The increasing epidemic proportions of diabetes mellitus (DM) are a major cause of premature illness and death. However, whether DM confers the same excess risk of gastrointestinal cancer for women as it does for men remains controversial. The purpose of this study was to estimate the relation between DM and gastrointestinal cancer in women compared with men after accounting for other major risk factors based on cohort studies.We performed a meta-analysis of cohort studies published through May 2017 from PubMed, Embase, and the Cochrane Library. Studies with cohort designs were stratified by sex and reported the relation between DM and esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), hepatocellular carcinoma (HCC), or pancreatic cancer (PC) risk. The ratio of relative risk (RRR) between men and women was employed to measure the sex differences in the relation between DM and gastrointestinal cancer with a random effects model with inverse variance weighting.p < 0.001), while the risk of HCC was lower  as compared with DM men. Further, there was no evidence of sex differences in the RRR between participants who had DM compared with those without DM for EC (p = 0.068), CRC (p = 0.618), and PC (p = 0.976). In addition, the pooled RRR showed a statistically significant association between DM and the risk of CC in women compared with men , and there was no evidence of sex differences for RC among participants with DM compared to those without DM (p = 0.648). Finally, the sex differences of the comparison between DM and non-DM for gastrointestinal cancer risk at different sites were variable after stratification for different effect estimates.We included 38 cohort studies reporting data on 18,060,698 individuals. The pooled RRR indicated DM women was associated with an increased risk of GC  contains supplementary material, which is available to authorized users. Diabetes mellitus (DM) is a growing global pandemic afflicting approximately three to 4 % of adults worldwide; it has caused around 1.3 million deaths worldwide . The IntIn 2004, the Cancer Prevention Study II reported that women with DM had a 38% greater reduction of HCC risk than did their male counterparts , 20. FurThis study was conducted and reported according to the meta-analysis of observational studies in epidemiology protocol . Any cohThe literature search and study selection were conducted by two authors independently using a standardized approach. Any inconsistencies between these two authors were settled by the primary author until a consensus was reached. A study was eligible for inclusion if the following criteria were met: (1) the study had to have a cohort design; (2) the study investigated the association between DM and the risk of gastrointestinal cancer including EC, GC, CRC, CC, RC, HCC, and PC; (3) the study reported the association between DM and gastrointestinal cancer in men and women simultaneously; and (4) the authors reported effect estimates  and 95% confidence intervals (CIs) for comparisons of DM and non-DM. Studies performed on single-sex populations were excluded. Further, we excluded all case-control studies because various confounding factors could bias the results.The data collection and quality assessment were conducted by two authors independently. Information was examined and adjudicated by an additional author referring to the original studies independently. The data collected included the first author or study group’s name, publication year, country, study design, sample size, mean age or age range, number of men and women, type of DM, percentage of smokers, reported outcomes, effect estimate, duration of follow-up, and maximum adjustment. For studies that reported several multivariable adjusted effect estimates, we selected the effect estimate that was maximally adjusted for potential confounders. The study quality was evaluated by the Newcastle-Ottawa Scale (NOS), which is quite comprehensive and has been partially validated for evaluating the quality of observational studies . Further2 and Q statistic, and we considered p values < 0.10 as indicative of significant heterogeneity [We examined the relation between DM and risk of gastrointestinal cancer on the basis of the sex-specific effect estimate and its 95% CI published in each study. HR was considered equivalent to RR in cohort studies. Given the low incidence of gastrointestinal cancer, OR could be assumed to be accurate estimates of RR. We first used the random-effects model to calculate summary RRs and 95% CIs for DM versus non-DM and the risk of EC, GC, CRC, CC, RC, HCC, and PC in men and women separately , 30. Theogeneity , 34. A sogeneity . Meta-reogeneity . Subgrouogeneity  and Beggogeneity  were empThe results of the study-selection process are shown in Fig. , and another article combined 10 cohorts in Japan [Of the 38 cohorts involving a total of 18,060,698 individuals, 29 were prospective cohort designs , 69–74 ain Japan , 74, 8 hin Japan , 71–73, in Japan , 46, 54,in Japan , 67, 68.The summary RRs for gastrointestinal cancer at different sites were calculated and presented in Additional file p = 0.068; Fig. 2 = 17.9%; p = 0.273). Further, the pooled RRR  based on SIR/SMR for the risk of EC was increased , while this sex difference based on RR/OR/HR was not associated with statistically significant . Sensitivity analysis suggested no sex difference between DM and EC based on SIR/SMR when excluding the study conducted by Wang et al. [p value for Egger: 0.452; p value for Begg: 0.755; Additional file A total of 11 cohorts in 16 studies reported an association between DM and subsequent EC risk , 67, 68.g et al. , a studyp < 0.001; Fig. 2 = 14.8%; p = 0.267). This sex difference was detected when the result based on SIR/SMR . Further, although women with DM had a 1o% higher risk of GC than men with DM, this sex difference was not statistically significant when combined results from RR/OR/HR . The findings of sensitivity analyses suggested the sex difference was statistically significant based on SIR/SMR when excluding the National Health Insurance Program study [p value for Egger: 0.664; p value for Begg: 0.415; Additional file A total of 21 cohorts in 26 studies reported an association between DM and subsequent GC risk , 67–72. am study , which sp = 0.618; Fig. 2 = 6.9%; p = 0.368). This conclusion was consistent whether the summary results were based on SIR/SMR  or RR/OR/HR . Sensitivity analysis was performed and the conclusion was not affected after the sequential exclusion of each study from all the pooled analyses . Further, this significant sex difference mostly came from pooled SIR/SMR data , and there was no sex difference when combined the study reported RR/OR/HR . The findings of sensitivity indicated no sex difference based on SIR/SMR when excluding the Danish Central Hospital Discharge Register study [p value for Egger: 0.982; p value for Begg: 0.767; Additional file Similarly, the pooled RRR  of DM versus non-DM for CC was 0.93 . This conclusion was not changed when pooled with SIR/SMR  and RR/OR/HR , respectively. A sensitivity analysis was conducted and after each study was sequentially excluded from the pooled analysis; the conclusion was not affected by the exclusion of any specific study . This significant sex difference existed if based on pooled RR/OR/HR , while no sex difference was based on pooled SIR/SMR . The findings of sensitivity analysis suggested these sex differences were variable after sequentially excluding a single study, which might be because the power was not strong enough; this should be verified in future studies . This insignificant sex difference persisted whether pooled with SIR/SMR data  or RR/OR/HR data . The conclusion was not affected after sequential exclusion of each study from the pooled analyses  and GC (SIR/SMR), while with reduced risk of CC (SIR/SMR) and HCC (RR/OR/HR) than in men with DM. The several possible reasons follow. (1) SIR and SMR were employed as an effect measure in 14 cohorts, and the general population were regarded as a non-exposed control; the comparability of characteristics was inferior to selection representativeness of cohorts as control group. (2) The small number of included cohorts might affect the sex difference of DM and EC risk. (3) Women with DM showed higher incidence of GC, while the prevalence of DM in Asian women was lower than in men, and the duration of DM was less. (4) Different compare control groups might play an important role in the progression of CRC. (5) The sex difference of CC was determined in individual studies, which contributed an important role and accounted for higher weight , 25. (6)The findings of subgroups suggested the sex difference of the relation between DM and gastrointestinal cancer might be variable according to pre-defined factors. First, we noted that publication year affected the sex difference on the risk of EC, GC, CRC, and CC. The possible reason for this could be that the diagnosis criteria and approach were different, which was associated with the risk of cancer at different sites. Further, the pooled RRR  was increased for EC and GC in Eastern countries, while this difference was reduced for CRC, CC, and HCC in Western countries. The reason for this could be that the prevalence of EC and GC was higher in Eastern countries than in Western countries and the prevalence of cancer between men and women was different. Third, the study design of included research might have affected the relation between DM and gastrointestinal cancer due to uncontrolled biases in studies with different designs. Fourth, sample size affected the sex differences on the risk of CC because the statistical power was enough to detect small differences. Fifth, different mean age affected the incidence of gastrointestinal cancer because the prevalence of EC, GC, and HCC was higher in younger individuals, while the incidence of CRC and CC was more common in older individuals. Sixth, the type of DM might affect the possible incidence of gastrointestinal cancer because patients with Type 1 DM were younger than those with Type 2 DM. Seventh, studies with longer follow-up and higher proportion of cancers than studies with shorter follow-up contributed higher weight to pooled results and more easily detected small sex differences. Finally, the