Conditional logistic regression was used to assess this association in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, including 307 in situ breast cancer cases and their matched control subjects.We analysed the relationship between pre-diagnostic prolactin levels and the risk of in situ breast cancer among all women . No statistically significant heterogeneity was found between prolactin levels and in situ cancer risk by menopausal status (Phet = 0.98) or baseline HT use (Phet = 0.20), although the observed association was more pronounced among postmenopausal women using HT compared to non-users (Ptrend = 0.06 vs Ptrend = 0.35). In subgroup analyses, the observed positive association was strongest in women diagnosed with in situ breast tumors <4 years compared to ≥4 years after blood donation  and among nulliparous women compared to parous women .We found a significant positive association between higher circulating prolactin levels and risk of in situ breast tumours and shows that higher circulating prolactin is associated with increased risk of in situ breast cancer.Our data extends prior research linking prolactin and invasive breast cancer to the outcome of  In situ breast tumours account for about 20% of all breast cancers diagnosed by mammography , although there was no heterogeneity comparing in situ versus invasive cancer  = 0.81) [in situ breast cancer did not provide estimates separately by in situ versus invasive disease [The association between prolactin and in situ breast cancer overall, by menopausal status and by use of postmenopausal hormone therapy (HT) at the time of blood donation within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.Therefore, in this study we examined the association between pre-diagnostic prolactin concentrations among pre- and postmenopausal women with subsequent risk of The EPIC cohort is based on 366,521 women and 153,457 men recruited between the years 1992 and 2000 in 10 European countries: Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, The Netherlands, and the United Kingdom. Details on the subject recruitment, baseline data and blood collection protocols have been reported previously . All EPIin situ incidence data were coded according to the International Classification of Disease (ICD-10 code D05). For the present study, the closure date for follow up was the last date of complete follow up for both cancer incidence and vital status, which ranged from 2003 to 2006, depending on the study centre. Sweden was not included in the analysis because independent studies were being completed on breast cancer risk and endogenous hormones [Details on vital-status follow up and ascertainment of breast cancer incidence across the study centres were reported previously . Brieflyhormones .General criteria for the inclusion of cases and matched controls into the study were: (1) women had an available blood sample; (2) could be clearly classified as being either premenopausal or postmenopausal at the time they provided their blood sample, and (3) did not have any previous diagnosis of cancer (except non-melanoma skin cancer). For each case, one matched control  with an available blood sample was chosen using incidence density sampling among appropriate risk sets consisting of all cohort members who were alive and free of cancer at the time of diagnosis of the index case. Matching criteria were: study recruitment centre, menopausal status at blood donation, age at blood donation (±6 months), time at blood donation (±2 h), fasting status, phase of menstrual cycle , late follicular (days 8 to 11), mid-cycle (days 12 to 16), early luteal (days 17 to 19), mid luteal (days 20 to 24), late luteal (days 25+), and current use of HT at the time of blood donation .in situ breast cancer cases and an equal number of control subjects were selected for the study. In our analysis, the majority of the cases (91%) were defined as ductal carcinoma in situ and 9% as lobular carcinoma in situ or carcinoma in situ NOS (not otherwise specified).In total, 307 Prolactin assays were performed in the laboratory of the Division of Cancer Epidemiology at the German Cancer Research Centre (DKFZ) and determined by immunoradiometric assay (IRMA (CT), IBL International GMBH, Germany) in blood collected at baseline. The case-control pairs were analysed in the same batch and quality controls were included in each analytical batch. Laboratory personnel were blinded to the case-control status of samples and quality controls. The detection range of the assay was 0.35 to 133 ng/mL. The mean inter- and intra-assay coefficients of variation were 4.62% and 2.17%, respectively.in situ occurrence. ORs were calculated across tertiles of circulating prolactin and on a continuous log2 scale. Linear trends for OR estimates were calculated over a continuous log2 scale of prolactin. Circulating prolactin levels vary by menopausal status [2 , due to modest variation in prolactin levels over these factors in healthy women [in situ breast cancer and our prior results on invasive breast cancer [P-values presented are two-sided and P <0.05 was considered statistically significant. Statistical analyses were conducted using SAS software, version 9.2 .Conditional logistic regression was used to estimate ORs and 95% CI for breast cancer l status , and thehy women . A more t cancer . All P-vin situ breast cancer, and an equal number of controls. For the premenopausal case-control pairs, the median age at blood donation was 46.4 years (range 34.1 to 56.4 years), and the median age at diagnosis for the cases was 50.6 years (range 37.3 to 61.3)  for patients who developed invasive disease after diagnosis of in situ disease and 6.8 ng/mL (range 2.6 to 128.3 ng/mL) in patients who did not develop invasive disease during further follow up (data not shown).This nested case-control study consisted of 307 cases diagnosed with in situ breast cancer risk among all women , with a statistically significant 35% increase in risk for each one unit increase in prolactin on the continuous log2 scale , Ptrend = 0.03) ). We observed no statistically significant heterogeneity in stratified analyses by menopausal status (Phet = 0.98). However, after additional stratification by baseline HT use among postmenopausal women, we observed a suggestive association among the HT users , Ptrend = 0.06), but not among the non-users , Ptrend = 0.35). However, case numbers in these subgroups were small, CIs overlapping and the test for heterogeneity between HT users and non-users was not statistically significant (Phet = 0.20).In conditional logistic regression analyses adjusting for parity, smoking status, and BMI, there was a positive association between prolactin concentrations and in situ breast cancer risk by time between blood donation and diagnosis  among all women (Phet = 0.04). Higher concentrations of prolactin were significantly associated with in situ breast cancer diagnosed less than 4 years since blood donation , Ptrend = 0.01), but not with breast cancer diagnosed 4 or more years since blood donation , Ptrend = 0.63; Phet = 0.04). Similarly, the estimated association of prolactin with in situ breast cancer risk appeared stronger among nulliparous women compared to parous women, more pronounced in analysis restricted to postmenopausal women , Ptrend = 0.02 in nulliparous women versus ORlog2 = 1.22 , Ptrend = 0.24 in parous women; Phet = 0.02). It should be noted, however, that the case numbers for nulliparous women were small and the CIs for risk estimates wide. There was no significant heterogeneity by age at tumour diagnosis in either premenopausal or postmenopausal women (Phet = 0.87) (data not shown).In subgroup analyses Table , we obsePinteraction = 0.84) (data not shown).Additional statistical analyses showed no evidence for major confounding effects by other lifestyle and reproductive factors nor was there an interaction between prolactin and BMI  versus invasive breast cancer tumors (n = 2250) were 8.9 (in situ) versus 8.6 ng/mL (invasive) for premenopausal women and 6.2 (in situ) versus 6.1 (invasive) ng/mL for the postmenopausal women (data not shown). A heterogeneity test comparing in situ versus invasive disease was not statistically significant .Finally, we compared the results from our present analysis on t cancer . The medin situ breast cancer. Our data showed no evidence for heterogeneity in the relationship of prolactin levels and in situ cancer risk by menopausal status or postmenopausal HT use at