Supplemental periconceptional folic acid is recommended to reduce the risk of fetal neural tube defects. A previous report indicated an elevated risk of breast cancer and all cancer deaths in later life among women randomised by alternate allocation to high-dose (5 mg/day) folic acid in pregnancy compared with placebo; however, findings were based on small numbers of cases. Our aim was to extend the previous analysis by including data from an additional 10 years of follow-up.Records of participants in a large (n=2928) trial of folate supplementation  in pregnancy in the 1960s were linked to central registries in Scotland. Unadjusted and adjusted HRs were calculated for all-cause, cardiovascular, all cancer and breast cancer mortality, and all cancer and breast cancer morbidity. Analyses were done using (1) data from the time of the previous linkage (2002) to March 2013; and (2) data from 1980 to March 2013.There was no evidence to suggest an excess risk of morbidity or mortality in either supplementation group compared with placebo for 2002–2013 and no associations were seen for the full time period (1980–2013).Findings from this extended follow-up do not support our previous observation of an elevated risk of mortality from breast cancer or all cancers in later life among women who had taken 5 mg folic acid/day during pregnancy. Furthermore, there were no associations with risk of mortality from all-causes, all cancers or cardiovascular disease. Folate (found in foods) or folic acid (synthetic form) acts as a coenzyme in several single-carbon transfers. These transfers lead to the synthesis of purine nucleotide and deoxythymidylic acid which, in turn, are essential for DNA and RNA synthesis. It is well established that periconceptional folic acid supplementation substantially reduces the risk of neural tube defects in offspring.712 deficiency, neurotoxicity, drug interactions, reduced zinc absorption and hypersensitivity reactions.9The synthetic form of folic acid is nearly twice as bioavailable as folate occurring naturally in food and is more stable. Supplementation therefore leads to relatively higher blood levels of the unmetabolised form that remains in the blood for longer than the natural form.It has also been suggested that there is an association between increased folic acid intake and cancer promotion,Folic acid supplementation may, however, be protective against cardiovascular disease (CVD): high levels of homocysteine have been associated with an increased risk of CVD, and folic acid supplementation is known to reduce homocysteine levels.23The long-term effects of folic acid supplementation during pregnancy on maternal mortality and morbidity in later life have not been well studied. In a previous follow-up of a large (n=2928) trial of folic acid supplementation in pregnancy from the 1960s it was shown that randomisation to a high dose of folic acid  was associated with a higher risk of mortality from cancer  and possibly breast cancer specifically  in later life.The parent study has been described in detail elsewhere.28For determination of the primary outcomes , records of the participants in this trial were linked to those held by the Scottish NHS Central Registry in Edinburgh to provide data on vital status and cause of death for those who had died from January 1980 to March 2013. As per the previous follow-up, the cause of death was assigned using the following codes: cardiovascular mortality International Classification of Diseases, Ninth Revision (ICD-9) 410–414, 430–439 and ICD-10 120–125, 160–169; all cancers ICD-9 140–208, ICD-10 C00–C97; breast cancer ICD-9–174, ICD-10–C50). For determination of the secondary outcomes , the records of participants were also linked to the Scottish Morbidity Records (SMR), specifically to the hospital admissions (SMR01) and cancer registrations (SMR06), using both deterministic matching on the Community Health Index (CHI) numbers and probabilistic matching on names, dates of birth and postcodes of residence. The SMR registers are held by the Information and Services Division (ISD) of National Health Service (NHS) Scotland.et al.Baseline data were summarised as means and SD (continuous data) or number and percentage . We calculated unadjusted and adjusted HRs for the primary and secondary outcomes using Stata v.13.1 . In contrast to our previous data linkage we do not have data on mortality prior to 1980 as the costs of obtaining such data were prohibitive. We are therefore unable to completely replicate the findings that were presented in Charles The baseline characteristics of the women in the three treatment groups were broadly comparable , with thIn this extended follow-up of women who had participated in the Aberdeen folate trial in the 1960s, we did not see any strong evidence of an association between either dose of folic acid taken during pregnancy and mortality from cancer or CVD in later life.In the previous analysis,A ‘dual effect’ theory for the effects of folic acid has previously been proposed by KimPregnancy is likely to be to be a critical time for the determination of risk of subsequent breast cancer. To the best of our knowledge, no other studies have undertaken a long-term follow-up after folic acid supplementation in pregnancy, a time during which breast tissue undergoes anatomical changes in response to hormonal action and develops the ability to secrete milk.Meta-analyses have provided conflicting information on the role of long-term folic acid supplementation or dietary intakes in non-pregnant participants on overall cancer incidence and site-specific cancers. A recent meta-analysis of randomised trials found no effect of 5 years of supplementation on the overall cancer incidence or incidence of site-specific cancers .MTHFR gene, which may be related to the risk of colorectal and other gastrointestinal cancers.40Our study has a number of strengths. The parent study was a randomised controlled trial that included random allocation  was associated with a higher risk of mortality from cancer and possibly breast cancer specifically. However, the analyses were based on relatively small numbers of cases and the findings may have been due to chance.We did not find any strong evidence to suggest an effect of either dose of folic acid taken during pregnancy on mortality from all-causes, cancer or cardiovascular disease in later life with an extended follow-up time. Further data linkage studies should be conducted in the future to confirm whether this remains the case with a longer period of follow-up and additional deaths.We did not find any strong evidence to suggest an effect of either dose of folic acid taken during pregnancy on mortality from all-causes, cancer or CVD in later life, or on morbidity from all cancer or breast cancer. Further data linkage studies could be conducted in the future to confirm whether this remains the case with a longer period of follow-up and additional deaths.


Background. Cancer and cardiovascular diseases are the leading causes of mortality and morbidity worldwide. The purpose of this meta-analysis is to synthesize the evidence evaluating the association between obesity and 13 cancers shown previously to be significantly associated with obesity. Methods. Relevant papers from a previously conducted review were included in this paper. In addition, database searches of Medline and Embase identified studies published from the date of the search conducted for the previous review  until May, 2011. The reference lists of relevant studies and systematic reviews were screened to identify additional studies. Relevance assessment, quality assessment, and data extraction for each study were conducted by two reviewers independently. Meta-analysis was performed for men and women separately using DerSimonian and Laird's random effects model. Results. A total of 98 studies conducted in 18 countries from 1985 to 2011 were included. Data extraction was completed on the 57 studies judged to be of strong and moderate methodological quality. Results illustrated that obese men were at higher risk for developing colon (Risk Ratio (RR), 1.57), renal (1.57), gallbladder (1.47), pancreatic (1.36), and malignant melanoma cancers (1.26). Obese women were at higher risk for esophageal adenocarcinoma (2.04), endometrial (1.85), gallbladder (1.82), renal (1.72), pancreatic (1.34), leukemia (1.32), postmenopausal breast (1.25), and colon cancers (1.19). Conclusions. The results of this meta-analysis illustrate a significant, positive, and, for some cancers, strong association between obesity and cancer incidence. Given that approximately 23% of Canadians are obese, a significant proportion of cancer in Canada could be avoided if obesity was eliminated or significantly reduced. Chronic diseases are the leading cause of mortality and morbidity and contribute significantly to the overall health expenditures from both a societal perspective as well as an individual one . Common 2 or greater. Approximately a quarter of Canadian men and women are considered obese /[1 + P(RR − 1)], where, P is the population prevalence of obesity, and RR is the pooled risk ratio . The mosIn total 141 articles were identified from Renehan et al., 1723 from the database searches and 69 from reference lists; the total is 1933 papers. Of the 141 articles included in Renehan et al., 94 articles were relevant to the 13 cancers included in this paper. The remaining 47 articles from Renehan et al's review explored the association between obesity and cancers other than the thirteen of interest in this paper, and therefore were excluded. Of the 1723 articles identified in the database searches, 75 were judged to be relevant. Finally, of the 69 articles identified from the reference lists of relevant studies, 33 were deemed relevant. A total of 202 articles were deemed relevant for this paper. When papers were grouped according to independent studies, a total of 101 unique studies were relevant. The Kappa score for agreement between reviewers on relevance assessment was 0.835, indicating high agreement. Reasons studies found to be not relevant were data not reported on the 13 cancers, and/or the association between obesity and cancer in adults aged 18 years and older was not the focus of the study.One hundred and one studies were assessed for methodological quality. It was identified during quality assessment that three studies  reported data in a way that was inconsistent with the other studies, therefore could not be aggregated with other studies. These studies were excluded from the meta-analysis. Of the remaining 98 studies one was assessed as being of strong methodological quality, 56 were rated as moderate and 41 as weak. Data was extracted on the 57 strong and moderate studies. The following criteria distinguished strong and moderate studies from weak studies: strong and moderate studies tended to use measurement tools with proven validity and reliability, demonstrated that obesity preceded cancer incidence, and established a dose-response gradient. Studies of weak methodological quality rated poorly on these criteria as well as research design. A summary of the quality assessment of the 57 studies included in the meta-analysis is presented in The study designs included 43 cohort and 14 case-control studies published between 1985 and 2011. The majority of studies were conducted in the United States (19), followed by Sweden (7), Norway (4), and Japan (5). Most studies had follow-up rates of 80% or greater. Education level ranged from primary school to postsecondary. Among the cohort studies participants were followed up between 6 and 39 years. P = 0.68). The pooled risk ratio illustrated that obese women had an increased risk of colon cancer compared to women of normal weight . There was significant heterogeneity observed across studies (heterogeneity P = 0.08). Sixteen studies were included in the meta-analysis assessing the association between obesity and colon cancer among men  and 13 sP = 0.00001). The pooled risk ratio from 16 studies illustrated that obese women had an increased risk of endometrial cancer compared to women of normal weight  . There wP = 0.02). Among obese women, however, the pooled risk ratio indicated a sizable increased risk of esophageal adenocarcinoma compared to women of normal weight . There was