration  and duration of residence in Sweden .There were 4,749,611 women registered in the Swedish Population Register who were born after 1 January 1930 and lived in Sweden at any time during 1 January 1961 and 31 December 2007. We excluded women with an unknown birthplace (0.03%), with a history of breast cancer before the start date of the study (0.01%), for whom we found a death date (0.01%) or an emigration date (2.5%) before entry into the cohort .The final cohort was followed from 1 January 1961, date of birth or first immigration date for immigrants, whichever occurred last, until they exited from the cohort, which was the date of diagnosis of breast cancer , first emigration date, death or end of follow-up (31 December 2007), whichever came first.We calculated the incidence rate ratios (IRRs) with 95% confidence intervals (CIs) using Poisson regression models. All analyses were adjusted for age at follow-up  and calendar period of follow-up  women who died within one month of diagnosis.Breast cancer patients were followed from date of diagnosis until date of death, first emigration date, or end of follow-up (31 December 2007), whichever came first. In breast cancer-specific case fatality analysis, the patient's follow-up was censored if either death for other reasons or emigration took place. Hazard ratios (HRs) with 95% confidence intervals (CIs) for breast cancer patients were calculated using stratified Cox proportional hazards regression model. Point estimates and 95% CIs were produced using the maximum partial likelihood for the effect estimates. The validity of the proportional hazards assumption was evaluated using a martingale residual based graphical and numerical approach.Our cohort comprised 4,553,484 women, of which 760,214 (16.7%) were immigrants, 495,917 (10.9%) were immigrants' daughters and 3,297,353 (72.4%) were native Swedish women. We observed 76,152 cases of breast cancer during 133 million person-years of follow-up in our cohort. Immigrants  and native Swedish women  had a similar age at diagnosis. Age at diagnosis among immigrants' daughters was on average 48.6 (SD ± 9.4). Mean age at immigration was 22.6 (SD ± 13.4) years ranking from the highest among immigrants from Bosnia  and lowest among immigrants from the Republic of Korea . Mean duration of residence was 15.9 (SD ± 4.8) years, ranking from the highest among immigrants from Austria  and the lowest among immigrants from China .Overall, immigrants had lower incidence  of breast cancer while their daughters had a similar incidence  compared with native Swedes Tables .Except for Northern America and Oceania, immigrants born in all other continents were at significantly lower incidence of breast cancer compared to native Swedes, with women born in Africa having the lowest incidence  followed by immigrants from Latin America  Table . Within As shown in Table Irrespective of background, women with the highest educational level had significantly higher incidence of breast cancer compared to those with lower education Table . The incThe incidence rate of breast cancer increased to a maximum at age 65 years and then dropped among both immigrants and Sweden-born women. The differences in rates between immigrants and Sweden-born women increased by increasing age at diagnosis Figure .Age-specific incidence rates stratified by age at breast cancer diagnosis before and after age 50 are presented in Figure To find whether calendar period of follow-up has any effect on the incidence of breast cancer, we divided our results into four categories of calendar period follow-up. The incidence increased slightly with increasing year of follow-up in that incidence was 20% higher during most recent years; 2001 to 2007, compared with incidence during 1961 to 1985. When we stratified results by place of residence at diagnosis, we found those who were residing in Stockholm at diagnosis had a higher incidence of breast cancer compared with those from other areas in Sweden. However, results were statistically significant only among native Swedes Table .Age at immigration and duration of residence significantly altered the incidence of breast cancer Table . When stThe final cohort included 75,893 women with breast cancer, of which 8,818 (11.6%) were immigrants, 2,800 (3.7%) were immigrant's daughters and 64,275 (84.7%) were native Swedes.We observed a total of 14,024 deaths due to breast cancer among 75,893 women with breast cancer; 1,578 death in immigrants, 446 in immigrants' daughters and 12,000 in native women. Women with more education had a better survival compared to women with less education (data not shown in table), irrespective of country of birth. Women with the lowest educational level had around 30% statistically, significantly higher risk of dying from breast cancer compared with women with the highest level of education (data not shown in table).We found improving survival over calendar years among native Swedes and immigrants' daughters Table . HoweverWe further observed an increasing risk of dying due to breast cancer by decreasing age at diagnosis, irrespective of birth country. The risk was 25% higher if breast cancer was diagnosed at an age younger than 50  than that if cancer was