confounders, whether adjusted or not, were affected by the sex difference relation between DM and gastrointestinal cancer. The possible reasons are presented as follows: (1) Patients with Type 2 DM always had higher BMIs, which might affect the incidence of cancer. This factor should adjust because individuals with higher BMIs more easily suffer DM, and participants with prediabetes were associated with the risk of cancer . (2) SmoFour strengths of our study should be highlighted. First, only cohort studies were included, which should eliminate uncontrolled bias. Second, the large sample size allowed us to quantitatively assess the sex difference in the association of DM with the risk of gastrointestinal cancer, and thus, our findings are potentially more robust than are those of any individual study. Third, the consistency in the findings of this study and the lack of significant publication bias also support the robustness of the study findings. Finally, the study provided evidence supporting the sex difference of DM and gastrointestinal cancer risk in patients with specific characteristics.The limitations of our study are as follows: (1) the adjusted models are different across the included studies, and these factors might play an important role in the development of gastrointestinal cancer; (2) inconsistencies among included studies in DM types, assessment of DM, and DM duration were identified; (3) the effect modification of gender on the associations of DM with gastrointestinal cancer were neglected due to data were not available in all of included studies; (4) stratified analyses based on large numbers of factors might induce multiple comparisons; and (5) the individual data were not available, and the findings of this study were based on pooled data, which restricted us from performing a more detailed relevant analysis and obtaining more comprehensive results.In summary, the findings of this meta-analysis suggested that women with DM was associated with an increased risk of GC, and reduced risk of HCC and CC as compared with men with DM. Further, a sex difference might exist for EC, and CRC. The true associations of DM with the risk of gastrointestinal cancer between men and women might be variable in the study of individuals with specific characteristics. Future studies should focus on specific populations and compare the association between DM and gastrointestinal cancer risk in groups of participants categorized by potential confounders.Additional file 1:Newcastle–Ottawa scale for quality assessment of the included studies. (DOC 99 kb)Additional file 2:STATA program for calculate the ratio of relative risk. (DOC 37 kb)Additional file 3:Effect estimate of relationship between diabetes mellitus and gastrointestinal cancer in each included studies. (DOC 174 kb)Additional file 4:The summary results for the relationship between diabetes mellitus and gastrointestinal cancer. (DOC 45 kb)Additional file 5:The details of sensitivity analyses for gastrointestinal cancer. (DOC 254 kb)Additional file 6:The findings of meta-regression for gastrointestinal cancer based on publication year, sample size, mean age, percentage of smoker, and follow-up duration. (DOC 36 kb)Additional file 7:Subgroup analyses for the relationship between diabetes mellitus and gastrointestinal cancer in women compared with men. (DOC 643 kb)Additional file 8:Publication biases for gastrointestinal cancer. (DOC 129 kb)


After more than 20 years of increased incidences of breast cancer, the year 2000 heralded a welcome statistic: The number of breast cancer cases had begun to decline. The biggest factor in the incidence of breast cancer is thought to be a decline in the use of hormonal therapy after menopause The American Cancer Society (ACS) estimates that in the year 2015, approximately 241,840 new cases of breast cancer will have been diagnosed in women, with 40,290 deaths occurring from the disease. The trend toward a decreased number of cases is good news. Women following the ACS guidelines for early detection of the disease previously received mammograms starting at age 40 and clinical breast exams (CBEs) during provider visits.The recent announcement by the ACS regarding the age at which women should begin mammogram exams has received national attention. The new ACS guidelines state that mammograms should begin at age 45 instead of 40 .The new ACS guidelines do not recommend CBE for breast cancer screening among average-risk women at any age, as the data did not support the practice. Although there are several studies suggesting a possible benefit for the use of CBE in some settings, the extensive review by the authors of the guideline did not definitively show evidence for CBE as an effective screening tool for breast cancer, particularly when mammography is available for patients .This recommendation may be received with trepidation by some patients who have become accustomed to a CBE within the context of their provider visit. These patients may continue to ask for a CBE, and it’s my personal belief that patients who request the exam should receive one.As a nurse practitioner, I often use the exam to reinforce techniques of breast self-exam so that patients can replicate the process at home. I also feel that a patient interview can be conducted during a breast exam, using the time to continue to get valuable information regarding the patient’s history while performing a thorough CBE (which can take 5 to 6 minutes; Advanced practitioners should incorporate the new guideline as appropriate into their clinical settings. Whether or not there will be insurance coverage for exams conducted outside of the guideline remains to be seen. The ACS guideline does recommend that all women become familiar with the potential benefits, limitations, and harms associated with screening for breast cancer. It is also important to note that women should have the opportunity to begin annual screening between the ages of 40 and 44, as the recommendation to begin screening at age 45 is for women with an average risk of breast cancer.There is no doubt that screening mammograms have been effective in reducing the number of breast cancer deaths. The good news regarding the incidence of breast cancer is still relevant: The numbers have declined. But the disease remains the second-leading cause of cancer death in women. We must stay vigilant.


A first full-term birth at an early age protects women against breast cancer by reducing lifetime risk by up to 50%. The underlying mechanism resulting in this protective effect remains unclear, but many avenues have been investigated, including lobular differentiation, cell fate, and stromal composition. A single pregnancy at an early age protects women for 30–40 years, and this long-term protection is likely regulated by a relatively stable yet still modifiable method, such as epigenetic reprograming. Long-lasting epigenetic modifications have been shown to be induced by pregnancy and to target the IGF pathway. Understanding how an early first full-term pregnancy protects against breast cancer and the role of epigenetic reprograming of the IGF system may aid in developing new preventative strategies for young healthy women in the future. An early first full-term birth (FFTB) is the most effective modifiable breast cancer prevention method, with the potential of reducing a woman’s lifetime risk up to 50%. The first documented observation of this preventative behavior was by Bernardino Ramazzini in 1700. He noted that “tumors of the breast are found more often in nuns than any other women” and speculated that this was due to a life of celibacy . Since tThe abovementioned study identified a positive linear correlation between age at FFTB and breast cancer risk . NullipaThe protective effect of pregnancy has been replicated in multiple animal models including mice and rats using both carcinogen and spontaneous carcinoma models , 12, 13.The stage of the pregnancy cycle  most important in reducing breast cancer risk is unclear. The previously mentioned study  chose toSurprisingly, in a rodent model, lactation is not obligatory to elicit protection against mammary cancer. Parous rats that were not permitted to nurse and animals that did nurse were equally protected from mammary cancer . AdditioIn an attempt to identify the underlying cause of parity-induced protection against breast cancer, several morphogenic and molecular mechanisms have been investigated including differentiation state, cell fate, and stromal alterations of the mammary gland. One of the first comprehensive studies investigating differentiation of the breast reported that parous women displayed a higher proportion of differentiated lobules in the breast. Four lobule types were identified with type 1 being the least and type 4 being the most differentiated. Cells isolated from the least differentiated lobule type were the most susceptible to carcinogenic insults, displaying increased survival efficiency and multinucleation . Of peakn = 10), there was no difference in lobular composition of the breast , have likely undergone lobular involution, and actually have a decreased risk for breast cancer , 31. The+p27+ cells  in circulation has been shown in many studies to be associated with breast cancer risk –59. In aWhile it is well accepted that circulating IGFI levels are associated with breast cancer risk, interestingly, parity is associated with lower circulating IGFI levels. In the Nurses Health Study, 1037 healthy women were used to investigate circulating IGFI and lifestyle factors. This study identified age, smoking, parity, and hormone use to be significantly associated with circulating IGFI levels . CirculaThe Nurses Health Study data also show an inverse relationship between IGFI levels and age . This fiA link has also been found between IGFI and lobular differentiation. The Nurses Health Studies I and II used 472 women with benign breast disease in a cross-sectional design to show that higher circulating IGFI or a higher IGF:IGFBP3 ratio was associated with decreased odds of having predominantly type 1 lobules . Type 1 The relationship between IGFI and pregnancy is modified in women afflicted with gestational diabetes and preeclampsia, although the data are conflicting. One study reported an inverse