significant heterogeneity across studies (heterogeneity P = 0.003).There were 3 studies that assessed the association between obesity and esophageal adenocarcinoma in men  and 4 stP = 0.77). Similarly, among obese women the pooled risk ratio demonstrated an increased risk of gallbladder cancer compared to women of normal weight . There was no significant heterogeneity across studies (heterogeneity P = 0.15). There were 3 studies each assessing the association between obesity and gallbladder cancer in men  and womeThere were 2 studies that assessed the association between obesity and leukemia among men  and womeP = 0.28). The pooled risk ratio for obese women showed no increased risk of malignant melanoma compared to women of normal weight . There was no significant heterogeneity across studies (heterogeneity P = 0.83).Four studies assessed the association between obesity and malignant melanoma among men  and 3 amP = 0.39). Only one study for men  and two P = 0.46). Among obese women, however, the pooled risk ratio showed a reduced risk of non-Hodgkin lymphoma compared to women of normal weight . There was significant heterogeneity across studies (heterogeneity P = 0.0001). Four studies in men  and six P = 0.01). Among obese women the pooled risk ratio also showed an increased risk of pancreatic cancer compared to women of normal weight . There was no significant heterogeneity across studies (heterogeneity P = 0.81). Nine and ten studies, respectively, assessed the association between obesity and pancreatic cancer in men  and womeP = 0.0001).Eleven studies assessed the association between obesity and postmenopausal breast cancer . The pooP = 0.00001). Similarly among obese women the pooled risk ratio illustrated no increased risk of rectal cancer compared to women of normal weight . There was significant heterogeneity across studies (heterogeneity P = 0.00001). There were 11 studies for men  and nineP = 0.76). Similarly, among obese women the pooled risk ratio illustrated an increased risk of renal cancer compared to women of normal weight . There was no significant heterogeneity across studies (heterogeneity P = 0.22). There were 3 studies each for men  and womeP < 0.00001). Likewise, among obese women the pooled risk ratio demonstrated no increased risk of thyroid cancer compared to women of normal weight . There was significant heterogeneity across studies (P < 0.004). There were 6 studies included in the meta-analysis assessing the association between obesity and thyroid cancer among men  and 4 stAs an example to illustrate the use of meta-analysis results reported in this study, the PAR% for men and women in Canada was calculated on cancers for which a statistically significant association between obesity and cancer incidence was observed . The popAmong women PAR% ranged from a low of 4.2% to a high of 19.4%. The PAR% for obesity among women was greatest for esophageal adenocarcinoma (19.4%), endometrial (16.5%), gallbladder (16%), and renal cancer (14.3). When the 95% confidence intervals for PAR% for women are considered the results are also noteworthy. For example, at the upper limit of the confidence interval, PAR% was as high as 37.2% for esophageal adenocarcinoma, 27.7% for endometrial cancer, and 25.8% for gallbladder cancer. However, at the lower limit the PAR% was as low as 0.9% for colon cancer, 1.6% for postmenopausal breast cancer, and 1.8% for malignant melanoma.The results of this meta-analysis demonstrate a significant association between obesity and some of the 13 cancers for men and many of the 13 cancers for women. Obesity was significantly and positively associated with 5 of the possible 11 cancers relevant to men including, colon, gallbladder, malignant melanoma, pancreatic, and renal. A significant association was not observed among obese men for esophageal adenocarcinoma, leukemia, multiple myeloma, non-Hodgkin lymphoma, rectal, and thyroid cancer. Among women obesity was significantly and positively associated with 8 of the 13 cancers including, colon, endometrial, esophageal adenocarcinoma, gallbladder, leukemia, pancreatic, postmenopausal breast, and renal cancer. A significant association was not observed among women for malignant melanoma, multiple myeloma, non-Hodgkin lymphoma, rectal cancer, and thyroid cancer. The magnitude of the associations between obesity and cancer incidence in men and women, including the 95% confidence intervals, is particularly noteworthy. For example, obese men have an increased risk of developing colon and renal (RR both 1.57), gallbladder (1.47), pancreatic cancer (1.36), and malignant melanoma (1.26) in comparison to nonobese men. When the 95% confidence intervals are considered the results become even more compelling. For example the risk ratio is as high as 1.77 for renal cancer, 1.73 for pancreatic cancer and 1.65 for colon cancer. Even at the low end of the 95% confidence interval, cancer risk is still noteworthy at 1.48 for colon cancer, and 1.38 for renal cancer. The results for obese women are equally concerning. Obese women are not only at higher risk for developing cancer at more sites than men, the risk associated with some of the cancers is significantly higher. For example, obese women have an increased risk for developing esophageal adenocarcinoma (RR 2.04), endometrial (1.85), gallbladder (1.82), and renal cancer (1.72). Where statistically significant associations are observed only one risk ratio is less than 20% (colon 1.19), while the remaining risk ratios range between 1.25 , 1.32 (leukemia), and 1.34 (pancreatic). The 95% confidence intervals are also alarming. For example, at the upper limit of the confidence interval the risk ratio is as high as 3.55 for esophageal adenocarcinoma, 2.65 for endometrial, and 2.50 for gallbladder cancer. The results also clearly demonstrate that a significant proportion of cancer incidence could be avoided, in Canada, by reducing the percentage of obese adults. The population-attributable risk percent for obesity in Canada was highest in men for five cancers: colon, renal, gallbladder, pancreatic, and malignant melanoma. Significant reductions in obesity therefore would dramatically decrease the incidence of those cancers. For women the greatest benefits from obesity reduction and prevention efforts would be observed for esophageal adenocarcinoma, endometrial, gallbladder, renal, pancreatic, leukemia, postmenopausal breast, and colon cancer. Significant reductions in these cancers for men and women in Canada would result in decreased health care expenditures and improved quality of life for many men and women in Canada. When the results of this meta-analysis are compared to those of Renehan et al. , who revThere was greater similarity between the results of this paper and Renehan et al. for women. For example, there were only two cancers, multiple myeloma and thyroid cancer where Renehan et al. reported a positive and significant association with obesity for women, and this paper did not. There were no differences for the remaining eleven cancers on the relationship between obesity and cancer in women. The second important difference between the two meta-analyses concerns the observed magnitude of the association and the coinciding 95% confidence intervals. Generally the results of our meta-analysis demonstrated higher magnitude of associations and confidence intervals. The most notable differences occurred for four cancers among men: renal, colon, pancreatic, and gallbladder cancer. For example, we reported a pooled risk ratio and 95% confidence interval of 1.57  for renal cancer, while Renehan et al. reported 1.24 . Likewise, for colon cancer, we reported 1.57 , while Renehan et al. reported 1.24 , and for pancreatic cancer, we reported 1.36  and Renehan et al. reported 1.07 . Finally, for gallbladder cancer, we reported 1.47  while Renehan et al. reported 1.09 . Similar differences existed for obese women with the greatest differences in the pooled risk ratios and 95% confidence intervals being for three cancers: endometrial, renal, and gallbladder. For these cancers the magnitude of associations we reported is larger than those reported by Renehan et al. For endometrial cancer we reported a risk ratio of 1.85 , while Renehan et al. reported 1.59 . For renal cancer we reported 1.72  while Renehan reported 1.34 , and for gallbladder cancer we reported 1.82  and Renehan, 1.59 . There was only one cancer where Renehan et al. reported a larger risk ratio than we did, which was for non-Hodgkin lymphoma. There are some plausible explanations for these differences. Likely the most significant factor contributing to the differences in the results of the two meta-analyses are the different approaches to the statistical methods used to aggregate the data across studies. The approach used by Renehan assessed the risk in developing cancer as BMI increased every 5 points, from the lowest BMI category up to the highest category. This strategy incorporates the risk of those who have a BMI slightly above normal, to above normal to those identified as obese. Given the risk of developing cancer at lower BMI levels is generally less than that of obese persons which provides some explanation why Renehan et al's results generally illustrate lower overall risk and more narrow confidence intervals. In this paper we compared the risk of developing cancer between those in the lowest BMI category  and those considered obese (BMI 30+) category. Our meta-analysis therefore did not incorporate into the pooled risk ratio and 95% confidence intervals, the risk associated with developing cancer among those with slightly above normal and above normal BMI. Given the primary objective of this paper was to assess the relationship between obesity and cancer incidence we believe this was the most appropriate statistical analysis to answer the research question. The question Renehan et al. answered was broader in that they were interested in assessing across the spectrum of BMI from normal to obese, the relationship between BMI and cancer risk. A second major difference between the two reviews was our exclusion of studies judged to be of weak methodological quality. The results of studies of weak methodological quality are less trustworthy. The exclusion of these studies likely contributed to the higher pooled risk ratios observed in this meta-analysis in comparison to Renehan et al. The combined effect of the different statistical approaches and the exclusion of studies of weak methodological quality likely explains much of the observed differences between the reviews.  Finally, it may be that studies published since the Renehan et al. meta-analysis, report higher relative risks than had been reported previously. Given several studies published since 2007 were added to this paper, this may further explain the higher pooled risk ratios and 95% confidence intervals observed in this paper. It is important to note that the results from some of the studies included in this paper may not be relevant to a Canadian context. For example, studies conducted in South East Asian countries may have limited applicability in Canada. However, a rigorous and systematic meta-analysis process should not limit study inclusion by the country in which the study was conducted. As a result a decision was made to be more rather than less inclusive. Furthermore, in most instances, studies conducted in countries quite dissimilar to Canada constituted relatively little overall weight in the point estimate, and therefore the impact of the results of these studies on the point estimates is relatively small. These findings have important implications for public health practice globally as well as Canada. First, the evidence reported here continues to establish the evidence base suggesting a statistically significant and positive association between obesity and cancer risk. In comparison to nonobese men and women, obese men and women have considerably increased risk of developing cancer. Women are at particularly high risk for as many as eight cancers, and the magnitude of the association is very high. Similarly among obese men, there is an increased risk for five cancers. Given obesity generally is preventable public health efforts to implement effective population wide programs to reduce and prevent obesity are needed.


