Human inbreeding generally reduces breast cancer risk (BCR). When the parents are biologically related, their infants have a lower birth weight due to smaller body organs. The undersized breasts, because of fewer mammary stem cells, have a lower likelihood of malignant conversion. Fetal growth is regulated by genomically imprinted genes which are in conflict; they promote growth when derived from the father and suppress growth when derived from the mother. The kinship theory explicates that the intensity of conflict between these genes affects growth and therefore the size of the newborn. In descendants of closely related parents, this gene clash is less resulting in a smaller infant. In this review, we elucidate the different mechanisms by which human inbreeding affects BCR, and why this risk is dissimilar in different inbred populations. BRCA1 and BRCA2, being incompatible with life, are not transmitted to the next generation [MLH1, MSH2, MSH6) that cause a severe cancer syndrome, also fail to reproduce [The link between human consanguinity and malignancy is important for understanding carcinogenesis. Cancer has a strong genetic component and human consanguinity, still very common in many parts of the world, increases gene homozygosis. Homozygosis of low penetrance tumor genes, and its frequency in the population, can increase or decrease the risk of cancer –6. Homozneration –12. Homoeproduce . Thus, ieproduce –16. Thuseproduce –27. Simieproduce –34.The various studies on BCR in inbreeding families, similar to other types of cancer, have also produced contradictory results. BCR is lower in Arab inbreeding families than non-inbreeding families –23. HoweR) which indicates the fraction of autosomal genes two individuals share by common descent (Table F) is a fraction of autosomal genes that are homozygous by common descent and measures the risk of genetic harm in offspring of biologically related individuals (F = R / 2). In any population, the mean R correlates with the consanguinity rate, but former is a more precise an indicator of biological closeness.Human consanguinity is more frequent than generally appreciated. Worldwide, 1.1 billion of people have consanguineous parents . Such unp = 0.02) [p = 0.19) and their parents were less often first and double first cousins (p = 0.09) than the parents of non-cancer controls [p = 0.0125) [P53 gene was associated with a lower BCR [BRCA1 and BRCA2 cancer cases as homozygotes of these genes are early aborted [The age-standardized incidence of breast cancer is inversely related to the rate of consanguinity Fig. . In five = 0.02) , and b)  0.0125) . In Moro 0.0125) . Similar 0.0125) . One posower BCR . Howeverower BCR . In Arabower BCR . In theo aborted –12. In A aborted , 42; henBRCA1 and BRCA2 mutations has been proposed to explain these epidemiological findings. However, most of the gene variants are unique to Pakistan, and they have not been convincingly shown to be carcinogenic [BRCA1 and BRCA2 which is not a case in this population. In the absence of any obvious environmental risk factor for breast cancer that contrasts Pakistan from its neighbors, a higher frequency of low penetrance cancer genes that increase cancer risk in homozygotes is a more likely explanation. Until now, however, only a few of the known low penetrance breast cancer genes have been studied and none of them can explain the high breast cancer rates in both general population and daughters of consanguineous parents [CHEK2 gene, which moderately increases risk of breast cancer in heterozygotes, were found in rare patients from a few tested ethnic groups [CHEK2 mutation are at higher risk of breast cancer development than heterozygote which could explain increased BCR in both general population and daughters of consanguineous parents [In contrast to the decrease in risk, breast cancer in Pakistan positively correlates with parental consanguinity –27. Pakiinogenic –26. In ac groups , 45. The parents . NonetheAnother possible mechanism that could increase breast cancer rate among Pakistani women is negative heterosis (NH) . This phn = 10,289) and well-controlled study, infants of consanguineous parents were 1.8% smaller (than newborns of non-consanguineous parents) [The lower newborn weight in consanguinity is a less well known phenomenon that remains largely unexplained. In a large (parents) . In thisparents) , 52. In In general, a newborn’s size at birth  is determined by both genetic and environmental factors . In one From an evolutionary perspective, bigger individuals survive better than smaller ones, and the birth size correlates with body size during adulthood . From a IGF-2) (which is expressed when inherited from father and inactivated when inherited from mother), and negatively with PHLDA2  [The neonatal birth size is a well-established risk factor for breast cancer. Studies during the last two decades, from several countries, have consistently shown that birth weight and birth length positively correlate with breast cancer in women <50 years old –63. Bigg father) –75. In sThe change in gene expression (without the change in DNA nucleotide sequence) is produced by methylation, histone modification, and small RNA interference (imprinting). Generally, with few exceptions, imprinting inactivates genes. Genomic imprinting is a special form of gene inactivation depending on parent from whom it originates. As a rule, a gene in the fetus if inherited from mother is suppressed while the same gene if inherited from father is expressed. This results in mono-allelic inheritance and, in effect, transforms one into two genes, each with identical DNA nucleotide sequence but with different biochemical structure  and function (decreased or increased expression) depending on parent of origin. In humans, genomic imprinting is confined to about 100 genes that regulate cell proliferation during fetal and early postnatal development, behavior and cognition, and are expressed mostly in the placenta and the brain , 77. TheThe theory of genomic imprinting  posits that, in mammals, the genomic imprinting of genes is a consequence of the interactions between the fetus, the mother, the father and their genes, as follows: a) both maternal- and paternal-derived developmental genes regulate growth of the fetus; b) the mother provides disproportionally more resources for the offspring’s growth than the father; c) mothers can have offspring from more than one male (polyandry). Bigger babies survive better but they also utilize more resources from the mother, which could lower her fitness by decreasing her resources available for future offspring. To conserve her resources and maximize fitness, mother’s growth promoting genes are suppressed. On other hand, the father’s genes are expressed to promote growth as this increases the odds of their survival due to a bigger baby. In short, the maternally-derived and paternally-derived genes in the fetus are in conflict about how much growth to promote as this determines the number of their copies in future generations due to a) asymmetry of biological investments in their progeny and b) polyandry which creates different future life trajectories of their gene copies –81. In oR of parents and is shown in Table In a first cousin marriage, the wife carries 0.125 of autosomal genes of her husband by common descent. In future, if she conceives a child with another man, that child would carry 0.0625 of the genes of her current husband, her first cousin and the child’s uncle. In her current child, half of those 0.0625 genes are identical by common descent  and maternally-derived genes (Rm), however, is different from the non-genomically imprinted genes (R) and are shown in Table Rp > 0; in such families, the production of smaller babies is expected. Among four types of first cousin families, likewise, only the FBS family type (more common amongst Arabs) is expected to produce significantly smaller newborns.However, the genomically imprinted genes are more important for fetal growth than other genes. As per the kinship theory, they are genomically imprinted for that very reason and, consequently, they exert a stronger effect on size of newborns in any consanguineous family. The coefficient of relatedness of the genomically imprinted paternally-derived  cancer increase due to NH, ii) homozygosis of unidentified breast cancer susceptibility genes or iii) the additive effect of both these mechanisms.In Arab women, the decrease in BCR by parental consanguinity could be a result of i) decreased gene conflict that is enhanced by a larger number of first cousin marriages of the FBS type, ii) protective effect of homozygosis of some still unidentified breast cancer gene(s), or iii) additive protective effect of both these mechanisms against breast cancer. However, in Pakistan parental consanguinity increases BCRThere are several cofounders in consanguinity – cancer risk besides infant size. Theoretically, the frequency of lethal cancer alleles is reduced by inbreeding in proportion to its duration and intensity. Inbreeding coexists with socioeconomic underdevelopment, which is associated with lower risk factors for breast cancer . In consanguineous populations, women generally marry earlier and earlier first pregnancies protects against breast cancer . In someIn future studies, for more clarity, the effect of autosomal gene conflict on birth size can be verified by comparing the parental coefficient of relatedness, the offspring coefficient of inbreeding and infant size from consanguineous and non-consanguineous families in the same population. The validity of genomic imprinting hypothesis of inbreeding can be tested by comparing the parental coefficient of relatedness of genomically imprinted genes and birth size. Furthermore, measuring growth hormones like IGF-2 in fetal blood and expression of developmental genes in the placenta (from women married to different types of cousins) would provide additional pieces of the puzzle. Then, we can be sure of the relative role of genomic imprinting in reducing the risk of breast cancer in inbred populations – and add further to our understanding of carcinogenesis.