blood donation, although the observed positive association was more pronounced among HT users versus non-users. In addition, the associations were strongest among women diagnosed with in situ breast tumors less than 4 years after blood donation and also among nulliparous women.In this prospective study, we observed a significant positive association between pre-diagnostic circulating prolactin levels and risk of in situ breast cancer risk are similar to those observed for invasive breast cancer. Prior analyses limited to invasive cases found modest significant associations between circulating prolactin and risk of invasive breast cancer, with up to a 50% increase in risk contrasting top versus bottom quartiles [in situ breast cancer was more pronounced among postmenopausal HT users as compared to non-users. Although in situ carcinomas in the breast may not have invasive characteristics [in situ lesions, if left untreated, progress to invasive disease [in situ lesions to invasive disease. However, the very similar associations between prolactin and breast cancer risk observed in our previous study of invasive disease [in situ disease suggest that circulating prolactin may influence risk of invasive and in situ breast cancer via the same aetiological pathway. Prolactin may also play a role in progression from in situ to invasive breast cancer. However, out of 307 in situ cases selected for this analysis, only 15 developed invasive breast cancer during further follow up. Therefore, we were unable to assess the association between prolactin and progression from in situ to invasive disease in this study.Our findings of modest, positive associations between prolactin and uartiles . Moreoveeristics , up to 5 disease . Little in vitro, and epidemiological studies strongly supports the involvement of prolactin in breast cancer development [Although a vast body of evidence from animal, elopment ,6,13,14,elopment . Evidencelopment ,17.in situ breast cancer risk was confined to tumors diagnosed within the first 4 years from blood donation. Interestingly, this differential association by time between blood collection and diagnosis was not evident for invasive breast cancer risk in our previous analysis [in situ tumors, the earliest detectable breast carcinomas.The relationship between prolactin and analysis . Whetheranalysis ,18. Thisanalysis , and demanalysis . Howeverin situ breast cancer among postmenopausal nulliparous women but not in parous women. Parity, a well-established protective factor for breast cancer [In the current study, prolactin was associated with t cancer , has beet cancer ,21. Our in situ breast cancer. A general limitation of our study is that prolactin levels were measured only at a single point in time. However, reliability studies in which repeat blood samples were taken over intervals of up to three years have shown relatively high intra-class correlation (ICC coefficients of up to 0.76) between individuals’ serum prolactin levels over time [situ breast cancer is largely diagnosed as a result of mammography; however, we were not able to adjust our models for the participation in mammographic screening, nor were we able to compare rates of screening in cases and controls. Our study had relatively limited numbers of case subjects for subgroup analysis, and thus the statistical power for detecting associations of prolactin with risk in these subgroups was limited. Due to very limited information available for the molecular characteristics of in situ tumors, we were not able to perform the analysis by molecular subtypes of the lesions.Our study is the second largest prospective study on the association between prolactin and breast cancer risk, to provide risk estimates for ver time -24. In sin situ breast cancer. Our study shows that higher circulating levels of prolactin may be associated with increased risk of in situ breast cancer. It is estimated that up to 50% of untreated in situ breast lesions will progress to invasive disease. However, we are currently not able to distinguish between indolent and more aggressive in situ carcinomas, and the side effects of the medical management of in situ lesions  are not negligible. Therefore, identification of risk factors for in situ breast carcinomas is important both from the perspective of characterizing the risk of the disease as diagnosed and treated, as well as providing insight into the aetiology of the in situ carcinomas, which represent pre-invasive disease. Additional work to characterize circulating prolactin and risk of invasive disease, particularly after the development of in situ breast disease, is needed.In conclusion, we have extended prior research showing an association between prolactin and invasive breast cancer to the outcome of


Women with a family history of breast cancer face considerable uncertainty about whether to pursue standard screening, intensive screening, or prophylactic surgery. Accurate and individualized risk-estimation approaches may help these women make more informed decisions. Although highly penetrant genetic variants have been associated with familial breast cancer (FBC) risk, many individuals do not carry these variants, and many carriers never develop breast cancer. Common risk variants have a relatively modest effect on risk and show limited potential for predicting FBC development. As an alternative, we hypothesized that additional genomic data types, such as gene-expression levels, which can reflect genetic and epigenetic variation, could contribute to classifying a person’s risk status. Specifically, we aimed to identify common patterns in gene-expression levels across individuals who develop FBC.We profiled peripheral blood mononuclear cells from women with a family history of breast cancer (with or without a germline BRCA1/2 variant) and from controls. We used the support vector machines algorithm to differentiate between patients who developed FBC and those who did not. Our study used two independent datasets, a training set of 124 women from Utah (USA) and an external validation (test) set from Ontario (Canada) of 73 women . We controlled for expression variation associated with clinical, demographic, and treatment variables as well as lymphocyte markers.Our multigene biomarker provided accurate, individual-level estimates of FBC occurrence for the Utah cohort (AUC = 0.76 [0.67-84]) . Even at their lower confidence bounds, these accuracy estimates meet or exceed estimates from alternative approaches. Our Ontario cohort resulted in similarly high levels of accuracy (AUC = 0.73 [0.59-0.86]), thus providing external validation of our findings. Individuals deemed to have “high” risk by our model would have an estimated 2.4 times greater odds of developing familial breast cancer than individuals deemed to have “low” risk.Together, these findings suggest that gene-expression levels in peripheral blood cells reflect genomic variation associated with breast cancer risk and that such data have potential to be used as a non-invasive biomarker for familial breast cancer risk.The online version of this article (doi:10.1186/s12920-015-0145-6) contains supplementary material, which is available to authorized users. BRCA1 or BRCA2 mutations, never develop breast cancer. Indeed, 40-50 % of women with a BRCA1 or BRCA2 mutation do not develop breast cancer by 70 years of age [Current clinical standards define a woman's breast cancer risk based on population averages. For individuals deemed to have a lifetime risk over 20 %, based primarily on family history, a strict surveillance regimen is recommended; this regimen typically includes twice-yearly clinical breast exams, yearly mammograms, and yearly breast MRI. For the five to ten percent of women who have a strong inherited predisposition to breast cancer , more ags of age , 4. Thusnormal cells has previously provided information about disease development [BRCA1 or BRCA2 mutation status, even when the mutations lie at different genomic loci within these genes [BRCA1 and BRCA2 mutations may not be reflected phenotypically in peripheral-blood cells; however expression levels in these cells may indicate a propensity for normal cellular activity within breast cells to become disrupted. Gene-expression levels in breast tumors have been shown to reflect functional germline variation. For example, expression patterns in tumors from patients with germline BRCA1 and BRCA2 variants exhibit distinctive patterns compared to tumors from individuals who do not