TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may indicate whether the findings initially identified in a European population are generalizable to other populations, and may provide new insight into the role of genetic variants in the etiology of breast cancer. In this case-control study, 623 Chinese female breast cancer patients and 620 cancer-free controls were recruited to investigate the role of five SNPs in TOX3/LOC643714 ; Linkage disequilibrium (LD) pattern analysis was performed. Additionally, we evaluated how these common SNPs influence the risk of specific types of breast cancer, as defined by estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status. Significant associations with breast cancer risk were observed for rs4784227 and rs8051542 with odds ratios (OR) of 1.31 , 1.10–1.57)) and 1.26 , respectively, per T allele. The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. Our results support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations, which may together explain an appreciable fraction of the genetic etiology of breast cancer.The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs) in  Most of these studies focused primarily on women of European descent [Breast cancer continues to be a major contributor to overall morbidity and mortality among women, accounting for 23% of all cancers in women in 2008 , and its descent , and rep descent –15. FailTOX3, a gene of uncertain function containing a tri-nucleotide repeat motif, as well as the hypothetical gene LOC643714 (http://www.sanger.ac.uk/genetics/CGP/cosmic/) [in vitro evidence implicating TOX3 rs4784227 as a functional variant for breast cancers in Asian women [TOX3/LOC643714 affect breast cancer risk remain unclear.cosmic/) , encodescosmic/) . Its procosmic/) . A recenan women ; howeverTOX3/LOC643714 locus to provide confirmatory replicative results of several studies in multiple populations. As subtypes stratified by receptor status suggest that the heterogeneity of genetic associations might result from different etiologic pathways, we also determined whether the presence of ER+/−, PR+/−, and HER2+/− subtype tumors modifies the association with breast cancer risk. Further investigation of these loci in non-European populations may reveal the generalizability of these initial findings and shed new light onto the biological mechanisms by which genetic variants affect breast cancer etiology.In this breast cancer case-control study among Chinese women, we assessed the association of breast cancer with five SNPs  in the 2.2.1.in situ), and stages 1 to 4 accounted for 24.6% (153), 24.7% (154), 30.0% (187), and 9.5% (59) of patients, respectively. The cases consisted of 300 (48.2%) ER-positive tumors and 217 (34.8%) ER-negative tumors, while the remaining 106 (17.0%) were untested; 42.9% of patients had PR-positive tumors and 40.0% had PR-negative tumors, with 17.2% untested; and 36.9% of patients had HER2-positive tumors and 41.7% had HER2-negative tumors, with 21.3% of unknown status. Triple-negative  breast cancer carriers accounted for 11.9% (74) and luminal A tumors  for 29.7% (185).Baseline characteristics of 623 patients with breast cancer are shown in 2.2.TOX3/LOC643714 gene using the SEQUENOM MassARRAY® platform to test the hypothesis that these SNPs were associated with breast cancer risk in Chinese women. Of the five successfully genotyped SNPs, significant associations with breast cancer risk were found for rs4784227 and rs8051542, with ORs of 1.31  and 1.26  per T allele, respectively  in the ectively . The twop = 0.034, 0.051, respectively; The T-rs4784227 allele exhibited significant associations with the status of three receptors  in an additive model with the per-allele OR ranging from 1.39 to 1.51; the T-rs8051542 allele was associated with ER-positive and HER2-negative breast cancer carriers  showed no significant associations with breast cancer risk in the entire data set  in the additive and dominant models. The combined OR showed a significant stepwise increase, depending on the combined number of minor alleles present, with a maximum OR of 1.37  in the additive model and 1.49  in the dominant model .2.4.TOX3/LOC643714 region are contained in a 133-kb LD block [r2) of 0.89. The r2 values were 0.15, 0.30, and 0.23 for rs8051542, rs12443621, and rs3112612, respectively , is located on 16q12.1 and is one of the low-penetrance breast cancer risk genes newly identified in GWAS [TOX3 has been identified as a calcium-dependent transactivator in neurons, and exerts its effect through interaction with both cAMP-response-element-binding protein (CREB) and the CREB-binding protein (CBP) complex [TOX3 remains unclear.The five SNPs examined are located close to the function ,21. TOX3 in GWAS . TOX3 ha complex ,23. Addi complex  and SMAD complex . HoweverTOX3/LOC643714 locus, we confirmed two breast cancer susceptibility loci (rs8051542 and rs4784227) among the southern Chinese population . Logistic regression analysis in the additive model indicated that the T-rs4784227 allele exhibited significant association with overall breast cancer, regardless of ER, PR, or HER2 receptor statuses. The T-rs8051542 allele was found to be associated with the risk of ER-positive and HER2-negative breast cancer. In contrast, none of the other three polymorphisms was significantly associated with breast cancer risk in either the whole data set or that stratified by the status of the three receptors.Among five SNPs in the TOX3, was one of significant variants associated with breast cancer risk identified through GWAS [et al. confirmed the significant association of both rs3803662 and rs8051542 and breast cancer risk in the genetic score contributing to the full risk assessment model, which showed promise for stratifying Asian women into different risk groups [et al. confirmed that the variant was associated more strongly with ER-positive than ER-negative disease [SNP rs3803662 (C-to-T transition), which lies 8 kb upstream of ugh GWAS ,13,26,27 disease . In our et al. reported that a borderline significantly increased risk was observed for the variant genotypes (CT/TT) of rs8051542, as well as an association with risk of ER-positive breast cancer in a Chinese population [TOX3/LOC643714 region in the different populations. In Europeans, moderate LD was observed for rs12443621-rs3803662 and rs12443621-rs4784227 . Conversely, no LD was observed among these SNPs in our data  or in the HapMap CHB population   .A recent study showed that SNP rs3112612 had moderate predictive power for establishment of genetic risk models for early identification and optimal treatment of breast cancer in Ashkenazi Jewish women [in vitro [The significant association was observed between rs4784227 and breast cancer risk, with an adjusted OR of 1.31  per allele in the entire data set. Rs4784227 is also consistently significantly associated with breast cancer risk among European, Asian, and Korean women ,19,26; hin vitro . It was in vitro .TOX3 as a breast cancer susceptibility gene is contradictory, which may account for the negligible effects of some polymorphisms on breast cancer risk. Furthermore, differences in the LD structure in the TOX3/LOC643714 region between populations of European and Chinese origin are likely to play a role. Spanning a 133-kb LD block in a chromosomal region that exhibits evolutionary conservation, the five SNPs lie in the 5′ end of TOX3 and near the last exon (exon 4) of LOC643714 [r2 of 0.89, while moderate correlations were observed with rs8051542, rs12443621, and rs3112612. However, in both the HapMap CHB population and our data, the five SNPs showed weak correlations with each other. Therefore, it is possible that the causal variant(s) tagged by SNP rs3803662 and/or rs4784227 in European ancestry populations would be tagged by SNP rs4784227 or rs8051542 in Chinese populations. Additionally, the number of identified SNPs was inadequate to explain the genetic variation across the TOX3/LOC643714 locus. Ruiz-Narvaez et al. [LOC643714 gene, which may tag the same causal variant of breast cancer in African-ancestry populations instead of rs3803662, consistent with our results. We also provided the supplement data of LD structure between the four new SNPs and the five SNPs examined exhibiting moderate to low correlation in the HapMap CHB population, except for rs3112612-rs3104793 with high correlation . Despite the limitations, a strength of our study was the substantial number of cases and controls, which significantly increased the statistical power. Additionally, we provided evidence for molecular etiologic heterogeneity by evaluating the association between SNP polymorphisms and receptor status.A limitation of this study was that it was not possible to investigate precise established risk factors  to detect gene-environment interaction effects. We did not collect these data. In addition, detailed tumor characteristics of 3.3.1.The study was approved by the Nanfang Hospital Ethics Committee and all subjects provided written informed consent for clinical genetic testing and were anonymized for research studies prior to enrollment. 