Leptin is a confirmed breast cancer susceptibility gene. However, published studies reported mixed results. This meta-analysis was conducted to systematically get a more accurate estimation of the association between the Leptin (-2548G/A) gene polymorphism and breast cancer risk.To assess the effect of Leptin (-2548G/A) gene polymorphism on breast cancer susceptibility, we searched PUBMED, ISI Web of Knowledge, EMBASE, Chinese National Knowledge Infrastructure (CNKI) databases until September 2015 to identify eligible studies, without restriction. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to breast cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and country.P = 0.002, PhetP < 0.00001). Following further stratified analyses, in the subgroup analyses by ethnicity, a significantly increased risk was observed among Caucasian . No publication bias was found in the present study.A total of 9 case-control studies on Leptin (-2548G/A) gene polymorphism and breast cancer risk, including 3725 cases and 3093 case-free controls were identified. The results revealed that compared with the G allele, the A allele was associated with modestly increased risk of overall breast cancer  gene polymorphism plays an important role in breast cancer susceptibility, especially in Caucasian. It is a heterogeneous disease in regard to its clinical, histological, and molecular profile.4 At present, genetic polymorphisms are increasingly recognized as contributors to breast cancer risk.5Breast cancer is the most frequently diagnosed cancer among women,6 plays an important role in body weight homeostasis through effects on food intake and energy expenditure.8 Obesity has been identified as a risk factor for breast cancer in postmenopausal women,11 and increased leptin levels have been frequently found in obese subjects, with higher expression in women relative to men.14 Moreover, studies have indicated that the leptin is involved in carcinogenesis of breast tissue and acts to favor the proliferation, angiogenesis, progression, and poor survival of breast cancer cells,17 especially in higher grade tumors and are associated with distant metastasis. Delort and coworkers18 suggested that the multifaceted role of leptin in breast cancer development and the different molecular pathways involved such as inflammation, oxidative stress, and antitumor immunity. Further, over expression of leptin in breast cancer appears to be associated with higher tumor grade and size.23 These data suggest that leptin is likely to play a key role in carcinogenesis. However, the mechanisms of leptin and tumorigenesis still remain poorly understood.Leptin, a 16 kD polypeptide hormone encoded by the obese gene,24 The functional influence of the -2548G/A polymorphism on leptin expression stimulates great interest of many investigators to examine its association with breast cancers.31 However, only a few studies with inconsistent results have addressed the relationship between leptin and breast cancer.39 Liu and coworkers40 suggested that the A allele of -2548G/A polymorphism may be a determinant of cancer development. However, it was not concentrated on studying breast cancer. A meta-analysis of Niu et al41 suggested that the leptin level plays a role in breast cancer and has potential for development as a diagnostic tool. Therefore, we performed a meta-analysis of early-release publications to clarify whether the -2548G/A polymorphism acts on breast cancer susceptibility in the first place.In recent years, most studies concern leptin gene polymorphism involvement in breast cancer, including rs2060713C/T, rs7799039, G-2548A, G-223A, G-2549A. Interestingly, G-2548A is a rather popular polymorphism and focus on studying breast cancer. The A allele of -2548G/A polymorphism was found to be associated with higher leptin levels before lower BMI (body mass index) loss in women.Computer searches were carried out independently by 2 authors, in PubMed, Web of Knowledge, Embase, and the Chinese National Knowledge Infrastructure (CNKI) database  to collect articles with case-control studies related to the association of the Leptin (-2548G/A) gene polymorphism and breast cancer risk.The keywords were as follows: breast cancer/carcinoma/neoplasm/tumor, Leptin (-2548G/A), variant/genotype/polymorphism/SNP. Furthermore, reference lists of main reports and review articles were also reviewed by a manual search to identify additional relevant publications. Searches were limited to papers published in English only. The study was approved by the Conduct of Human Ethics Committee of the Second Affiliated Hospital, Xi’an Jiaotong University.Two investigators independently screened all titles and abstracts of the identified studies. Studies included should be in accordance with the following criteria: (1) a case-control study with matching control subjects; (2) clinical trials studying the association between Leptin (-2548G/A) gene polymorphisms and breast cancer risk; (3) all cases were diagnosed by the pathological examination; (4) contained at least 2 comparison groups (cancer group and control group); (5) reported available genotype frequencies dates for both patient and control populations. Accordingly, the following exclusion criteria were also used: (1) no controls; (2) the source of cases and controls, and other essential information were not provided; (3) no sufficient data reported; (4) abstracts, comments, reviews, meta-analysis, and duplicated publications.All the available data were extracted from each study by 2 of the authors independently, and then discussed by the research team. For each included study, the following information was collected: the first author, year of publication, country of origin, ethnicity, source of control, numbers of cases and controls, and numbers of GG, GA and AA genotypes in cases and controls. Different ethnic ancestries were categorized as Caucasian, and “mixed”. The “mixed” group means mixed or unknown populations. All the case and control groups were well controlled. The non-cancer controls had no history of gynecologic disease, and there was no present evidence of gynecologic cancer, any malignant disease, or genetic disease, and there was no present evidence of any malignant disease. When studies included subjects of >1 ethnicity, genotype data were extracted separately according to ethnicities for subgroup analyses.Q test and I2 statistic were used to measure the extent of inconsistency among the results. Heterogeneity was considered significant if Phet ≤ 0.1 or I2 > 50 %. When significant heterogeneity existed, we selected a random effects model for statistics. Otherwise, a fixed effects model was used. Sensitivity analysis was also tested by removing 1 study at a time to calculate the overall homogeneity and effect size. Publication bias were evaluated by funnel plots and further assessed by Egger's linear regression test.We carried out this meta-analysis referring to PRISMA Guideline. The associations between the Leptin (-2548G/A) gene polymorphism and breast cancer risk were measured by odds ratios (OR) with 95% confidence intervals (CI) for A vs G, AA vs GG, AA + GA vs GG, AA vs GA + GG, and GA vs GG genetic models. Cochran P values in the meta-analysis were 2-sided, and P values <0.05 were considered significant.All statistical analyses were carried out with the review manager  and the Stata software version 10 . All 39 The characteristics of 9 studies are presented in Tables By reading the relevant articles, there are 26 studies to identify preliminarily for further detailed evaluation. The results of excluding 17 irrelevant studies, for example: 4 studies were not case-control studies, 4 studies were not focused on Leptin (-2548G/A) gene polymorphism, 4 studies did not have genotyping data, 4 studies were review articles .The frequency of the A allele varied widely across the 12 studies, ranging from 0.36 to 0.72 . However, there were no significant associations between the Leptin (-2548G/A) gene polymorphism and breast cancer risk in other genotype distributions . Furthermore, when stratified by clinico-pathological parameters of breast cancer, there were no associations between Leptin (-2548G/A) genes and the parameters in the dominant model, such as menopausal status , clinical stage , ER/PR receptor , and lymph nodes . However, there were significant associations between Leptin (-2548G/A) genes and the parameters in the dominant model, such as BMI .The main results of this meta-analysis are listed in Table P = 0.006, Phet = 0.00001; AA vs GG: OR = 1.21, 95%CI = 1.04–1.41, P = 0.01, Phet = 0.001; AA + GA vs GG: OR = 0.69, 95%CI = 0.62–0.77, P < 0.00001, Phet = 0.00001), but no associations in other genetic models .Seven articles, including 3278 cases and 2682 controls, were used to investigate the association of the Leptin (-2548G/A) gene polymorphism with breast cancer susceptibility in Caucasians. The results showed .Begg's funnel plot and Egger's test were performed to assess the publication bias. As show in Figure 42 The Leptin (-2548) A allele, which result in high leptin secretion, was associated with increased risk of breast cancer. A leptin G-2548A gene polymorphism in the promoter region of leptin gene has been shown to correlate with variations in serum leptin levels, degree of obesity, as well as cancer susceptibility and has been shown in several reports to promote tumor growth.44 A broad range of investigations have demonstrated strong evidence for an involvement of leptin in breast cells proliferation stimulation, apoptosis inhibition, cell migration, and angiogenesis.48Breast cancer is one of the most common malignant tumors and leading causes of cancer-related death among women in the world, and it is a threat to women's health. Terrasi and his colleagues studies have manifested that Leptin is overexpressed in human breast tumors.A recently published meta-analysis demonstrated that the Leptin-2548G/A gene polymorphism was associated with overall cancer. In our meta-analysis, we combined all publications addressing the association of the Leptin -2548G/A gene polymorphism and breast cancer risk before August 10, 2015, and the results revealed a significantly elevated breast cancer risk, we pooled all 9 eligible case–control studies to estimate the breast cancer risk of the Leptin-2548G/A genes. We found that Leptin-2548G/A A > G variant had a significantly increased risk of breast cancer in overall population.In the subgroup meta-analysis based on ethnicity, compared with G allele, a significantly increased breast cancer risk is associated with A allele in Caucasian population. We stratified between Leptin (-2548G/A) gene polymorphism and clinico-pathological parameters and habits of the breast cancer patients based on the dominant models. Furthermore, compared with AA genotype, a significantly increased risk of breast cancer is associated with GG genotype, the combined AG/GG genotypes subgroup. However, there were 9 studies based on Caucasian background and Mixed among the eligible studies, and there was no study based on Asians background among the eligible studies. Hence, need to further investigations on a large scale on Asians and still need to further investigations on a large scale on Caucasian populations are needed to verify this result.Some limitations in this meta-analysis must be addressed. First, the detailed individual information in some studies was unknown; thus, we could not assess the risk of breast cancer according to stratification of environment factors, and other risk factors of cancer. Second, we considered the comparison HER2  and Leptin case subjects, in a similar fashion HER2 case subjects. But 7 of 9 references did not list some stratified data of HER2. Hence, we cannot continue to further analysis and sorting data. Moreover, further large-scale multicenter studies with more detailed individual data, with different environmental background are warranted to further validated gene–gene and gene–environment interactions on Leptin-2548G/A gene polymorphism and breast cancer risk.In summary, our present meta-analysis provides evidence of the association between Leptin-2548G/A gene polymorphism and breast cancer risk, and suggests that Leptin-2548G/A gene polymorphism has an increased risk with breast cancer. Further studies based on different ethnicity and various cancer types are warranted to verify our findings.