association between IGFI or IGFBP1 and risk for gestational diabetes ; anotherThese findings beg the question whether pregnancy disorders have associations with breast cancer risk. Again, the data are conflicting with many papers finding no association between gestational diabetes or preeclampsia with breast cancer risk –84. In sIn conclusion, long-term exposure to excessive IGFI in circulation leads to an increase in breast cancer risk as described above, and parous women display lower circulating IGFI and breast cancer risk indicating that IGFI contributes to the effect of parity on lifetime breast cancer risk Figure . On the IGF1 expression to be decreased with parity  are completely resistant to carcinogen-induced tumors  and 6 months postpartum (late)  . This stCsn2 and Wap and was mediated by P4 (As previously mentioned, histone modifications are also likely to play a role in reprograming the breast epigenome during pregnancy. In the breasts of nulliparous women, nuclei were large and euchromatic in contrast to parous women displaying small heterochromatic nuclei with strong methylation of histones at repressive marks H3K9me2 and H3K27me3 . One stued by P4 .Investigations probing the mechanism underlying the protective effect of pregnancy against breast cancer have been conducted in many areas including lobular differentiation, cell fate, and stromal composition. However, no single cause has been identified, and likely these mechanisms complexly interact to elicit the protective effect. The long-lasting effect of an early FFTB on reducing breast cancer risk implies that a relatively persistent modification may contribute to this phenomenon such as epigenetic reprograming Figure .While an early FFTB provides the greatest protection against breast cancer compared to any other risk factor, a method to exploit this phenomenon for a preventative strategy has not been developed. Currently, the most widely used preventative measure is tamoxifen, but due to toxicities, this is only available to high-risk women. Tamoxifen therapy causes unpleasant side effects leading to a drastic diminishment in its use in more recent years , 103. ThTK conducted literature searches and wrote the review article.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Breast cancer is the most common type of cancer among women. In Kazakhstan, breast cancer holds first place among causes of women death caused by cancer in the 45–55 year age group. Many studies have shown that the risk of acquiring breast cancer may be related to the level of calcium in the blood serum. One of the important regulators of calcium metabolism in the body is the parathyroid hormone. Single nucleotide polymorphisms in the gene encoding the parathyroid hormone (PTH) are associated with breast cancer development risk, and may modify the associative interaction between the levels of calcium intake and breast cancer. Experimental studies have shown that PTH gene has a carcinogenic effect. At least three studies showed a weak positive correlation between the risk of acquiring breast cancer and primary hyperparathyroidism, a state with high levels of PTH and often high levels of calcium. The aim of this investigation was to evaluate potential association between PTH gene polymorphism and breast cancer risk among Kazakhstani women.DNA Purification Kit . Detection of PTH gene polymorphism (rs1459015) was done by means of the TaqMan® SNP Genotyping Assay of real-time PCR. Statistical analysis was conducted using SPSS 19.0.Female breast cancer patients (n = 429) and matched control women (n = 373) were recruited into a case – control study,. Genomic DNA was extracted from peripheral venous blood of study participants using p > 0.05). Distribution was 59% CC, 35% CT, 6% TT in the group with breast cancer and 50% CC, 43% CT, 6% TT in the control group. Total difference (between the group with breast cancer and the control group) in allele frequencies for PTH polymorphism was not significant (p > 0.05). No association was found between rs1459015 TT and breast cancer risk .PTH gene alleles were in Hardy–Weinberg equilibrium (We found no association between PTHrs1459015 polymorphism and breast cancer in our present study. Further studies are required to confirm our results and clarify role of PTH gene genotypes on breast cancer risk.


Preeclampsia is frequently linked to reduced breast cancer risk. However, little is known regarding the underlying genetic association and the association between preeclampsia and mammographic density.This study estimates the incidence rate ratios (IRRs) of breast cancer in patients with preeclampsia, when compared to women without preeclampsia, using Poisson regression models in two cohorts of pregnant women: a Swedish nationwide cohort  and the Karolinska Mammography Project for Risk Prediction of Breast Cancer . To identify the genetic association between preeclampsia and breast cancer, we used logistic regression models to calculate the odds ratios (ORs) of preeclampsia in sisters of breast cancer patients, and in women with different percentiles of breast cancer polygenic risk scores (PRS). Linear regression models were used to estimate the mammographic density by preeclampsia status in the KARMA cohort.A decreased risk of breast cancer was observed among patients with preeclampsia in both the nationwide  and KARMA cohorts . Women with high breast cancer PRS and sisters of breast cancer patients had a lower risk of preeclampsia . Mammographic density was lower in women with preeclampsia compared to women without preeclampsia . Additionally, among sisters in the KARMA cohort (N = 3500), density was lower in sisters of patients with preeclampsia compared to sisters of women without preeclampsia .Preeclampsia is associated with reduced risk of breast cancer and mammographic density. Inherited factors contribute to this inverse association.The online version of this article (doi:10.1186/s13058-017-0930-6) contains supplementary material, which is available to authorized users. Preeclampsia is a pregnancy-related disease originating from the placenta and characterized by hypertension and proteinuria . PreeclaWhile an inverse association between preeclampsia and breast cancer risk has consistently been shown since the 1980s –7, severAlthough it is hypothesized that hormonal changes due to preeclampsia are associated with mammary gland development, and a subsequent reduction in breast cancer risk , we are This study assessed the risk of breast cancer after preeclampsia diagnosis, using Swedish population-based registers. We further investigated the genetic association between preeclampsia and breast cancer, by testing the risk of preeclampsia in cancer-free sisters of patients with breast cancer and in women with different polygenic risk scores (PRS) for breast cancer. The association between preeclampsia and mammographic density was also analyzed in the mammographic screening cohort to confirm this biological association.This study included two cohorts: 1) a Swedish nationwide cohort of pregnant women (nationwide cohort in short) and (2) a Swedish mammographic screening-based cohort  , and ended on the date of first breast cancer diagnosis, date of death, date of emigration or end of follow up (31 December 2011), whichever came first. Information on breast cancer diagnosis, death and emigration was obtained through cross-linking the cohort to the Swedish Cancer Register, Swedish Causes of Death Register and the Swedish Migration Register, using unique Swedish personal identification numbers . Breast Mammograms in the mediolateral oblique (MLO) position were obtained from four Swedish hospitals in women participating in the KARMA cohort during 2011–2013. The fully automated software STRATUS was used to measure area-based mammographic density (details of this method have been described elsewhere) [Blood samples from a subset of 9263 women without breast cancer from the KARMA cohort were genotyped using a custom Illumina iSelect array (iCOGS), comprising 211,155 single nucleotide polymorphisms (SNPs) . Detailsβ is the per-allele log odds ratio (OR) of breast cancer associated risk allele for SNP k, xk is the number of alleles for the same SNP , and n is the total number of the disease SNPs included in the profile. The SNPs and corresponding log ORs (weights) used for the derivation of PRS are summarized in Additional file where e SNP 0, , 2, and An age-adjusted incidence rate of breast cancer was calculated in both the nationwide and KARMA cohorts, taking the 1990 Swedish national census population as the standard population. Considering the few cases of breast cancer in the age category 70–80 years in the KARMA cohort (n = 5), the age-adjusted incidence rate was restricted to an age band of 20–70 years. Poisson regression models were used to calculate incidence rate ratios for breast cancer in patients with preeclampsia. In this analysis, preeclampsia was considered as a time varying exposure, in which the exposed person-time was counted from the time of preeclampsia diagnosis. The underlying time scale was attained age. We constructed two models to analyze the association between preeclampsia and breast cancer incidence: (1) a basic model (model 1) adjusted for calendar period (10-year categories) and (2) model 2: with additional adjustment for number of births (time varying covariate), age at first birth, weight status categories  body mass index (BMI) cutoff points (underweight (<18.5), healthy weight 18.5–24.9), overweight (25.0–29.9), obese (≥ 30.0)), smoking status and education level. In the analysis of the KARMA cohort, model 2 was additionally adjusted for alcohol use, age at menarche, physical activity at age 18 years, body shape at age 18 years  among cancer-free sisters of the patients with breast cancer, compared to women in the nationwide cohort without history of breast cancer and without a sister with history of breast cancer, adjusting for number of births. We also calculated the OR of preeclampsia by percentiles of breast cancer PRS for women in the KARMA cohort who did not have breast cancer and were genotyped, adjusting for number of births and batch effect of genotyping. For both of the analyses, we additionally adjusted for age at first birth, weight status categories, smoking status and