623 case patients and 620 control subjects included in the present case-control study were recruited from the outpatient and inpatient clinics of Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, from 2009 to 2010. Patients selected for the study were those with histologically confirmed breast cancer, which provided data regarding the ER, PR, and HER2 statuses of tumors. The control group comprised individuals without cancer and with no immediate family history of cancer.3.2.Peripheral blood samples were drawn from all participants and stored at −70 °C until DNA extraction. Genomic DNA was extracted using a commercial blood DNA kit , according to the manufacturer’s instructions, and stored at −70 °C until use.3.3.TOX3/LOC643714 locus at 16q12.1 from the confirmatory results from GWAS or meta-analysis in multiple populations [We selected SNPs  in the ulations .The five SNPs were genotyped using the SEQUENOM MassARRAY matrix-assisted laser desorption ionization-time of flight mass spectrometry platform . Primers for multiplex PCR and extended reactions were designed using proprietary software  provided by Sequenom Inc . In accordance with the manufacturer’s instructions, SNPs were genotyped using Sequenom MassARRAY genotyping technology  and amplified in multiplex PCR by a standard PCR protocol. The genomic amplification product was cleaned using shrimp alkaline phosphatase  to neutralize any unincorporated dNTPs, followed by a single-base extension reaction using the iPLEX enzyme  and mass-modified terminators . The products of the iPLEX reaction were desalted and transferred onto a SpectroCHIP  by the MassARRAY nanodispenser , which was then analyzed by the MassARRAY analyzer by combining base calling with the clustering algorithm.3.4.2 analysis was used to test for independence of the alleles (HWE), selected variables, and frequencies of the genotypes of the five SNPs between cases and controls. All SNPs with a deviation from HWE in controls at p < 0.05 were excluded. The case-only p value was used to test for heterogeneity with receptor status. The associations between TOX3 genotypes and the risk of breast cancer were modeled using an unconditional logistic regression model with two degrees of freedom  adjusted by age at diagnosis/selection. Odds ratios (OR) and 95% confidence intervals (CI) were calculated from these models for homozygote and heterozygote genotypes and per allele, which was used to test for a linear trend on a log scale in a dose-response relationship. We also performed case-control analyses by subgroups stratified according to ER/PR/HER2 status . p < 0.05 was considered to indicate statistical significance. All statistical analyses were performed using SPSS version 13.0 . Haplotypes were estimated using the web-based tool SNPstats (http://bioinfo.iconcologia.net/SNPStats) [Pearson’s χNPStats) .4.TOX3/LOC643714 rs8051542 and rs4784227 polymorphisms are significantly associated with the breast cancer risk. In addition, T-rs8051542 was significantly associated with ER-positive and HER2-negative tumors. However, no associations between rs12443621, rs3803662, and rs3112612 and risk of breast cancer were identified. Our results support the hypothesis that genetic factors differ according to ethnicity. Susceptibility loci common to various genetically admixed populations should be identified to explain the genetic variance in breast cancer risk and to improve our understanding of the complex biological mechanisms. Furthermore, it is necessary to conduct studies with larger sample sizes and that assess gene–gene and gene–environment interactions to establish powerful risk prediction models. This will reduce the incidence and mortality associated with breast cancer.In the present study, our data suggest that


Breast cancer is the most frequent cancer among women and the leading cause of death among middle-aged women. Early detection by mammography screening and improvement of therapeutic options have increased breast cancer survival rates, with the consequence that late side effects of cancer treatment become increasingly important. In particular, patients treated with adjuvant chemotherapy regimens, commonly including alkylating agents and anthracyclines, are at increased risk of developing leukemia, further enhanced by the use of radiotherapy. In the last few years also the use of growth factors seems to increase the risk of secondary leukemia. The purpose of this review is to update epidemiology of therapy-related myeloid neoplasms occurring in breast cancer patients. Despite the high incidence, the mortality rate is low (15%), and, as a result of early diagnosis and the increasing use of adjuvant therapy, there is a rising number of long-term survivors.5Excluding skin cancers, breast cancer (BC) is the most common malignancy among women in developed country, accounting for about one-third of all new cancer cases in the United States  are collectively known as therapy-related myeloid neoplasms (t-MN), included among “Acute myeloid leukemias and related precursor neoplasms” in the 2008 WHO classification.de novo AML, has been historically poor, with a higher frequency of poor-risk cytogenetics and shorter survival times.de novo leukemias.Currently accounting for 10–20% of all cases of AML,Chemotherapy with DNA-targeted antiproliferative drugs in the adjuvant setting has contributed to significant progress in the management of BC, substantially increasing the number of long-term survivors. As the risk of developing cancer increases with age, longer survival is associated with an increased probability of new cancer occurrence, particularly of developing t-AML/MDS. In the majority of cases they are represented by AML, but a secondary acute lymphoblastic leukemia is possible, although less common.10cancer susceptibility.Several studies have reported an increased risk for AML in BC patients treated with adjuvant therapy , but it p<0.05).p<0.001). Although the incidence of AML rose sharply with age in all cohorts, the age-specific relative risk was highest in the 30–49 age groups and decreased with increasing age. An age-dependent risk of a subsequent diagnosis of AML was confirmed in women <50 years and in the range 50–64 years with previous BC, but not in those older than 65 years, if compared with the expected incidence of AML. A similar age-dependent pattern was observed for second BC and ovarian cancers; this association may be explained by either chemotherapy exposure or an interaction between therapy and genetic predisposition.versus 1.2% among patients who did not received chemotherapy).23A population-based study from a French Cancer Registry evaluated the risk of developing a new primary invasive cancer during the first five years of follow up for 14353 cancer patients , comparing with the expected numbers, based on primary cancer incidence rate using the standardized incidence ratio (SIR). Overall, 690 second cancers were registered, including 15 AML. In particular, among 5663 women treated for BC, 10 developed t-AML, which results into a greater risk than the general population . Incorporation of taxanes (paclitaxel and docetaxel) into anthracyclines-based schedules yielded an additional benefit in both disease-free survival (DFS) and overall survival (OS) in most studies, and dose-dense drug administration have shown to be more effective than the conventional dosing schedule.versus 0.27%, respectively).In the past, alkylating agents were the class of antineoplastic drugs unequivocally associated with t-MN . The antThe latency period between exposure to anthracyclines and the onset of leukemia is usually about 2 years, and generally there is no previous myelodysplastic phase . In orde26versus docetaxel/cyclophosphamide (TC) in early BC, reported no secondary leukemia in the TC arm, compared to two cases in 510 patients (0.4%) in the AC arm.25Antineoplastic activity of taxanes appears to be related to their ability to promote microtubular assembly and to inhibit microtubular disassembly. A SEER database analysis did not document an increased risk of secondary malignancies with these drugs.In vitro data suggest that G-CSF may increase the risk of AML/MDS, but its leukemogenic effect is still debated. An analysis of the SEER-medicare population-based database including 5510 women with BC treated with adjuvant chemotherapy, found that the addition of G-CSF is associated with a doubling of the risk of subsequent AML or MDS when compared with chemotherapy alone, even if the absolute risk is low.p=0.0001).Recently, increasing numbers of women receiving adjuvant chemotherapy for BC have also received granulocyte stimulating factors to reduce the myelosuppressive effects of dose-intense chemotherapy. versus one case only in the group not receiving radiotherapy. The relative risk adjusted for chemotherapy and hormone treatment was 6.67 (95% CI 0.76–58.00) and the median time from exposure was 4.5 years, with the suggestion of a raised incidence of leukemia within the first two or more years after radiotherapy.33Radiotherapy may also play a significant role . A cohorIn BC survivors, there is a small but significant and increasing number of secondary myeloid neoplasms after adjuvant chemotherapy, particularly after treatment with alkylating agents and/or topoisomerase II inhibitors, that lead to two distinctly and different forms of t-MN.The risk of leukemia appears very low if the cumulative dose of anthracyclines and cyclophosphamide is not very high. Clinical trials attempting to improve therapeutic benefit by dose escalation need to take into account the increased risk for leukemia, when assessing potential benefits and risks.cancer susceptibility.The incidence of t-MN appears to be also increased in patients treated for BC with surgery alone, and these cases are not “therapy-related”. Thus, t-MN may be part of a cancer-risk syndrome involving BC, and possibly a general A raised risk of t-MN is associated with radiotherapy, particularly for women treated after the menopause.The concurrent use of G-CSFs as supportive care in order to deliver intensive adjuvant chemotherapy could further enhance this risk, so that their use should be limited to the settings with available strong evidence.