The exclusion of the ethanol component from the MDS did not materially modify the ORs . Results were similar in pre- and post-menopausal women. Adherence to the Mediterranean diet was associated with a reduced breast cancer risk.The Mediterranean diet has been related to a reduced risk of several common cancers but its role on breast cancer has not been quantified yet. We investigated the association between adherence to the Mediterranean diet and breast cancer risk by means of a hospital-based case-control study conducted in Italy and Switzerland. 3034 breast cancer cases and 3392 controls admitted to the same network of hospitals for acute, non-neoplastic and non-gynaecologic diseases were studied. Adherence to the Mediterranean diet was quantitatively measured through a Mediterranean Diet Score (MDS), summarizing the major characteristics of the Mediterranean dietary pattern and ranging from 0 (lowest adherence) to 9 (highest adherence). We estimated the odds ratios (ORs) of breast cancer for the MDS using multiple logistic regression models, adjusting for several covariates. Compared to a MDS of 0–3, the ORs for breast cancer were 0.86  for a MDS of 4–5 and 0.82  for a MDS of 6–9 ( Despite considerable research, the role of diet in the aetiology of breast cancer is still an open issue. Apart from a consistent direct association with alcohol intake ,2, evideDietary patterns assess diet as a whole and capture the complex inter-relationships among dietary components and their cumulative effects. Therefore, they may be more predictive of disease risk than individual foods or nutrients. However, the available evidence based on dietary patterns is still limited . The MedAn inverse association between this dietary pattern and breast cancer has been suggested by some studies ,18,19 buA protective role of the Mediterranean diet on breast cancer is biologically plausible since the Mediterranean dietary pattern is rich in fibre, antioxidants, including flavonoids, vitamins, carotenoids and squalene (mainly from virgin olive oil). It may modulate breast cancer risk by decreasing endogenous oestrogens , increasIn addition, promising results suggesting a beneficial role of the Mediterranean diet in the prevention of  breast cancer came from the PREDIMED randomized trial, which estimated a hazard ratio of 0.32  for the Mediterranean diet with extra-virgin olive oil group and of 0.59  for the Mediterranean diet with nuts group, versus the control diet group .Given the inconsistent results and the fact that several studies on the topic were conducted outside the Mediterranean region, where a high compliance with the Mediterranean diet is unlikely, it is worthwhile to provide new epidemiological data on the association between this dietary profile and breast cancer in a Mediterranean setting. We have therefore evaluated if a high adherence to the Mediterranean diet is associated with a decreased risk of breast cancer in a large study undertaken in Italy and French-speaking Switzerland, where large segments of the population still adhere to the Mediterranean diet.Study population and data collection. Data were from a multicentric case-control study on breast cancer conducted in 6 Italian areas  in 1991–2008 and in the Canton of Vaud, Switzerland, in 1992–2008 ,36. OverCentrally trained interviewers administered to cases and controls a structured questionnaire, including information on sociodemographic characteristics and anthropometric measurements , lifestyle habits , personal medical history, menstrual and reproductive factors, oral contraceptive use, menopausal hormone-replacement therapy use and family history of cancer. Information on dietary habits before diagnosis (for cases) or hospital admission (for controls) was based on a validated and reproducible food frequency questionnaire (FFQ) ,38,39 inMediterranean Diet Score (MDS). The adherence to the Mediterranean diet was assessed through an a priori score , developed by Trichopoulou and colleagues , which i2; categorically), level of physical activity at workplace/home at age 30–39 (at age 19–30 for the few women aged < 30)  [Statistical analysis. We estimated odds ratios (ORs) of breast cancer and their corresponding 95% CIs for categories of MDS  and for an increment of one point in the MDS using unconditional multiple logistic regression models. We included terms for study centre, age , education , body mass index  ,44, tobaWe conducted analyses stratified by age, menopausal status, education, parity, BMI, oral contraceptive use and hormone-replacement therapy use. Heterogeneity across strata was tested by likelihood ratio tests.We computed the population attributable fraction (PAF) to estimate the proportion of breast cancer cases that might have been avoided by shifting all subjects to the highest MDS category , according to the method of Bruzzi et al. . In addiAll the analyses were performed using the SAS software, version 9.4 .Among controls, the median values used to define adherence for single components were 17.5 weekly portions for fruit, 11.0 for vegetables, 22.5 for cereals, 0.5 for legumes, 1.5 for fish, 1.3 for monounsaturated/saturated fatty acid ratio, 10.1 for dairy products and 5.8 for meat. No major differences emerged in the distribution of these dietary items between Italian and French speaking Swiss women.p-value = 0.008). The OR for one point increment in the MDS was 0.95 (95% CI 0.92–0.99). When we excluded the alcohol component from the score, the ORs were 0.81  for 4–5 and 0.81  for 6–8 components. Estimation of the PAF indicated that 7.2% of breast cancer cases in this population would be avoided by shifting all women towards the highest category of the score . The PAF associated to the one category upward shift of subjects in the lowest and middle categories of MDS  was 6.1%.The association between the MDS and breast cancer risk in subgroups of potential effect modifiers is described in By using a simple, intuitive and frequently used dietary score to assess compliance to the Mediterranean diet, this large investigation from southern Europe found that adherence to the Mediterranean dietary pattern is related to a reduced risk of breast cancer, as documented for several other cancers . In partAvailable epidemiological data on Mediterranean diet and breast cancer appear conflicting, with some studies reporting null findings ,21,22, sp for trend = 0.03) for ER-negative breast cancer [p trend = 0.032), whereas the associations with total  and ER-positive breast cancer  were weak and non-significant [p trend = 0.048), which appeared limited to postmenopausal breast cancer , compared to premenopausal breast cancer  [p for trend = 0.09) [Among major prospective investigations, the Nurses’ Health Study (with 3580 breast cancer cases) did not find a relation between Mediterranean diet and total or ER-positive breast cancer but an inverse association was observed for ER-negative breast cancer . The HRst cancer . Similarnificant . In addi81–1.15) . Convers = 0.09) . Finding = 0.09) . When fi = 0.09) .p for trend = 0.009) [p trend = 0.01) and a significant 11% decreased risk per one standard deviation increase in the score [Among case-control studies, an investigation among Asian American women with 1248 breast cancer cases found a significant inverse association with a score of Mediterranean diet which considered alcohol among the non-Mediterranean components  ; a Spanihe score ; and a she score .Thus, there is a partial consensus of findings on Mediterranean diet and breast cancer between cohort and case-control studies. This strengthens the consistence of a real inverse association. Available studies were conducted on different populations and they measured adherence to the Mediterranean diet through various scores, which differed in the components included , the specific food items considered in a component  and the scoring system for the level of adherence . Moreover, while moderate alcohol intake is a distinctive feature of the Mediterranean diet, given its unfavourable role on breast cancer risk, some studies excluded alcohol from the score calculation ,23 and sStrengths of our study include the large sample size, the Mediterranean setting, the comparable catchment areas of cases and controls, the very high participation, the reproducibility ,39 and vAmong the limitations, we had no adequate information on various subtypes of breast cancer. Selection bias should be limited, as we excluded from the control group subjects admitted to hospitals for chronic and gynaecologic conditions or diseases related to diet modifications or known risk factors for breast cancer. Information bias was minimized by the direct interview of cases and controls by the same trained interviewers in similar hospital conditions.In conclusion, we found a modest but relevant at both individual and public health level, reduced risk of breast cancer for a high adherence to the Mediterranean diet, in Southern European populations where this dietary pattern is still prevalent.


Plausible biological reasons exist regarding why smoking could affect breast cancer risk, but epidemiological evidence is inconsistent.We used serial questionnaire information from the Generations Study cohort (United Kingdom) to estimate HRs for breast cancer in relation to smoking adjusted for potentially confounding factors, including alcohol intake.P = 0.010) for ever smokers, 1.24  for starting smoking at ages < 17 years, and 1.23  for starting smoking 1–4 years after menarche. Breast cancer risk was not statistically associated with interval from initiation of smoking to first birth (P-trend = 0.97). Women with a family history of breast cancer  had a significantly larger HR in relation to ever smokers (P for interaction = 0.039) than women without . The interaction was prominent for age at starting smoking (P = 0.003) and starting smoking relative to age at menarche (P = 0.0001).Among 102,927 women recruited 2003–2013, with an average of 7.7 years of follow-up, 1815 developed invasive breast cancer. The HR (reference group was never smokers) was 1.14  contains supplementary material, which is available to authorized users. The carcinogenic potential of tobacco smoke is unarguable , 2, and The Generations Study is a cohort study of over 113,700 women aged 16 years or older from the United Kingdom, from whom questionnaire information and informed consent were gained at recruitment since 2003 . Initialsee below) for those lost to questionnaire follow-up. Confirmation of diagnosis was obtained from cancer registries in the United Kingdom, ‘flagging’ at the National Health Service Central Registers , pathology reports and correspondence with patients’ general practitioners.Breast and other cancers occurring in the cohort were identified from recruitment and follow-up questionnaires, spontaneous reports to the study centre, and from ‘flagging’ ’, if they still smoked regularly, age started and stopped, and number of cigarettes smoked per day in different periods of their lives . For analysis, we defined the period of ‘current smoking’ to include both current smokers and the year immediately after stopping, to