education level in model 2.As mammographic density is widely considered to be an intermediate phenotype of breast cancer, we tested the association between percentage mammographic density and previous diagnosis of preeclampsia in cancer-free women in KARMA. For this analysis, linear regression models with robust “sandwich” standard errors for confidence intervals were used, to avoid assuming normally distributed error terms and homoscedastic variance of the outcomes. We only adjusted for age at mammogram (continuous) in model 1, and additionally for BMI categories, age at menarche, number of births, age at first birth, menopausal status at mammogram, irregular menstrual cycle, physical activity at age 18 years, body shape at age 18 years, education level, smoking status and alcohol consumption in model 2. In order to test the genetic association between preeclampsia and mammographic density, we selected the cancer-free women in KARMA who have a sister in the cohort (N = 3500) and investigated the differences of mammographic density in sisters of patients with preeclampsia, compared to women without a sister with preeclampsia.Statistical analyses were performed using SAS  and Stata software , at a two-tailed alpha level of 0.05.Table In the Swedish nationwide cohort of pregnant women, 27,626 of the 1,337,934 women developed breast cancer during a median follow up of 21.6 years, corresponding to an age-adjusted incidence rate of 1.5/1000 person years (20–70 years old). Compared to women without history of preeclampsia, patients with preeclampsia had 10% decreased risk of breast cancer  in the multivariable adjusted model. Furthermore, the reduced risk of breast cancer was even lower in women with repeated occurrence (two or more times) of preeclampsia  . This association was confirmed in the genetic analysis. Among women without breast cancer, those who had the highest 10% of PRS for breast cancer were less likely to have preeclampsia during their pregnancy   as compared to the women without preeclampsia, after adjusting for reproductive factors. When restricting the analysis to 3500 women with a sister in the cohort, sisters of patients with preeclampsia also had a reduced percentage density  compared to women who did not have a sister with preeclampsia  observed in our nationwide cohort are in agreement with findings from Danish and Norwegian studies , 6. The ACE, VEGF, IGF1R and FLT1 [We found an inverse association between preeclampsia and sisters’ history of breast cancer. The effect of family history is confirmed by a previous study using sister controls, where the protective effect of preeclampsia on breast cancer risk was attenuated . Our stuand FLT1 –33. Howeand FLT1 . For breand FLT1 , which iIGF-1) in patients with preeclampsia [IGF-1 is found in patients with breast cancer and women with high mammographic density [VEGF) was also observed among patients with preeclampsia [VEGF and IGF-1 receptor genetic variations may modify the inverse association between gestational hypertension (a symptom of preeclampsia) and mammographic density [IGF1R genetic variations may predict breast cancer risk in patients with preeclampsia [Our study showed reduced mammographic density in patients with preeclampsia and among patients’ sisters. This finding supports the inverse association between breast cancer and preeclampsia, and the effect of family history. Considering the established association between mammographic density and breast cancer, it is biologically plausible that the association between preeclampsia and breast cancer is to some extent mediated by mammary gland development. Several studies had shown a lower level of insulin-like growth factor .We acknowledge several limitations of this study. Although a diagnosis of preeclampsia in the Swedish Medical Birth Register has an approximately 93% validation , self-reWe found that women with previous preeclampsia had a lower risk of breast cancer and lower mammographic density than women without a diagnosis of preeclampsia. This finding could partly be explained by genetic factors, shared between breast cancer and preeclampsia. The exact mechanism underlying genetic association between these two diseases remains to be defined. In addition, our results suggest that history of preeclampsia should be considered in the evaluation of women’s risk of breast cancer.


Environmental exposures are known to play a role in the development of cancer, including breast cancer. There are known associations of breast cancer with environmental factors such as sunlight exposure, diet and exercise and alcohol consumption as well as physiological factors.This study examines the prevalence of risk factors for breast cancer related to dietary intake, environment and lifestyle in the female population of Malta. Malta has had little research in this area, and therefore an exploratory study was carried out.A retrospective case-control design was applied. Two hundred cases and 403 controls were included. Both cases and controls were subjects without a known family history for breast cancer. Controls were age-matched to cases in an age-decade category roughly at a 2:1 ratio. Interviews were carried out face-to-face using a questionnaire designed by Maltese and Sicilian researchers, encompassing various factors including diet, lifestyle, physiological factors and medical history. Breast cancer risk was then analysed using both univariate and multivariate analyses. For factors having a metric scale, the Mann-Whitney test was used to compare mean scores, while for categorical factors, the chi-square test was used to compare percentages between the case and control groups. Statistical modelling was carried out using binary logistic regression to relate the likelihood of breast cancer to over 50 risk/protective factors analysed collectively.Univariate analysis showed around 20 parameters of interest, 14 of which were statistically significant at a 0.05 level of significance. Logistic regression analysis identified 11 predictors of interest that were statistically significant. Tomato, coffee and canned meat consumption were associated with lower likelihood of breast cancer , whereas beans and cabbage consumption and low sodium salt were positively associated with breast cancer . Premenopausal status was associated with a lower risk of breast cancer compared to postmenopausal status (OR = 0.067). Not having experienced myocardial infarction was associated with lower odds of breast cancer (OR = 0.331). Increased height was also found to have a strong association with risk of breast cancer, with the odds of having breast cancer increasing for every centimetre increase in height (OR = 1.048). In terms of quantity, odds of having breast cancer were lower in those exposed to sunlight (OR = 0.891). The odds of having breast cancer were also lower in those not using the oral contraceptive pill (OR = 0.454).Various factors in this exploratory study were found to be associated with development of breast cancer. While causal conclusions cannot be made, tomato consumption is of particular interest, as these results corroborate findings found in other studies. A negative association of breast cancer with sunlight exposure and oral contraceptive pill use corroborates findings in other studies. Other associations with dietary intake can be explained by dietary changes. More robust studies in this area, including possible longitudinal studies, are warranted.The online version of this article (doi:10.1186/s13167-016-0069-z) contains supplementary material, which is available to authorized users. BRCA1 and BRCA2 genes [Breast cancer is the most common type of cancer in women in Europe, with an estimated incidence of 494,100 cases in 2012 alone [A2 genes –10.With a growing body of literature in this area of research, there are now known physiological, lifestyle and environmental risk factors that play a role in breast cancer. Alcohol consumption, obesity, physical activity and parity are some of the factors known to affect the risk of developing breast cancer –24. WhilThis exploratory retrospective case-control study was carried out in Malta in order to investigate potential associations of environmental and lifestyle factors with breast cancer risk and highlight areas for future research.a woman without a family history of breast cancer according to the NICE criteria who had breast cancer since 2009” and a control was defined as “a woman without breast cancer who has not had a history of breast cancer” [A retrospective case-control study design was adopted. NICE criteria were used to exclude individuals having a family history of breast cancer from this study . Ethical cancer” .Contact details of potential cases were obtained from the 2009–2013 Malta breast clinic register. Cases were first contacted via telephone by nurses working at the breast surgical clinic. This was expected to increase participation rate as breast cancer patients would have interacted with and developed familiarity with nursing staff during previous visits to the clinic. The nurses also received training in telephone surveying skills following a script as a guideline. If they voluntarily agreed to participate in the study, participants’ information was passed on to the research team. These potential cases were then assessed by the research team engaged in this study for eligibility according to the NICE criteria prior to recruitment in the study. Controls were contacted first through a letter containing information about study and subsequently followed by a telephone call by members of the research team to offer further explanation, confirm eligibility and clarify any queries. Controls were recruited at a 2:1 ratio ; that for beans and cabbages was one cup 28 g); that for canned meat was one tin (≈70 g); that for low sodium salt was one teaspoon; and that for coffee consumption was one cup (200 ml). A large number of other food items were measured in the food frequency questionnaire but as they were not found to have a significant impact in the multinomial regression, they were not included in further analysis and are listed in Additional files 10 g; tha8 g; thatBetween the age of 10 and 29 did you use to spend at least an hour per day exposed to the sun during the summer months (July and September)? If yes, how