Studying mechanisms underlying social inequality in postmenopausal breast cancer is important in order to develop prevention strategies. Standard methods for investigating indirect effects, by comparing crude models to adjusted, are often biased. We applied a new method enabling the decomposition of the effect of educational level on breast cancer incidence into indirect effects through reproductive patterns (parity and age at first birth), body mass index and health behavior . The study was based on a pooled cohort of 6 studies from the Copenhagen area including 33,562 women  aged 50–70 years at baseline. The crude absolute rate of breast cancer was 399 cases per 100,000 person-years. A high educational level compared to low was associated with 74 (95% CI 22–125) extra breast cancer cases per 100,000 person-years at risk. Of these, 26% (95% CI 14%–69%) could be attributed to alcohol consumption. Similar effects were observed for age at first birth , parity , and hormone therapy use . Educational level modified the effect of physical activity on breast cancer. In conclusion, this analysis suggests that a substantial number of the excess postmenopausal breast cancer events among women with a high educational level compared to a low can be attributed to differences in alcohol consumption, use of hormone therapy, and reproductive patterns. Women of high educational level may be more vulnerable to physical inactivity compared to women of low educational level. Breast cancer is the most common cancer among women worldwide , and theSeveral studies support an etiological role of sex-steroid hormones in the development of postmenopausal breast cancer -10, and In line with this, previous studies have focused on indirect effects in social inequality in breast cancer -22. A reThe objective of this study was to investigate the underlying mechanisms linking educational level to breast cancer by quantifying the indirect effects through health behaviors, BMI and reproductive patterns. We apply a newly developed method for mediation analysis , which qThe analyses were based on the Social Inequality in Cancer (SIC) database derived by pooling several large independent population studies from the Copenhagen area: The Diet, Cancer, and Health Study (DCHS) , The CopThe SIC-database was linked to sociodemographic information from Statistics Denmark from 1980 and onwards. SEP was defined as highest attained educational level one year before baseline and categorized as: “low” (8–11 years of basic schooling), “medium” , and “high” (15+ years) education. Educational level was chosen over income or occupation because it is a more constant measure of lifelong social status ,29.Alcohol was assessed as consumption of beer, wine, and spirits in response categories of “never/almost never”, “monthly”, “weekly”, and “daily” as well as the average number of drinks per week within these categories. We categorized the total intake in groups of <1, 1–7, and >7 drinks/week. Leisure time physical activity was assessed in a similar manner across studies: In the DCH study, the average number of hours spent in the past year on various types of activity  was assessed along with number of hours becoming sweaty or short of breath as a result of these activities. Similarly, the CCHS and the CRCPH assessed the weekly level of physical activity during the past year in four categories ranging from being almost entirely inactive to engaging in vigorous physical activity. As very few participants (7.5 %) reported being highly physical active the measures were harmonized to a 3-level variable ranging from sedentary  to active (>4 hours of light activity or >2 hours of vigorous activity per week). Parity was classified into four groups ranging from 0 to 3+ children. Age at first birth was grouped as <25 years, 25–29 years, 30+ years, and nulliparous. Current HT use was classified as yes vs. no.2), and thus BMI was categorized as normal weight (<25 kg/m2), overweight (25–29.9 kg/m2), and obese (30+ kg/m2).Only 1.4% of the women were underweight (BMI < 18.5 kg/mThe end-point was defined as first incidence of breast cancer. Time and cause of disease were obtained from The Danish Cancer Registry which is based on ICD 7 and ICD 10 codes (ICD7 code 174 and ICD10 code C50) . InformaThe study was approved by the Danish Data Protection Agency. All participants signed written consent before participating.high to low), but leaving the mediators unchanged (corresponding to high exposure). Likewise, natural indirect (i.e. mediated) effects are defined as the change in outcome when exposure is kept fixed, but the mediator is changed to the value it would take if exposure was changed. Thus, natural indirect effects can be thought of as the effect of SEP mediated through a specific factor. Natural direct and indirect effects were directly parameterized following the method of Lange et al [The individual studies were pooled ,32, and ge et al . A step-ge et al . Mediatege et al . The analyses include multiple potential mediators. For each potential mediator both the effect mediated through that variable and the effect through other causal pathways are estimated. It must be stressed that the analysis only includes one mediator at a time; thus the direct effect associated with one mediator can (partly) constitute the indirect effect of another, i.e. the effects are intertwined . To addrSensitivity analyses included: 1) Assessing heterogeneity between study-specific effects by including an interaction term between educational level and study. Also, pooled estimates were compared by systematically removing each individual study at a time to confirm that no single study strongly influenced the pooled estimates; 2) excluding the first 3 years after baseline to rule out reverse causality; 3) assessing the association between educational level and breast cancer stratified by birth cohort (i.e. women born ≤ 1939 or after) to account for the fact that younger birth cohorts generally have a higher educational level and the shortest follow-up time; and 4) Assessing indirect effects of other anthropometric measures of adiposity: waist-to-hip-ratio and waist circumference adjusted for BMI (N=30 453) ,38.In total, the pooled cohort comprised 33 562 women aged 50 to 70 years at baseline who experienced 1733 breast cancer events during 434 260 years of follow-up . The perhigh to low under the assumption that the observed associations provide reasonable estimates of causal effects. The effect of a medium educational level was similar to that of women with a high, that is 74 (95% CI = 22–125) extra cases per 100 000 person-years at risk compared to women with a low educational level. An alcohol consumption of 7+ drinks/week was associated with 123 (95% CI = 69–178) extra cases compared to abstinence. Being nulliparous compared to having 3+ children was associated with 180 (95% CI = 108–251) and 155 (95% CI = 80–230) extra cases compared to women giving birth before the age of 25 years. Being a current user of HT was associated with 270 (95% CI = 222–318) extra cases compared to current non-users. We did not observe an association between breast cancer and BMI or physical activity.The crude absolute rate of breast cancer in this cohort was 399 cases per 100 000 person-years at risk. The total effect of educational level and the effect of each mediator on breast cancer are presented in high educational level was changed to those of low. Correspondingly, the direct effect is the effect associated with a change in the women’s educational level – but assuming their alcohol consumption remained unchanged. The indirect effect of alcohol consumption for high educational level compared to low was 19 (95% CI = 11–27) additional cases per 100 000 person-years at risk corresponding to a mediated proportion of 26% (95% CI = 14%–69%). The effect mediated through parity was 14 (95% CI = 8–19) additional cases corresponding to 19% (95% CI = 10%–45%). The corresponding mediated proportion for age at first birth was 32% (95% CI = 10%–257%) and 10% (95% CI = 6%–18%) for current HT use. We observed an interaction between SEP and physical activity (P for interaction = 0.01) with an indirect effect through physical activity of 2 (95% CI = -1–5) for high compared to low educational level, and a mediated interactive effect of -10 (95% CI = -16 - -4). This means that women of low educational level may be less vulnerable to physical inactivity than women of high educational level.Direct and indirect effects as well as mediated proportions of each mediator on breast cancer risk are presented in high compared to low educational level was 69 (95% CI = 11–126) additional breast cancer cases where 39 (95% CI = 28–51), or 57% (95% CI = 33%–183%), could be attributed to the factors combined. In additional analyses we combined the factors showing indirect effects into a variable with 8 levels corresponding to all unique combinations of the three (binary) factors (≤7 vs. >7 drinks/wk), reproduction (<30 years at first birth vs. ≥ 30/nulliparous) and HT use. The total effect for P for interaction = 0.50). We also performed four sensitivity analyses of which the first showed that removing one individual study at a time did not affect the risk estimates. In the second analysis, we found that excluding cases occurring within the first 3 years after baseline also did not affect the risk estimates. Thirdly, we did not observe evidence of differential effects of educational level on breast cancer according to birth cohort (P for interaction = 0.81). In women born before 1940, 77 (95% CI = 21–172) extra cases per 100 000 person-years at risk were observed for women with a medium vs. low educational level. The corresponding number of additional cases was 63 (95% CI = -14–139) for women with a high educational level compared to a low. In women born after 1940, the number of additional cases was 62 (95% CI = -0.4–124) for women with a medium vs. low educational level and 86 (95% CI = 10–162) for women with a high educational level. Finally, the subanalysis investigating the indirect effect of waist-to-hip ratio and waist circumference adjusted for BMI did not show results markedly different from those of BMI (data not shown).Analyses of the heterogeneity between study-specific effects confirmed that the pooled estimates can be considered appropriate summaries of the study-specific data Click here for additional data file.


The Institute of Medicine (IOM) recently set out to review the current evidence on links between breast cancer and the environment. Their conclusions, published in a report issued 7 December 2011,Commissioned by Susan G. Komen for the Cure®, a Dallas, Texas–based cancer research advocacy group, the report was prepared by a 15-member panel from academia and community health centers. The panel defined “environment” as any factor that isn’t inherited through DNA and relied on evidence compiled by the International Agency for Research on Cancer and the World Cancer Research Fund International, in addition to findings from the scientific literature.Breast cancer risk factors were divided into 3 categories—established, possible, and biologically plausible—on the basis of the strength of the data, according to panelist Robert Hiatt, a professor of epidemiology and biostatistics at the University of California, San Francisco. “Established” risk factors were supported by strong human epidemiologic data, in addition to positive results from animal and mechanistic studies. Risk factors were assigned a “possible” status if the available human data were in conflict and a “biologically plausible” status if they were supported solely by animal and mechanistic studies.Remarkably, only a few established risk factors were identified, among them combined hormone therapy with estrogen and progestin, exposure to ionizing radiation (such as that delivered by computed tomographic scans), excess weight in postmenopausal women, and excessive alcohol use. Possible risk factors include nighttime shift work and exposure to secondhand smoke, benzene, ethylene oxide, and 1,3-butadiene. The biologically plausible category is populated mainly by industrial chemicals, including metals, pesticides, and the plastics constituent bisphenol A, which is ubiquitous in consumer products, the environment, and people, and therefore exceedingly challenging to study in controlled epidemiologic studies, according to Hiatt.By emphasizing lifestyle changes in prevention, the IOM distinguished itself from the President’s Cancer Panel (PCP), which in spring 2010 released a headline-grabbing annual reportBut Hiatt says the IOM panel was charged with reviewing the current evidence, not recommending regulatory policy. In most cases, he says, more human data are needed to bolster cause–effect relationships between chemicals and breast cancer. “We usually couldn’t find solid human evidence of effect,” he says. “Either the data wasn’t there or it was conflicting, and we had to make the call based on what we know in 2011.”The chief recommendation of the IOM is that researchers adopt a “life course” approach to studying breast cancer and the environment, with more emphasis on early-life human exposure. “One reason that we might be missing the boat on the human data is that we’re looking at adult women, while carcinogenic effects may result from exposures that happen while the breast is still developing,” Hiatt says. “We know from animal experiments that this is a window of vulnerability to chemical insults.”Along those lines, Hiatt adds, the National Institute of Environmental Health Sciences and the National Cancer Institute are collaborating on the Breast Cancer and the Environment Research Program, which recruits subjects starting at the age of 6 years. The two institutes also collaborate on the Interagency Breast Cancer and Environmental Research Coordinating Committee, a congressionally mandated body currently preparing a comprehensive report on federal research on the environmental and genomic factors related to breast cancer. This report is expected in mid-2012.Michael Thun, vice president emeritus of surveillance and epidemiology research at the American Cancer Society, lauds the IOM report for systematically reviewing the available evidence. “It fills an important gap,” he says. “I agree with its position that we have issues of concern as research needs, but they’re in a different category than well-established risk factors.”Adds Diana Rowden, vice president for survivorship and outcomes at Susan G. Komen for the Cure, “The report shows that women can reduce their breast cancer risk with actionable items undertaken now. And it challenges us to think more about how we explain cancer risk to the general population—about how different factors have their own unique influence on risk. That’s an important takeaway point.”