To date, because of limited budgets and lower incidence of breast cancer, the majority of Asian countries do not have population-based screening programmes, but instead offer opportunistic screening. However, there have been few studies which have assessed the motivators for women attending such programmes and the appropriateness of the programmes in terms of targeting women at risk.We conducted a prospective cross-sectional study of 1,619 women aged 40 to 74 years attending a subsidized opportunistic screening mammogram from October 2011 to October 2013 at a private hospital in Malaysia. Breast cancer risk was estimated using the Gail Model and two-step cluster analysis was used to examine the motivators of attending screening.Although Malaysia comprises 54.5 % Malay, 24.5 % Chinese and 7.3 % Indian, the majority of women in the MyMammo Study were Chinese (70.1 %) and 99.2 % had a <2 % ten-year risk of breast cancer. The most commonly cited barriers were the perception of not being at risk and fear of painful mammography. We found that highly educated women, cited doctors, family and friends as their main motivators. Of those with only secondary school education, their main motivators were doctors.Taken together, our results suggest the women attending opportunistic mammography screening in Asia are at low risk of breast cancer and this poses challenges to cost-effective and equitable strategies for cancer control. We propose that to improve uptake of screening mammography, awareness programmes should target both doctors and members of the public. Breast cancer is the most common cancer in women and accounts for ~12.7 % of all cancer deaths in Asian women . The incIn high-income Asian countries with higher breast cancer incidence, such as Singapore, Korea and Japan, organized national mammographic screening is available, but uptake varies from 20 to 57 % –12. In tFaced with limited budgets and an increasing incidence of breast cancer, the governments of Asian countries are facing difficult decisions on how to offer screening equitably and cost-effectively, and in particular, how to target limited resources to women at higher risk of developing breast cancer. However, there is paucity of data on the risk profile of Asian women attending opportunistic screening and limited data on how to motivate women to come forward for screening. In this study, we sought to describe the risk profile of women attending opportunistic screening at a private hospital in Malaysia, to examine the barriers and motivators of women attending screening, and to explore whether there are subgroups of healthy women with similar self-reported motivators for attending screening in Malaysia. Findings from these analyses may inform the utility of opportunistic mammography screening and further, the functional clustering may provide insight into how screening messages should be framed for more effective promotion of screening mammography in the future.The Malaysian Mammography Study [MyMammo] is a subsidized opportunistic mammogram screening programme in a private tertiary hospital located in a suburban area in Malaysia. Screening was offered to women who did not have a personal history of breast cancer and who have not had a mammogram for at least one year prior to participating in the programme. Participants were recruited using flyers and posters at the hospital, and articles in the mainstream English, Chinese and Malay media. From October 2011 to October 2013, 1,619 women were enrolled into the study. Participants had a digital mammogram, donated a blood sample for research and completed a questionnaire of information in relation to demographic characteristics, anthropometric factors, menstrual and reproductive history, family history of cancer and, motivators and barriers for participating in the MyMammo study. Women were excluded if they were younger than 40 years old (n = 6), older than 74 years old (n = 4), previously diagnosed with other cancer (n = 23) or symptomatic (n = 133), leaving 1,453 in the final analysis. All women provided informed consent and this study was approved by the Sime Darby Medical Centre Independent Ethics Committee.The ten-year risk of breast cancer in all women were calculated at age of participation in MyMammo study using the publicly available Gail Model by including the following variables: age at menarche , age at first live birth , history of previous breast surgery and the number of first degree relatives affected with breast cancer. Subjects were categorized as parous if they have had at least one full term pregnancy (live or still births) and the family history of breast cancer in a first degree relative included affected mothers and sisters. For calculations of population risk to breast cancer, the population risk of the Malaysian Chinese was based on that of the Chinese Asian-Americans while the population risk of Malaysian Malay and Indian women was based on that of other Asian-Americans .t test and chi-square test for continuous and categorical variables respectively. A two-step cluster analysis was used to identify sub-groups of women with similar self-reported motivators for participating in the MyMammo Study. Women with previous breast biopsy (n = 136) were excluded, leaving a total of 1,317 women for analysis. Initial analysis included all variables and thereafter, variables without significant association with mammography history were removed sequentially (starting with the least significant variables). Models with acceptable cluster quality, smallest Schwarz’s Bayesian Criterion and significant differences between socio-demographic variables and motivators were selected. Differences between clusters were determined by Kruskal-wallis test for continuous variables and chi-square test for categorical variables.SPSS software [Version 21] was used for all data analysis. The association between mammography history and baseline characteristics was investigated using Student’s The MyMammo study is an opportunistic mammography screening programme established at a private hospital in the suburban area of Subang Jaya in Malaysia. The mean age was 50 years old, the majority of participants were Chinese 70.1 %], >90 % had secondary or tertiary education and 19 % were considered high income. The mean age of menarche was 13 years old and 84 % of women were parous, with a mean age of first live birth of 28 years old. Whilst 30 % of women had ever used oral contraceptives, less than 10 % had used hormone replacement therapy. Only 10 % of women report a family history of breast cancer and 9 % had previously had a breast biopsy. Twenty one percent of patients had previously had gynaecological surgery. Overall, the mean ten-year risk for women aged 40-79 was 0.77 %, ranging from 0.4 % to 14.4 %. The majority of women  were estimated to have a <2 % risk of breast cancer, with only 0.8 % (n = 19) at 2 % risk , tend to have higher socio-economic status , more likely to be menopausal (p < 0.001), have first live birth at an older age (p = 0.001), and more likely to have had hormone replacement therapy (p < 0.001) compared to women without previous mammogram. They also have higher proportion of positive family history of breast cancer (p < 0.001) and diabetic (p = 0.05). The remaining variables, namely ethnicity, age at menarche, smoking status and previous breast or gynaecological surgery, did not differ significantly between the two groups  that cited the MyMammo Study as their first breast screening mammogram, 30 % (209) cited perception that they are not at risk, 20 % (139) cited fear of painful mammography, and 10 % (68) cited cost, as barriers of attending opportunistic screening.Whilst the association analyses revealed the differences between women who have previously attended mammogram compared with those who had not, it did not reveal whether there were subgroups of healthy women with similar self-reported motivators for attending opportunistic screening in Malaysia. To do this, we conducted a cluster analysis to determine the characteristics of women presenting for opportunistic screening, starting first with a model containing all variables in Table The first and largest cluster (N = 451) comprised older women (mean age 52 years), all of whom have had a mammogram previously (mean age of first mammogram 44 years). Notably, women in cluster 1 had the most significant family history of breast cancer (13.1 %) and the motivators for participating in opportunistic screening were varied .Cluster 2 is the smallest group (N = 262) and consists of younger participants (mean age 45 years), the majority of whom have never had a mammogram (98.5 %). They are the most highly educated (75 % have attended college or university) and have the highest monthly income . Women of this cluster had the smallest proportion of overweight (35.9 %) or diabetic women (2.7 %) and the lowest use of hormone replacement therapy (2.7 %). These women were motivated to attend opportunistic screening by their doctors, family or friends.Cluster 3 (N = 276) consists of older women (mean age 51 years), the majority of whom have never had a mammogram previously (93.8 %). Women in this cluster had the lowest socio-economic status: 98.9 % were educated at primary or secondary level, and 85.5 % reported a monthly income of lower than RM5,000. Women from this cluster had their first live birth at the youngest age (25 years), had the least significant family history of breast cancer, and the largest proportion of diabetic (14.9 %) and overweight women (52.2 %). Significantly, amongst these older women from a lower socio-economic group, the majority were motivated by their doctors to attend opportunistic screening.Although ethnicity was excluded from cluster analysis, further examination indicated that cluster 1 had the highest proportion among Indian women  and cluster 2 the highest among Malay women .The incidence of breast cancer is rising in most parts of Asia and Asian governments, particularly those from low and middle-income countries, face significant challenges in providing cost-effective and equitable screening for breast cancer. To date, the majority of low and middle-income Asian countries only offer opportunistic screening and the aspiration is that through health education and community health programmes, awareness and uptake of screening can help to ensure earlier presentation. In this study, we show that the majority of women attending opportunistic screening have an estimated <2 % risk of breast cancer in the next ten years, a threshold which is often considered where the benefits of screening outweigh the potential harms of over-diagnosis. This suggests that opportunistic screening in a private hospital in Malaysia does not target the women at high risk of breast cancer.Previous studies using logistic regression have demonstrated a number of variables are associated with participation in mammography screening, but these studies provide limited information on how to target different groups of women , 18, 22.The strength of the MyMammo study is the relatively large sample size and availability of data on breast cancer risk factors, which in turns enable the determination of the estimated risk of breast cancer. To date, reports on barriers and motivators among developing Asian countries have been limited to small cohorts, with limited information about breast cancer risk factors. However, the MyMammo study has a number of limitations. First, the study is conducted in a private hospital and study participants were asked to contribute a blood sample for research to determine genetic determinants of mammographic density. It is unknown whether these would have affected participation levels and the profiles of participating women. Second, as this is an opportunistic screening program, findings from this study cannot be extrapolated to the general population as it only represents a subset of women that came forward for screening.The MyMammo Study has shown that the avenues for women to become aware of and be motivated to participate in opportunistic screening is different in high-income and low socio-economic women. Findings from this study may have implications on the approach of future health education and community awareness programmes in Malaysia and other Asian countries.