diagnosed at age 50 or older (data not shown in table). In addition, immigrants whose cancer was diagnosed after age 50 had a significantly higher risk  of dying from breast cancer, while those with cancer diagnosed before age 50 had a lower risk  compared with natives (Table Compared with Stockholm, all regions had similar case fatality except for Umeå, where the case fatality was higher Table .When we stratified breast cancer case fatality by country of birth, we found a similar case fatality for most immigrants compared with native Swedes Table . The risWhen stratifying the results by age at immigration we found an overall similar HR among immigrants who immigrated at ages younger than 35 compared with those who immigrated at older ages Table . HoweverIn this large, nation-wide cohort study among women with diagnosis of invasive neoplasm of the breast in Sweden, we found that women with the most education, as an indicator of socio-economic position, had statistically, significantly 20% to 30% higher incidence of breast cancer, but 30% to 40% better breast cancer survival compared with women with the lowest educational level irrespective of country of birth. Furthermore, our study showed increasing breast cancer incidence over the last decades in native Swedes and immigrants, albeit not in immigrants' daughters. We found immigrant women overall had a lower incidence of breast cancer than native Swedes with the lowest risk, almost half that of native Swedes, observed among women born in China, South Korea, Thailand, Viet Nam, Turkey and ChileThere are a number of known risk factors for breast cancer; high socioeconomic status ,16, radiOur finding of younger age at diagnosis among immigrants' daughters could simply be due to the younger age of the population at risk in this group.per se nor considered age at immigration and duration of residence [Our finding of the convergence of incidence towards the Swedish incidence level was observed among immigrants' daughters, particularly among those whose parents were from low-risk areas, such as Asia and Latin America. This is in agreement with studies on immigrants from Asia and Latin America in the US and immigrants from Ireland in the UK ,25,26. Aesidence -34. Someesidence . Our finesidence ,35,36.In this study, we found that women with the most education had statistically significantly 30% to 40% better breast cancer survival compared with women with the lowest educational level, irrespective of country of birth. Furthermore, our study showed decreasing breast cancer case fatality over the last decades in native Swedes and immigrants but not in immigrants' daughters. We found disparities in breast cancer case fatality by age at diagnosis and calendar period of diagnosis. Immigrants whose cancer was diagnosed after age 50 or in 2001 to 2007 had higher breast cancer case fatality compared with corresponding native Swedes.Our findings of increasing incidence -39 and iThe disparities we found between immigrants and native Swedes by age and calendar period of diagnosis are novel. These disparities might be due to lack of absorbance in the screening program among older and recently arrived immigrants. Establishment of mammography screening in Sweden has progressed from a pilot study in 1974 through clinical trials to service screening ,46. ScreInequalities in case fatality within different education groups among both immigrants and Swedes found in this study is in line with the cumulative evidence from different epidemiological studies, including studies from Sweden with equal access to a uniform health care system, indicating higher breast cancer mortality among socio-economically disadvantaged women -56.It has already been shown that breast cancer mortality is lower in Sweden than in Denmark . In contDifferent pathological stage at diagnosis and biological markers, including estrogen, progesterone and HER2 receptor status, have been indicated as probable factors responsible for disparities found among different ethnic and socio-economic groups in US and Sweden -68. TherThe major strength of our study is the population-based design with a long follow-up of all native Swedes and foreign-born women during the study period. Because information on exposure was collected before the diagnosis of cancer, misclassification with regards to exposure is unlikely and, if any, is most likely independent of breast cancer and thus, non-differential.In conclusion, our finding of convergence of breast cancer incidence towards the Swedish level among immigrants' daughters plus effect-modification by age at immigration and duration of residence among immigrants indicates the importance of pre-migration factors, and highlights the importance of early-life exposures. Disparities found in cases of fatality among immigrants when stratifying results by age and duration of residence, age at immigration and country of birth emphasize the importance of designing and implementing active interventions in order to reduce incidence and, particularly, fatality in susceptible sub-groups of the female population. In addition, the lower risk of breast cancer among immigrant women outlines the importance of understanding how lifestyle factors in these