PTEN gene showed the Asp24Gly mutation. According to the latest literature data, the lifetime risk of breast cancer for Cowden syndrome patients is 81% and surgery is a justified option to reduce the risk of breast cancer. Bilateral risk-reducing mastectomy with immediate reconstruction was performed to eliminate further risk of breast cancer. 3 years after the risk-reducing breast surgery the patient is satisfied with the outcome. This is to our best knowledge the first reported Cowden syndrome case with follow-up data after risk-reducing measures have been taken.We would like to present a patient with a classical phenotype of a rare disorder - Cowden syndrome, its diagnostics and management challenges. A breast surgeon has to be aware of this rare condition when treating a patient with breast manifestations of Cowden syndrome and has to refer the patient to a clinical geneticist for further evaluation. Sequencing of the  PTEN [Cowden syndrome (CS) is an uncommon disorder with an estimated incidence of 1 per 200,000 of the population, characterized by germline mutations in the tumor suppressor gene PTEN .PTEN mutations is up to 85% for breast cancer, up to 35% for thyroid cancer, and up to 28% for endometrial cancer [CS is characterized by multiple hamartomas in a variety of tissues and indicates an increased risk of developing malignancies. In female patients the syndrome is associated with up to 50% lifetime risk of developing breast cancer, 5-10% risk of developing endometrial cancer, and 10% lifetime risk of developing follicular thyroid cancer . In recel cancer . LifetimPTEN mutation and breast cancer diagnosis in CS has been reported [Other features of the disorder include macrocephaly, gastrointestinal polyps, benign breast, thyroid and endometrial manifestations, and characteristic mucocutaneous lesions. The diagnosis of CS in most cases is primarily based on the presence of mucocutaneous features, estimated to have 99% penetrance before the age of 30 . A correreported . 34% of reported .The proband is a female born in Latvia in 1973. She has a remarkable medical history from the age of 32 when she underwent total thyroidectomy due to a benign nodular goiter. Cavernous angioma of the right temporal lobe (2.1 × 1.7 cm) was present on brain MRI with contrast and liver angioma was detected at a size of 0.8 cm on abdominal ultrasound at the age of 33.The patient also suffered from hypochromic anemia secondary to metrorrhagia. Stage IA endometrial adenocarcinomawas detected at 34 and a following hysterectomy with bilateral salpingo-oophorectomy was performed.Gastroscopy at the age of 34 revealed numerous asymptomatic polyps 6 cm below the cardia level (4-10 mm in size). Biopsies from the polyps were taken, histology showed hyperplastic polyps without malignancy.At the age of 35 she visited a breast surgeon, complaining of palpable breast lesions. She had already had several bilateral breast fibroadenoma surgeries in the past. T1-weighed breast MRI  kit and the PTEN gene was sequenced as described earlier [The diagnosis was further supported by the presence of the missense mutation Asp24Gly in the  earlier . No clinde novo germline mutation, but it is impossible to establish its either paternal or maternal origin. The proband's level of intelligence is standard, she has socially active parents and two sisters.The family history of the proband did not reveal any significant pathology, a DNA sample was taken from the proband's parents and one of the two sibs who all appeared to be non-carriers of the mutation. Consequently, we can assume that the proband has received a Preoperative ultrasound-guided breast fine-needle aspiration from several abnormal areas was obtained, but no malignancy was detected.Considering high future risk of breast cancer, prophylactic bilateral mastectomy was recommended by the multidisciplinary team as the most effective available risk-reducing measure for breast cancer. The indications of risk-reducing mastectomy and alternative management options were discussed with the patient. The patient chose to undergo a risk-reducing surgery. Bilateral skin-sparing mastectomy with immediate two stage expander/implant reconstruction was successfully performed. At the first stage, immediately after skin-sparing mastectomy, tissue expanders  were placed in a complete submuscular position under the pectoralis major muscle. Partially for coverage the serratus anterior and pectoralis minor muscles were elevated. Intraoperatively, each tissue expander was filled with 200 ml saline.The surgical specimen revealed mastopathy areas with features of fibroadenoma, areas of ductal hyperplasy, fibrosing adenosis, apocrine metaplasia, microcalcinates, and intracanalicular fibroadenoma.During 6 weeks the expansion of tissue expanders was started biweekly with 50 - 100 ml until 550 ml were reached in each side.Eight months later the expanders were replaced by permanent implants . Finally, nipple reconstruction using C-V flap technique was performed seven months after the placement of the implants. A three-year follow-up shows good clinical results and the proband feels well. Screening gastroscopy, colonoscopy, and abdominal CT scan were performed. Polyps were found only in the stomach and duodenum, histopathologic examination of biopsies showed hyperplastic polyps. Abdominal CT scan revealed that liver hemangioma had increased in size up to 3.5 cm and a new hemangioma of 3.3 cm in size was detected.PTEN mutation relates to a significant aspect - increased cancer surveillance, regarding the predisposition to a variety of cancers. The National Cancer Comprehensive Network (NCCN) issues are the most widely approved guidelines for the management of cancer risk in individuals with CS.Because of the rarity of Cowden syndrome the management examples are insufficient in existing literature. Treatment for the benign and malignant manifestations in CS patients is the same as for the sporadic counterparts in the general population. The management of an individual with a PTEN mutation carriers and an increased lifetime risk for colorectal cancer of up to 16% in patients with CS [Recent studies have reported gastrointestinal polyps in 93% of  with CS ,11. Half with CS , as in tElevated lifetime risk (15% and 33.6%) for renal cancer has also been found [PTEN-positive patients published to that date, found breast cancer in 32% (28/90) of female patients, with the mean age at molecular testing of 47.6 years (range 33-64 years) [PTEN mutation at 85.2% [BRCA1 and BRCA2 mutation carriers [Breast cancer is the most common component cancer of CS. Pilarski et al., reporting on the largest single cohort of 4 years) . Recentlcarriers ,15.PTEN gene among her tested family members  and the only one who is affected by CS. Obviously, this is not sufficient to certainly identify this mutation as a cause of CS but it should be noted that in tumors of various localizations  somatic mutations in this position  have been found (COSMIC). This mutation was predicted to be possibly damaging (score 0.539) by PolyPhen-2 analysis.The presented patient is the only carrier of the Asp24Gly mutation in the To control the possible development of breast cancer for CS patients without a family history, the NCCN recommends mammography and breast magnetic resonance imaging to be commenced at the age of 30-35 (or 5-10 years before the earliest known breast cancer in the family or whichever is earlier) [in situ), strong family history and positive mutation in the BRCA1 or BRCA2 genes [BRCA1/2 gene mutation carriers. Only two cases of bilateral risk-reducing mastectomy for CS patients with no breast lesions where PTEN mutation is genetically confirmed have been described thus far [Breast cancer prevention also involves removal of the breast prior to the development of malignancy. At present, the most frequent indications for bilateral risk-reducing mastectomy are high risk histology (such as a typical ductal or lobular hyperplasia and lobular carcinoma A2 genes . AlthougA2 genes  that bilthus far .The hamartomatous lesions of the breasts for CS patients are frequently diffuse, multifocal, bilateral and feature various complex histopathologic abnormalities . The lesIn some CS cases diagnostic difficulty is associated with dense breast tissue. This may lead to multiple biopsies with increased scarring during healing and further complicated physical examination and radiological evaluation. Moreover, the benign findings at core biopsies do not exclude that invasive carcinoma might arise within densely fibrotic, hamartomatous areas of the breast . PsycholIn conclusion, as risk-reducing surgery is becoming a more acceptable option for high risk individuals, surgeons need to balance their decisions between individual risk assessment, potential psychological benefits and accepted guidelines .If Cowden syndrome is confirmed by molecular examinations, risk-reducing bilateral mastectomy may be an effective preventive measure of breast cancer. This is to our best knowledge the first reported CS case with follow-up data after risk-reducing measures have been taken..A written consent was obtained from the patient before the publication of this case report. A copy of the written consent is available for review on request.PTEN: Phosphatase and tensin homolog; CS: Cowden syndrome; NCCN: National Cancer Comprehensive Network; DNA: Deoxyribonucleic acid; MRI: Magnetic resonance imaging.The authors declare that they have no competing interests.PTEN mutation testing. AI and EM advised and assisted in drafting and writing the report. GT and JG coordinated the study. All the co-authors have read and approved the final version of the manuscript.IMG did the primary literature research and wrote the manuscript. IS and AA performed histopathological examinations. AI performed preoperative communication with the patient regarding risk-reducing surgery, the operations and postoperative treatment of the patient. SS and AG provided clinical consultations. EM and DB performed the