carry these mutations [One existing method for estimating breast-cancer risk is based on personal health history, family health history, and demographic variables ; howeverelopment –13. Thiselopment , 14, 15.se genes . Aberranutations . AccordiBRCA1/BRCA2 mutation status. Our findings indicate that this approach has potential to provide women from breast cancer families with individualized estimates of breast cancer risk and therefore to guide patient decisions regarding medical management.For this study, we examined the potential to use peripheral-blood gene-expression levels to identify women who possess the highest risk for developing FBC. We obtained peripheral blood mononuclear cells (PBMCs) for two independent patient cohorts and evaluated how well this gene-expression data could be used to differentiate between women who have developed FBC and women who have not, independent of BRCA1 or BRCA2. We excluded women who carried a BRCA1/BRCA2 mutation but lacked a family history of breast cancer. To ensure that our findings were specific to familial breast cancer, we recruited 41 individuals with no known family history of breast cancer; 22 of these women had developed sporadic  breast cancer. We matched the patients by age. The median age of blood draw was consistent across all patient subgroups in the Utah cohort (Table p = 0.064). In addition, because our goal was to demonstrate an ability to differentiate between individuals who developed familial breast cancer and individuals who did not, we also verified that there was not a significant difference in ages between these two groups .We recruited participants via the High Risk Breast Cancer Clinic at the Huntsman Cancer Institute  under Institutional Review Board approved protocols (#00022886 and #00004965). We have obtained consent from these patients to report individual patient data. We collected blood samples after breast cancer occurrence and after participants had been in remission for at least six months. In general, we considered participants to have a family history of breast cancer if two or more first-degree relatives  had been diagnosed with breast cancer. Among eligible participants who met these criteria, we included all those from whom we could obtain fresh mononuclear cells at the time of the study. Among 83 individuals in the Utah cohort who had a family history of breast cancer, 39 had been diagnosed with breast cancer, whereas 44 women had never been diagnosed with breast cancer and were at least 55 years of age Table . Of the We obtained de-identified samples via the Ontario, Canada site of the Breast Cancer Family Registry (BCFR). We also obtained consent from these patients to report individual patient data. This cohort included 28 samples from women with a family history of breast cancer who had developed breast cancer, 32 from women who had a family history of breast cancer but had not developed breast cancer, and 13 from women with no family history of breast cancer, 8 of whom had developed breast cancer. Of these 73 women, approximately half were post-menopausal. We obtained, isolated, and stored blood samples for these women when they first enrolled in the BCFR.We used the RNeasy Kit  to isolate PBMCs from whole blood in cell-preparation tubes following manufacturer (Becton-Dickinson) protocol. Within two hours, we extracted RNA using the RiboPure RNA Isolation Kit, and hybridized the RNA to Affymetrix Genechip Human Exon 1.0 ST microarrays. Hybridization and scanning were performed at Duke University  and at Boston University School of Medicine (for the remaining Ontario samples).PLANdbAffy database [To correct for array- and probe-level background noise, we applied our Single-channel Array Normalization algorithm  to the Adatabase  to limitComBat tool [ComBat two separate times: 1) to the Utah samples and Ontario samples that were processed at Duke University and 2) to the same Utah samples (processed at Duke University) and to the Ontario samples that were processed at Boston University. Strong batch effects existed before adjustment, but after ComBat adjustment, no clear pattern remained between batches and gene-expression levels , alcohol use, tobacco use, occupational history, immunological disorder history, hypertension drug use, and anti-inflammatory drug use. Additional files We downloaded data from Gene Expression Omnibus (GSE17072), which had been produced by Lim, et al. . These dSVMAttributeEval module within the Weka software package [To identify genes whose expression differed most between FBC patients and controls, we used the Support Vector Machines-Recursive Feature Elimination (SVM-RFE) algorithm. We used the  package  and confe1071 R package (http://cran.r-project.org/package=e1071) and the LIBSVM library [We used the Support Vector Machines (SVM) classification algorithm to predict whether each participant had or had not developed FBC. To facilitate this analysis, we used the  library . We used library  to execuROCR package [To plot receiver operating characteristic curves, we used the  package . We used package .https://github.com/srp33/BCSP.Software scripts used for this study are available from p = 0.001). We also repeated cross-validation 1,000 times on the Utah data and observed that on average the best prediction results were attained using 250 genes; however accuracy was consistently high, independent of gene number , showing a consistently high level of accuracy between the cohorts  breast cancer and had received treatment. In our initial analysis, we grouped these women with the participants who had no history of breast cancer and broadly classified this group as “controls”. To further assess whether the predictive gene-expression patterns we identified are specific to women who develop FBC and thus have potential to predict disease risk, we assessed how well the SVM algorithm could distinguish between individuals who developed FBC and those who developed a sporadic tumor. This comparison was identical to the initial assessment, except that the control group excluded individuals who did not develop breast cancer. In this setting, the predictions attained similar levels of accuracy  as the initial analysis, although the confidence intervals were wider due to the smaller sample sizes. These findings indicate that PBMC gene-expression patterns may be useful to predict FBC risk.In addition, we tested whether similar genes were dysregulated in our predictive model if the sporadics-only control group was included or not. The SVM-RFE algorithm ranks each gene according to how strongly the gene-expression values differ between the patient groups. We found that the rankings were highly similar (Spearman's rank correlation rho statistic = 0.43), whether the control group contained sporadic patients only or the full control set. This finding suggests that individuals who develop familial breast cancer exhibit different gene-expression patterns than individuals who do not develop familial breast cancer, even when compared solely against individuals who had received prior diagnosis/treatments.http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE12517). We applied the Support Vector Machines algorithm to rank the genes according to differences in expression between women who had received a given treatment and post-menopausal women who had not received either treatment. We compared these gene rankings from this study to the original analysis that compared women who had developed familial breast cancer against controls. The gene rankings were not correlated for either treatment . This result suggests that the genes perturbed by hormone treatments are different from those that discriminate between women who develop familial breast cancer and those who do not.To affirm that the expression differences in the FBC women were not confounded by treatment with estrogen receptor pathway inhibitors, we independently evaluated a publicly available data set that profiled PBMC gene-expression levels for post-menopausal women who had or had not been treated with tamoxifen or aromatase inhibitors, respectively . However, the accuracy of our results indicates that gene expression based biomarkers hold promise for assessing individual breast cancer risk in a minimally invasive manner and that they can be applied broadly to women from high-risk families.The institutional/ethical review boards at the University of Utah and Mount Sinai Hospital approved collection and dissemination of data for this study.