avoid potential ‘reverse-causation’ bias from women who may have stopped smoking during the workup to a formal breast cancer diagnosis. For alcohol use, we asked women if they had been a regular drinker ‘in the sense of drinking at least one glass of alcohol per week on average’, ages started and stopped, and quantity consumed in different periods of life . We converted the quantity of alcohol consumed in each period of life into daily grams of alcohol. We split into three groups the women who reported current drinking , and we classified women who had reported stopping drinking as former drinkers. For some women, we did not know their current drinking status during follow-up, but we knew they had consumed alcohol in the past, and these women were classified as ‘ever drinkers’. Because we had collected ages or dates at which certain events or changes in lifestyle occurred, we were able to update smoking status, alcohol use, parity, oral contraceptive (OC) use, menopausal hormone therapy (MHT) use and menopausal status at the ages these episodes occurred through the time of the second follow-up questionnaire. We updated duration of smoking for current smokers, as well as time since cessation for former smokers, in yearly increments, using smoking start and stop ages from the recruitment and second follow-up questionnaires. We updated cigarettes smoked per day, pack-years smoked, alcohol consumption and post-menopausal body mass index (BMI) at the date of the second follow-up questionnaire.The present analytic cohort is based on all women who were recruited into the study during June 2003–December 2013 without prior invasive or in situ breast cancer or other malignant cancer (except non-melanoma skin cancer) or prior mastectomy. The recruitment cut-off at December 2013 was selected because at the time of analysis the second follow-up was practically complete for this group of recruits, two-thirds of the cohort had reached the third follow-up, and we had ‘flagging’ information to June 2017. Women entered risk at their date of recruitment and were censored at the earliest date of invasive breast cancer or in situ breast cancer; other malignancy (except non-melanoma skin cancer); death; most recent follow-up questionnaire (depending on date of recruitment) if completed, or the date the most recent follow-up questionnaire was due if cancer and vital status was known from ‘flagging’; or previously completed questionnaire if lost to follow-up. We censored follow-up at in situ breast cancer or other malignancy because we reasoned that if smoking is related to risk of in situ breast cancer or other malignancy, and ensuing treatments or their consequences alter risk of subsequent invasive breast cancer, including subsequent follow-up may obscure associations between smoking and invasive breast cancer.https://acorn.caci.co.uk/) as trend, or missing indicator); age at menarche ; age at first pregnancy ; parity ; duration of breastfeeding ; current OC use during follow-up, before menopause (yes/no); alcohol consumption ; physical activity ; pre-menopausal BMI at age 20 years ; post-menopausal BMI ; MHT use ; menopausal status ; and age at menopause . BMI was used to create two separate variables: pre-menopausal BMI  and post-menopausal BMI . We used BMI at age 20 to represent pre-menopausal BMI. Separately, if a woman was post-menopausal at entry to the cohort we used her BMI at entry for her post-menopausal BMI . If a woman was post-menopausal at the time of the follow-up questionnaire, we updated from this point in time her post-menopausal BMI with the value from this follow-up questionnaire. Statistical trends were evaluated using continuous values, except for duration and time since cessation of smoking, which were based on discrete time-varying, annually updated values. For trend analyses where there was an unexposed group , the unexposed group was not assigned a zero magnitude but was treated as a separate categorical term, as was any missing value group. In particular we adjusted our analyses of smoking and breast cancer for alcohol using daily current alcohol consumption as a continuous measure if within the range 1 to < 60 g/day, and categorical terms for non-drinkers, for those with consumption ≥ 60 g/day (because we did not want a minority of women who reported very high consumption to influence unduly the trend with daily consumption), past drinkers, and those for whom details of consumption were missing, by fitting appropriate interaction terms in the Cox regression model. Heterogeneity in HRs by subtype of breast cancer defined by oestrogen receptor (ER) status or morphology was assessed using a data augmentation method [Left-truncated and right-censored Cox proportional hazards regression  with attn method  and Waldn method . All stan method .During 2003–2013, a recruitment questionnaire was completed by 102,940 women who had no previous invasive or in situ breast cancer or other malignancy (except non-melanoma skin cancer). At censoring date, 1.1% of women had died. Of the remainder, cancer and vital status were known for 96.5% who had completed the relevant follow-up questionnaire and for a further 2.4% from ‘flagging’ at the National Health Service Central Registers. The remaining 1.1% were lost to follow-up at an earlier date. Thirteen women (including one with breast cancer) were excluded from subsequent analyses because of self-contradictory information for parity or smoking, leaving 102,927 subjects for analysis.Table During 788,361 person-years  of follow-up, 1815 invasive breast cancers were diagnosed, of which 1813 were confirmed through national cancer registration or medical records, and the remaining 2 were self-reported with treatments that imply breast cancer. ER status data were available for 99.3%, and of these 83.7% were ER-positive. Invasive ductal carcinoma accounted for 78.8%, and lobular 16.4%, of tumours. Further descriptive characteristics of the breast cancer cases are given in Additional file P = 0.0009) when adjusted only for attained age, 1.13  when also adjusted for alcohol consumption, and 1.14  when further adjusted for other potentially confounding variables  and ER-negative  breast cancer, and the difference between the HRs was not significant (P = 0.40). Breast cancer risk increased significantly with number of cigarettes smoked per day for all breast cancer (P-trend = 0.0060) and for ER-positive tumours (P-trend = 0.023). Breast cancer risks were raised significantly after 10+ years’ duration of smoking (10+ years vs never smoking P = 0.0004). Breast cancer risks did not further rise beyond 10 years’ duration, and because of this non-linear relationship, there was no significant linear trend with duration of smoking (P-trend = 0.24), nor was there significant heterogeneity in the trend by ER status. Pack-years of smoking was associated with breast cancer risk overall (P-trend = 0.0069) and ER-positive breast cancer (P-trend = 0.024) but not for ER-negative (P-trend = 0.16) tumours; there was no significant heterogeneity of the pack-years trend by ER status (P = 0.66).Table P = 0.34) and former  smokers, although only the latter reached statistical significance; there was no significant heterogeneity by ER status. Breast cancer risks were significantly raised within the first 20 years after cessation of smoking and decreased with greater time since cessation, although the trend was not significant (P-trend = 0.071), and there was no significant heterogeneity in this trend by ER status.The HR within the year after smoking cessation was 2.68 (95% CI 1.60–4.46), based on 15 cases, but for reasons described in the P-heterogeneity = 0.018; not presented in Table P = 0.0023) or 17–19 years  relative to non-smokers, but not if it started at older ages. The risk was significantly increased for ER-positive subjects, only for smokers starting at ages < 17 years, and no significant risk increase was noted for ER-negative breast cancer. When adjusted for pack-years, the breast cancer risk (HR) for starting smoking at age < 17 years was 1.12 , and when adjusted for duration of smoking, it was 1.16  (not presented in Table There was significant variation in risk of breast cancer by age at start of smoking Table  (P-heterP = 0.061) or 1–4 years after , with a significant downward trend in breast cancer risk with increasing interval from age at menarche to age at starting smoking (P = 0.031). A similar pattern was seen for ER-positive, but was less clear for ER-negative, breast cancer. A weaker relationship was seen with age at thelarche . When adjusted for pack-years of smoking, the HRs for age at start of smoking 1–4 years after menarche  or thelarche  were attenuated (not presented in Table P-trend = 0.013); for an interval of 15+ years, the HR was 1.46 . However, these results were not adjusted for age at first childbirth and parity (not presented in the tables), and when we adjusted  but a significantly raised breast cancer risk in those who had ever been drinkers , although the difference in HRs was not significant (P-interaction = 0.41) , although for nulliparous ever smoking women, there was a statistically significantly increased risk of breast cancer (P = 0.012)  , whereas the latter did (P = 0.040). Nor did we find significant interactions with birth cohort (P = 0.092), BMI at age 20 years (P = 0.55) or post-menopausal ages (P = 0.26), but we did see a significant interaction with family history of breast cancer (P = 0.038). There were significant interactions between family history and age at start of smoking (P = 0.0029) and starting smoking relative to age at menarche (P = 0.0001) in relation to risk of breast cancer (Table P = 0.0028) or < 20 years , and if started 5+ years after menarche , and we noted that these were somewhat different from the results among women without a family history of breast cancer.We examined further potential risk factor interactions with smoking but found no significant interactions with parity , whereas after stratification by age at first birth, the trends in each stratum were weaker  [Young age at first birth and increasing parity confer long-term protection against breast cancer , 35, andsee review [BRCA1/2 carriers , studien cancer ). There er [NAT2  and CYP1 [CYP1A1 , 45 as w [CYP1A1 , 47. Morr cancer ), and stAs in previous studies, we excluded from analysis women with prevalent breast or other malignant cancer , 28, 32 If our results are not due to chance, residual confounding, or unidentified bias, they suggest that certain biological mechanisms deserve further attention, such as those involving exposure at peri-menarcheal ages, and gene-environment interactions, either of which may be the direct result of chemical carcinogenesis or an indirect consequence on hormonal pathways during this susceptible period of breast development.We found that smoking was associated with a modest but significantly increased risk of breast cancer, particularly among those who started at adolescent or peri-menarcheal ages, and that the relative risk of breast cancer associated with smoking was significantly greater for women with a family history of the disease.