women differ from those with high risk, so that preventative measures may be implemented.CI: confidence interval; HR: hazard ratio; ICD-7: International Classification of Disease, Seventh Edition; IRR: incidence rate ratio; LISA: Database for Health Insurance and Labor Market studies; PIN: personal identity number; SEP: socioeconomic position.The authors declare that they have no competing interests.TM and OB had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. OB and TM conceived and designed the study. TM acquired the data. Analysis and interpretation of data were undertaken by OB, PH, AE and TM. OB drafted the manuscript. Critical revision of the manuscript for important intellectual content was conducted by OB, PH, AE and TM. Statistical analysis was conducted by OB. TM obtained funding. All authors read and approved the final manuscript.


We investigated associations of known breast cancer risk factors with breast density, a well-established and very strong predictor of breast cancer risk.This nested case–control study included breast cancer-free women, 265 with high and 860 with low breast density. Women were required to be 40–80 years old and should have a body mass index (BMI) <35 at the time of the index mammogram. Information on covariates was obtained from annual questionnaires.P for trend<0.001), and parity (P for trend=0.02) and positively associated with alcohol consumption . Alcohol consumption was positively associated with density, and the association was stronger in women with a family history of breast cancer (P<0.001) and in women with hormone replacement therapy (HRT) history (P<0.001). Parity was inversely associated with density in all subsets, except premenopausal women and women without a family history. The association of parity with density was stronger in women with HRT history (P<0.001).In the overall analysis, breast density was inversely associated with BMI at mammogram (The associations of alcohol and parity with breast density appear to be in reverse direction, but stronger in women with a family history of breast cancer and women who ever used HRT. Mammographic breast density is a strong predictor of breast cancer with odds ratios (ORs) varying from 1.8 to 6.0 . Light .Several studies have evaluated predictors of breast density in women who have not been diagnosed with breast cancer. Inverse associations with breast density were reported for older age, parity, postmenopausal status, and high body mass index (BMI) . The FMMP was a voluntary community-based medical surveillance program for residents living within five miles of the perimeter of the former uranium processing plant  in Fernald, Ohio for at least a 2-year interval between 1952 and 1984 (Detailed description of this cohort has been published elsewhere (−2) was calculated from participants' height and weight measured by FMMP staff at the time of each medical exam.Extensive disease risk factor information was collected by the FMMP using the initial and the yearly questionnaires. The data on the reproductive history were collected using the baseline FMMP reproductive history questionnaire, the annual reproductive history updates, and the menstrual history questionnaire administered in 2007–2008. History of HRT was established from codes used by the FMMP to characterise the medication taken by the participants throughout the follow-up years that were reported at each exam and on the questionnaire. Family history of breast cancer was available from the questionnaire and physician's history forms. From those data, a total number of relatives with breast cancer, number of first-degree relatives with breast cancer, and the maternal history of breast cancer were extracted for each participant. Each questionnaire asked about the number of drinks per week of different alcoholic beverages. Smoking data were collected at the time of the first exam and annually thereafter using a set of standardised questions from the American Thoracic Society. BMI  Medical Center, although some were done at the satellite offices. All the films (both screening and diagnostic) were sent to UC and were read by the same group of Board-certified radiologists (University Radiology Associates) throughout the entire program. Six of those expert radiologists read 70% of all FMMP mammograms over the years. If the woman had a mammogram at another location, she was asked to sign a release for obtaining that mammogram report; these mammograms represented only 2.2% of the mammograms in the database and were not used in this study.Many FMMP mammograms were performed before 1995 and thus the BI-RADS classification was not included in those mammography reports. However, the radiologist provided a text description of the degree and localisation of breast density on each film. Mammographic reports kept in the FMMP medical charts/database were assigned special FMMP codes from a set of over 230 standardised codes representing specific descriptors in the written mammogram interpretation by the physician, including qualitative breast density assessment. For example, the code 704 (breasts high in density/markedly dense) was assigned to the following description ‘The breast tissue is markedly dense…’. All narrative reports and the corresponding codes were entered into a comprehensive SAS database.