Anal cancer incidence increases with age and is higher in women than men. Risk factors in this group other than high-risk human papillomavirus infection are unclear.In all, 1.3 million women were recruited in 1996–2001 and followed for incident anal cancer. Cox regression models were used to calculate relative risks (RRs) for anal cancer by various potential risk factors.vs 0.89, P for heterogeneity=0.04).Five hundred and seventeen incident anal cancers were registered over 13 years of follow-up. The largest RR was associated with a history of cervical intraepithelial neoplasia grade 3 . Other factors associated with significantly increased risks in multivariate analyses were: ever smoking ; previous use of oral contraceptives ; nulliparity ; tubal ligation  and not living with a partner . The association with smoking was significantly greater for squamous cell carcinoma than adenocarcinoma of the anus (RR 1.66 History of CIN 3, smoking, past oral contraceptive use, nulliparity, tubal ligation and not living with a partner are risk factors for anal cancer in women. There was a significant increase in risk associated with smoking for squamous cell anal cancers but not adenocarcinomas. In the past 20 years there has been more than a doubling in incidence of female squamous cell anal cancer registrations in the UK, the rise being most marked in middle-aged and older women . There aHigh-risk human papillomavirus (HrHPV) infections, which cause the majority of cases of cervical cancer , but theSeveral high-risk populations for anal cancer are already known, including human immunodeficiency virus (HIV)-positive individuals . Self-reported data from the recruitment and subsequent resurvey questionnaire were used to define most exposures; exposures were not updated. Deprivation index was calculated using post-code and 1991 census data .in situ cancer: CIN 3 registrations (ICD-10 D06) that occurred prior to recruitment were also identified from the cancer registry data.Million Women Study participants are flagged on the UK National Health Service Central Registers, which provide the study team with regularly updated information on incident cancers and deaths. Cases of incident anal cancer are those coded as C21 ‘malignant neoplasm of anus and anal canal' according to the (ICD-10) . CervicaRisk factors with sufficient numbers of cases in exposed and unexposed women were also examined separately for the two most common histological subtypes of anal cancer: squamous cell carcinoma and adenocarcinoma. These were identified using ICDO-3 (ICD for Oncology version 3) morphology codes. Squamous tumours included the following ICDO-3 codes: M80810/3, M8070/3, M8071/3, M8072/3, M8083/3, M8094/3, M8123/3, and M8124/3. Adenocarcinomas included codes M8140/3, M8210/3, M8263/3, M8480/3, and M8481/3.Cox proportional hazards models were used to examine the relationship between exposures and subsequent risk of anal cancer. Hazard ratios, described here as relative risks (RRs), were estimated with attained age as the underlying time variable. Participants entered the analysis from the date they reported the relevant exposure . The small number of women who were under the age of 50 at recruitment (3%) entered the analysis at age 50. Women were followed to the earliest of date of first cancer registration, death, emigration, or 31 December 2012, the date of the most recent ONS follow-up.vs ever); oral contraceptive pill use (never vs ever); parity (parous vs nulliparous); tubal ligation (no/yes); deprivation (quintile of Townsend Deprivation Index); age at menarche ; alcohol use ; and body mass index . Where smoking and oral contraceptive pill use were examined as exposures, responses were categorised by amount smoked: smoking ; and duration of use oral contraceptive pill use .Analyses were stratified by region of residence , North West (Manchester/Lancashire), Scotland) and adjusted where appropriate for previous registration of CIN 3 (yes/no); smoking  and hormone therapy use (never/ever) were examined as exposures in postmenopausal women only; the association with age at menopause was further restricted to naturally postmenopausal women or those reporting a bilateral oophorectomy, who had never used hormone therapy. Apart from CIN 3 registration and deprivation quintile, these exposures were all based on self-reported questionnaire data collected from participants at baseline.We also examined the impact of being married or living with a partner (yes/no), and of self-reported attendance for cervical cancer screening (ever/never) in fully adjusted models. These exposures were asked about on the first resurvey, which was sent out on average 3 years after recruitment.The small number of women with missing data (fewer than 2% for each variable) were included in a separate category for each variable of interest and included in the analysis but these data are not shown. Relative risks are reported with 95% confidence intervals. Analyses were performed in Stata 13 .We used a competing hazards model to examine the interaction between anal cancer histological subtype and past CIN 3, smoking, and oral contraceptive use.In all, 1.3 million women were followed for 16.9 million person-years, giving an average of 13 years of follow-up per woman. During this time, 517 were registered with incident anal cancer. P<0.0001), after adjustment for smoking, alcohol use, BMI, age at menarche, ever use of the oral contraceptive pill, parity, tubal ligation, and deprivation (About 1% (12 531) of the women in the cohort had a registration of CIN 3 prior to recruitment, and this was the strongest predictor of risk of anal cancer after the age of 50  compared with never smokers. Current smokers who reported smoking >15 cigarettes per day at recruitment had more than a doubling of risk   . No signP<0.0001) for ever vs never use. When stratified by years of use, women who reported 5 or more years of oral contraceptive use had a significantly increased risk of anal cancer, RR=1.68   see .P<0.0001). Women who reported ever having given birth had a lower risk of developing anal cancer, irrespective of the number of children they had, with a RR of 0.58  for those reporting 1–2 children, and a RR of 0.69  for women with 3+ children, compared with the nulliparous group.Overall, nulliparous women had a 60% greater risk of anal cancer when compared with parous women, with a RR of 1.61 . Neither age at menopause nor use of hormone therapy was significantly associated with anal cancer risk   reported not living with a husband or partner, and their risk of anal cancer was increased  . Only 4%<0.0001) .vs adenocarcinomas of the anus  were SCCs. Glandular tumours were less common, with 62 adenocarcinomas (12%) registered. The remaining 27 (5%) were rarer histological subtypes, including anal melanoma; this group had insufficient numbers to examine separately.We also compared associations for squamous cell cancers (SCC) the anus . The majP for heterogeneity=0.04) from the risk in women with squamous cell tumours . In contrast, the association between past CIN 3 and oral contraceptive use were similar in the two subtypes. We were not able to examine all factors by histological subtype; the other exposures that showed a positive association with anal cancer  had an insufficient number of cases of adenocarcinoma to permit valid subgroup analysis.The RR of adenocarcinoma of the anus in women who reported any lifetime smoking was 0.89 (95% CI 0.51–1.54), which was significantly different ; ever having smoked, with a doubling of risk in current smokers of >15 cigarettes a day; ever having used the oral contraceptive pill; nulliparity; a