Pregnancy characteristics have been associated with breast cancer risk, but information is limited on their relationship with breast density. Our objective was to examine the relationship between first pregnancy characteristics and later life breast density, and whether the association is modified by genotype.The Marin Women’s Study was initiated to examine breast cancer in a high-incidence mammography population . Reproductive characteristics and pregnancy information including pregnancy-induced hypertension (PIH) were self-reported at the time of mammography. Forty-seven candidate single nucleotide polymorphisms were obtained from saliva samples; seven were assessed in relation to PIH and percent fibroglandular volume (%FGV). Breast density assessed as %FGV was measured on full-field digital mammograms by the San Francisco Mammography Registry.b = −0.31, 95 % CI −0.52, −0.11), while each month of breast-feeding after first birth was associated with a statistically significant increase in %FGV . PIH and breast-feeding associations with %FGV were modified by age at first birth. In a subsample of 1,240 women, there was evidence of modification in the association between PIH and %FGV by specific vascular endothelial growth factor (VEGF) (rs3025039) and insulin growth factor receptor-1 (IGFR1) (rs2016347) gene variants.A multivariable regression model including 2,440 parous women showed that PIH during first pregnancy was associated with a statistically significant decrease in %FGV (These findings suggest that first pregnancy characteristics may exert an influence on extent of breast density later in life and that this influence may vary depending on inherited IGFR1 and VEGF genotypes.The online version of this article (doi:10.1007/s10552-014-0386-2) contains supplementary material, which is available to authorized users. Parity and age at first birth consistently have been shown to be associated with breast cancer risk in women worldwide . The meThe relationship between pregnancy characteristics and breast density has received little attention. Breast density has an established, strong relationship to breast cancer. Research has suggested that this relationship is causal rather than correlational  thus prA better understanding of the association between first pregnancy and breast density could inform breast cancer prevention efforts. If first birth characteristics are found to be associated with breast density in the same direction as their association with breast cancer, this would indicate that these pregnancy events affect breast cancer through their impact on breast density. This study therefore aimed to examine the association between first pregnancy and breast density (Study 1). We additionally endeavored to further explore whether the association between first pregnancy and breast density varied by candidate germline gene variants, specifically single nucleotide polymorphisms (SNPs) known to be related to breast cancer, breast density, or pregnancy characteristics (Study 2).This study was conducted using data from women enrolled in the Marin Women’s Study (MWS). The MWS is a cross-sectional study conducted at mammography centers in Marin County, California associated with Kaiser Permanente, Sutter Health , and Marin General Hospital. It is estimated that 80 % of mammograms conducted in Marin residents are conducted at centers affiliated with these health care facilities, representing approximately 38,000 women annually. These mammography sites are also included in the San Francisco Mammography Registry (SFMR), one of seven registries included in the National Cancer Institute Breast Cancer Surveillance Consortium. Risk factors and saliva specimens collected in the MWS are linked with breast density, measured as percent fibroglandular volume (%FGV), and breast cancer outcome.n = 80), if they reported ever having been diagnosed with breast cancer (n = 751), if they reported taking antiestrogens (n = 107), if they had never had a live birth , if they did not have a measure of breast density assessed as %FGV , if they had missing data on any of the model variables (n = 639), if they reported having had a hysterectomy with ovarectomy (n = 160), or if their first birth was not a singleton birth (n = 44), leaving an analysis population of 2,440.At the time of analysis, there were 11,361 women enrolled in the MWS; for purposes of this analysis (Study 1), women were excluded if they were missing data on age , preterm birth, pregnancy weight gain (pounds), and high blood pressure during pregnancy [or pregnancy-induced hypertension (PIH)] (yes/no). Self-reported height and weight are collected from the SFMR.At the time of entry into the MWS, women are asked whether they are willing to donate a saliva specimen. Those who consent to donate a saliva sample (89 % of population) are sent a kit in the mail and asked to return the tube of donated saliva in a preaddressed and postage-paid envelope to the Buck Institute for Research on Aging where the saliva is logged, stored, and processed. The specimens are processed by separation into supernatant available for steroid hormone analysis, and a cellular component from which DNA is isolated using Invitrogen’s PureLink Genomic DNA kits. Samples are stored in the MWS Biorepository housed at the Buck Institute in Novato, California.For Study 2, participants were also selected from the MWS population and were drawn from among 2,400 participants for whom SNP data were available from donated saliva samples.Twenty-five preselected candidate SNPs were multiplexed and analyzed in the MWS DNA samples by InterGenetics, Inc  in parallel with analysis of their panel of 22 OncoVue SNPs. All SNP assays were performed and evaluated as previously described , and theEach participant in the study was required to have undergone a screening mammogram. One of the novel features of this study is the measure of %FGV assessed by the method single-energy X-ray absorptiometry (SXA) –20. ThisThe MWS was approved by the participating institutions, and participants provided written informed consent for participation in the study.Multivariable linear regression analyses were conducted to examine the associations between %FGV and reproductive factors, controlling for relevant confounders. Robust regression techniques were used to minimize the effects of outliers and influential observations . All models controlled for a base set of confounding variables, including current age, BMI, race, education, smoking, family history of breast cancer (whether a first degree relative has been diagnosed with breast cancer), hysterectomy status, menopausal status, and exogenous hormone use at the time of the mammogram. Prior to regression, %FGV was square root transformed to normalize the distribution.χ2 goodness-of-fit test. Bivariate associations between the genotypes of the SNPs and %FGV were examined. Multivariable linear regression models were constructed adjusting for potential confounders including current BMI, age, race, and age of first live birth, and interaction terms were generated for the genotype of each SNP compared to a baseline genotype. Statistical tests were conducted to examine the interaction term for each level of the SNP compared to the baseline level of the SNP, as well as for the joint interaction effect of each SNP overall and PIH, and p values examined for statistical significance.All genotyping data were checked for compliance of single-gene allelic frequencies with Hardy–Weinberg frequency expectations using The distribution of covariates and the mean %FGV for each level of the covariate are presented in Table The distribution of reproductive characteristics and the mean %FGV for the different levels of the characteristics is presented in Table Table Overall, having experienced high blood pressure during the first pregnancy was associated with a significantly lower %FGV . In addition, each month of breast-feeding was associated with a significantly increased %FGV . Late menarche (age 15+ vs. before age 10) was associated with a borderline significant increase in %FGV . This model explained 49 % of the variance in %FGV.Models were stratified by whether the first birth occurred before age 30 or at age 30 or later to examine whether these associations varied by age at first birth . For this analysis, participants were excluded if they had a history of breast cancer or use of antiestrogens, if they did not have a valid %FGV measurement, or if they had never had a live birth, leaving an analysis sample size of 1,240, which was further reduced in multivariable models because of missing data on one or more of the variables included in the model, including SNP results when genotyping was not successful for that SNP. In line with the Study 1 analysis that was limited to reproductive characteristics in the first pregnancy, our Study 2 definition for the exposure was limited to the development of PIH in first pregnancy. All of the seven SNPs were found to be in compliance with Hardy–Weinberg frequency expectations. In this Study 2 subset, %FGV was lower in women with a history of PIH, although this finding did not reach statistical significance. None of the bivariate associations between the genotypes of the seven selected SNPs and %FGV were statistically significant.p = 0.063) (compared to the CC genotype). The TT genotype, which has the lowest frequency, did not occur in any of the women with PIH in the first pregnancy and thus does not appear in the results. Statistically significant interactions were found between PIH and the GT genotype of the IGFR1 SNP (p = 0.01) (compared to the GG genotype); those with PIH and the GT genotype had significantly lower %FGV than those with GG genotype of the IGFR1 SNP . A borderline significant interaction was found between the TT genotype of the IGFR1 SNP and %FGV (compared to the GG genotype) (p = 0.07). This group was only half the size of the GT group, which may explain why, despite the apparent larger effect seen in the graphic, this did not reach statistical significance. The main effects terms for the GT and TT genotypes of the IGFR1 SNP were both 0.18 in this multivariable model that included the interaction terms. Both of these sets of interactions are presented visually in Figs. Multivariable analyses indicated no significant interactions between PIH and five of the seven SNPs tested Table ; howeverIn this case, it can be seen that having PIH and the CC genotype resulted in no change in %FGV, while having PIH with the CT genotype resulted in a decrease in %FGV.In this cross-sectional study, we found that PIH during first pregnancy was associated with significantly reduced breast density measured by %FGV in later life, the effect of which was greatest in those women whose first birth occurred at age 30 or later, where preeclampsia and gestational hypertension (or PIH) are more prevalent. To our knowledge, this is the first study to identify an association between experience of a pregnancy affected by PIH/gestational hypertension and %FGV. PIH has been fairly consistently associated with a reduction in breast cancer risk e.g., , 21), th, th21]),In this study, PIH was shown to significantly interact with specific allelic variants of insulin growth factor receptor-1 , and borderline significantly with a specific allelic variant of vascular endothelial growth factor-A  genes, indicating that the protective effects of first pregnancy PIH on later life breast density and breast cancer risk may depend on inherited functional variants in these two growth factor receptor and angiogenic factor genes. Prior studies involving these allelic variants support this conclusion, since the VEGF-A SNP investigated (rs3025039) has been repeatedly linked to decreased plasma levels of VEGF and reduced breast cancer risk, –33 whileDuration of breast-feeding in first pregnancy was associated with increased %FGV later in life in our overall study population and in women regardless of age at first birth (though these findings were of borderline significance). Our finding of a positive association between duration of breast-feeding and %FGV is in agreement with that of Lope et al. , who fouA number of other first pregnancy factors were less consistently associated with %FGV, but were suggestive in certain sub-analyses, including gestational weight gain, infant birthweight, and preterm birth. Other authors have found associations between breast density and birthweight , 14 and This study has a number of important strengths, including a large sample size, a contemporary sample, a novel measure of breast density, and the availability of a wide variety of reproductive characteristics for study. The primary limitation in this study is the use of self-reported data for reproductive history. Though it is possible that women may not accurately recall information about their first pregnancy, particularly if it occurred in the distant past, we would expect that they would accurately recall the major events including their age, an experience of PIH, and breast-feeding. To the extent that recall bias is present, it would be nondifferential , and would thus bias the results toward the null. Another limitation is that, despite the fact that the overall sample size in this study was large, the sample size was small for specific subgroup analyses. Studies with larger populations may be better able to detect significant associations between birth characteristics and breast density where they exist. Selection bias may be present in the sample of patients providing saliva samples for the SNP analyses; women who consented to donate saliva were significantly more likely to be of White Non-Hispanic race and to be of higher socioeconomic status based on education and income, but were not significantly different in terms of family history of breast cancer or current age. While this may limit the generalizability of the findings indicating an interaction between PIH and VEGF and IGFR1 on %FGV, any selection bias present should not limit the validity of the findings. Finally, this study was intentionally restricted to first births, but it will be important to determine whether the findings for first birth characteristics hold for all births or whether they are unique to the first birth .In summary, we found associations between first birth characteristics and breast density measured as %FGV that confirmed and extended the few published findings on birth characteristics and breast density. PIH was associated with adecrease in breast density and breast-feeding a increase in breast density, which may help elucidate the pathway by which they operate to affect breast cancer. Variation in the association between PIH and %FGV by genotype of IGFR1 and VEGF suggest that the protective effect of PIH on breast density may vary between women depending on genotype.Supplementary material 1 (DOCX 12 kb)Below is the link to the electronic supplementary material.