Breast cancer is recognized as a major public health problem in developing countries; however, there is very little evidence of behavioral factors associated with breast cancer risk. This study was conducted to identify lifestyles as risk factors for breast cancer among Central African women. A case-control study was conducted with 174 cases confirmed histologically by the pathology unit of the National Laboratory and 348 age-matched controls. Data collection tools included a questionnaire with interviews and medical records of patients. Data were analyzed using SPSS software version 20. Odd ratio (OR) and 95% confidence intervals (95% CI) were obtained by unconditional logistic regression. In total, 522 women were studied with a mean age of 45.8 (SD = 13.4) years. By unconditional logistic regression model, women with breast cancer were more likely to have attained illiterate and elementary education level [11.23  and 2.40 ], married [2.09 ], positive family history [2.31 ], radiation exposure [8.21 ], consumption charcuterie [10.82 ], fresh fish consumption [4.26 ], groundnut consumption [6.46 ], soybean consumption [16.74 ], alcohol [2.53 ], habit of keeping money in bras[3.57 ], overweight [5.36 ] and obesity [3.11]. However, decreased risk of breast cancer was associated with being employed [0.32 ], urban residence [0.16 ], groundnut oil consumption [0.05 ], wine consumption [0.16 ], non habit of keeping cell phone in bras [0.56 ] and physical activity [0.71]. The study showed that little or no education, marriage, positive family history of cancer, radiation exposure, charcuterie, fresh fish, groundnut, soybean, alcohol, habit of keeping money in bras, overweight and obesity were associated with breast cancer risk among Central African women living in Bangui. Women living in Bangui should be more cautious on the behavioral risk associated with breast cancer. Breast cancer (BC) is one of the commonly diagnosed cancers that leads to mortality and morbidity in women worldwide . NowadayIn addition, the number of new cases diagnosed in women was 1.7 million , with 883,000 cases observed in developed regions against 794,000 cases in developing countries . The ageAccording to the 2012 report by the World Health Organization (WHO), breast cancer-related mortality is the leading cause of death 24.5%) among Central African women ,9. The r.5% among2, will significantly reduce the risk of BC [Several studies have reported independent effects of various lifestyle factors such as eating habits, physical activity, smoking, alcohol consumption and anthropometric characteristics, such as Body Mass Index (BMI) with the incidence of BC , sedentask of BC . TherefoIn Central African Republic (CAR), diseases induced by lifestyle are considered to be the main causes of disability and death. In addition, in recent decades, when the CAR began recording a significant reduction of infectious diseases through different national programs implemented, new diseases, including cancer and other non-communicable chronic diseases began emerging as new public health priorities. Unfortunately, only few hospital studies had been conducted in this domain, and none have studied the risk factors associated with this disease in the population ,16.Given increasing prevalence of BC in CAR, the absence of an operational plan for the fight against cancer and the lack of appropriate support structure, it is necessary to study the lifestyle factors and risk in people with this disease. Thus, this case-control study aimed to identify lifestyle factors associated with BC risk in women with BC confirmed by Pathology unit of the National Laboratory of Bangui. The data obtained will allow for the development of new strategies to fight this disease and its complications.This case control study was carried out in the pathology unit of the National Laboratory, and the general surgery and gynecology services of two tertiary care institutions in Bangui, CAR.The studied population was women, included in the cases and controls. All cases were women with invasive BC histologically confirmed between September 2003 and September 2015. The controls were randomly recruited from women who came for other pathologies at the National Laboratory of Bangui. For each case, two controls were included in the study. All controls were free of any cancer. They were matched for age (same age) because BC is an age-related disease and increasing age is the single most important risk factor after female gender . In addiAll women living in Bangui, aged ≥ 15 years, who presented with BC, which was confirmed by histology, and gave consent were included in the cohort/study. However, all women aged less than 15 years, not residing in Bangui or those whose pathological diagnosis dates were outside the study period or refused to participate in the study were excluded.Investigators reviewed the records and reports of laboratory for each patient to identify BC cases confirmed during the study period. Information about each patient was recorded on a data collection sheet. Then the contact was made with the consultant physicians to supplement information on certain medical parameters and addresses of patients. For cases of those who had died, relatives were selected as next of kin to provide data relating to the patient’s lifestyle. The controls were randomly recruited from women who came for other pathologies at the National Laboratory of Bangui.Data was collected from a cancer register held in the pathology unit of the National Laboratory; from medical records of patients seen at the general surgery and gynecology services. The main details of the risks and benefits of the study were explained to all eligible participants. Those who agreed signed an informed consent form before the interview. This interview was conducted in Sango . For participants who did not understand Sango, adult relatives interpreted the content of the questionnaire and consent form for better understanding. For minors or children, the written consent form was obtained from close relatives or caretakers before being enrolled in the study. Each potential participant had the choice to accept or refuse to participate in the study. Questions were also granted to volunteers who wish clarification.The following variables were considered: age, occupation, economic status, education level, areas of residence , ethnic group and marital status. In addition, family history of cancer was included as hereditary factors. Finally, radiation exposure and certain foods consumed in CAR as cassava, rice, charcuterie, red meat, vegetables, fish, groundnuts, palm oil, soybean, coffee, physical activity, alcohol, tobacco, use of bra, habit to keep money or cell phones in bras, height, weight and BMI were included as lifestyle factors.Age was categorized as age groups. The occupation was classified as housewife  or as being employed. Economic status has been defined in terms of family income according to international poverty threshold. Low income if below 2 dollars a day, moderate between 2 and 4 dollars, good between 5 and10 dollars and excellent above 10 dollars . The res2) and women were grouped into different categories such as recommended by WHO; normal range (BMI ≤ 24 kg / m2), overweight (BMI = 25–29.9 kg / m2) and BMI ≥ 30 kg / m2 is synonymous with obesity [Measurements of height and weight of the control subjects were taken by the investigators. The height was measured using a vertical strip affixed to the wall and the weight with a calibrated scale. BMI was calculated by dividing weight by height squared (kg / m obesity .χ2) tests or Fisher’s exact were used to compare the frequency distribution of categorical variables and whereas t-tests Student were used to compare the mean values for the continuous variables between various groups of cases and controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between hereditary or lifestyle factors and BC. Based on the comparison of baseline characteristics between cases and controls, the following variables, including occupation, economic status, education level, residence area, marital status, family history of cancer, radiation exposure, cassava flour, rice, charcuterie, red meat, vegetables, fish, groundnuts, palm oil, soybean, coffee, physical activity, alcohol, tobacco, use of bras, habit of keeping money or cell phones in bras, height, weight and BMI were selected to be adjusted for as potential confounding factors. Potential confounders were included in a multivariate logistic regression model when the Chi-square test or t-test showed a positive association with BC or if the inclusion of the variable in the analysis changed the risk estimation by ≥10%. All statistical tests were based on a probability of 2 sides, with a significance level of 0.05, and were performed using Statistical Package for Social Sciences  Version 20.Pearson chi-square , and University of Bangui (No 2068/UB/FACSS/CSCVPER/16) according to standards of the Declaration of Helsinki. All participants gave informed written consent.In total, 174 cases and 348 controls matched for ages were included. The response rate was 85.99% (522/607). The age at diagnosis for the cases ranged from 16 to 90 years with a mean of 45.83 (SD = 13.5) years. The mean age for the control was 45.79 (SD = 13.3) years .2) tests revealed significant differences between cases and controls with respect to occupation (p = 0.001), economic status (p = 0.01), education level (p < 0.001), area of residence (p <0.001), ethnic group (p< 0.001), marital status (p <0.001) and parity (p = 0.008). There was no significant difference in the mean age observed between BC patient and control group. Over 69% (121/174) of the cases as compared to the controls 82% (287/348) were housewives with a moderate economic status (56.9% and 66.4%). Nearly 13% (23/174) and 14% (51/348) of the cases and controls, respectively, had a level of academic study and lived in cities (85.6% and 96.9%). The most represented ethnic groups were the Banda (18.6% of cases and 32.2% of controls), the Gbaya (12.8% and 19.4%), followed by Mandja (19.2% and 15.7%) and Yakoma (22.1% and 13.9%). Unmarried women held 75.9% (132/174) in the case group against 89.9% (313/348) in the control group, however, a small proportion of cases (17.9%) and controls (9.8%) were nulliparous.The odds for the socio-demographic factors associated with risk of BC were summarized in Predictor effects (risk factors) on BC in Central African women have been shown in Tables 2 in the cases and 26.29 ± 8.3 kg / m2 in controls at the limit of overweight according to WHO criteria. The median was 24.0 kg / m2. However, over 71% of cases compared to 62% of controls had a BMI below 25 kg / m2. Note that also a small proportion of cases (0.6%) had a BMI above 30 kg / m2. 2) and obese (BMI ≥ 30 kg / m 2) compared to those with BMI less than 25kg / m2 .The weight and height were collected and recorded for all cases and controls included in the study (522 samples). The mean BMI was 24.06 ± 3.11 kg / mThe present study shows that education level, marital status, positive family history of cancer, radiation exposure, consumption of: charcuterie, fresh fish, peanut, soybean and alcohol, habit of keeping money in brassiere and high a BMI are risk factors for BC in CAR. Occupation, residence, consumption of wine and groundnut oil, no habit of keeping cell phones in bras, physical activities and unsweetened coffee consumption were protective against BC.The mean age of BC patients in this study was 45.8 ± 13.5 years, which is slightly below the previous studies in Iran (47.6 ± 10.7 years) and confirms a younger age for BC development among Central African women .According to previous studies, socio-economic status was a strong predictor of health status . Indeed,With regard to education level and its association with BC, some studies have suggested that education level is associated with BC risk ,26. HoweOur study found that, coming from an urban environment decreased the risk of developing BC. However, we expected that there would be differences between rural and urban areas because of perceived differences in lifestyle in terms of diet and environmental factors. Our results are in disagreement with cancer epidemiology prevention in 2006 and rural urban differences in BC in India in 2014 that showed a higher risk of BC, respectively, among people living in an urban area and protector for those in the rural area ,29. On tAccording to this study, the risk of BC increases among married women compared to unmarried. The difference was statistically significant. Our results were corroborate form India in 2013, who reported that women who had an age of marriage more than 20 years had a 2.69 (95% CI: 1.77–4.07) times higher risk of BC . In contThe results of our study showed that positive family histories of BC are highly associated with BC. Especially the mother affected by BC is much more contested than other family members. Our results corroborate some previous studies worldwide which found that family history of BC is a factor associated with BC –35.The International Agency for Research on Cancer (IARC) and the World Cancer Research Fund (WCRF) found that diet strongly influences cancer prevention, and provided advice and recommendations for the management of body weight in BC for primary and secondary prevention . TraditiRecently, a meta-analysis study published by the National Institute of Public Health (NIPH) in Poland in 2015, showed no significant association between risk of BC and coffee consumption , or onlyIntensive surveys of several groups showed that the breast is one of the most sensitive organs to radiation effects . The resAccording to our results, groundnut oil consumption significantly reduces the risk of BC. However, consumption of charcuterie, fresh fish, groundnut and soybean was significantly associated with risk of BC. Our results disagree with a study in Mexico City published 2015, who asserted that large groundnut consumption significantly reduces the risk for BC by 2–3 times . RegardiIn our study, physical activity was associated with a risk reduction of BC; this confirms the results of prospective studies in the world –53. ConvHowever, we have found that a non-habit of keeping cell phones in bras significantly reduced BC risk 0.56 times. In contrast, women that used bras to keep money were 3.57 times more likely to achieve BC compared with those who did not have this habit. Indeed, some African women particularly in rural areas have the habit of using bras for a wallet; they completely ignore the fact that it may be a risk factor for BC. In view of the assumptions made, a more specific study will illuminate the effect of the composition of these items compared to BC. Similar studies have not been found to compare our results.2) or obese (BMI ≥ 30 kg /m2) and the incidence of BC has been found in numerous studies [According to the literature review, the higher BMI is significantly increased risk of BC, but with some differences in age and condition of menopause. The association between overweight (defined as a BMI of25 to 29.9kg /m studies ,56. Howe studies ,57. In a studies .Some limits must be considered to explain the results of this study. First, the study was carried out on a low population density of CAR; therefore known risk factors may be differing in the general population of women of Central Africa. Another limitation of this study is that the majority of the data was obtained from self-reporting of women. In addition, all information provided to investigators are not entirely reliable, because some questions were using memories such as family history of BC, average alcohol consumed and the duration of a practice session of physical activity. Note also that the quality of data obtained from relatives of deceased cases remains low. However, the results and limitations of the study are very useful in that they contribute to the ongoing research in the field of BC in CAR. In addition, this study was conducted in a developing country where changes in lifestyle can provide other important information about BC risk factors.Findings of this study have shown that educational level, marriage, positive family history of cancer, radiation exposure, consumption of charcuterie, groundnut, soybean, alcohol, habit of keeping money in bras, overweight and obesity were associated with BC risk among Central African women in Bangui. Women living in this region should be more cautious on the risk associated with BC. Further studies are needed to investigate other unknown determinants of BC. Finally, a public awareness concerning schooling, occupation, residence area, groundnut oil consumption, physical activities, wine consumption and no habit of keeping cell phone in bras which are protective factors against BC will be useful for the prevention and reduction in the incidence rate.The results suggest that lack of education and self-awareness in CAR women may be associated with low levels of self-reporting. The results suggest the need for further research to examine other likely behaviors to develop BC in women, and the roles that ethnicity and culture may play in their expression.