history of tubal ligation; and not currently living with a husband or partner. Among smokers, the risk of squamous cell anal carcinoma differed significantly from the risk of adenocarcinoma, with an elevated risk of squamous cell tumours but not of adenocarcinoma.The strongest association with risk of anal cancer in our study was in the 1% of women who had a registration of CIN 3 before they were recruited. Women with HrHPV-associated neoplasia in one part of the anogenital tract are known to be more likely to have it elsewhere .Anal cancer, and other HPV-related anogenital cancers are increased in women with a history of anogenital warts , and preThough smoking has been found to be a risk factor for anal cancer in some other studies (We also found that the risk associated with smoking varies significantly by tumour histology, with an increase in anal SCCs, but not in adenocarcinomas. Similar heterogeneity has previously been reported for cervical cancer—smoking was significantly related to cervical SCCs but not adenocarcinomas . The hetPast use of oral contraceptives was a clear predictor of risk of subsequent anal cancer in our study, particularly for women with longer-term use of 5 or more years. This is a little-investigated association; we found only one previous study of anal cancer risk that mentioned oral contraceptive use, and no significant association was found . It has The increased risk of anal cancer in women who reported a history of tubal ligation has not, to our knowledge, previously been reported. Tubal ligation is highly correlated with parity; over 97% of the women in our cohort who reported being sterilised had given birth to at least one child. Sterilised women had more children, with 49% reporting three or more children, compared with 33% of women in the cohort overall. Given that in our analysis the risk of anal cancer was decreased in parous women, the relationship between tubal ligation and increased risk was unexpected. Adjusting for parity, age at first birth, or number of children did not affect the association.HPV infections are sexually transmitted. The risk of anal cancer and its precursor lesions have been shown to be closely related to sexual behaviour in both women and men, including number of partners and sexual practices (Given that HPV is sexually transmitted, this might seem counter-intuitive; however, most women aged over 50 years who are not married or living with a partner are widowed, separated, or divorced , and it In a large cohort of over a million women with prospectively collected information on exposures, with an average 13 years of follow-up, we found that prior CIN 3, smoking, past use of the oral contraceptive pill, nulliparity, tubal ligation, and not currently living with a husband or partner were risk factors for incident anal cancer in women over 50 years of age. Anal cancer has the closest relationship to HrHPV after cervical cancer (When we looked separately at the two main histological subtypes of anal cancer, we found a significant difference in risk associated with smoking for tumours with squamous cell morphology compared with adenocarcinomas. To our knowledge, this has not previously been reported in anal cancer; however, similar heterogeneity between squamous and adenocarcinomas has been reported for other cancers, including cancer of the cervix , and lunAnal cancer, like the other anogenital cancers, has a strong relationship with high-risk strains of HPV. HrHPV infections are extremely common, but the cancers they cause are rare. We have identified several additional risk factors with strong associations to anal cancer risk in older women, particularly smoking and past oral contraceptive use.


Around one third of breast cancers in post-menopausal women could be prevented by decreasing body fatness and alcohol intake and increasing physical activity. This study aimed to explore views and attitudes on lifestyle intervention approaches in order to inform the proposed content of a lifestyle intervention programme amongst women attending breast cancer screening.Women attending breast cancer screening clinics in Dundee and Glasgow, were invited to participate in focus group discussions (FGD) by clinic staff. The groups were convened out with the clinic setting and moderated by an experienced researcher who attained brief details on socio-demographic background and audio-recorded the discussions. Data analysis was guided by the framework approach. The main topics of enquiry were: Understanding of risk of breast cancer and its prevention, views on engaging with a lifestyle intervention programme offered through breast cancer screening and programme design and content.Thirty one women attended 5 focus groups. Participant ages ranged from 51 to 78 years and 38 % lived in the two most deprived quintiles of residential areas. Women were generally positive about being offered a programme at breast cancer screening but sceptical about lifestyle associated risk, citing genetics, bad luck and knowing women with breast cancer who led healthy lifestyles as reasons to query the importance of lifestyle. Engagement via clinic staff and delivery of the programme by lifestyle coaches out with the screening setting was viewed favourably. The importance of body weight, physical activity and alcohol consumption with disease was widely known although most were surprised at the association with breast cancer. They were particularly surprised about the role of alcohol and resistant to thinking about themselves having a problem. They expressed frustration that lifestyle guidance was often conflicting and divergent over time. The concept of focussing on small lifestyle changes, which were personalised, supported socially and appropriate to age and ability were welcomed.Offering access to a lifestyle programme through breast screening appears acceptable. Explaining the relevance of the target behaviours for breast cancer health, endorsing and utilising consistent messages and identifying personalised, mutually agreed, behaviour change goals provides a framework for programme development. Breast cancer accounted for 15 % of all cancer diagnoses in Scotland in 2012 . In addi2 at baseline who gained > 5 kg of body weight during the follow up period (median 13 years) had a 36 % increase risk of developing breast cancer. It is notable that whilst high weight gain in midlife has been associated with an increased risk of breast cancer diagnosis before or at age 50 in women,  that they are always hitting you with” (FG4). There was also a sense of exasperation that the content of messages was perceived to be inconsistent, and therefore unreliable:“they say one thing one month and then six months later they say, oh don’t do that because it’s not good for you” (FG3)“they tell you at one point this is really not good for you…then maybe four or five years down the line they will say, no, it’s really ok, you can have that” (FG4)It was notable that women described encouragement to engage in lifestyle change as ‘preachy’ or nagging. It was clear that women felt ill at ease about health messages which they had repeatedly been exposed to in the past: “I think if the professionals can’t get it right, why do we bother?” (FG1).Not only did this result in frustration among the participants, but also a loss of confidence in those disseminating these messages conveyed in comments such as “I think in general people are fed up to the back teeth being told that this is not healthy and that’s not healthy and you mustn’t eat this and you can’t eat it, this is negative health messages and I think that is not good” (FG5). There was a sense that “folk just