κ)=0.73), but agreement between radiologist's reading and density assignment from digitised images was fair (κ=0.27). When analysis was restricted to extreme density categories (low and high), the agreement between radiologists was perfect (κ=0.81), whereas agreement between radiologist's reading and density assignment from digitised images did not improve (κ=0.24) (κ statistic 0.81 vs 0.24).In designing the current study, there were two potential approaches for characterisation of breast density. The level of breast density for each mammogram could be assigned using the radiologist's report , resulting in a categorical assessment of density. Alternately, breast density could be evaluated quantitatively using the computer algorithms applied to the digitised images of the mammograms. In order to increase the degree of certainty about the breast density phenotype, a preliminary study of breast density assessment was conducted in the summer of 2007. The details of this study have been described elsewhere . As the cohort is >99% Caucasian, participants of other races were not included. A woman was not eligible for the study if she had a history of breast cancer, genetic syndromes/disorders with underdevelopment of breast/small stature , a history of mammoplasty or was transsexual.any of their mammograms in the FMMP database (FMMP code 704) and also had at least one of the 14 additional codes. These additional codes represented a set of codes from the mammogram coding system that were assigned to high-density mammograms by the two radiologists  and therefore indicated a more precise assignment of high density. High breast density was equivalent to BI-RADS category IV (extremely dense). Women who had no codes that would indicate high or intermediate density on any of their mammograms in the FMMP database were included in the low breast density group. In addition, the low-density mammogram report had to contain one of the descriptors indicative of a ‘normal’ mammogram . Low density was equivalent to BI-RADS category I (fatty breasts).We used a case–control sampling frame to identify women with dense breasts (high-density phenotype) and women who never had high or moderate breast density on any of their mammograms in FMMP database, that is, have sustained low density on all mammograms throughout the cohort follow-up (low-density phenotype). High and low breast densities were defined using the FMMP mammogram coding system and these code criteria were applied to all of the mammograms of the eligible women in the database in order to establish their life-long density history rather than using a single mammogram. Women with high breast density had high density on An index (reference) mammogram for a woman was selected from all of her mammograms if she met high- or low-density definition. The index mammogram was required to have FMMP codes used to define the density phenotype, be a screening (93% of the mammograms) or diagnostic (7% of the mammograms) study, and be a part of FMMP medical examinations. The woman was required to be 40–80 years old at the time of the index mammogram and to have a BMI<35 at the time of the mammogram, to exclude a few morbidly obese women, as BMI⩾35 has been consistently reported to be associated with lower density .Statistical analyses were done using SAS software . The relationship between the potential predictors and the breast density phenotype was examined using logistic regression. Variables in the analysis included age and BMI at index mammogram date, reproductive history, smoking, alcohol, HRT, and a family history of breast cancer. For variables cumulative in nature , the information was extracted from all the questionnaires completed before the index mammogram (reference) date. Information on reproductive history and family history of breast cancer was obtained from the last completed questionnaire available from before/on the reference mammogram date. Menopausal status at the time of the index mammogram was determined from the annual reproductive history updates and the menstrual history questionnaire completed before the date of the index mammogram. Age was modeled as a categorical rather than continuous variable, as the relationship between age and breast density is not linear and changes with menopausal transition.vs never). BMI at mammogram was categorised as <25, 25–29, ⩾30. Age was modeled as categorical in all the analysis , as this approach provided a better model fit compared to continuous age.Parity was defined as the number of pregnancies that resulted in single, multiple birth, or stillbirth with ⩾34 weeks of gestation. In an adjusted logistic regression analysis, parity and age at first child's birth were modeled as categorical with three levels . Nulliparous women had no value for the age at first child's birth  and were included in the category ⩾30. Menopausal status at mammogram and HRT were represented by one variable with three levels . We did not separate current and past HRT users as the small numbers of women in some subsets did not provide sufficient power to draw meaningful conclusions. Alcohol use, smoking, and HRT were