many hours per day on average?Interviewees were asked about lifetime use, frequency and type of oral contraceptive pill (OCP) used. However, as few respondents were able to elaborate on the type of OCP used, this variable was excluded from further analysis. In the case of sun exposure, the question asked looked at exposure during the summer months in order to assess the likelihood of sunbathing, specifically when they were 10–29 years of age. This age bracket was specified because it was assumed that exposure would be highest at that age, and it is also indicative of an individual’s sunlight exposure at its greatest intensity, during summer:The number of hours of exposure was then estimated.Interviewees were also asked about their menopausal status, their age at onset of menopause and whether they had ever been diagnosed with an acute myocardial infarction by a medical professional.work exposure risk.During the interview, questions relating to chemical exposures that are suspected to increase the risk of developing breast cancer in certain studies were asked. These included solvents, pesticide use, use of cosmetics (with parabens known to trigger cancers in vitro), animal feed and medication (often containing hormones with unknown effect on humans) and industrial chemical exposure –42. ThosThe research was subsequently carried out face-to-face by trained interviewers at a location and time convenient for the interviewee, which in the vast majority of the cases was at the home of the interviewee in a private room without other family members present. Interviews were carried out in English or Maltese; questionnaires were available in both languages. The questions were asked, and the answers inputted by the interviewer. Prior to commencing all interviews, consent was obtained from the subject. The interview questionnaire on average lasted around 35 min. Data was later inputted into Microsoft Excel, cleaned and analysed using SPSS v22.0.p value less than the 0.05 level of significance was taken as significant, implying that the odds ratio is significantly different from 1 (95 % confidence for odds ratio excludes 1).Univariate logistic regression models were used to assess the association between the likelihood of breast cancer and any one of the predictors related to physiological characteristics, lifestyle, work, diet, illness and medication. Besides descriptive statistics, the table below displays the odds ratio for each predictor and its corresponding 95 % confidence intervals. A predictor with a p value of less than 0.1 were included in a multivariate logistic regression model. The Akaike Information Criterion Index (AIC) and the Pseudo R-Square values  were used in deciding the best parsimonious model selection. Variables that had considerable missing data were not included in the model. Using a forward stepwise model, odds ratios (OR) of the most significant variables in the model were obtained. The parsimonious multinomial logistic model  to a number of risk/protective factors identifies 11 significant predictors, which include the consumption of tomatoes, beans, cabbage, low sodium salt consumption, canned meat, coffee consumption, use of oral contraceptive pills, menopausal status, incidence of myocardial infarction, exercise, height and exposure to sunlight. This parsimonious model explains 31.7 % of the total variance in the breast cancer outcomes (Nagelkerke).The Pseudo R-square value is rather low indicating that there are predictors (not included in this study) that explains the remaining 68.3 % of the total variance. One of these predictors is undoubtedly age, where it has been found in literature that an increase in age increases the prevalence of breast cancer. This variable was excluded in this logistic regression analysis since cases and controls had been matched according to age category.The 11 significant predictors shown in Table The parsimonious model identifies six significant dietary predictors, which include tomatoes, beans, cabbage, canned meat and coffee consumption. For every medium-sized tomato consumed per month, for every tin (approx. 70 g) of processed meat consumed per month and for every cup of coffee consumed per month, the odds of having breast cancer decreases by 1.2, 10.8 and 9.9 %, respectively. These three diet predictors were found to be significant protective factors.On the other hand, for every cup (28 g) of fava beans consumed per month, for every cup of cabbage consumed per month and for every teaspoon of low sodium salt consumed, the odds of having breast cancer increases by 4.5, 83.4 and 2.8 %, respectively. These three diet predictors were found to be significant risk factors.The parsimonious model also identifies three significant physiological factors, which include history of myocardial infarction, menopausal status and height of the female. For subjects with no history of heart attack, the odds of having breast cancer is 66.9 % lower compared to subjects who have reported at least one episode of heart attack. For premenopausal and perimenopausal women, the odds of having breast cancer are, respectively, are 93.3 and 38.3 % lower compared to postmenopausal women. On the other hand, for every centimetre increase in height, the odds of having breast cancer increases by 4.8 %. Hence, tall postmenopausal women with reported episodes of cardiac problems are more likely to develop breast cancer than short premenopausal women who have no history of heart problems.The parsimonious model identifies two significant predictors of breast cancer, which include exposure to summer sunlight and use of the oral contraceptive pill. For every additional hour of sunlight exposure during summer, the odds of having breast cancer decreases by 10.9 %. For women not taking oral contraceptive pills, the odds of having breast cancer is 54.6 % lower than that for women taking oral contraceptive pills.As described above, work exposure risk was measured in this study. However, it did not appear as significant in the univariate analysis, and work exposure also was not significant in the parsimonious model.The results above show that tomatoes and canned meat consumption seem to decrease the odds of developing breast cancer. On the contrary, beans, low sodium salt and cabbage consumption seem to increase the odds of developing cancer.Other food items are being consumed with the item analysed, which are contributing to the risk or protective factors of breast cancer; however, these items are not included in the study.Dietary changes followed by subjects after being diagnosed with breast cancer.The list of item being analysed may be too generic—for instance, the study makes reference to fava beans; however, the subject may mix it up with other types of beans that may have a different effect on breast cancer.There are a number of confounding issues when identifying food items as risk or protective factors of breast cancer.The onset of a health condition is very often followed by a change in the food diet. For instance, concerns over high blood pressure levels may lead subjects to change regular salt intake with low sodium salts. Similarly, patients diagnosed with breast cancer may change their food diet to a healthier one. Beans and cabbages are often considered to be part of a healthy diet and normally are not associated with adverse effect on breast cancer. Our study shows that cabbages, beans and low salt intake are more likely to increase the risk of breast cancer, while canned meat and American coffee are more likely to protect against cancer. These anomalous results may be attributed to the fact that subjects diagnosed with breast cancer tend to change their food diet to a healthier one. Hence, there are larger proportions in the case group eating cabbages, beans and low salt and larger proportions in the control group taking canned meat and American coffee. At least one study has found that in premenopausal women, regular coffee drinking appears to be linked with a reduced risk of the disease .In the case of tomato consumption, our result complements other findings in literature, which identify tomato consumption as a protective factor against breast cancer. Other studies , 45 founExposure to sunlight seems to be associated with a decrease in the risk of breast cancer. This corroborates findings found in other studies , 46. It Our study shows that exposure to sunlight has a positive effect on the prevention of breast cancer. This finding is also corroborated in other scientific analyses of this nature , 46, 47.is 54.6 % lower in subjects not taking oral contraceptive pills compared to those who take oral contraceptive pills. This is quite a large effect, and corroborates established scientific evidence that oral contraceptive pill use increases breast cancer [As reported in the results section, the odds of having breast cancer t cancer .The three physiological factors emerging as highly significant were height, a history of myocardial infarction (heart attack) and menopausal status.p value <0.001; CI = 1.021 cm, 1.077 cm). Large-scale studies carried out elsewhere which have examined height as a continuous variable also found such an association [Height came as a much unexpected factor in this analysis, appearing as significant in virtually every model run in this study. The model selected showed a 4.8 % increase in the odds of having breast cancer for every centimetre increase in height Additional file 2:List of variables analysed. (DOCX 14 kb)


The age-specific rate of breast cancer rises rapidly through premenopausal years and significantly more slowly after menopause. Reproductive factors affect cell proliferation and the accumulation of genetic changes. Lifetime risk of breast cancer is linearly related to the length of the interval from menarche to first birth. Lifestyle changes that accompany industrialization, together with shifting reproductive patterns, drive up incidence rates. Prevention must begin early in the life as almost one-quarter of cases are diagnosed before age 50 in high-income countries. This requires greater emphasis on prevention across the life course to address the global burden of breast cancer. Moreover, low- and middle-income nations cannot afford the costs of widespread technology-based medical care for their populations, whereas in wealthy nations, projected expenses for clinical treatment are soaring.2The burden of breast cancer is worldwide and growing. In 2012, nearly 1.7 million new cases of breast cancer were diagnosed worldwide, accounting for 25% of all new cancer cases in women.3It is time to place more emphasis on breast cancer prevention, that is, lowering the risk or reducing the incidence of new cases. Evidence from a wide range of studies—randomized trials, epidemiological, animal—has identified specific lifestyle and behavioral factors that affect breast cancer risk. Researchers also now better understand that breast cancer risk develops early in life and accumulates across a woman’s entire lifespan. This article discusses specific actions that women and their physicians can take to reduce breast cancer risk, and argues that, depending on when in her lifespan a woman integrates risk-reduction behaviors, as much as 50–70% of breast cancer can be prevented through primary prevention.4 but they are among the most common. Let us start with hormones. There is very strong evidence that hormones such as estrogen and progesterone are major drivers of breast cancer growth. For example, combination estrogen plus progestin therapy has been classified as a carcinogen based on laboratory, epidemiologic, and randomized trial evidence.5 And data from randomized trials show that selective estrogen receptor modulators and aromatase inhibitors significantly reduce breast cancer incidence.6 These hormones, whether endogenous or exogenous, promote tumor growth.What is heightening the risk of breast cancer? It is the interplay of (1) increases in hormonal drivers, (2) the changes in women’s height growth rate and reproductive patterns, and (3) lifestyle changes arising from economic development. These are not the only modifiable factors that affect breast cancer risk ,7 and the Institute of Medicine8 urge the nation to focus on risk factors at time periods in a woman’s life that are important in the etiology of breast cancer. These time periods begin in childhood, before and during first breast development, and before the full differentiation of breast tissue that occurs with the birth of a woman’s first baby.9Second, recent task force reports on breast cancer prevention from the US National Institutes of Environmental Health Sciences jointly with the National Cancer Institute11 After menarche, cell proliferation decreases with age through premenopausal years.10 The rate of breast cancer increases rapidly up to menopause and then far more slowly after menopause.10 Early menopause  reduces subsequent risk of breast cancer.10–13Breast cancer incidence models show breast tissue aging or the underlying rate at which the carcinogenic process is taking place occurs most rapidly from menarche to the first birth with cyclical production of estrogen and progesterone during each menstrual cycle with increased mitotic rate during the luteal phase of the cycle.14 This is when breast tissue is most susceptible to carcinogenesis. Height is related to increased risk of breast cancer before and after menopause,15 and reflects nutrition intakes through childhood. Controlled trials show milk intake, for example, increases height growth rate.16 A prospective study of childhood diet and growth shows higher vegetable protein intake at ages 3–5 is related to slower height growth rate and later age at menarche, whereas higher animal protein intake is related to increased peak height growth velocity.14 In a prospective analysis of weight and height from school records of over 117,000 women in Denmark, height growth rate from 8 to 14 years of age independently predicted risk for beast cancer, accounting for 15% of the population of burden of breast cancer.17 Higher peak height growth velocity is positively related to the risk of premenopausal and postmenopausal breast cancer18 indicating that growth rate, independent of age at menarche, has a direct influence on lifelong breast cancer risk.18 China Health and Nutrition Survey data show that among ages 2–18 over the 20-year period from 1991 to 2011, a marked decrease in intake of legumes (22% decrease) and coarse grains (71% decrease) with an increase in animal-source foods (50% increase).19 Yet evidence supports higher fiber intake during adolescence protecting against benign breast disease and invasive breast cancer.20–22Third, childhood exposure to three factors—excess energy intake leading to weight gain and obesity, high animal protein intake and low intake of fruits, vegetables, and whole grains, and little or no physical activity—influences both onset of menarche and height growth rate.23 For example, in traditional rural life with menarche at 17, a typical woman had perhaps 26 menstrual cycles (±2 years) between menarche and the birth of her first baby. Now, with earlier menarche at, say, age 12 and a much later age of first birth ,24 a woman has about 234 cycles (18 years×13 cycles/year), before the full cellular differentiation that accompanies breast development during first pregnancy; this is an increase of more than 200 cycles compared with pre-industrialization reproductive patterns. This means that she is exposed to over 200 additional luteal phase proliferative cycles of breast cell growth and the potential to accumulate genetic alterations.10These three factors plus alcohol have dramatically affected both the amount of hormones and the length of time women’s bodies are exposed to them. Beginning three centuries ago in Europe, then in the United States, economic development spurred increases in these factors that have driven these endogenous hormonal exposures within women to new levels.27 In Singapore, Hong Kong, and China, similar changes have occurred.28 In association with these societal changes, the incidence of breast cancer in Korea for women of age 45–49 has tripled from 45 cases/100,000 among women in born 1943–1945  than those who did not, after controlling for all other risk factors, education, and race/ethnicity.31The how and when of breast cancer prevention. It is neither desirable nor feasible to shift reproductive patterns back to pre-industrial levels. However, the nation can support women in tackling the same four factors that originally caused shifts in societal reproductive patterns. Excess energy intake that leads to weight gain and obesity; high animal protein intake and low intake of fruits, vegetable, and whole grains; little or no physical activity; and excess alcohol consumption create a toxic physiologic context that is directly related to increased breast cancer risk at any age.33 and is often more aggressive than cancers diagnosed in postmenopausal women, it makes sense to start prevention early in life when it can have maximum impact. For example, prevention begun in childhood and continuing through adolescence and early adult years can reduce development of premalignant or intermediate lesions that are on the pathway to breast cancer.34 The evidence for this comes from prospective data recorded in childhood, adolescence, and early adult years and includes evidence for alcohol, a known breast carcinogen. Women who avoided alcohol intake through adolescence and early adult years have significantly lower incidence of premalignant and invasive breast cancers.34Timing of prevention therefore matters. Because 22% of breast cancer is diagnosed in premenopausal women8 the World Cancer Research Fund/American Institute for Cancer Research,35 and the American Cancer Society,36 when applied across the life course, generate the following potential reductions in breast cancer burden  in childhood and in the critical window from menarche to first pregnancy that offer the greatest protections.7 Given this lopsidedness of resources, surely some reallocation of focus and funding is possible. Making prevention happen requires not just a plan, but the political will to acquire and sustain the resources needed to deliver breast cancer prevention across all sectors will be necessary to implement and sustain prevention with the long-term outcomes benefiting women worldwide.Meeting this challenge will require increasing the proportion of breast cancer research that is devoted to prevention. Review of budget allocations to breast cancer research shows that at most 7% of all National Institutes of Health breast cancer research projects (not dollars) focus on breast cancer prevention, whereas only 1% of dollar expenditures in the U.S. Department of Defense Breast Cancer Research Program is allocated to research on prevention.41 and increasing excise taxes on alcohol and tobacco products reduce consumption and lowering risk of cancer and risk of many other chronic diseases.43 We must put these cancer-reducing behaviors into practice, including concerted action from communities, policy makers, schools, families, and individuals alike.44 The fact that the same four factors are implicated not only in breast cancer but also in other cancers, heart disease, and diabetes means that there can be economies in the prevention outreach and engagement. Making these appropriate for women at differing ages is amongst the highest priorities.Implementing a breast cancer prevention plan involves the systematic integration of evidence-based messages and strategies into women’s everyday lives. Evidence-based strategies show that installing bikeways and sidewalks increase exercise, changes in diet reduces weight gain in children,46 This subpopulation must be identified, limiting applicability. These treatments would do little to stem the increasing incidence of breast cancer globally.Also informing prevention, impressive progress has been made in identifying genetic factors that increase breast cancer risk  and in developing new treatments. However, the prevention treatments available today for BRCA1/2 carriers  would eliminate only 5% of breast cancers worldwide and would primarily benefit women in high-income countries.If we act and act now, shifting the balance and focus to earlier life, supported by additional resources devoted to implementing prevention, bringing messages and bolstering lifestyle and risk-reduction behaviors during the critical time points in life, we stand a good chance of significantly reducing the burden of breast cancer now and for future generations.