Breast cancer develops over a timeframe of 2–3 decades prior to clinical detection. Given this prolonged latency, it is somewhat unexpected from a biological perspective that obesity has no effect or reduces the risk for breast cancer in premenopausal women yet increases the risk for breast cancer in postmenopausal women. This conundrum is particularly striking in light of the generally negative effects of obesity on breast cancer outcomes, including larger tumor size at diagnosis and poorer prognosis in both pre- and postmenopausal women. This review and analysis identifies factors that may contribute to this apparent conundrum, issues that merit further investigation, and characteristics of preclinical models for breast cancer and obesity that should be considered if animal models are used to deconstruct the conundrum. In 2012, 1.7 million new cases of breast cancer were diagnosed globally, and breast cancer was responsible for nearly 700,000 deaths. Worldwide, cumulative lifetime risk for women of developing breast cancer between the ages of 0 and 74 currently stands at 4.6%, and lifetime risk of dying from breast cancer is 1.4% [BRCA1/2, cell–cell adhesion gene CDH1, tumor suppressor phosphatase and tensin homolog PTEN, serine threonine kinase SKT11, tumor suppressor TP53, and DNA mismatch repair genes MLH1, MSH2/6, and PMS2 [The American Cancer Society divides breast cancer risk factors into two categories based on whether they are related to lifestyle . Relativ2)) is frequently used as a proxy for body fatness; a BMI ≥ 25–29.9 kg/m2 is considered overweight, and BMI ≥ 30 kg/m2 is considered obese [et al. concluded that lifestyle modifications, including maintaining or returning to BMI < 25, engaging in moderate physical activity, and limiting alcohol to <3 drinks per week, can cumulatively reduce breast cancer risk by >30% [Of the risk factors related to personal choice, chronic positive energy balance, manifested as excess adiposity, has been linked to the development of cancer ,5,6. Boded obese ,8. Breas by >30% . This rei.e., (a) sex hormone metabolism; (b) deregulated insulin signaling; (c) chronic low grade inflammation; and (d) altered adipokine expression.Menopausal status is the fulcrum on which the association between obesity and breast cancer has been reported to hinge. However, inconsistencies in the data suggest that the complexity of the relationship between obesity and breast cancer remains inadequately understood. The inconsistencies exist at the level: (1) of population data for incident disease risk; (2) of clinical data on the characteristics of the disease at diagnosis and on disease prognosis and outcomes; and (3) of the four mechanisms broadly cited to explain the obesity-breast cancer linkage, p = 0.001; approximately 10% reduced risk per 5 kg per m2) [2) [ptrend = 0.01) women compared to women of BMI < 25 [Most studies report a null or inverse association of obesity with breast cancer risk in premenopausal women (relative risk (RR) = 0.92 ,  per m2) ,12,13,14 m2) [2) . While tBMI < 25 . While rBMI < 25 . Consequ2) [Other notable exceptions to the obesity and premenopausal breast cancer risk paradigm comes from studies of Asia-Pacific women, in which increased BMI is associated with an increased risk of premenopausal breast cancer (approximately 15% increased risk per 5 kg per m2) ,18. Like2) ,20,21. I2) ,23.p < 0.001; a 12%–13% increase in risk per 5 kg per m2) [ptrend = 0.17) [versus self reported BMI , is unclear [In postmenopausal women, the majority of evidence supports a direct link between obesity and postmenopausal breast cancer risk (relative risk (RR) = 1.12 ,  per m2) ,14. Whil2 BMI increment [When limited to ER/PR positive breast cancer, a 33% risk increase in postmenopausal women is estimated per 5 kg per mncrement . The prencrement . This hyFor molecular subtypes other than luminal breast tumors, results have been mixed. While most cohort studies find no association ,27,28,29N = 462 premenopausal women and N = 972 postmenopausal women, gaining >5% of pre-diagnosis weight within two years of a breast cancer diagnosis was associated with increased all-cause mortality ) [Unlike the situation described above, the effect of obesity on breast cancer outcomes is independent of menopausal status. Obese women with breast cancer typically have larger tumors, advanced disease stage at diagnosis, higher rates of metastasis, and higher rates of distant recurrence ) ,36,37,389–47.8)) . Given tA number of years ago, the seminal reviews of Calle and Kaaks  and moreThe co-existence of deregulated insulin signaling in conjunction with obesity has been recognized for decades, leading Astrup and Finer to coin the term “diabesity” . BMI is Higher insulin and IGF-1 have the potential to create a pro-carcinogenic environment. Specifically, binding of insulin or IGF-1 to their cognate receptors activates a series of events including the phosphatidyl inositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signal transduction cascade. This pathway culminates in the activation of S6 kinase and releasing the inhibition of the eIF4e transcription factor. Cumulatively, these effects induce expression of proteins involved in cell cycle progression, including cyclin D1 and c-Myc ,48,49,50Beyond breast cancer risk, insulin and IGF-1 stimulate cancer progression and invasion. High levels of insulin signaling promote tumor angiogenesis through upregulation of vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-1α, stimulation of endothelial cell proliferation, and promotion of vascular tube formation . High civersus the inverse association commonly reported. In the Cecchini study [Nonetheless, when this information is considered relative to the effects of obesity on cancer characteristics at the time of diagnosis, there are many inconsistencies; e.g., a direct effect of IGF-1 on premenopausal cancer ni study  of pre- ni study . As adju(1)The difficulty in measuring circulating levels of bioavailable IGF-1, as no validated assays are currently available;(2)Uncertainty relative to the usefulness of reported levels of serum insulin, which are highly dependent on the state and duration of fasting, assay characteristics and genetic factors;(3)Possible reporting bias for studies describing significant associations between either insulin or IGF-1 and cancer risk ;(4)Recognition that if insulin signaling is invoked as a candidate mechanism to explain adiposity and cancer risk, one would expect that exogenously administered insulin in patients with diabetes might be associated with increased cancer risk, but it is not ,56;(5)Concern that the extensive preclinical literature on supraphysiological levels of insulin on tumor development are not applicable to humans ; and(6)2, thereafter declining with increasing weight [Total levels of IGF1 in mice increase with increasing fatness across a wide range of weights, yet this is not observed in clinical populations, in whom total levels of IGF-1 increase only to a BMI of approximately 27 kg per mg weight ,59.Other concerns or inconsistencies relative to insulin signaling as a candidate mechanism driving the relationship between obesity and poor breast cancer outcomes include:As a compensatory mechanism for chronic positive energy balance, obesity is characterized by both adipocyte hyperplasia (differentiation of preadipocytes into mature adipocytes) and adipocyte hypertrophy (increased size of existing mature adipocytes). Compared to smaller adipocytes, hypertrophic adipocytes display increased rates of lipolysis, increased free fatty acid turnover from adipocytes, and increased risk of adipocyte death ,61,62,63From a physiological perspective, inflammation is a necessary response to tissue injury associated with obesity induced adipocyte dysfunction. Expression of pro-inflammatory cytokines, including interleukin (IL)-1 α/β, IL-6, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)-α/β, is usually closely followed by the production of anti-inflammatory cytokines within the tissue, including IL-10, IL-13, and IL-14, under normal acute conditions (reviewed in ). HoweveN = 706 postmenopausal breast cancer cases and N = 706 matched-controls, reported a positive, albeit non-linear, association between circulating CRP and breast cancer risk, even after adjustment for BMI and other breast cancer risk factors [Epidemiologic data on the association of inflammatory factors with obesity and breast cancer are limited primarily to investigations of systemic biomarkers which have short half-lives and that are unlikely to reflect local, tissue-specific effects of obesity on inflammation. Of the biomarkers evaluated, C-reactive protein (CRP), an inflammation-associated, nonspecific biomarker is most commonly studied with the advantage that it has a longer half-life than other circulating biomarkers of inflammation . Circula factors . A prosp factors .et al., women with primary breast tumors had 1.5-fold elevations in circulating TNF-α compared to cancer-free women, and TNF-α levels were positively correlated with increasing tumor stage and tumor size [In women with primary breast cancer diagnosis recruited to the Health, Eating, Activity, and Lifestyle (HEAL) Study, circulating levels of inflammatory biomarkers serum amyloid A (SAA) and C-reactive protein were associated with reduced disease-free survival ; CRP: HR = 2.05 ) . In a semor size . Most remor size .While previously thought of as a passive storage depot for excess energy, adipose tissue is now recognized as a powerful endocrine organ with far-reaching effects on multiple disease processes. These actions are exerted via adipose-derived