modeled as dichotomous variables , cumulative pack years of smoking , current number of drinks per week , and cumulative number of drinks per week  were substituted with the median value for women with low density.A multi-step approach was used to impute values for the missing menopausal status and the age at menopause (P>0.05).After the logistic regression with all women in the study, the analysis was stratified by menopausal status at mammogram, HRT history, and a family history of breast cancer. The risk estimates are presented as ORs and their corresponding 95% confidence intervals (CI). Statistical difference in subset-specific risk estimates were determined using test of heterogeneity . Significance in all the analyses was assessed at 0.05 level. For all of the presented models, Hosmer–Lemeshow test of goodness of fit indicated reasonable model fit (This nested case–control study included 265 women with high and 860 women with low breast density. The distribution of breast density risk factors in the study population is presented in P for trend=0.02) and parity (P for trend <0.001). Postmenopausal women with a history of HRT had increased breast density compared with premenopausal women, but this association was only marginally significant . Women with a history of alcohol use were at a greater risk of increased breast density .The results of the adjusted logistic regression are presented in P for trend<0.01) and was positively associated with alcohol consumption  (P for trend<0.001) and positively associated with HRT history  and alcohol consumption . We observed no significant association of BMI with breast density in postmenopausal women .In premenopausal women, breast density was inversely associated with BMI (1.4–3.5) . In postP for trend <0.001) and alcohol use  and decreased with larger parity (P for trend <0.001) (P for trend<0.001), BMI (P for trend <0.01), and parity (P for trend=0.02), and was positively associated with alcohol consumption . The associations of parity and alcohol consumption with density in this subset were less strong than those associations in women with HRT history (P for interaction <0.001 for both variables).In women with a history of HRT, breast density significantly increased with age ( <0.001) . In the P for interaction<0.001). Among women with no family history of breast cancer, breast density was inversely associated with parity (P for trend <0.001). In this subset, the risk of high breast density was marginally increased in postmenopausal women with a history of HRT as compared with premenopausal women .In women with a family history of breast cancer, breast density was positively associated with alcohol use  . SimilarThis retrospective study of 265 women with high breast density and 860 women with low breast density was designed to explore differences in the direction and strength of associations between the potential predictors of breast density and the breast density phenotype. Analyses were conducted in subsets of women based upon their menopausal status, history of postmenopausal hormone use, and a family history of breast cancer.Using the FMMP population had several advantages. The extensive and detailed exposure estimation done by CDC allowed the selection of women who were unexposed to uranium and radiation for this study. The FMMP database contains comprehensive information on breast cancer risk factors collected prospectively over an 18-year period using standardised questionnaires and medical examinations. The extensive FMMP mammography database (31 043 mammograms) allowed defining the breast density phenotype based on the life-long density history for each woman rather than by a single mammogram. Mammograms were carefully coded using the FMMP coding system; however, there is a possibility of inter-observer variation in assessment of the density, as the films were evaluated by different radiologists. To overcome this limitation, the results of the preliminary study were used to improve definition of the breast density phenotype. Prospective data collection and sampling of the extreme breast density phenotypes allowed assessment of breast density predictors in an efficient design.Of the 2168 women eligible for the study, only 1504 (69%) met the definition for either high or low-density study group. Selection of women with extreme density categories increases certainty about the outcome and removes chances for density misclassification. Inter-rater agreement in density assessment has been reported to be substantial to perfect within a given density assessment method regardless of the assessment approach, and was the best for the extreme density patterns  women and an increased density in HRT users (The association between alcohol use and breast density has been reported (Our findings suggested that BMI, parity, HRT, and alcohol consumption appear to be important predictors of breast density in different subsets of women. Some associations differ by family history of breast cancer and HRT history. When possible, reduction in breast density by limiting alcohol and HRT not only reduces the risk of developing breast cancer but also facilitates an early detection of breast cancer in the less dense breast tissue.