Prevention offers the most cost-effective long-term strategy for the control of cancer and at least one-third of all malignancies are preventable. A number of strategies have been developed over the last decades to provide opportunities for cancer prevention at different levels: primary prevention by reducing levels of exposure to high risk factors or causative agents, secondary prevention through establishment of cancer screening programs and tertiary prevention with interventions aimed at the modification of cancer outcomes, such as clinical trials and tailored therapies. In this scenario, the identification of individuals at high risk of developing certain cancers can provide an important opportunity for prevention, at different levels. The example of breast cancer will be used to further explore this concept.Breast cancer is a significant health care problem worldwide. Among women with this diagnosis, a subset of patients with previously identifiable risk factors can be easily recognized. Two main groups of high-risk women can be described. The first is composed of women with a significantly increased lifetime risk of developing the disease when compared to the general population, and this is due to a combination of reproductive, behavioral and low-penetrance, common genetic risk factors. Several mathematical models have been developed to identify this subset of women, and specific risk-reducing interventions have been proposed . A significant proportion of women, at the populational level may benefit from cancer risk assessment. In Southern Brazil, for instance, a population-based study of 9,128 women from the public primary health care system identified a lifetime breast cancer risk estimate > 20% in 8% of women in that cohort . Thus, aBRCA1, BRCA2, TP53, PTEN, ATM, among others. The magnitude of risk associated with mutation carriage is significant, i.e. carriers of mutations in the BRCA1 and BRCA2 genes have an estimated lifetime risk of 70-85%, compared to the lifetime risk of women in the general population which is close to 10%. In addition, women with these mutations are at increased risk for contralateral breast tumors (40-60%) compared to those without genetic forms of the disease (5%). Taking the same example of hereditary breast and ovarian cancer syndrome due to BRCA mutations, several strategies for preventive interventions have been developed over the last two decades, including risk reducing surgeries, intensified and early-onset cancer screening and development of targeted therapies for tumors mainly caused by hereditary mutations. On the other hand, several challenges are still present in the diagnosis and management of hereditary breast cancer. These include our still limited knowledge of the functional impact of certain sequence alterations in known cancer predisposition genes, the absence of specific cancer predisposing mutations in certain cases (even with an obvious hereditary phenotype), the occurrence of significant phenotypic overlap between the different syndromes rendering molecular diagnosis a difficult task in certain situations and the low sensitivity and specificity of criteria currently used to define syndromes by cancer family history. Finally, there is also limited understanding of the impact of genetic modifiers and environment on the phenotype in hereditary cancer families, as well as limited knowledge on population-specific or geographically localized mutations. As example we can cite a population-specific situation related to a founder germline mutation in the tumor suppressor gene TP53.The second group of women at high risk for breast cancer are those who carry a germline mutation related to hereditary predisposition to the disease. Hereditary cancer syndromes underly 5-20% of all breast tumors and carriers have a significantly increased risk of developing multiple tumors at an early age . The ideTP53 germline mutations to the overall burden of cancer is still only partially known [TP53 mutations (TP53 mutation database). Studies in Brazil have shown that a particular mutant, p.R337H, has incomplete penetrance and may be present in a significant number of subjects due to a founder effect , which may not easily recognized as risk patients due to weak family history of the disease and/or later onset of tumors [TP53 germline mutations may be much more common than recognized so far. This is likely the case in Southern and Southeastern Brazil for p.R337H, but may also occur in other Brazilian regions, or other parts of the world, due to similar founder mutations of incomplete penetrance; and (b) the cohort of p.R337H subjects and patients from Brazil provides a basis for both mechanistic and clinical studies.The exact contribution of f tumors ,7. This TP53 mutation identified so far, and identification of carriers will have significant impact on design of public health interventions related to cancer control in Brazil.In a recent study designed to assess the prevalence of p.R337H in breast cancer-affected women the mutation was present in breast cancer affected women with positive familial histories but no phenotypic criteria for LFS/LFL syndromes, and in a significant proportion (average among different Brazilian regions ˢ8%) of women with breast cancer and unselected for familial cancer history [There are no competing interests in this presentation.


Breast cancer belongs to the most common malignancy diagnosed in women. The major inherited susceptibilities to breast cancer are germline mutations in mutations in high risk genes, eg. BRCA1, BRCA2, BRIP, PALB2, RAD51C, RAD51D (5-10%), mutations in moderate risk genes, eg. CHEK2, ATM, NBS1 (10-20%) which however, explain only a small number of breast cancer cases. The latter are alterations in low risk genes and other possible changes in genome, eg. constitutional methylations of BRCA1.http://www.genome.gov/gwastudies/index.cfm?pageid=26525384#searchForm) have been performed on breast cancer cases and 21 variants associated with modest risk of BC (OR <1.3) have been identified.Genome – Wide Association Study (GWAS) was thought to help in identification of low risk alleles associated with the risk of particular disease. Up to know 14 GWAS conducted on Caucasian and 6 GWAS on Asian population (In 2005 have been initiated Breast Cancer Association Consortium (BCAC), an international multidisciplinary forum of investigators interested in the inherited risk of breast cancer. The aim of the consortium is to combine data from many studies in order to identify genes/SNPs and provide a reliable assessment of the breast cancer risks. Currently the BCAC gathers 69 centers from 29 countries, including Poland, and has access to demographic, clinical and epidemiological data from over 76,000 breast cancer patients and 83,000 unaffected women. In GWAS performed by BCAC 14 SNPs have been identified to be associated with modest risks of breast cancer.The aim of this study was to assess usefulness of SNPs identified in BCAC GWAS in diagnostics of breast cancer risk in Polish population.We found that 6 out of 14 SNPs identified in BCAC GWAS were associated with breast cancer risk in Polish patients. Four additional SNPs have been found to be associated with moderate risk of breast cancer in Polish study. Overall, out of 10 SNPs strongest in Polish study 3 seem to be valuable markers for breast cancer diagnostics in Poland: OR 1.91, 95%CI 1.39-2.65, p 0.0001 for carriers of 2 risk alleles and OR 3.2, 95%CI 1.87-5.47, p<0.0001 for carriers of 3 risk allele.


Approximately 5% of all endometrial cancers are due to a hereditary disposition, and a majority of the cases were found in families with Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Whilst both men and women with Lynch syndrome have a significantly increased risk of developing colorectal cancer (18-69%), women face the additional lifetime risks of developing endometrial cancer – between 27% to 71% as compared to 2% in the Australian general population. Despite the increased risk, many eligible women who may benefit from genetic assessment are not being referred by their treating clinician. The purpose of this study is to evaluate the patterns of referral of women diagnosed with endometrial cancer to genetic services. Using the diagnostic, clinical and referral databases from three different sites, we were able to link data of endometrial cancer cases in Queensland from May 2005 to December 2007. We determined the percentage of women diagnosed with endometrial cancer who could have been referred based on at least one risk factor suggestive of Lynch syndrome, the percentage of women that were referred and the percentage of women that attended genetic services. The revised Amsterdam and Bethesda criteria guidelines were adapted and used to assess the appropriateness of referral. Preliminary results show that of the 955 new diagnosis of endometrial cancer, 29 women (3%) were referred and 17 (1.8%) attended. This suggests that women who may benefit from genetic assessment do not ultimately attend their scheduled appointment. The mean age of referral is 61.7 years, with seven women diagnosed under the age of 50. Of the seven women, three were found to be mutation carrier. The results will be used to improve identification and referral of women at risk of Lynch syndrome to genetic health services in Queensland, and to increase awareness of hereditary gynaecological cancer.