cytokines, known as adipokines. Of the more than 40 adipokines that have been identified thus far, leptin and adiponectin are among the most abundant in human serum . Whereaset al. reported that levels of circulating leptin were associated with increased breast cancer risk in both premenopausal women ; comparison of highest to lowest tertile) and postmenopausal women ) [Data on the association of leptin with breast cancer risk are mixed ,86,87,885–3.06)) . Express5–3.06)) . Normal 5–3.06)) . Breast 5–3.06)) ,92. Two 5–3.06)) ,94, althin vitro [At a molecular level, leptin displays considerable cross-talk with estrogen signaling . Leptin in vitro , to stimin vitro , and to in vitro . Leptin in vitro ,100. In in vitro ,102. Plain vitro .et al. reported that circulating adiponectin is associated with reduced breast cancer risk in both premenopausal women ) and postmenopausal women (summary RR = 0.80 (0.63–1.01)) [i.e., [Adiponectin was inversely associated with breast cancer incidence in some prior prospective investigations ,104 but 3–1.01)) , though ) [i.e., ,109,110)lepob/lepob mice was associated with reduced macrophage infiltration of fat, corresponding to an anti-inflammatory phenotype. Administration of adiponectin induced a switch from M1-type macrophages (pro-inflammatory) to M2-type macrophages (anti-inflammatory) in lepob/lepob obese mice (reviewed in [Adiponectin exerts systemic insulin-sensitizing effects through increased glucose uptake and increased β-oxidation in muscle . Likewisiewed in ). There The biological effects of adipokines such as leptin and adiponectin depend not only on relative circulating concentrations but also the form present in tissue and the tissue-specific expression of receptor subtypes. Moreover, studies in fatless A-Zip/F1 mice, which have undetectable adipokine levels in the circulation but display accelerated tumor formation, suggest that adipocyte derived adipokines are not essential for tumor development . Given tThe cancer genome atlas project has created a wealth of information which has informed current understanding of the mechanisms that underlie the development of cancer and that potentially impact the resolution of the obesity-breast cancer conundrum . There aTomasetti and Vogelstein recently advanced the hypothesis that a primary driver of the development of cancer is the occurrence of mutations during DNA replication . The ratDevelopment of the mammary gland is regulated at three critical stages: embryogenesis, puberty, and pregnancy, and is further influenced by lactation and involution . The horversus luminal-derived stem cells [Likewise, it is currently unknown how the molecular subtypes of breast cancer relate to specific stem cell populations and the cell populations they generate, e.g., basal-derived stem cells em cells . Of equaem cells ,128,129,em cells  and adipem cells . Many ofversus disease progression based on menopausal status and molecular subtypes of breast cancer, and how the four widely embraced mechanisms discussed above may be operating, if at all, in affecting the course of the disease in the presence or absence of obesity.At this point, it must be reiterated that cancer is not a continuous process, but rather that it occurs in steps . The stei.e., personalized medicine. For an individual, risk can be affected in numerous positive and negative ways, by intrinsic genetic, epigenetic, and environmental influences [While most of the discussion about obesity and cancer presented in preceding sections is based on aggregated data and statistical analyses, it is widely recognized that the field is moving beyond this approach towards understanding each individual, fluences ,133. Beyfluences . Obesityfluences . In addifluences . MicroRNfluences . Changesfluences  and in bfluences . MiRs cafluences ,139).Z-score, the most common cancer hallmark to which these 85 genes mapped was sustained proliferation , SURF1 (surfeit 1), CYCS (cytochrome c (somatic)), GNPDA1 (glucosamine-6-phosphate deaminase 1), PHKA1 ). The second most common hallmark to which these 85 genes mapped was evasion of apoptosis (Top 5 genes: LEP (leptin), PDIA5 , ALDH5A1 , SDHD , PHKG2 ). These data suggest that the balance between proliferation and apoptosis is an important mechanism whereby the promotional effects of obesity on the carcinogenic process in the breast are mediated, a finding consistent with a recent report on the effect of obesity on breast cancer growth rates in a premenopausal model in the rat [Obesity has been reported to reduce survival among women with ER+ breast tumors ) . Likewis the rat .With all the new information that is emerging, it is easy to lose sight of the trees in the forest: namely, that the development of cancer does not occur if clonal expansion of cancer initiated cells does not result in cell mass accumulation due to the selective growth advantage conferred by driver mutations . While tClearly, the relationship between obesity and breast cancer is extremely complex. Preclinical models are valuable tools that can be used to deconstruct the biology of this problem in a stepwise manner by interrogating specific pieces of the puzzle. However, models must be selected carefully based on the clinical question under investigation, such that the biology involved in humans is adequately represented in the chosen preclinical model.lepob/lepob and leprdb/leprdb strains, which possess mutations in the genes that encode leptin and the leptin receptor, respectively. These models have provided important mechanistic information relative to obesity, although their use in resolving the obesity-breast cancer conundrum must be carefully considered given the above-cited evidence that leptin plays a role in that relationship.Heritable cases of obesity in humans typically display mutations associated with leptin deficiency, truncated leptin receptor, pro-opiomelanocortin (POMC) deficiency, melanocortin-4 receptor deficiency, and prohormone convertase (PC)1 deficiency . Thus, met al. has reported identification of subpopulations of FVB mice with polygenic predisposition to obesity and such populations already exist in the B6 mouse strain [The majority of obesity cases in humans are attributable to multiple factors including polygenic susceptibility . To devee strain ,151,152.e strain .et al. have characterized subpopulations of Wistar rats with acute sensitivity or resistance to diet-induced excess weight gain [In contrast to mice, most rat strains are resistant to diet-induced obesity (DIO) in the short term; however, MacLean ght gain ,156,157.ght gain ,159,160)Mouse and rats models exist for breast cancer and this topic has been reviewed extensively ,162,163.In contrast, most mammary tumors that arise in mice are hormone receptor negative (ER/PR-) tumors, although gene targeted knockouts  are being reported that overcome this limitation. In general, mouse models for breast cancer are better suited for studying how obesity affects hormone receptor negative and Her2/neu overexpressing molecular subtype of the disease, as well as hormone refractory luminal breast cancer. On the other hand, the rat mammary gland is more similar to the human mammary gland in terms of fibrous and connective tissue content . HoweverWe argue that obesity is a complex, multifaceted condition and that active avoidance of excessive weight for height, irrespective of menopausal status, has a direct and consistent bearing on the number of women who die from this disease. Thus, it is critical to fully investigate how obesity impacts the carcinogenic process in the breast. This effort will be facilitated via the identification of pivotal mechanistic questions and the informed use of preclinical models to assist with the deconstruction of the complex interrelationships that underlie the obesity-breast cancer conundrum. For success, it is essential to move the analysis of the effects of obesity on breast carcinogenesis from the population-based framework to a level consistent with the progress being made in oncology via precision medicine. In this regard, prevention of breast cancer via weight control must consider the emerging approaches to prevention as recently summarized ,133 and


This study evaluates the use of annual breast MRI surveillance for high-risk women, evaluating the recall rate for further imaging, biopsy and cancer detection rate. We have used breast MRI for surveillance of high-risk women since 2008.High-risk women identified by the Regional Genetic Service between 2008 and 2013 underwent annual breast MRI (1.5 T), in some cases in conjunction with digital mammography. This included those with a genetic predisposition of breast cancer  or equivalent high risk and previous thoracic radiotherapy. Women were offered MRI screening between the ages of 20 and 50.in situ was identified. The remaining 17 lesions were benign. Women who had a normal ultrasound either had an interval MRI after 6 months or were returned to routine yearly screen.Over 6 years, 184 women underwent 477 screening MRIs. There were 44 lesions recalled for second-look ultrasound in 39 women. Twenty-seven lesions had a core biopsy, from which 10 malignant lesions were identified. Nine of these were invasive ductal carcinoma, of which all were either grade 2 or 3, varying in size from 4 to 34 mm. One case of ductal carcinoma MRI screening of high-risk women is effective, with a cancer detection rate of 2.1% and a recall rate of 9.2% which are within the standards set by UK national guidelines. There has been one false negative screen to date. Breast MRI screening provides a viable alternative to prophylactic mastectomy for women at high risk of breast cancer.