Current ovarian cancer screening guidelines in high-risk women vary according to different organizations. Risk reducing surgery remains the gold standard for definitive treatment in BRCA mutation carriers, but research advancements have created more short-term options for patients to consider. The decisions involved in how a woman manages her BRCA mutation status can cause a great deal of stress and worry due to the imperfect therapy options. The goal of this review was to critically analyze the screening recommendations and alternative options for high-risk ovarian cancer patients and evaluate how these discrepancies and choices affect a woman’s management decisions.  More than 14,000 deaths from ovarian cancer are predicted in the year 2017 . The ovaThere is no perfect screening method to detect ovarian cancer. Surveillance is especially critical for women with BRCA1 and BRCA2 mutations due to the increased risk of ovarian cancer. There is still no absolute consensus on screening frequency and method for these high-risk women. The current recommendations from the American College of Obstetricians and Gynecologists (ACOG) suggest that women at high risk may choose screening with CA-125 serum levels and transvaginal ultrasound (TVUS) starting at age 30–35, although screening is generally not recommended ,14. The The tumor antigen CA-125 and TVUS have remained the focus of many large ovarian cancer screening trials to date. Serum levels of the biomarker CA-125 can be monitored in known ovarian cancer patients to recognize recurrence or initiate suspicion if the level is greater than the designated cutoff value of 30–35 U/mL ,18. CA-1p = 0.10) and the TVUS group 11% (p = 0.21) [In 1992, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCOCS) was initiated with the primary objective of determining the effect of screening average-risk women with CA-125 and TVUS on mortality . For the = 0.21) . Also en = 0.21) . An annup = 0.009). The median interval from detection screen to surgery was 79 days in the ovarian cancer patients. Protocol-driven follow-up time was implemented in Phase II of the UKFOCSS to decrease surgery delay. This portion of the study took place during the last two years. Screening in these women was increased to once every four months instead of annually. Only 42% of cancers detected were stage I/II, but 92% of all detected were able to be completely cytoreduced compared with 62% in Phase I [To assess women at high risk of ovarian cancer (>10%), the first large prospective trial of this population screened 3563 women in the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) . Phase I Phase I .In a large US trial published in 2017, data from the Cancer Genetics Network and Gynecological Oncology Group trials was used to screen 3692 high-risk women. CA-125 was measured every three months and assessed using ROCA [Despite the developments in recent trials, there is still no effective ovarian cancer screening test for high-risk women. Therefore, RRSO remains the gold standard for women at high risk of developing ovarian cancer. ACOG and the SGO agree that RRSO in these women should be performed after completion of child bearing or by the age of 40 after discussing risks vs. benefits of surgery ,13,14. TBRCA1 mutations (odds ratio 0.56 (95% CI 0.45–0.71); p < 0.0001) and carriers of BRCA2 mutations (0.39 (95% CI 0.23–0.66); p = 0.0004) [As a means to an alternative for patients not desiring surgery however, chemopreventive agents have been evaluated in high risk women. Chemoprevention has been defined as the inhibition of carcinogenesis using natural or synthetic agents ,34. Oral 0.0004) . Some st 0.0004) . A large 0.0004) . There iDespite risk reducing surgery prevailing as the gold standard for treatment, there are substantial risks to undergoing RRSO. If performed at the recommended age of 40, women will experience surgical menopause on average an entire decade earlier than women who retain their ovaries. Postmenopausal ovaries will continue to produce a low level of hormones, even in elderly women, that provides a protective effect. The dramatic drop in estrogen will cause vasomotor symptoms, loss of libido, and dyspareunia in 90% of premenopausal women . In addiIn light of these increased risks, research has been focusing on a less radical alternative to RRSO as the solution in high-risk women. The increase in RRSO procedures over the years and number of pathology specimens it has provided has led to improved knowledge of ovarian cancer development. The rate of RRSO specimens found to have an occult malignancy has been 3–8% ,46. The With these research advancements and increasing implementation of bilateral salpingectomy in the low risk population, bilateral salpingectomy with ovarian retention is being considered by some as a temporary bridge in high-risk women. A radical fimbriectomy is a procedure involving removal of both fallopian tubes including the entire fimbriated end. This removal of the fimbrio–ovarian junction involving a small portion of the ovary also removes at-risk cancer precursors ,61. A biThis lack of understanding about the true origin of ovarian cancers is also a potential problem with bilateral salpingectomy with ovarian retention if the fraction of true tubal origins is less than anticipated. Despite the “simple” label given to a laparoscopic procedure, the surgical morbidity is still of concern due to the need for a second surgery to remove the ovaries at a later date. The effect of breast cancer risk reduction is also diminished when the ovaries are not removed prior to menopause in BRCA carriers . Lastly,High-risk women are thus left with the choice of imperfect screening methods or invasive and life-altering surgery. An individual woman’s perception of risk versus actual risk of developing cancer is based on complex dynamics and influences. It has been shown in the study of other diseases that affective states such as worry, fear, and emotions tend to emerge as stronger predictors of behavior than cognitive risk . CognitiDue to the nature of BRCA mutation carriers’ increased frequency of screening, it was predicted that the likelihood of experiencing a false-positive test result may lead to increased perception of elevated cancer risk . In thisA systematic review that analyzed the psychological impact in BRCA mutation carriers also found that the anxiety and depression associated with the distress experienced in the first 12 months after genetic testing generally does not linger in the intermediate and long term . To assess effects of identified cancer burden, a large Gynecologic Oncology Group (GOG) trial evaluated 2287 questionnaires in high risk women that measured worry, perceived cancer risk, risks vs. benefits, and quality of life. The more invasive RRSO option, which 40% of the participants chose, was associated with higher perceived risk and worry . Half ofIn a large UK study, women who chose screening over RRSO will return to the surgical option many years after being diagnosed with BRCA status. This emphasized the need for close follow up, as decision making is often delayed in high-risk women. Postmenopausal women were 2.16 times more likely to choose RRSO . The maip = 0.1) [Investigators from MD Anderson reviewed 313 patient responses regarding satisfaction after RRSO and compared them to those who opted for periodic screening. Using the Satisfaction With Decision (SWD) scale, the median score was significantly higher in the RRSO group compared with the periodic screening group (p = 0.1) . Lower sTo evaluate the need for social support and how it impacts decision making, a group from Norway enrolled BRCA mutation carriers in an educational support group . It was The current screening guidelines generally do not endorse routine screening in high risk patients. Nonetheless, screening with CA 125 and TVUS for ovarian cancer in these patients may be done beginning around 30–35 years of age with plans for eventual RRSO. Bilateral salpingectomy with ovarian retention is another potential option for interval treatment management in BRCA mutation carriers. The individualization of therapy options leads to a difficult decision compounded by worry and stress that may not be fully appreciated by practitioners. BRCA mutation carriers should be encouraged to maintain regular visits with their physicians to discuss current guidelines and their changing personal goals. The cancer risk should be discussed again at each encounter, and all patients should be given the option of incorporating a support group into the treatment plan to minimize misperceptions and address concerns that affect decision making.