Insulin-like growth factor 1 (IGF1) stimulates mitosis and inhibits apoptosis. Some published results have shown an association between circulating IGF1 and breast-cancer risk, but it has been unclear whether this relationship is consistent or whether it is modified by IGF binding protein 3 (IGFBP3), menopausal status, oestrogen receptor status or other factors. The relationship of IGF1 (and IGFBP3) with breast-cancer risk factors is also unclear. The Endogenous Hormones and Breast Cancer Collaborative Group was established to analyse pooled individual data from prospective studies to increase the precision of the estimated associations of endogenous hormones with breast-cancer risk.Individual data on prediagnostic IGF1 and IGFBP3 concentrations were obtained from 17 prospective studies in 12 countries. The associations of IGF1 with risk factors for breast cancer in controls were examined by calculating geometric mean concentrations in categories of these factors. The odds ratios (ORs) with 95% CIs of breast cancer associated with increasing IGF1 concentrations were estimated by conditional logistic regression in 4790 cases and 9428 matched controls, with stratification by study, age at baseline, and date of baseline. All statistical tests were two-sided, and a p value of less than 0·05 was considered significant.IGF1 concentrations, adjusted for age, were positively associated with height and age at first pregnancy, inversely associated with age at menarche and years since menopause, and were higher in moderately overweight women and moderate alcohol consumers than in other women. The OR for breast cancer for women in the highest versus the lowest fifth of IGF1 concentration was 1·28 . This association was not altered by adjusting for IGFBP3, and did not vary significantly by menopausal status at blood collection. The ORs for a difference in IGF1 concentration between the highest and lowest fifth were 1·38 (95% CI 1·14–1·68) for oestrogen-receptor-positive tumours and 0·80 (0·57–1·13) for oestrogen-receptor-negative tumours (p for heterogeneity=0·007).Circulating IGF1 is positively associated with breast-cancer risk. The association is not substantially modified by IGFBP3, and does not differ markedly by menopausal status, but seems to be confined to oestrogen-receptor-positive tumours.Cancer Research UK. Insulin-like growth factor 1 (IGF1) is a peptide which stimulates mitosis and inhibits apoptosis.22Around 99% of IGF1 circulates bound to IGF binding proteins, with most bound to IGF binding protein 3 (IGFBP3) in a ternary complex with an acid labile subunit. Less than 1% of IGF1 circulates unbound.Oestrogens are important in the aetiology of breast cancer, and there is laboratory evidence for crosstalk in cells between the signalling pathways for oestrogens and IGF1.The Endogenous Hormones and Breast Cancer Collaborative Group was established to do pooled analyses of individual data from prospective studies to increase the precision of the estimated associations of endogenous hormones with breast-cancer risk.Studies were eligible for the collaborative analysis if they had prospectively collected blood samples and data on circulating IGF1, IGFBP3, and breast-cancer risk. Potentially eligible studies were identified through PubMed using the terms “IGF1”, “IGFBP3”, and “breast cancer”, by searching the reference lists of identified studies, and by correspondence with study investigators. 17 eligible studies were identified: CLUE I and CLUE II from the USA;Of the 17 studies that contributed data, 11 provided data for women who were premenopausal at blood collection, and 15 provided data for women who were postmenopausal at blood collection. Data from premenopausal women and postmenopausal women in the same cohort were treated as separate sub-cohorts. For the cross-sectional analyses, data were included from all women in the original studies who had not been diagnosed with breast cancer (n=10 022); in the analyses of breast-cancer risk the data were arranged in matched sets, and some potential controls were not matched; therefore, the number of controls with data on IGF1 is less in the risk analyses (n=9428).Concentrations of IGF1 and IGFBP3 were positively skewed; therefore, log-transformed concentrations were used for all parametric analyses. Correlations between IGF1 and IGFBP3 among premenopausal and postmenopausal controls were calculated using standardised log-transformed concentrations within each study, the standardised values being calculated by subtracting the mean log concentration and dividing by the standard deviation of the log concentration. The associations of IGF1 with risk factors for breast cancer were examined in the controls using linear regression, calculating geometric mean concentrations and 95% CIs according to categories of these factors. Geometric means were adjusted for study and age  for breast cancer in relation to the plasma concentrations of IGF1 and IGFBP3, categorising women in each study according to the quintiles of hormone concentration for the controls in that study. Study-specific cut-points were used because the absolute concentrations of IGF1 and IGFBP3 vary between studies because of laboratory variation; further explanation of this approach is provided in previous publications.2); previous use of oral contraceptives (never or ever); and, for postmenopausal women only, type of menopause ; time since menopause ; previous use of hormone-replacement therapy (never or ever). For postmenopausal women, we also investigated the associations of IGF1 with breast-cancer risk after adjustment for plasma concentrations of oestradiol and testosterone, and the associations of IGF1 with breast-cancer risk with joint classification according to plasma oestradiol and testosterone concentrations.We examined the effect on the association with breast-cancer risk of adjusting IGF1 and IGFBP3 for each other. We also investigated the associations of IGF1 with breast-cancer risk after adjusting, one factor at a time, for various established reproductive and hormonal risk factors for breast cancer: age at menarche ; parity ; age at first full-term pregnancy ; body mass index  to 17 (IQR 8–18) years. Geometric mean concentrations of IGF1 ranged from 19·3 (95% CI 18·4–20·3) to 33·9 (32·9–34·9) nmol/L for premenopausal women, and from 14·6 (13·9–15·2) to 28·2 (24·9–31·8) nmol/L for postmenopausal women. Geometric mean concentrations of IGFBP3 ranged from 68·0 (95% CI 65·7–70·4) to 179·4 (175·9–183·0) nmol/L for premenopausal women and from 69·7 (66·8–72·7) to 160·6 (157·9–163·3) nmol/L for postmenopausal women.2 than in thinner or more overweight women. IGF1 was higher in women who drank up to 19 g/d of alcohol than in women who did not drink or who drank at least 20 g/d of alcohol, and was 4% lower for women who had undergone menarche at ages 14 years and over than for women who had undergone menarche before age 12 years. IGF1 varied according to parity, but not in a clear pattern, and was positively associated with age at first full-term pregnancy among parous women. For postmenopausal women, IGF1 was higher for those who had had their menopause most recently. IGF1 was higher for women who had previously used hormonal contraceptives than for those who had not. IGF1 was not significantly associated with smoking, family history of breast cancer, type of menopause, or previous use of hormonal therapy for menopause. The associations of IGF1 with other factors were similar in premenopausal and postmenopausal women (results not shown). Variation in IGFBP3 concentrations by breast-cancer risk factors was less pronounced than that for IGF1 . IGF1 and IGFBP3 were associated with each other, with correlations of 0·38 and 0·50 (data not shown) in premenopausal and postmenopausal women, respectively (both p<0·0001). The associations of IGF1 with selected reproductive and other factors in control women are shown in for IGF1 .IGF1 was weakly positively associated with breast-cancer risk for premenopausal women  and strongly positively associated with breast-cancer risk for postmenopausal women  and after adjustment was 1·24 (1·10–1·41). By contrast, adjustment of the association between IGFBP3 and breast-cancer risk for IGF1 reduced the OR for linear trend from 1·12 (95% CI 1·00–1·26) to 0·99 (0·87–1·14). Analyses of breast-cancer risk in relation to the molar ratio of IGF1 to IGFBP3 showed a significant positive association, but the magnitude was less than for the analyses of IGF1; ORs in increasing fifths of the ratio were 1·17 (95% CI 1·04–1·32), 1·12 (0·99–1·26), 1·14 (1·01–1·29) and 1·23 (1·08–1·40) (test for trend p=0·009). Further stratified analyses showed that IGFBP3 was not associated with breast-cancer risk within thirds of IGF1 .We examined the effect on the association of IGF1 with breast-cancer risk of adjustment, one factor at a time, for height, age at menarche, number of full-term pregnancies, age at first full-term pregnancy, use of hormonal contraceptives, type of menopause , time since menopause , previous use of hormonal therapy for menopause , BMI , plasma oestradiol concentration , plasma testosterone concentration , time of day of blood collection, and the phase of the menstrual cycle at blood collection . None of these adjustments altered the OR for IGF1 and breast cancer by more than 2% (data not shown) with the exception of adjustment for testosterone in postmenopausal women, which reduced the OR for an 80 percentile difference in IGF1 from 1·30 (95% CI 1·08–1·55) to 1·24 (1·04–1·49).The relationship of IGF1 with breast-cancer risk for postmenopausal women was examined together with the associations with oestradiol and testosterone . In bothIGFBP3 was not significantly associated with breast-cancer risk in any study of premenopausal women, and was significantly positively associated with risk in three out of 15 studies of postmenopausal women . There wThe results of this collaborative analysis show that plasma concentrations of IGF1 are positively associated with breast-cancer risk. The association is not substantially modified by menopausal status at blood collection or by IGFBP3 concentrations, but seems to be confined to oestrogen-receptor-positive tumours.The strengths of our study are that the data and plasma samples were all collected prospectively, that it includes almost all the available data from published studies worldwide, and that we were able to adjust for other potential risk factors, including endogenous sex hormones. A potential weakness is that the study designs and methods for measuring IGF1 and IGFBP3 and other risk factors were not standardised. IGF1 and IGFBP3 concentrations varied substantially between studies, and this is likely to reflect differences in assay methods. Our analysis allowed for this by defining study-specific quintiles of IGF1 and IGFBP3 concentrations. This