start to switch off…” (FG1) from health messages and “[People will] do what they want to do” (FG3) or ignore it all completely reporting that I’ll just go on as I’m doing possibly” (FG2)Women also reported a sense of overload of messages (many of which were perceived as negative) “I’m…thinking to myself, my sister had breast cancer about 2011, she’s the very opposite to me, she’s slim…she’s very active, she doesn’t drink, she’s not overweight, she got cancer. I’m the opposite and I haven’t” (FG1)Whilst it was not surprising to participants that body weight, physical activity and alcohol consumption all play a role in cancer risk the direct link between them and breast cancer was surprising. Several participants expressed doubt about the validity of the statistics, and both acceptance and equivocation were reinforced by anecdote and personal experience:it’s trickier [to talk about] than smoking” (FG4)”. Moreover, it was felt that many people tend to downplay or underestimate their own alcohol intake illustrated by a wide range of comments including “A lot of people hide it” (FG5) and “they have some perception that they are going to be judged, even if they are not a heavy drinker” (FG4)Most of the participants who took part in the focus groups reported drinking low to moderate levels of alcohol. Most agreed that alcohol consumption was a sensitive subject in general with one group noting that ““Everybody drinks” (FG4), whether in a social context or at home. For example “It’s become a social thing, hasn’t it, women get together and say bring a bottle of wine, then they have one glass, they have another glass and they forget just how much they are taking” (FG1). Because alcohol plays such a deeply embedded role in social relationships it was suggested that particular attention should be paid to balancing messages, to avoid being perceived as preaching or controlling.It was generally thought that alcohol was a predominant and inescapable feature in modern life, and that they did not generally have a problem with alcohol it was a big problem for young people and in FG3 they broadened the topic out to the Scottish Government’s plans to introduce minimum unit pricing on alcohol:Participant 1 in exchange: And because they [the Scottish Government] have this agenda to reduce, well I think its young people who are drinking too much and then causing violence.Participant 2 in exchange: They’re never going to, you cannot stop people drinking, I don’t care what the Scottish government think they’re going to.Keeping track of personal alcohol intake was seen as challenging for individuals, not least because of difficulties estimating volume of alcohol consumed and confusion over alcohol units. The middle-aged women in the FGDs expressed the view that whilst I think the ones who are having the big glasses of wine and thinking its ok are our age group”.So the topic of breast cancer risk and alcohol was transformed into a discussion of the problem that alcohol causes more broadly and was resolutely among young people, although it was noted in FG1 that ““I got through the menopause really with no flushing, I never went on HRT, and I was really fine; but the weight…” (FG3)“My weight crept up during the menopause but I didn’t know that it was the menopause I was going through” (FG5)Many participants were surprised to find there was a direct link between breast cancer risk and body weight. The majority of those taking part had struggled with their weight, either throughout life or following menopause, and most were either overweight or obese. There was no awareness that menopause itself was associated with weight gain, although there were some references to an expectation of becoming heavier as one ages.I lost two stone. I mean I feel so much younger and more active and I didn’t have any back pain, [or pain] in my knees and my ankles” (FG5)“The discussions illustrate that many women struggle with post-menopausal weight gain. Many women reported a history of dieting, either informally or through attending commercial slimming clubs. However, such efforts were deemed only temporarily successful, with weight rising once contact with the group or adherence to stricter plans loosened. Motivations to lose weight were described as changing over time. One woman described how, as a younger woman, she associated keeping her weight under control with physical attractiveness. Now, however, she had begun to lose weight gradually over time in order to improve her healthHer commitment to lose weight very gradually was indicative of an important factor for many of the participants in light of the ease of weight gain and difficulty in losing it they had experienced, which was to have achievable targets and realistic expectations of sustainable changes:“I did it with a friend and each week we could share, have we succeeded, have we not succeeded, what we have found difficult, what we didn’t. (FG4)“You get to meet different women, different sizes” (FG5)Women did not distinguish physical activity for weight loss with physical activity for general reasons. They did describe participating in a range of activities, ranging from gardening to running and climbing and daily routines which incorporated some element of physical activity such as twice-daily dog-walking and taking grandchildren to school. While the participants all agreed that being physically active had unquestionable health benefits, several mentioned the social aspect of their physical activity, both in formal and informal settings:in an everyday kind of situation” (FG2); that enjoyment was central - “I think it’s the fun element that attracts people” (FG5); and that motivation should ultimately focus on the individual - “[doing it] for themselves” (FG2). Yet some participants found their ability to exercise was restricted most commonly as a result of physical impairment or ailment. Comments referring to comorbidities such as “I’m really restricted because of the spasms in my back and the tiredness and the pain” (FG4) and “I’ve knackered my knees and I’ve got a touch of arthritis” (FG5) highlight some of the challenges of being physically active amongst older women. Even in the absence of specific medical problems, participants felt that age and its effect on lifestyle impacted on both their attitude towards exercise generally, and the type of activity they would be uncomfortable doing such as “hectic or vigorous activity”.Participants said that it was important that activity was encouraged within the context of women’s particular lives - “Who’s got the money to go and join a gym?” (FG3)““I think even if you want to go to the gym there’s not a lot of option for anybody our age, because it’s all spin fit, whatever…too much geared to young people” (FG4)These views affected attitudes towards formal settings such as health clubs and the gym, which were seen as often financially unaffordable, but also unappealing:“I find in the winter it’s not just exercise, the winter I don’t want to go out the door, so my treat…if I’m not working…is a full day in the house. But in the summertime it’s different…it’s brighter in the morning so you are up and you’re doing more” (FG4)Reported lack of time, personal preferences and sensitivities might nudge people towards less formal forms of exercise, specifically walking. However, potential barriers to regular walking included the climate and the social surrounding.The aim of focus group discussions is to seek the opinions of a range of people at the same time, and to examine points at which individual views converge and conflict. Overall, there was a high level of consensus, both within and between focus groups in