There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer.We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis.P = 0.03). We observed no association for ER-negative cases .BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01–1.22, Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases. Observational studies have reported an association between elevated body mass index (BMI) and reduced survival for women with breast cancer. However, the causal nature of the association is unclear.We conducted a large Mendelian randomization analysis in order to examine a potential causal effect of BMI on breast cancer survival, using both individual genotype data and summary data.Our study provides evidence that the reported association between BMI and survival for estrogen receptor-positive breast cancer is likely to be causal.Breast cancer is the most common form of cancer for women worldwide.,Mendelian randomization (MR)The aim of this study was to utilize germline genotype data for genetic variants known to be associated with BMI, in a breast cancer case-cohort to evaluate the association between BMI and breast cancer survival in an unbiased way. There are three assumptions under which genetic variants provide valid instrumental variables for the effect of BMI on breast cancer survival: first, the genetic variants are associated with BMI; second, the variants are not associated with any confounder of the BMI-breast cancer survival association (pleiotropy); third, the variants are conditionally independent of the survival, given the BMI and confounders (exclusion restriction).IJE online). Genotypes for common variants across the genome were imputed using a reference panel from the 1000 Genomes Project (March 2012) for each dataset. All patients provided written informed consent, and each study was approved by the relevant institutional review board. Data on age at diagnosis, vital status, breast cancer-specific mortality, follow-up time, time between diagnosis and blood draw, lymph node status, histological grade, tumour size and estrogen receptor status were also available. In addition, some case-cohorts from the COGS study provided data on height and weight (self-reported) at date closest to diagnosis (cases) or study entry (controls) for 65 582 participants. BMI was calculated as weight in kilograms divided by height in metres squared (kg/m2).We included six datasets where a genotyping array providing genome-wide coverage of common genetic variation had been used to genotype multiple breast cancer case-cohorts in populations of European ancestry . A summary of these case-cohorts has been described in detail previously.2 of all 94 single nucleotide polymorphisms (SNPs) in the breast cancer dataset is greater than 0.4.The Genetic Investigation of Anthropometric Traits (GIANT) consortium involving over 300 000 individuals of European descent has reported 97 common variants associated with BMI, of which three were only associated with BMI for men.We verified the first assumption of Mendelian randomization by evaluating the association between BMI GRS and BMI in a set of control subjects from the COGS study. MR analysis was performed using Cox proportional hazard models, to evaluate the associations of the BMI genetic risk scores with breast cancer-specific mortality based on 36 210 cases with 2475 events over 170 504 person-years of follow-up. The date of diagnosis was used to calculate time-to-event with follow-up being censored at death, last follow-up or 10 years, whichever came sooner. As several studies include prevalent cases, the date of study entry was used to determine time under observation in order to adjust for the potential bias of prevalent cases in a prospectively recruiting study (left-truncation).We assessed the relationship between BMI GRS and breast cancer survival using summary statistics for the association of each BMI- associated SNP with survival, for each dataset. We used both an inverse-variance weighted method and a likelihood-based method2  increase in BMI and explained 1.6% of the BMI variance (F statistic = 450). Self-reported BMI was significantly associated with breast cancer survival for both ER-negative and ER-positive disease in the COGS data (We observed strong positive associations between the BMI GRS and observed BMI using a set of 28 190 controls from the COGS study. A one-unit increase in GRS corresponds to a 0.94 kg/mOGS data . Both asP = 0.03) per one-unit increment of the GRS (P = 0.93).We performed MR analysis for all available ER-negative and ER-positive breast cancer cases. The GRS was found to be associated with reduced breast cancer-specific survival for ER-positive cases with hazard ratio (HR) of 1.11 . The differences between the estimated associations with genetic score for ER-positive and ER-negative were not significant (P = 0.07). The association between BMI and breast cancer survival was also evaluated using standard inverse-variance weighted meta-analysis of summary statistics for the association of each BMI-associated SNP with survival. The results were similar to those based on individual-level data , suggesting no overall directional pleiotropy. A funnel plot of the minor allele frequency-corrected genetic associations with the BMI against the individual causal effect estimates for each SNP shows little evidence for asymmetry .We tested each GRS SNP for association with either node status or grade or tumour size or stage. Sixteen of the BMI SNPs were associated with one or more of these variables. We then repeated the individual data MR analysis using a GRS-78 that excluded these SNPs. The magnitudes of the associations with ER-positive breast cancer were similar to those for the results based on all the BMI SNPs . However, there was no association between smoking and prognosis . It is unlikely that the association between smoking behaviour and BMI can explain the association between BMI GRS and prognosis.We explored a potential complex relationship between smoking behaviour, BMI and prognosis by investigating the association between BMI GRS and smoking behaviour and between smoking behaviour and prognosis. There was a very weak correlation between GRS and number of pack-years smoked , the genetic variants may be associated with these confounders for the subpopulation of breast cancer patients. This is due to conditioning on a collider: if BMI is a causal risk factor for breast cancer risk, then conditioning on breast cancer risk  means that all common causes of breast cancer risk (including the genetic variants and confounders) are conditionally associated. In simple terms, even if genetic variants are distributed randomly in the population as a whole, they are not necessary randomly distributed in the ascertained population of breast cancer patients. This may lead to bias in the analysis, although it is unclear how serious this bias might be. In order to evaluate the potential for collider bias, we performed a simulation study in which we simulated data on a genetic risk score and an exposure (BMI in our example) for 100 000 individuals. For each individual, we simulated whether that individual had a positive breast cancer diagnosis as a binomial random variable. For each individual with a positive breast cancer diagnosis, we simulated the time-to-event for breast cancer progression as an exponential random variable. The genetic risk score was simulated as a normally distributed random variable, as was the confounder (assumed unmeasured), and the independent error term. The probability of breast cancer diagnosis was modelled as a function of the exposure. This leads to the collider (selection) bias: individuals with a breast cancer diagnosis  will have higher average levels of the exposure and confounder than those not included. While collider bias was observed for extreme values of the effect of the risk factor on disease status, it was not observed for values that are in line with the effect of BMI on breast cancer diagnosis as observed in previous investigations. Hence, while we would be cautious not to generalize the result of this limited simulation study to other analysis contexts, in this case there seemed to be little potential for bias and type 1 error rate inflation to arise due to collider bias.While our results suggest a causal association between BMI and survival for women with ER-positive breast cancer, BMI is, in itself, a complex phenotype. It is conceivable that more specific phenotypes related to body fat composition and distribution might be better predictors of outcome. Untangling such complex relationships with survival will require data on the association between germline genetic variation and specific body fat composition and distribution phenotypes. Potential mechanisms underlying effects of obesity on breast cancer survival are mediators such as members of the insulin/insulin-like growth factor family, adipocytokines secreted from adipose tissue and inflammatory cytokines.Our study, based on data from multiple large-scale genetic association studies of breast cancer, provides evidence that the reported association between BMI and survival for ER-positive breast cancer is likely to be causal. This suggests that BMI reduction in overweight women with ER-positive breast cancer might improve clinical outcomes.IJE online.Supplementary DataClick here for additional data file.