TP53 gene  in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 . Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.A coding region polymorphism exists in the  A gene variant found in people of African descent may increase the risk of breast cancer—but only among pre-menopausal women. In a study of more than 14,000 women of African ancestry, a team led by Maureen Murphy from the Wistar Institute in Philadelphia, Pennsylvania, USA, and Christine Ambrosone from Roswell Park Cancer Institute in Buffalo, NY, USA, tested for an association between breast cancer and a rare genetic polymorphism in the TP53 gene that’s found almost exclusively in African-descent populations. This variant alters the p53 tumor suppressor protein and has been shown to increase cancer risk in a mouse model. Murphy and colleagues showed that the variant increased risk by about 72% in women who had not yet experienced menopause—which could help explain the earlier onset of the disease among women of African ancestry. TP53) holds distinction as the most frequently mutated gene in human cancer. In addition to inactivating mutations in human cancer, there are a number of single-nucleotide polymorphisms (SNPs) in TP53, and in genes whose protein products regulate p53, MDM2, and MDM4; these SNPs modify TP53 (hereafter p53) pathway signaling, and can confer increased risk for cancer.3 Of note, the proline 72 allele in TP53, and the G allele of SNP309 in MDM2, have previously been associated with increased breast cancer risk in pre-menopausal women.5 More than two decades ago, an inherited polymorphism in TP53 that converts the proline residue at amino acid 47 to a serine was reported in African Americans .6 We showed that the serine 47 (hereafter S47) variant has significantly impaired ability to induce programmed cell death in multiple human cell lines engineered to contain inducible human forms of WT p53 and S47  of 1.6%, and is extremely rare in populations of non-Finnish Europeans (3/126766), and non-existent in populations of Finnish Europeans (0/26082) or East Asian descent (0/18924), according to the recently released GnomAD data (http://gnomad.broadinstitute.org/variant/17-7579548-G-A). Because of the functional significance of this variant in cell lines and mouse models, we sought to test the hypothesis that the S47 variant might be associated with breast cancer risk in African American women, particularly among pre-menopausal women.The p53 tumor suppressor (p = 0.34)  were available for 3130 cases and 3698 controls. As shown in Table 800371 wep = 0.01).As noted above, previous studies of SNPs in p53 and MDM2 observed associations with breast cancer only among premenopausal women. Thus, we performed analysis among that group only. In both AMBER and ROOT, there were suggestions of increased risk of breast cancer with per allele ORs of 1.79  and 1.39 , respectively. Because the SNP was imputed from genotype data in AMBER, we repeated this analysis limited to the >98% of pre-menopausal samples for which the maximum posterior genotype probability was >90%. The comparable OR was 2.07  and Sco2. We showed that mice expressing S47 in homozygous or heterozygous form are susceptible to spontaneous cancers of diverse histological types. Because of the strong functional significance of this variant, and it’s specificity to populations of African ancestry, it could play a role in the earlier onset and more aggressive nature of breast cancer among women of African descent.We previously showed that, in human cell lines and a mouse model, the S47 variant exhibits a modest decrease in apoptosis in response to most genotoxic stresses compared with wild-type p53, but exhibits a significant defect in cell death induced by cisplatin.Collaborating with three large consortia of breast cancer in women of African ancestry, our findings suggest that the S47 variant may contribute to increased risk of pre-menopausal breast cancer in individuals of African descent. However, because of the low prevalence of the variant, despite the fact that the studies are the largest available for breast cancer in women of African descent, associations were of borderline significance in AMBER and non-significant in ROOT. The combined meta-analysis, including 1942 pre-menopausal cases and 2388 controls, was also of borderline significance.8 strengthens our hypothesis that this rare variant may increase risk among women of African ancestry, but the sample sizes do not allow for clear associations. The observed increased risk among premenopausal women from the meta-analysis might be driven by AMBER studies, which has a higher MAF than ROOT studies (1.5% vs. 1.1%). If admixture with European ancestry dilutes associations with this African-specific variant, which appeared to be more apparent in ROOT than in AMBER, that could explain the lack of significance in ROOT. It may thus need much larger studies to be able to observe a strong association of this rare SNP in African American populations, especially for testing heterogeneity by tumor estrogen receptor (ER) status. It is also possible that there truly is no effect of the S47 variant on human breast cancer. Even though the tumor suppressive function of the Pro47Ser protein is compromised in mice, the effect may be tissue specific, and not relevant in the mammary gland; similar findings have been found for other p53 variants.9 Nonetheless, studies such as these, taking findings from cell lines and mouse models to human populations, are needed to understand the basis of cancer etiology.Although the suggestions of increased risk could be interpreted as null because of the borderline significance of the associations, the high frequency of sporadic cancer in the S47 mouse10 All studies were approved by the affiliated institutional review boards. BWHS is a prospective cohort study with participants across the US enrolled by mailed questionnaires and followed with biennial and 5-year interval follow-up questionnaires. CBCS and WCHS are both case–control studies, with CBCS 1 and 2 conducted with population-based sampling and in-person interviews from 1993–2001 in 24 counties in North Carolina. WCHS, initiated in 2002 in metropolitan New York City and several counties in eastern New Jersey, is still ongoing in NJ. For these analyses, we included samples from women with invasive cancer or ductal carcinoma in situ (n = 3130), confirmed by pathology reports or registry records from which we also obtained data on ER status, and 3698 controls. Genotyping was performed at the Center for Inherited Disease Research as part of a larger project, using the Illumina HumanExome Beadchip Plus v1.1 plus 200,000 custom beadtypes. Imputation based on 1000 Genomes data was carried out at the University of Washington. The observed:expected variance ratio, a measure of squared correlation between the imputed genotypes and the true genotypes for the imputed SNP was 0.91. We examined associations between the imputed SNP rs1800371 in TP53 and breast cancer overall, ER positive cancer, and ER negative disease. Because previous studies of SNPs in TP53 and MDM2 have found associations only in pre-menopausal women,5 we also limited analyses to only that group. The odds ratios and 95% confidence intervals (CIs) were derived from multivariable logistic regression models, which adjusted for study , age (in 10 year groupings), DNA source  and geographic location . Because ancestry is a recognized confounder of genetic associations, principal components of the genotypes for ancestry with p < 0.1 after including the covariates listed above in the model were also included. We genotyped twenty samples in a blinded manner using Taqman analysis and primers from Applied Biosystems for the rs1800371 SNP in the Wistar Institute Genomics Facility; all Taqman genotyping was 100% concordant with imputed data. All analyses were conducted using SAS 9.4 .Based upon our laboratory findings, we collaborated with investigators from the AMBER Consortium, which includes data and samples from the Black Women’s Health Study (BWHS), the Carolina Breast Cancer Study, and the Women’s Circle of Health Study (WCHS).12 All studies were approved by the affiliated institutional review boards. Genotyping was performed using the Illumina HumanOmni2.5-8v1 array as part of a genome-wide association study.Because of the relatively low frequency of the S47 SNP, we sought to expand our analysis by collaborating with two additional consortia. The ROOT consortium includes 1657 breast cancer cases and 2029 controls from six studies in African American, African Barbadian, and African women, including the Nigerian Breast Cancer Study, the Barbados National Cancer Study, the Racial Variability in Genotypic Determinants of Breast Cancer Risk Study, the Baltimore Breast Cancer Study, the Chicago Cancer Prone Study, and the Southern Community Cohort.13 Although WCHS and CBCS participated in AABC, samples from those studies were included as part of the AMBER consortium described above.AABC includes cases and controls from the following epidemiologic studies: The Multiethnic Cohort study, 734/1003; The Los Angeles component of The Women’s Contraceptive and Reproductive Experiences (CARE) Study, 380/224; The San Francisco Bay Area Breast Cancer Study, 172/23; The Northern California site of the Breast Cancer Family Registry, 440/53; The Nashville Breast Health Study, 310/186; and The Wake Forest University Breast Cancer Study, 125/153). The present analysis includes AABC GWAS data for 2225 AA women with invasive breast cancer and 1983 controls.We also performed a fixed effects meta-analysis of risk of pre-menopausal breast cancer using data from AMBER and ROOT. Because the sample size of some participating studies in ROOT was small, especially after stratification by menopausal status and ER status, the study-specific estimates for this rare SNP were not stable. Therefore, in the meta-analysis we used risk estimates from ROOT as one study but study-specific risk estimates from BWHS, WCHS, and CBCS, where adequate sample size and reliable estimates were available from each study. AABC was excluded from these analyses because menopausal status was not known for their participants.Supplementary Information