method assumes the true concentrations across the quintiles are similar in all the studies, and if this assumption is not correct then the estimates of ORs might be biased.Previous studies have examined the associations of IGF1 with other factors. Relevant publications are cited below, but it should be noted that some of these are from the studies contributing to this collaborative analysis.IGF1 was inversely associated with age, with no obvious additional decline in concentrations around age 50 years, suggesting that menopause itself does not have a marked effect on IGF1. This is consistent with previous observations.322 than in thinner or more overweight women, as described previously.IGF1 was 7% higher in the tallest women than in the shortest women. No significant association of IGF1 with height was noted in two previous analyses in adults,IGF1 was not associated with smoking, consistent with previous observations.42IGF1 did not differ between women with or without a first-degree family history of breast cancer. The inverse association we observed between IGF1 and age at menarche has been noted previously.The associations of IGF1 with height, age at menarche, age at first full-term pregnancy, and time since menopause are compatible with the possibility that these factors affect breast-cancer risk partly through their relationships with IGF1.IGF1 concentrations were positively associated with breast-cancer risk, with a highly significant trend and no evidence of heterogeneity between studies. Women in the highest fifth of IGF1 had a 28% higher risk of breast cancer than women in the lowest fifth. This association did not vary significantly according to menopausal status at blood collection or according to the risk factors for breast cancer examined, and was not attenuated by adjustment for other risk factors including IGFBP3, reproductive factors, and, for postmenopausal women, BMI, oestradiol, and testosterone. If the association was due to an effect of preclinical tumours on IGF1 ,A previous meta-analysis based on studies published up to 2006 concluded that the association of IGF1 with breast-cancer risk is limited to premenopausal women,Our analyses were all based on a single hormone measure for each woman. Measurements of hormone concentrations are subject to largely random error associated with assay variation and fluctuations in plasma concentrations within individual women. Five studies have reported the reproducibility of IGF1 over periods of between 1 and 15 years in samples of between 13 and 138 women. The correlations (intra-class or Spearman) between baseline and repeat measures ranged from approximately 0·4 to 0·9 over 1 to 15 years.The association of IGF1 with breast-cancer risk was confined to oestrogen-receptor-positive tumours. Further work is needed to examine the potential biological basis for this observation. Laboratory studies have shown that oestrogen increases IGF receptor levels in breast-cancer cells,IGFBP3 was positively associated with breast-cancer risk, but this association was weak, and was eliminated by adjustment for IGF1, suggesting that the association of IGFBP3 with risk is due to its positive correlation with IGF1. It seems that, at least in the current dataset, the IGFBP3 measures do not add substantial information in assessing the relationship of IGF1 with breast-cancer risk. In addition to its role in transporting IGF1, laboratory studies have shown that IGFBP3 can have direct effects on cell behaviour which can promote apoptosis, but under other circumstances can act against apoptosis.The OR for IGF1 is smaller than the ORs for both oestrogens and androgens and breast-cancer risk in postmenopausal women, which have been shown in data mostly from the same epidemiological studies; high concentrations of oestradiol and testosterone are associated with around a doubling in breast-cancer risk.The association of IGF1 with breast-cancer risk was not altered by adjusting for age at menarche, parity, age at first full-term pregnancy, use of exogenous hormones, and BMI, suggesting that the relationship of IGF1 with breast-cancer risk is not confounded by these other risk factors.This collaborative analysis has confirmed a positive association between IGF1 and breast cancer risk. It is not known whether this association is causal, but there are plausible biological mechanisms that could explain such an effect.


Low dietary folate intake is associated with several neoplasias, but reports are inconsistent for breast cancer. Additionally, the association of folate with breast cancer estrogen receptor (ER) status is not well established.2, B6, B12) and methionine are associated with breast cancer risk and ER status in Hispanic, and non-Hispanic White women in the southwestern US.To determine if dietary intakes of folate, B-vitamins  in the 4-Corners region , diagnosed between October 1999 and May 2004, were identified through state cancer registries. Controls  were frequency-matched by ethnicity and age (±5 years). Dietary intake, physical activity and other exposures were assessed using in-person interviews. Risk was assessed through multivariable and multinomial logistic regression with adjustment for relevant covariates.12 intake was inversely associated with breast cancer also , particularly for the highest quartile of ER+ breast cancer , among NHW women  and invasive breast cancer . Methionine intake was also inversely associated with ER+ breast cancer , primarily among Hispanic women .While there was no overall association with breast cancer, the highest quartile of folate intake was marginally inversely associated with ER− breast cancer (Odds Ratio (OR) = 0.50, 95%CI 0.25–1.00, p for trend = 0.07). Vitamin BHigher intake of folate is marginally associated with a lower risk for ER− breast cancer, and higher intakes of vitamin B-12 and methionine are marginally associated with a lower risk of ER+ breast cancer. Dietary folate, methionine, vitamins B6 and B12 participate in one-carbon metabolism, which is essential for DNA methylation, synthesis and repair The majority of women have estrogen receptor (ER) positive tumors and respond to hormone therapy 2, B6, B12), and methionine with breast cancer risk and ER status among Hispanic and non-Hispanic White (NHW) women using data from the 4-Corners Breast Cancer Study (4-CBCS), a multi-centered, population-based case-control study 2, B6, B12) and methionine. Additionally, we evaluated the potential modification of these associations by menopausal status, ethnicity, and alcohol intake.We investigated the association of dietary intake of folate, B-vitamins  or driver’s license lists  and from Center for Medicare Services lists if > = 65 years, during the same time-period as cases, and were frequency-matched to cases by ethnicity and age within five years. The computer program, Generally Useful Ethnic Search System Participants in the 4-CBCS were women between 25 and 79 years of age residing in Arizona, Colorado, New Mexico and Utah. Subject selection methods, participation rates, data collection, and quality control procedures are described elsewhere All participants were asked to complete an in-person interviewer-administered computerized questionnaire in English or Spanish, based on the participant’s preference, blood draw, and anthropometric measurements. Data on demographic characteristics and breast cancer risk factors prior to the referent year  were collected, including reproductive, medical and medication history, height, weight history, diet, physical activity, education, cigarette smoking, and alcohol consumption. There were few American Indian participants (0.85%) and their data were combined with Hispanic women in analyses. Findings based on analyses by genetic admixture supports this combined grouping A diet history questionnaire 2) for the referent year. Menopausal status was determined by an algorithm based on age (<57 vs. > = 57 years) at referent date and responses to eight questions regarding menstrual status, hormone replacement use, and surgical or medical menopause Physical activity was measured using a modified version of the Cross Cultural Activity Participation Survey 2, B6, B12, and methionine were also calculated. Cases and controls were compared by ethnicity, as well as the two ethnicities. All the differences were evaluated by least-squares regression analysis of variance, adjusting for age, center and total energy intake. Groups were compared for covariates using t tests for continuous variables and chi-square tests for categorical variables. Unconditional logistic regression models were used to estimate the odds ratios, and 95% confidence intervals for associations between folate, vitamins B2, B6, B12 and methionine with breast cancer risk. Nutrient intakes were log-transformed and adjusted for total energy intake using the residual method Separate calculations were made for dietary folate based on pre- and post-fortification, which was initiated in 1998 2, B6, B12 and methionine adjusted for center, age, and ethnicity; and (2) additional adjustment for education, BMI, energy intake/day, fiber intake/day, total weekly MET hours of physical activity, cigarette smoking status, recent alcohol consumption, parity, family history and oral contraceptive use five years prior to referent date. Although the impact of any one covariate was minimal (<15% for the 4th folate quartile), all variables were retained in the final models for consistency with previous studies. Multinomial logistic regression was used to estimate risk by ER tumor status. Effect modification of folate (continuous) by menopausal status, ethnicity, and alcohol consumption was evaluated by comparing models with and without interaction terms using likelihood ratio test Analyses were based upon two models: (1) folate, vitamins BAll participants signed an informed written consent prior to participation. The study was approved by the following Institutional Review Boards: The Human Research Protections Office of University of New Mexico; University of Utah Institutional Review Board; Human Subjects Research and Institutional Review Board of University of Arizona and Human Research and the Institutional Review Board of University of Colorado.in situ vs. 82% for women with invasive cancer. Analyses based on ER status therefore included a total of 1,480 cases. Hispanic cases were significantly more likely to have ER− tumors than non-Hispanic white cases . The average age of the participants was 55 (±12) y.A total of 2,325 cases  and 2,525 controls  participated in the study. Of these, 152 subjects with extreme values for BMI (<16 kg/m2 or >50 kg/m2) or caloric intake  were excluded, leaving a total of 2,262 cases  and 2,436 controls . ER status was present for 65% of all cases; 17% for women diagnosed with There were statistically significant differences between