The scientific and public debate concerning organized mammography screening is unprecedentedly strong. With research evidence concerning its efficacy being ambiguous, the recommendations pertaining to the age-thresholds for program inclusion vary between – and even within – countries. Data shows that young women who are not yet eligible for systematic screening, have opportunistic mammograms relatively often and, moreover, want to be included in organized programs. Yet, to date, little is known about the precise motivations underlying young women’s desire and intentions to go for, not medically indicated, mammographic screening.n = 918) from Switzerland.A cross-sectional online survey was carried out among women aged 30-49 years , perceived susceptibility , and ego-involvement  are the main predictors of screening intentions among women who are not yet eligible for the systematic program. Also, geographical location  and age  play a role. In turn, breast cancer knowledge, risk perceptions, and educational status do not have a significant impact.The findings show that high fear (Young women seem to differ inherently from those who are already eligible for systematic screening in terms of the factors underlying their intentions to engage in mammographic screening. Thus, when striving to promote adherence to systematic screening guidelines – whether based on unequivocal scientific evidence or policy decisions – and to allow women to make evidence-based, informed decisions about mammography, differential strategies are needed to reach different age-groups. Since the publication of the findings of the 25-year Canadian National Breast Screening Study (CNBSS) in February 2014, the scientific and public debate concerning organized mammography screening has flared up. The results of the CNBSS suggest that annual screening of women aged 40 to 59 years does not reduce breast cancer mortality beyond that of physical examination or usual care and that, as a result, policy makers should urgently reassess the rationale for mammography screening . TogetheCurrently, many countries in Western Europe and North America offer organized breast cancer screening programs. Reflecting the lack of scientific consensus about screening efficacy, the precise recommendations pertaining to the age-thresholds for program inclusion vary. In the United States, the Preventive Services Task Force advises women between the ages of 50 and 74 to undergo a biennial screening mammography , while tRecent studies suggest that, in the face of conflicting research evidence and diverging recommendations, young women (30-49) often do not accept the lower age-thresholds for screening and advocate their right to be included in organized screening programs –15. In fThere are several possible explanations for young women to seek mammographic screening against official recommendations and in absence of medical indications. First, women may not be aware of the lower age-thresholds. Breast cancer (screening) knowledge has been shown to be one of the key predictors of screening intentions among older women –23. SecoTo date, relatively little research has been done to investigate the precise motivations underlying young women’s intentions to go for mammographic screening prior to program eligibility . Yet, suIn January 2015, a cross-sectional survey was conducted across all Swiss cantons among a sample of 918 Swiss female residents , aged 30 to 49. Participants were recruited in collaboration with Polyquest, a Swiss-based market research agency that uses participant panels. The response rate was relatively low (16.5%) and the drop-out rate was high (26.25%). This was assumed to be due to survey length and sensitivity of the topic. Moreover, it was not allowed for participants to skip questions. While it was not possible to access personal data of those who had interrupted the survey, the sample ensured to provide a reflection of this particular segment of the Swiss population in terms of socio-demographics, including age, marital status, education, occupational status, and geographical location. For analytical purposes, the French- and Italian-speaking regions of Switzerland were oversampled relative to the German-speaking region. The overall sample size was determined on the basis of power calculations.Prior to filling out the survey, participants were informed that the study was aimed at improving the understanding of women’s views on and concerns about breast cancer and organized mammographic screening programs. Moreover, they were notified that the study had been funded by the Swiss National Science Foundation and that the protocol had been reviewed and, where applicable, approved by the relevant ethical committees . As approved by the ethics committees and following standard practice of the surveying partner, all participants provided informed consent within the online surveying tool and selected their preferred surveying language  by clicking ‘next’. The survey took approximately 30 min to complete and had to be filled out in one sitting.n = 22) confirmed the comprehensibility, accuracy, and feasibility of the online questionnaire.The survey consisted of standardized socio-demographic questions and validated scales. When necessary, the measures were adapted or newly developed, e.g., to account for the Swiss breast cancer (screening) context. All measures were translated from English to German, French, and Italian using a back-translation procedure. A pre-test  statistic was used. This statistic provides an index of test reliability for scales consisting of dichotomous items. The internal consistency of the overall 25-item scale was low, with KR20 = .36 .Knowledge scores were computed for each of the subscales and were expressed as the percentage of correctly answered questions. Biserial correlations of each separate item with the total score of the subscale were computed to determine the unidimensionality of each subscale. Items belonging to the Breast cancer fear was assessed using the validated instrument developed by Champion and colleagues . This meParticipants’ risk estimates were measured in two ways. Following Daly and colleagues , subjectYoung women’s involvement with breast cancer screening practices was assessed using an adaptation of Zaichkowsky’s personal involvement inventory – an attitude measure based on semantic differentials . While ZParticipants’ intention to have a mammogram was measured in two ways. First, participants were asked to respond to the statement “I intend to have (another) screening mammogram to check for breast cancer in the near future”, using a 5-point Likert scale (strongly disagree - strongly agree), adding the option ‘I have not yet thought about this’. Unless participants chose this last option, they were additionally asked at what age - provided that their health status would remain the same – they would consider to have a (next) mammogram.p-values. A p-value of < .05 was considered as statistically significant.Data were analyzed using the statistical package SPSS . To test the associations between the variables of interest, Pearson’s correlation coefficient was used. Hierarchical multiple linear regression was performed to adjust for potential confounders and to order the importance of predictor variables. Variables were entered block-wise and in hierarchical order, starting with socio-demographic (control) variables (block 1), then adding the presumed predictors in a step-by-step procedure based on theoretical assumptions of causality and importance: perceived risk and susceptibility (block 2), perceived fear (block 3), and ego-involvement and knowledge (block 4). The results of the regression are reported with 95% confidence intervals and Md = 39, Mo = 36, SD = 5.88, range: 30-49). 82.4% of participants indicated to have the Swiss nationality. Overall, 59.9% of participants hailed from the German-speaking region of Switzerland, 29.8% from the French-speaking region, and 10.2% from the Italian-speaking region. These numbers were reflected by participants’ choice of survey language . Cantons Zurich (14.1%), Berne (11.2%), and Vaud (11.1%) were most represented. In terms of screening availability, 52.18% of the participants lived in a canton which offered a systematic screening program at the time of the survey, while 47.82% lived in a canton offering opportunistic screening.Participants were on average 39.37 years old (Most participants were married or in a stable relationship (63.8%). 21.7% of the participants were single, 14.5% divorced, separated, or widowed. With regard to their educational background, 8.3% of the participants indicated to have a middle school degree, 62% a professional or high school degree, 15.4% a degree from a university of applied sciences, and 14.2% a degree from a (polytechnic) university. Of all participants, 0.2% indicated not holding any degree. The majority of participants were (self)employed (57.6%). 25.4% of participants were homemakers, 8.8% were unemployed (of which 7.6% in search of employment), 0.7% were students, and finally 0.4% were pensioners.SD = .88, range: 1-5). As expected, having been diagnosed with a chronic disease significantly impacted self-perceived health  = 129.39, p ≤ .001, η2 = .13). Furthermore, 27% of all participants indicated to have had a mammogram in the past. Lastly, 58 participants had been previously diagnosed with breast cancer (2.8%) or with a genetic predisposition to get this disease (3.5%). These participants were removed from the sample for subsequent analyses. See Table Participants evaluated their overall health as relatively good: On a scale ranging from 1 (“very poor”) to 5 (“very good”), participants scored an average of 3.74 , with a range between 28% and 96% corresponding to a minimum of seven and a maximum of 24 correct answers. In terms of general knowledge, women answered on average 66.9% of the questions correctly . The scores for curability knowledge were higher, with an average score of 78.1% . Lastly, with regard to Swiss program knowledge, women scored on average 68.2% . Close examination of the individual items revealed that while participants performed well on most questions, notably some questions elicited more erroneous than correct responses. These questions pertained in particular to the risk factors for developing breast cancer. Overall, participants displayed a lack of knowledge of known risk factors, such as being overweight, living in a Western country, and age. More specifically: 54.1% of participants did not know that being overweight is a risk factor for breast cancer; 56.3% of women were not aware that breast cancer is more common in Switzerland than in Africa and Asia. Moreover, 52.9% of participants answered (erroneously) that women without known risk factors rarely develop breast cancer. Further, 57.3% did not know that breast cancer is more prevalent under women aged 65 than 40. This latter finding was emphasized by the result that 42.1% of participants thought that women over 70 rarely develop breast cancer. In addition, 57.6% of women stated that mammograms are pain free. Lastly, participants were unaware of the age-thresholds for organized screening in Switzerland: The majority of participants (64.1%) answered that Swiss programs invite women from the age of 40 onward.Participants were relatively knowledgeable about breast cancer and mammography screening. On average, women answered 70.8% of the knowledge questions correctly, . Overall, 13.7% of the participants were characterized by low (score: ≤ 15), 30.2% by moderate (score: 16-23), and 56% by high levels of fear (≥24). When asked about their personal risk of developing breast cancer, participants on average estimated this at 20.45% , equivalent to a chance of 1 in 4.89. Participants’ self-perceived susceptibility to get breast cancer, however, was relatively low with a mean score of 2.24 .At the same time, participants appeared fearful of breast cancer and over-estimated their risk of getting breast cancer. On average, participants scored a 23.41 on the breast cancer fear scale, with scores ranging between eight and 40 . This implies that these women deem mammography screening of very high relevance to them personally and thus seem to have a very positive attitude towards mammography screening – despite their young age.Participants also appeared to be highly involved with the topic of breast cancer screening (N = 860) indicated to not have thought about that yet. Among those who responded to the statement, 44.2% indicated to (strongly) disagree, 21.2% to neither agree nor disagree; and 34.5% to (strongly) agree. On average, these respondents scored