each of the areas explored. While this might be attributed the nature of these groups discussions, participants were all strangers to one another and did not appear reticent in voicing contrasting positions (particularly on more sensitive topics) to contribute to the overall discussion.It is clear that any intervention focussed on reducing breast cancer risk factors needs to be take account of beliefs around genetics, fate and personal experience. Whilst these beliefs have been described in women who are known to be at increased risk  or have The provision of information in the waiting area prior to the mammogram enabled women to begin to reflect on the study, while the radiographer acted as an additional prompt was said to work well. This approach might address any concerns that radiographers would feel uncomfortable when raising the opportunity for a lifestyle intervention during their time-restricted consultations with individual women. Furthermore, participants in the focus groups described this approach as relaxed and informative thus it is plausible that a whole team approach to recruitment and engagement would be acceptable by screening attendeesThe most significant concern about the nature of support offered was whether this would be best provided one to one, or in a group setting. It was recognised that are issues with setting up groups such as dovetailing busy schedules for multiple participants. The concept of ActWell coaches and receiving personal support on a one to one basis was viewed positively. These findings underlines the desire for advice and support to be given within what is perceived to be a reciprocal and respectful relationship. It is likely that both  approaches are plausible for recruitment and engagement but ways to facilitate social support (which is associated with improved behaviour change adherence ) within There was evidence of confusion and frustration about public health lifestyle guidance which was seen as conflicting and changed over time. These findings suggest the need to maximise the opportunity to emphasise agreement from a multi-agency stakeholder group ) for the intervention in order to underline both the importance and consistency of messaging or perhaps explaining why lifestyle advice does change so rapidly.Whilst women liked the idea of being offered support for lifestyle change, their suspicion of public health interventions in general, suggest there may be some resistance to elements of the programme. This was manifested as a questioning of the science underpinning the association between bodyweight, alcohol consumption and cancer risk. Social psychological research would suggest that they may have responded defensively to the personal risk implied . AlcoholIt is useful to consider how these findings might shape the intervention dialogue. With respect to alcohol it seems appropriate to offer practical guidance such as a measuring guide for units of alcohol which would provide women with a tool for monitoring intake and raise awareness of their own alcohol consumption. In addition, the provision of clear, information that illustrates the scientific evidence about the link between lifestyle factors and breast cancer risk has the potential to increase credibility of advice both in the context of alcohol as a carcinogen and indirectly through the role of alcoholic drinks in increasing caloric intake and potential contributor to weight gain.Participants recognised the importance of physical activity, especially in connection with weight management but also described a range of personal, social and economic limitations to becoming more active. These findings highlight the importance of acknowledging what women already do, what they might like to do to increase physical activity and providing help to attain and sustain meaningful and practical goals. Women argued that changes to lifestyles as they aged were influenced by social roles and acknowledged it is easy to put on weight as their roles changed. They were, however, enthusiastic about the role of a lifestyle coach, who they thought would make the process of making changes easier (in part) due to personalised support.This study has several limitations. While these women were drawn from a cross section of the general population, it should be noted that they were recruited via breast cancer screening clinics, and were arguably already actively concerned about their health and wellbeing. This means that, in interpreting the results of the study we need to be aware that respondents were likely to be those most keen on the idea of supporting breast cancer risk reduction. It is possible that respondents who did not offer to take part were likely to be much more sceptical. Nevertheless, we are confident that participants were not just telling us what we wanted to hear given the breadth of challenges, issues and questioning of the links between weight, alcohol consumption and breast cancer risk.. These findings add to the existing evidence base on effective behaviour change techniques and highlight the need for personalised gender and age specific approaches to realising the potential of breast screening as an opportunity for a “teachable moment” [Offering access to a lifestyle programme through breast screening appears acceptable. Explaining the relevance of the target behaviours for breast cancer health, endorsing and utilising consistent messages and identifying mutually agreed, behaviour change goals provides a basic framework for programme development moment”  for breaFGD, Focus Group Discussion, NHSSBSP, NHS Scotland breast screening programme, NPT, Normalization Process Theory


Risk factors for breast cancer are often confusing and contradictory. Discrepancies are likely due to different subtypes having divergent risk factors. An important distinction between breast cancer subtypes is hormone-receptor status. Compared to women diagnosed with estrogen receptor positive (ER+) breast cancer, those with estrogen receptor negative (ER−) tumors are usually diagnosed at a younger age and have a higher mortality . Few stuet al. [In a recent meta-analysis, Aktipis et al.  demonstrLife history theory provides a framework for understanding how, when and why organisms allocate their resources . To maxiEnvironmental cues during critical periods of development help to guide an organism’s life history strategy. Environments with high extrinsic mortality and unpredictable resources tend to select individuals with a fast life history strategy, that is, mature and invest in reproduction earlier at the cost of growth and/or somatic maintenance . In contBRCA1 or BRCA2 are more likely than non-carriers to develop an ER− breast tumor [Accordingly, individuals with characteristics of a fast life history strategy may have a fertility advantage early in life that is accompanied by increased cancer risk later in life. There is preliminary evidence that suggests women at elevated risk for hormone-independent breast cancer have a different reproductive profile. Women who carry a germline mutation in st tumor ; carrierst tumor . AlthougIf women at risk for hormone-independent breast cancer invest more in reproduction, we should expect to see evidence for less investment in somatic maintenance. An individual’s overall cancer risk, including breast cancer, increases over their lifetime. One of the most important epidemiologic patterns of breast tumor subtypes is that ER− tumors are more common among younger women . One potEnvironmental cues, such as resource predictability and extrinsic mortality, impact an individual’s life strategy. SES provides an indicator of an individual’s environment and