Breast cancer is still considered as one of the most common female cancers worldwide regardless of the countries’ level of development. This study determines the incidence of breast cancer in Fars Province, Southern Iran.of Diseases for Oncology (ICD-O) and compromised all invasive cancers in ICD-10 categories of C-00 to C-80. The findings were shown as the number of cases by site (ICD-10) and gender, with crude incidence (CRs), age-specific incidence and age-standardized incidence rates (ASRs) per 100,000 persons per year, performed by direct method using the world standard population. This study used patients' records from Shiraz University of Medical Sciences Cancer Registry Centre, which is a Hospital-Based Registry of Nemazee Hospital. Data were recorded based on International Classification The age group of 40-49 years had the highest rate of breast cancer and naturally most cases were post-menopause ones. Most cases were diagnosed in moderate differentiated state with an increasing trend. Early diagnosis of in situ neoplasms has not increased over time in comprised with malignant cases. The number of diagnosed cases has sharply increased after year 2004 especially during post-menopause period.As the number of diagnosed cases has increased during post-menopausal period, screening and health programs seem necessary for menopause women. In Fars Province, southern Iran, it is the first common cancer in females with a crude incidence of 11.58 and ASR of 18.066 with a 5 years survival rate of 58%.7,8Breast cancer is still considered as one of the most common female cancers worldwide regardless of the countries’ level of development.3-5,9-17 It is difficult to predict the present and future patterns of breast cancer in Iran and carry out the most appropriate preventive and therapeutic measures to decrease the burden of the disease.18 In addition, concerning the high mortality rate of breast cancer in developing countries15 and its increasing incidence, an epidemiologic evaluation analysis focusing on the recent shift in the age of presentation should be considered for primary and secondary prevention of this cancer.17,19However, several studies specifically described the clinico-pathologic features, stages, and age distributions of breast cancer.6 Geographical variations in incidence and mortality rates of breast cancer suggest that the known risk factors for breast cancer may vary in different parts of the world and that environmental factors are of greater importance than genetic factors.20 For instance, in Iran; it has been shown that even after adjusting for age, young women are at relatively higher risk for developing breast cancer than are their Western counterparts.9Iran has a total population of just over 75 million and almost all studies of breast cancer in Iran are from the capital, Tehran with a population of approximately 14 million. Southern Iran has a population of approximately 4 million.21 Breast cancer incidence and death rates generally increase with age. Breast cancer begins in breast tissue, which is made up of glands for milk production, called lobules, and the ducts that connect lobules to the nipple. The remainder of the breast is made up of fatty, connective, and lymphatic tissue.21 Many of the known breast cancer risk factors, such as age, family history, age at first full-term pregnancy, early menarche, late menopause, and breast density, are not easily modifiable. However, other factors associated with increased breast cancer risk  are modifiable. Besides being female, age is the most important risk factor for breast cancer.21During 2002- 2006, 95% of new cases and 97% of breast cancer deaths occurred in women aged 40 and older.In this study we are trying to verify incidence rate of breast cancer in south Iran based on reports from Cancer Registry Center of Nemazee Hospital in Fars Province, Southern Iran and see if reported risk factors of breast cancer have changed. Women aging 15 years and older have been included in this study and several factors associated with breast cancer, like menopause status, pathology information and age, has been taken into consideration. This study used patients' records from Shiraz University of Medical Sciences Cancer Registry Centre, which is a Hospital-Based Registry of Nemazee Hospital, a tertiary care centre which delivers oncology services to a population of approximately four millions. In an active system, data were recorded in a sheet and coded based on ICD-O and all duplicate reports were eliminated. The personnel interviewed the patients to receive all information face-to-face. The registered cases comprised all invasive cancers in ICD-10 categories of C-00 to C-80. The cancer registry team actively collected and compiled the data for a period of 6 years from 2001 to 2006 from 4 hospitals of Shiraz University of Medical Sciences including Nemezee, Faghihi, Chamran and Zeynabieh hospitals comprising 87.8%, 8.3%, 1.7% and 2.2% of patient-referrals, respectively. As Nemezee Hospital is equipped with radio and chemotherapy centers, it supports most of the referrals. The findings were shown as the number of cases by site (ICD-10) and gender, with crude incidence (CRs), age-specific incidence and age-standardized incidence rates (ASRs) per 100,000 persons per year, performed by direct method using the world standard population. The data were statistically analyzed using SPSS , and MS EXCEL  softwares. A P value less than 0.05 was considered as significant. The primary site and morphology data were coded using the ICD-O.45 Information on other variables was coded as advised by International Agency For Research on Cancer (IARC). Women menopause age was considered 47 years based on previous studies in the target population.Statistical data about age group of patients is being shown in As is shown in 6,13 and we could not find any data comparing incidence of the disease in different time periods. In this report we tried to show the incidence of breast cancer in different age group of women and show how some reported risk factors were associated with this cancer, in southern Iran from 2002 to 2006. The incidence of this cancer has sharply increased especially after 2004, mainly after menopausal age.Clinico-pathological reports of breast cancer in southern Iran describing the age and stage patterns of patients are so spare9 and our study confirmed this report. The median age of breast cancer incidence was reported 61 years in United States from 2002 to 200622 but in our study, this age was shown to be 48 years. Our population is a young one and the lower incidence age may be related to this factor. So age standardization was performed to avoid misinterpretations.Some previous reports have shown that age of breast cancer is lower in Iran in comparison with western communities,11,12 some others reject this finding.13,14 However cause-specific mortality and the increment in incidence in most Asian countries are much higher than in Western countries,15 which can be due to increased life expectancy and changes in reproductive and behavioral patterns associated with a heightened breast cancer risk.16The increase was shown in number of cases after menopause age that could be related to the increase in use of estrogen hormones after menopausal age. But these findings should be interpreted with caution as there is no report admitting increase of estrogen hormone use in southern Iran. Although there are some reports showing that use of these hormones can increase risk of breast cancer,Musavi et al.4 reported as 17.81 and 23.65. As is shown in As the number of diagnosed cases in our study has increased during post-menopausal period, screening and health programs seem necessary for menopause women in our region.


CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.P = 0.2) and OR = 0.80 , respectively (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years  but not for those who had their menarche age ≤11 years .We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels. BRCA1 and BRCA2) explain most large multiple-case families, but account for only 15 to 20% of the excess familial risk [Family history is a well-established risk factor for breast cancer. First-degree relatives of women with breast cancer have an approximately twofold increased risk of developing the disease relative to the general population . Twin stial risk . Genome-ial risk  have ideial risk , and theCYP3A5, was associated with a reduction of 22%  = –28%, –15%; P = 10-9) in levels of urinary oestrone glucuronide, a metabolite that is highly correlated with serum oestradiol levels [r2 = 1.0), was also associated with a weak reduction in breast cancer risk but only in women aged 50 years or younger at diagnosis (odds ratio (OR) = 0.91, 95% CI = 0.83, 0.99; P = 0.03) [Endogenous sex hormones are well-established risk factors for breast cancer in postmenopausal women ; the evil levels . Analysi = 0.03) .The aim of the present study was to further investigate an association between rs10235235 and breast cancer risk using a much larger set of subjects – the Breast Cancer Association Consortium (BCAC) – comprising data from 49 additional studies, and to assess whether there was evidence of effect modification by age at diagnosis, ethnicity, age at menarche or tumour characteristics.Samples for the case–control analyses were drawn from 52 studies participating in the BCAC: 41 studies from populations of predominantly European ancestry, nine studies of Asian ancestry and two studies of African-American ancestry. The majority were population-based or hospital-based case–control studies, but some studies were nested in cohorts, selected samples by age, oversampled for cases with a family history or selected samples on the basis of tumour characteristics ). Full details of SNP selection, array design, genotyping and post-genotyping quality control have been published .n = 298); overall call rate <95% ; low or high heterozygosity ; individuals not concordant with previous genotyping within the BCAC (n = 702); individuals where genotypes for the duplicate sample appeared to be from a different individual (n = 42); cryptic duplicates within studies where the phenotypic data indicated that the individuals were different, or between studies where genotype data indicated samples were duplicates (n = 485); first-degree relatives ; phenotypic exclusions (n = 527); or concordant replicates .For the COGS project overall, genotyping of 211,155 SNPs in 114,225 samples was conducted using a custom Illumina Infinium array  in four centres. Genotypes were called using Illumina’s proprietary GenCall algorithm. Standard quality control measures were applied across all SNPs and all samples genotyped as part of the COGS project. Samples were excluded for any of the following reasons: genotypically not female XX . Two studies from Singapore (SGBCC) and Malaysia . Most studies were predominantly of a single ancestry (European or Asian), and women with >15% minority ancestry, based on the first two components, were excluded  for which there was substantial inflation not accounted for by the components derived from the analysis of all studies. Addition of further principal components did not reduce inflation further. Two principal components were included for the studies conducted in Asian populations and two principal components were included for the African-American studies.n = 5,452) [in situ/lobular carcinoma in situ, n = 2,663) or cancers of uncertain status (n = 960)). After exclusions there were 47,346 invasive breast cancer case samples and 47,570 control samples from 49 studies  used in the analysis  that were genotyped in the hypothesis-generating study   and women = 2,508) and controls  and from UKBGS cases  and controls  in this analysis. Age at menarche was not available for samples from BIGGS. Full details of genotyping of rs10235235 in BBCS and UKBGS samples have been published previously [P = 0.29 (BBCS); P = 0.92 (UKBGS)), and the duplicate concordance based on a 1% (BBCS) and 5% (UKBGS) random sample of duplicates was 100% for both studies.We did not test for an association between rs10235235 and age at menarche in our hypothesis-generating study . Therefoeviously . BrieflyQ statistic and quantified using the I2 measure [We estimated per-allele and genotypic log odds ratios (ORs) for the European, Asian and African-American subgroups separately using logistic regression, adjusted for principal components and study . To test measure .P values were estimated using likelihood ratio tests with one degree of freedom.Analyses stratified by oestrogen receptor status (+/–), progesterone receptor status (+/–), morphology , grade 1,2,3), lymph node involvement (+/–) or age at diagnosis (≤50 and >50 years) were restricted to studies of European ancestry due to the small number of studies of Asian and African-American ancestry. In addition, studies were excluded if they had selected cases on the basis of the stratifying variable, or had collected data on that variable for less than 5% of cases or less than 10 cases in total. Availability of data for each of the stratifying variables in each study is shown in Table S3 in Additional file ,2,3, lymP values reported are two-sided.We assessed whether rs10235235 was associated with age at menarche in cases and controls separately. Studies that had not collected data on age at menarche in both cases and controls were excluded  = 0). The overall MAF for European control women was 0.089 , but with strong evidence of between-study heterogeneity (Phet = 1 × 10-22) that was accounted for by the three Finnish studies ; no evidence of heterogeneity remained after taking account of these studies ; Phet = 0.23). Relative to Europeans, the overall MAF was higher for African-Americans  but much lower for Asians , with strong evidence of between-study heterogeneity for the latter (Phet = 4 × 10-14).The case–control analysis comprised genotype data for 47,346 invasive breast cancer cases and 47,569 controls from 49 studies, including 80,518 (84.8%) subjects of self-reported European ancestry, 12,419 (13.1%) of self-reported Asian ancestry and 1,978 (2.1%) of self-reported African-American ancestry. The mean (± standard deviation) age at diagnosis was 56.1 (± 11.6) years for European cases, 51.1 (± 10.5) years for Asian cases and 53.1 (± 10.7) years for African-American cases. There were ethnic differences in the estimated minor allele frequency (MAF) of rs10235235 (P for linear trend (Ptrend) = 0.02). Genotype-specific ORs were 0.98  for AG versus AA  for GG versus AA . There was, however, marginally significant evidence that the genotypic OR estimates departed from those expected under a multiplicative model with the inverse association of the GG genotype being more than the square of that of the AG genotype .The case–control analysis was consistent with a modest association between rs10235235 and breast cancer risk for women of European ancestry, with an estimated per-allele OR of 0.96 .Data for rs10235235 in women of Asian or African-American ancestry were more limited, with just two African-American studies  and nine Asian studies . In addition, this SNP was sufficiently rare in Asian populations (MAF = 0.002) that we were unable to estimate the heterozygote OR in two Asian studies  or progesterone receptor (Phet = 0.19) status, tumour grade (Phet = 0.63) or nodal involvement at diagnosis (Phet = 0.51) showed no evidence of effect modification (Table Phet = 0.03). For ductal cancers we estimated a very modest reduction of risk for heterozygotes  and a stronger, significant reduction for homozygotes . For lobular cancers there was no such trend .Stratifying cases by oestrogen receptor  that has been considered an a priori candidate for involvement in determining age at menopause and age at menarche [Phet = 0.89; Table Phet = 0.28). Data on age at menarche were available for 21,736 cases and 22,686 controls  reduction in breast cancer risk associated with each additional year’s increase in age at menarche. Mean age at menarche was positively associated with number of copies of the minor allele of rs10235235 for controls  or 19%  (Ptrend = 0.002) reduction in breast cancer risk for women who had their menarche at ages ≥15 years but there was no evidence of reduction for those with a menarche at age ≤11 years  (Ptrend = 0.29). There was no evidence that the inverse trend in the magnitude of ORs with mean age at menarche differed between heterozygous and homozygous carriers (P = 0.97) and no evidence that the trend was nonlinear (P = 0.70).The SNP rs10235235 maps to a locus , is associated with a reduction in breast cancer risk for women of European ancestry. Previously, our hypothesis-generating study of 10,000 breast cancer cases and 17,000 controls found a per-allele OR estimate of 0.96 , with marginally significant evidence of an inverse association for breast cancer diagnosed age 50 years or younger  but no evidence of an association for breast cancer at later ages  [P = 0.21) and a homozygote OR estimate of 0.80  with marginally significant evidence that the inverse association for homozygotes is greater than predicted by a multiplicative model (P = 0.04).This study of more than 47,000 breast cancer cases and 47,000 controls has confirmed that rs10235235, mapping to 7q22.1 ( = 0.82) . In thisCYP3A locus. rs10235235 was originally identified on the basis of a highly significant association with hormone levels, accounting for 4.9% of the variation in premenopausal urinary oestrone glucuronide levels [CYP3A variants and postmenopausal plasma oestradiol levels reflects a difference in the menopausal status of the study subjects, the hormone/metabolite that was analysed or chance.To our knowledge, rs10235235 is the first SNP to be associated with both breast cancer risk and age at menarche, consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk  and moree levels . In thise levels . In thatD′ ~ 1.0, r2 < 1.0), then there would be three types of chromosome in the population: type i, chromosomes carrying the common allele of rs10235235 and the common allele of SNP X; type ii, chromosomes carrying the rare allele of rs10235235 and the common allele of SNP X; and type iii, chromosomes carrying the rare allele of rs10235235 and the rare (protective) allele of SNP X. Only chromosomes carrying the rare allele of rs10235235 and the rare (protective) allele of SNP X (type iii) would be enriched in controls. Genotyping the marker (rs10235235) rather than the causal variant leads to misclassification. As the causal variant is associated with a protective effect on breast cancer risk, the proportion of chromosomes carrying both the rare allele of the causal variant and the marker (type iii) compared with the common allele of the causal variant and the rare allele of the marker (type ii) will be greater in controls than in cases such that the extent of misclassification will be greater for cases than controls. This will attenuate the association between genotype and age at menarche to a greater extent in cases than in controls creating an apparent effect modification. Fine mapping and functional studies will be required to identify the causal variant and to determine the true relationship between the causal variant, age at menarche and breast cancer risk.One possible explanation for the apparent effect modification of the rs10235235–breast cancer risk association by age at menarche is that this is a function of genotyping a marker SNP rather than the true causal variant. For example, if rs10235235 was perfectly correlated with a causal variant, SNP X, with a MAF substantially lower than that of rs10235235 (Phet = 0.03). Given the number of stratified analyses that we carried out (six stratifying variables) and given that there is no biological basis to support an interaction between rs10235235 and morphology, this is probably a chance observation.Despite our original finding of a strong association between rs10235235 and hormone levels, we found no evidence that the association between this SNP and breast cancer risk differed by the hormone receptor status of the tumour, and nor did we find any evidence that the association differed by stage, grade or lymph node involvement. There was marginally significant evidence that the association between rs10235235 and breast cancer risk differed between ductal and lobular cancers (n = 554) of cases, information on age at natural menopause was missing for 65.6%  of cases of European ancestry. Similarly, although rs10235235 is a plausible candidate for association with age at menopause, we did not test this due to the limited amount of data on age at natural menopause for controls of European ancestry  and the difficulty in ascertaining whether treatment for breast cancer had influenced reported age at menopause for cases.In contrast to our earlier study , we founThe strengths of our study include the large size of this combined analysis, and the availability of information on tumour characteristics for the majority of cases and on age at menarche for the majority of cases and controls. Limitations include low power of the study to examine an association between genotype and breast cancer risk for non-Europeans.CYP3A locus, probably tags a causal variant that affects expression of one or more CYP3A genes.In summary, we have confirmed that rs10235235 is associated with breast cancer, have shown for the first time that rs10235235 is associated with age at menarche in controls and have suggested a potential mechanism for these associations. rs10235235, which maps to the Ptrend: P value for linear trend; SNP: single nucleotide polymorphism.BCAC: Breast Cancer Association Consortium; CI: confidence interval; COGS: Collaborative Oncological Gene-environment Study; MAF: minor allele frequency; OR: odds ratio; The authors state that they have no competing interests.OF, FD and NO performed the statistical analyses. OF, IdSS and NJ drafted the manuscript. NJ, FD, NO, LG, MEJ, MJS, EJF, BPH, MG-C, MDo, AA, AJS, JP, IdSS and OF comprised the writing group that was responsible for the interpretation of the results and for critically reviewing the manuscript. AC, AJ, AHW, AMa, BBu, C-YS, DL, ES, GC-T, HN, HBre, HBra, ILA, JC-C, J-YC, JLH, LBa, MKB, HMi, PAF, PR, RW, SEB, TD, MKS and UH also significantly contributed to the interpretation of the results. OF, IdSS, NJ, JP, LG, DFE, MKB and JW conceived of the original design of the study and participated in subject recruitment and in acquisition of data. JBen, AG-N, RM, DCT, DV, FB, CL, JD, JS and KMi carried out the genotyping and/or data analysis. FD, NO, MEJ, MJS, EJF, BPH, JLH, MCS, GSD, CA, MKS, AB, LJVV, FA, KMu, ALo, PAF, MWB, ABE, SPR, ES, IT, MK, NM, BBu, FMa, AS, CS, PG, TT, EC, FMe, SEB, BGN, HF, RMi, MPZ, JIAP, JBen, LBe, HA-C, AZ, CCD, HBre, HMü, VA, AKD, AMe, JH, CRB, RKS, HBra, CJ, Y-DK, The GENICA Network, HN, TAM, KA, CB, KMa, TD, NVB, NNA, ALi, AMa, VK, V-MK, JMH, GC-T, JBee, kConFab Investigators, Australian Ovarian Cancer Study Group, AHW, DVdB, C-CT, DL, DS, PN, HW, JC-C, AR, SN, DF-J, PR, PP, BBo, VP, FJC, JEO, XW, ZF, VSP, GGG, GS, LBa, CH, JS, MSG, FL, MDu, PS, ST, CHY, SYP, BKC, VNK, GGA, A-LB-D, WZ, RW, KP, AJ-V, MG, ILA, JAK, GG, AMM, PD, JF, SJC, JLis, MES, PH, NS, MHo, AH, RAO, MT-L, JLiu, AC, IWB, MWRR, SSC, WB, LBS, PDPP, AMD, MS, DK, D-YN, SKP, J-YC, MHa, HMi, WYL, AT, UH, AF, TR, HUU, AJ, JLu, KJ-B, KD, SSa, VG, PB, JM, SSl, AET, CV, DY, C-YS, J-CY, C-SH, M-FH, AG-N, DCT, DV, FB, CL, JD, KMi, MKB, JW, DFE, MG-C, MDo, AA and AJS made substantial contributions in recruiting subjects and acquiring data, and in critically reviewing the manuscript. All authors take responsibility for the work and read and approved the final version of the manuscript.Contains Table S1 presenting details of participating BCAC studies; Table S2 presenting rs10235235 genotypes for breast cancer cases and controls from 49 BCAC studies; Table S3 presenting availability of data on age at diagnosis, hormone receptor status, morphology, grade and nodal status for breast cancer cases from 38 European BCAC studies; Table S4 presenting availability of data on age at menarche for breast cancer cases and controls from 40 European BCAC studies; and Figure S1 showing association of the rs10235235-AG genotype with breast cancer risk for women of Asian and African-American ancestry.Click here for filePresents details of ethical committees that approved each study.Click here for file