a 2.90 . When asked at what age they intend to have their (next) screening mammogram (N = 773), 272 women (35.2%) answered they do not plan to have a mammogram at all. The remaining women, indicated an average age for a (next) mammogram of 45.50, with a mode of 50 . In total, 56.7% of respondents indicated the intention to have (another) screening mammogram below the age of 50, thus below the lower age threshold for systematic screening in Switzerland . In the Swiss-Italian region the indicated average age was 44.10 , in the Swiss-German region 45.62 , and in the Swiss-French region 45.84 .Finally, when asked to respond to the statement “I intend to go for mammography screening in the near future”, 87 participants (r(858) = .24, p ≤ .001). Perceived susceptibility to get breast cancer, as well, was strongly correlated with breast cancer risk perceptions and fear (r(858) = .54, p ≤ .001); (r(858) = .49, p ≤ .001), respectively). Breast cancer fear and susceptibility, in turn, were moderately correlated with participants’ ego-involvement with breast cancer screening (r(858) = .32, p ≤ .001); (r(858) = .30, p ≤ .001). That is, participants who perceived themselves as fearful and highly susceptible to breast cancer judged mammography as more relevant to them personally and, thus, had a more positive attitude towards screening. Finally, the intention to go for screening in the near future was strongly associated with participants’ ego-involvement (r(771) = .45, p ≤ .001), their perceived susceptibility (r(771) = .29, p ≤ .001), and fear (r(771) = .29, p ≤ .001). The results show an association between participants’ involvement, fear, and perceived susceptibilityand their intention to engage in screening in the near future. In Table In a first step, the strength of the relationships between the variables of interest was tested. No meaningful associations were found between breast cancer knowledge and any of the other variables, including the main outcome variable ‘mammography intentions’. This applied to overall knowledge scores as well as to the three subscales. Bivariate correlation analyses revealed a significant, weak relationship between young women’s fear of breast cancer and their risk perceptions, as such that higher risk perceptions were associated with higher levels of fear , breast cancer fear , perceived susceptibility , geographical location , and age . Together, these variables explain 32% of the variance  = 38.78, p ≤ .001). Breast cancer knowledge, risk perceptions, and educational status did not significantly contribute to the final model  the Comprehensive Breast Cancer Knowledge Test and have reported varying KR20 results , 41. It While ample studies have been dedicated to identifying the factors underlying women’s intentions to engage in breast cancer screening, these studies have predominantly focused on those women who are indeed eligible for screening. Instead, this study investigates what motivates young women’s premature opportunistic screening behaviors among a sample of Swiss participants aged 30 to 49. This target group is of high relevance for several reasons. As these women form the potential screening population of the future, it is helpful to understand what motivates their behavior prior to inclusion in systematic screening programs. After all, these women are not only exposed to extensive media coverage about breast cancer (screening), but also to campaigns promoting mammography screening among the actual target group. As such, their opinions may be shaped by these campaigns and, potentially and partially, be induced by fear. Data shows that young women engage in opportunistic screening relatively often and, moreover, are of the opinion that they should be included in organized screening programs , 17, 19.The present study demonstrates that young women are indeed inherently different from women who are eligible for screening in terms of what drives their mammography behaviors. Among young women, breast cancer fear, perceived susceptibility, and mammography involvement were found to be the main predictors of screening intentions. Breast cancer knowledge was not found to be predictive of their intention to engage in mammography. Additionally, young women did not always correctly identify breast cancer risk factors. Taken together, this implies that in order to successfully promote adherence to screening guidelines – whether these are based on unequivocal scientific evidence or policy decisions – different public health communication strategies must be developed for women of different age groups. In doing so, efforts should be directed towards informing young women about the correct age-thresholds for mammography, correcting their erroneous beliefs about breast cancer and screening, and reducing excess levels of fear and involvement. Meanwhile, attention should be paid that women are not necessarily discouraged to engage in organized screening once they have reached program eligibility. To do so, public health efforts should be supported by patients’ interpersonal exchanges with their own providers. Overall, the findings suggest that, rather than a rational and knowledge-oriented approach, a targeted approach that takes young women’s underlying motivational orientation and psychological distance into account, could be promising when designing interventions to justify and promote public health decisions concerning the age-thresholds for mammography. Moreover, effective communication interventions will allow young women to make better-informed decisions about screening, both now and in the future.


Breast cancer incidence and survival is high, which results in high prevalence of breast cancer survivors. The risk of (death from) cardiovascular disease (CVD) is higher in patients exposed to cardiotoxic treatments, in particular if they have pre-existing CVD risk factors. This study systematically summarized the risk of death from CVD following breast cancer.Databases of Medline, Embase, and the Cochrane Library were systematically searched using the following terms and synonyms: breast cancer, cardiovascular disease, and cause of death. Articles reporting on both risk and risk factors of CVD mortality following breast cancer were eligible for inclusion. The methodological quality of each article was assessed using the Newcastle Ottawa quality assessment scale for cohort studies.Fourteen articles were included assessing the risk of CVD mortality among 1,217,910 women with breast cancer. The methodological quality was high for the majority of the studies. Studies were heterogeneous in design, study population, length of follow-up, CVD outcomes, and risk factors. 1.6–10.4% of all women with breast cancer died of CVD. Women with breast cancer had a higher risk of CVD mortality than women from the general population. The risk of CVD mortality was higher among women with breast cancer with older age at diagnosis, left-sided tumor, diagnosis in an earlier calendar period, and black ethnic origin.CVD is an important cause of death following breast cancer. Identification of patients at high risk of CVD is important to optimize CVD prevention and tailor breast cancer treatment. Breast cancer incidence has increased substantially over the last decades , 2, whicThe risk of (death from) CVD following breast cancer is increased in women exposed to cardiotoxic treatments such as mediastinal and left-sided radiotherapy, anthracycline-based chemotherapy, and trastuzumab, and is even higher in patients with pre-existing CVD risk factors such as diabetes and hypertension –12. WithAs an overview of the available evidence on the risk of dying of CVD in women with breast cancer is currently lacking, we systematically reviewed the literature on the risk and risk factors of death from CVD following breast cancer.This systematic review was conducted in accordance with the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) guidelines .A systematic search was performed, and last updated on April 1, 2017, to identify all studies reporting on the risk and risk factors of death from CVD following breast cancer. Databases of Medline (via PubMed), Embase, and the Cochrane Library were systematically searched using the following terms and their synonyms in the search strategy: breast cancer, cardiovascular disease, and cause of death  published before 1990, (2) written in another language than English or Dutch, (3) case reports, reviews, or abstracts. Cross-referencing was performed.After removal of duplicates, all titles and abstracts of the remained retrieved articles were screened. Abstracts that seemed potentially relevant, based on the in- and exclusion criteria, were screened for full text. The full text of these articles were assessed for eligibility by three investigators independently . Data were extracted using standardized data extraction forms and any disagreements were resolved by discussion. We extracted data on study size, characteristics of breast cancer patients , study design, International Classification of Diseases (ICD) codes for CVD mortality, absolute risk of death from CVD, absolute risk of death from breast cancer, absolute risk of death from any cause, statistical methods used to assess which factors increase the risk of death from CVD, and the risk of CVD mortality per risk factor.The methodological quality for each article was assessed by two authors independently (S.A.M. Gernaat and P.J. Ho) using the Newcastle Ottawa Quality Assessment Scale (NOS) for cohort studies . The NOSn = 3) or articles that did not report the risk and risk factors of death from CVD (n = 24). Cross-referencing identified two additional papers. In total, 14 articles were included in the current systematic review, including 4,773,576 women of which 1,217,910 were diagnosed with breast cancer [The systematic search yielded 10,170 citations including 5911 unique articles, which were screened for title and abstract using the predefined inclusion and exclusion criteria : <18.5) and obesity (BMI: ≥ 30), respectively, compared with women with a pre-diagnosis normal weight (BMI: 18.5–24.9) (Table Nichols et al.  includedy BMI: ≥ 0, respecVeal et al.  includedIn this review, we systematically summarized the evidence on the risk and risk factors of death from CVD following breast cancer.The absolute risk of dying of CVD following breast cancer ranges from 1.6%  to 10.4%Several mechanisms are proposed for the increased risk of CVD mortality in women with breast cancer. CVD risk factors, such as obesity and diabetes, may be more present among breast cancer survivors than women from the general population as breast cancer and CVD have shared risk factors . Also, cIn the current review, studies with longer follow-up, i.e. over 10 years , 6, 8, rThe association between left-sided breast cancer and radiotherapy treatment with a higher risk of CVD mortality was found among women diagnosed in the early 1980’s , 24, 26.The present systematic review shows that there are only a limited number of studies investigating the risk and risk factors of CVD mortality following breast cancer, and that these studies are heterogeneous in design, study population, and length of follow-up. Also, the determinants and outcomes, in terms of CVD risk factors and death due to CVD, respectively, vary. We acknowledge that, due to the heterogeneous designs of the included studies, we were unable to perform a meta-analysis, which limited the strength of evidence. Besides limitations, the current review has strengths. This is the first study that systematically summarized the literature on the risk and risk factors of death from CVD following breast cancer. Furthermore, the current systematic review includes a large variety of risk factors of death from CVD in women with breast cancer.To conclude, the combination of high breast cancer incidence, improved breast cancer survival, presence of CVD risk factors, and cardiotoxic breast cancer treatments has resulted into many breast cancer survivors at risk of CVD. Therefore, it is important to understand the incidence and etiology of CVD in these survivors. Furthermore, identification of women with breast cancer at high risk of CVD is important to minimize the number of women suffering and/or dying of CVD after breast cancer treatment and improve quality of life and long-term prognosis. Clinicians should be able to identify breast cancer patients at increased risk of CVD and provide accurate recommendations for CVD risk reduction strategies specifically for breast cancer survivors at high risk of CVD. The current systematic review, in combination with a recent guideline by Armenian et al.  on the p