ethnic groups for all covariates, regardless of case-control status, with the exception of oral contraceptive use , many ofP = 0.25). Hispanic and non-Hispanic white women differed significantly for most nutrients . Intake did not differ by case-control status within each ethnic group . Results for vitamins B2, B6, and methionine were non-significant. No statistically significant interactions were observed between folate and alcohol consumption (P = 0.30), menopausal status (P = 0.30) or ethnicity (P = 0.08). We also analyzed the joint effect of folate by vitamin B12. Each variable was categorized as low (Q1), moderate (Q2–Q3) and high (Q4) based on quartile distributions. The results showed that moderate folate-high vitamin B12 intake  and high folate-high vitamin B12 intake  had significant protective associations with breast cancer risk compared to low folate-low vitamin B12 intake. All other results were non-significant (data not shown).Odds ratios for the highest quartile of folate were less than 1.0, although not statistically significant  . VitaminPtrend = 0.07), particularly in post-menopausal women , while there was no association with ER+ cancer or in pre-menopausal women  (Ptrend = 0.01) and among invasive breast cancer women  (data not shown). Methionine was also inversely associated with risk for ER+ tumors , particularly in Hispanic women  (data not shown), but not with ER− cancer. The association was not modified by stage of cancer.Total folate intake was marginally inversely associated with ER− breast cancer  , particuBecause alcohol intake can influence the biological effects of folate and Methionine 12, in keeping with two previous case-control studies 12 intake for total breast cancer risk maybe due to differential effects on ER phenotypes. We also found a protective association of methionine intake for ER+ breast cancer (P for trend = 0.04), but no evidence for associations with vitamins B2 or B6, in keeping with previous studies This case-control study provides weak evidence that dietary folate and vitamin B intake is protective for breast cancer. Several other case-control studies also have reported protective associations 12 and methionine with ER+ breast cancer agree with the hypothesized role of one-carbon metabolism in carcinogenesis but suggest a different pathway 12 and methionine are established enzymatic cofactors in one-carbon metabolism 12 or methionine for alteration of DNA methylation, resulting in silencing of ER expression and the manifestation of the ER− breast cancer phenotype. In contrast, deficiency of B12 and methionine may influence the risk for the more common ER+ phenotype by a more general impairment of DNA synthesis and repair (29).A few studies to date have examined associations of dietary folate and B-vitamins with breast cancer according to ER status We used pre-fortification values for folate intake in our study because this was the relevant exposure before the introduction of fortification. In more recent studies conducted post-fortification, the protective association of increased folate intake on breast cancer risk may be nullified or even reversed The strengths of this study include a large population-based study sample including Hispanic and non-Hispanic white women with complete and extensive data for diet, dietary supplements, and numerous non-dietary confounding factors, collected with rigorous quality-control standards P = 0.41), and overall, it is unlikely that missing ER status is associated with folate intake. The participation rate was lower in our study than for some previous studies, increasing the potential for selection bias, although obtaining high response rates in minority populations is a universal problem Several limitations must be considered. We were unable to account for genetic variants that regulate one-carbon metabolism and that have been shown to be associated with increased breast cancer risk In conclusion, our results support the hypothesis that folate and B-vitamin intake influence breast cancer risk, but that folate intake may be related specifically to risk for the ER− phenotype. These risks may be different than those reported in studies conducted after folate fortification.


The inverse trend had been observed in both Western and Asian population, with a relatively lower percentage of obesity and higher percentage of leanness, suggested that the inverse trend could be explained not only by the protective impact due to obesity, but also by the increased risk of breast cancer due to leanness. Among post-menopausal women, however, an elevated BMI has been positively associated with the development of breast cancer, particularly in the cases of estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) tumors. Currently, the mechanisms underlying the heterogeneous impacts between BMI on breast cancer risk and the life-stage of women remain poorly understood. We reviewed several proposed biological mechanisms that may contribute to the various impacts of relative body weight on breast cancer risk across life-stage. We also discussed the impact of BMI upon the outcome of endocrine therapy, particularly for aromatase inhibitor, in breast cancer patients. To prevent breast cancer incidence and recurrence, the desirable BMI of women may differ throughout their life-stage. To define the underlying mechanism for the various impacts of BMI in the context of breast cancer across various female life stages, further studies will be required.A large amount of epidemiological evidence suggests that the impact of body weight on breast cancer risk should be heterogeneous throughout the life-stage of women. At birth, high weight has been positively associated with an increased risk of breast cancer. While, the body mass index (a relative body weight; BMI kg/m A subsequent increase in the secretion of ovarian hormones, including estrogens and progesterone, leads to the normal development of the mammary gland. Estrogens generally act in the development of the breast duct. Progesterone, in addition to estrogen, may also play an important role in the development of mammary gland lobes. Previous animal studies , 1979 suIn the early adult stage, a low BMI may indicate a lack of a mammary fat pad or a deficiency of progesterone, which may promote an accumulation of excessive body fat . For norThe inverse trend between BMI 20 years and breast cancer risk is observed both among Western population as well as Japanese population. In the light of a relatively low proportion of overweight among the Japanese female, the observed inverse trend should not explain that overweight-/obese-related mechanism. The development of breast tumor due to leanness needs to be considered as one of possible explanations.Previous studies suggested that mammary fat pad might play a number of vital roles in normal growth, differentiation in mammary gland morphogenesis epithelial–mesenchymal interaction according to animal studies. It has been suggested that body fat might play an important role in differentiation a normal mammary development. Recently, After menopause, epidemiological evidence found a substantial positive association between BMI and breast cancer risk . One of An insulin-related mechanism could also be one possible explanation for the positive association between post-menopausal body weight and breast cancer risk. Obesity leads to hyperinsulinemia with insulin resistance. Excess glucose levels could stimulate the cellular proliferation of breast tumors .High BMI and obesity are recognized as independent risk factors for the development of breast cancer, as well as for an increased rate of recurrence after primary disease . Previoup = 0.018] compared to control patients. However, overweight patients derived no benefit from anastrozole regarding DFS  compared to control patients. Identical results were also observed in pre-menopausal women in the ABCSG 12 trial in which a significant impact of BMI on the efficacy of anastrozole plus goserelin, but not of tamoxifen plus goserelin, was found  compared to tamoxifen , while obese patients (BMI ≥ 30) tended to benefit more from tamoxifen [RFS: p = 0.289; HR = 0.65 (95% CI: 0.29–1.45); The impact of BMI on treatment outcome has also been reported in patients receiving endocrine therapy. There have been consistent results indicating that the efficacy of aromatase inhibitors (AIs) vary with BMI; however, the efficacy of tamoxifen is not BMI-dependent. In the ATAC  trial, which compared the efficacy of anastrozole against tamoxifen as an adjuvant treatment for hormone receptor-positive post-menopausal breast cancer patients, anastrozole, a non-steroidal AI, was significantly less effective in post-menopausal breast cancer patients with a high BMI, whereas an equal efficacy of tamoxifen was shown across all BMI levels . Retrospas found . For anoIt is reported that estrogen levels are influenced by body weight, with overweight patients having higher levels compared to normal-weight patients . The conp = 0.01; However, as opposed to anastrozole and letrozole, in the TEAM trial, in which 5 years of exemestane use was evaluated against 2–3 years of tamoxifen followed by 3–2 years of exemestane, exemestane was found to be more effective in obese patients than tamoxifen, although the difference was not statistically significant and was only observed during the first 2.75 years, when exemestane and tamoxifen were compared directly . SimilarTable 1). Although the specific mechanism of these differences has not been explained yet, it is clear that the efficacy of the AI varies according to patient BMI; the efficacy of tamoxifen, however, does not depend on BMI. Further study would be warranted to define the mechanism of the effect of BMI on AI efficacy, which could lead to selective utilization of AIs and tamoxifen in post-menopausal women.From these observations, one can argue that the differences in the efficacy of AIs depending on BMI might depend on the type of AI, i.e., non-steroidal vs. steroidal . Although body weight control is an effective strategy for primary prevention of breast cancer among post-menopausal women, such recommendations should take women’s life stage into account, particularly among young adult pre-menopausal women. In addition, BMI has impact also on the prognosis of breast caner patients and responsiveness to the endocrine therapy with AI. To prevent breast cancer incidence and recurrence, the desirable BMI of women may differ throughout their life-stage. To define the underlying mechanism for the various impacts of BMI in the context of breast cancer across various female life stages, further studies will be required.In summary, the current epidemiological study has provided evidence of the impact of body weight on breast cancer risk across women’s life stages (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.