resources. Interestingly, incidence of breast cancer subtypes varies along the SES gradient. Compared to US women with other breast cancer subtypes, those diagnosed with a hormone-independent tumor are more likely to report Black or Hispanic ethnicity (versus non-Hispanic White) . And, stAs mentioned above, early environmental cues can steer an organism’s life history strategy. In humans, age at first menstruation signals the switch from investment in growth and/or maintenance to reproduction. In modern-industrialized samples, age of menarche can be delayed by family warmth and paternal investment, while pubertal timing can be accelerated in moderately stressful environments of nutritional adequacy . In USA,Eating nutritious food and leisure-time physical activity are examples of behavioral somatic maintenance. Individuals of low SES report investing less in their health; interestingly, this association was found to be completely mediated by perceived extrinsic mortality risk . TherefoThreatening stimuli early in life can increase the risk of adult-onset diseases via epigenetic changes . AlthougBRCA1 promoter hypermethylation [In vitro studies could help determine how ER+ and ER− breast cancer cells differ in life history characteristics, such as division rate and death rate. Another challenge in this domain of research is the heterogeneous expression of estrogen-receptor both within and between tumors categorized as ER+. How this widespread methodology affects our observations cannot currently be measured; the question would best be interrogated by comparing risk factor differences between breast tumor subtypes from various categorization schemes. Lastly, if hormone-independent breast cancer is a result of less somatic maintenance, we would predict these tumors to have greater genetic heterogeneity (via a higher mutation rate) and the individual to have a decreased immune function, which is consistent with ER− tumors’ more aggressive phenotype.The proposed connection between life history strategy and ER− breast cancer risk implies a few immediate predictions. Early life stressors that accelerate pubertal timing may be associated with increased promoter methylation of tumor suppressor genes, including those expressed in human breast epithelium. Women with hormone-independent breast cancer often have hylation . Informahylation . It is aIn summary, there appear to be different risk factors for different types of breast cancer. Greater cumulative estrogen exposure from delayed childbirth and fewer total offspring is associated with ER+ breast cancer, a cost of modern reproductive behavior. However, hormone-independent breast tumors exhibit a different profile of environmental risk factors. ER− breast cancer susceptibility shows no association with parity or age at first birth. Instead, genetic variants associated with higher fertility, racial and ethnic minority membership, low SES and eating fewer fruits and vegetables  are associated with a higher risk for ER− breast cancer. An accelerated life history strategy lends a framework for explaining these associations that will hopefully lead to clinical application, but at this stage, more mechanistic evidence is needed. Future research into the epigenetic effects of early psychosocial stress and malnutrition could enhance understanding of why some women are more vulnerable to the most lethal subtype of breast cancer.


Objective(s): Cytochrome P-450 1A1 is an important enzyme in the first phase of the metabolism of some carcinogens such as polycyclic aromatic hydrocarbons (PAHs), as well as estrogen. The present study evaluates the existence of CYP1A1 polymorphism in a number of breast cancer samples.Materials and Methods: One hundred breast cancer patients and the same number of healthy controls were analyzed for the A2455G polymorphism of cytochrome P-450 1A1 by the polymerase chain reaction-restriction fragment length polymorphism technique. Results: Frequency of heterozygote genotype (A/G) indicated significant increase in case group (17%) compared to control group (7%) . The related result of (A/A) genotype showed significantly decreased risk of breast cancer . Higher frequency of heterozygotes was mainly observed among premenopausal breast cancer patients. Conclusion: Our results suggest that the CYP1A1 polymorphism may be useful for predicting breast cancer risk in our study population. Breast cancer is the leading cause of cancer death among women in the world . The majCytochrome P-450 (CYP) 1A1 is a xenobiotic metabolizing enzyme (XMEs) which participates in the metabolism of a vast number of xenobiotic components as well as a small number of endogenous substrates . CYP1A1 encodes aryl hydrocarbon hydrolase (AHH), an enzyme involved in the production of reactive epoxide intermediates from polycyclic aromatic hydrocarbons, steroid hormones, and other aromatic compounds . Here, wSubjectsThis study included 200 unrelated subjects (100 controls and 100 patients), living in Eastern Azerbaijan, Iran. The patient samples were collected from women who were referred to Tabriz Hospitals  with unilathral primary breast carcinoma, without any radiotherapy background and family history of breast cancer. The patients received modified radical mastectomy or breast conserving surgery. To avoid confounding of ethnicity, we excluded patients from neighboring countries, judged by name, language and place of birth. The patient group had a mean age of 42±9 years. A detailed description of clinical and pathological characteristics of samples has been summarized in DNA extraction and polymerase chain reaction (PCR)About 3 ml of peripheral blood sample was collected from each individual participated in the study and used for DNA isolation by salting out procedure. The samples were centrifuged and the pellet was resuspended in RBC lysis buffer. Then, the pellet was mixed with WBC lysis buffer  in the presence of 200 µl of 10% SDS and 50 ul proteinase K (20 mg/ml) and incubated at 37°C for 16 hr following to addition of saturated salt solution. DNA was precipitated by 1-3 ml of isopropanol and washed using 1 ml of 70% ethanol. The DNA pellet was dissolved in sterile distilled water.2. PCR primers were designed as described by Cascorbi et al  and reverse (5´GGC TATCCTGCTGCAACGGGTGGAA3´) primers, 1.25 units of Taq DNA polymerase (Cinnagen), 200 µM of dNTPs, 2.5 µl of 10x PCR buffer  and 2 mM MgClGenotypinget al  for each genotype. The clinicopathologic parameters studied here were: age, nodal status, SBR  tumor grade and clinical tumor size.The results were analyzed by SPSS version 16. The genotype frequencies of the gene were tested for Hardy-Weinberg equilibrium for both patient and control groups using the χP-value=0.03. The risk appeared to be increased predominantly in pre-menopausal subgroup  . Genotype distribution in both case and control groups did not diverge significantly from Hardy-Weinberg equilibrium. In addition, we found no significant discrepancy among (A/G) genotype and clinic-pathological characteristics regarding the tumor size and grade. According to lymph node status, the frequency of heterozygote genotype was slightly increased in positive lymph nodes. In the present study allele frequencies of the variant allele CYP1A1 (A2455G) among the cases and controls were 0.1 and 0.04, respectively. The genotype frequencies and the results of the case control study have been summarized in et al reported the association of A2455G variant with increased risk of breast cancer in women with premenopausal status in Indian population  exhibit higher risk of breast cancer compared to the heterozygous carriers and homozygous normal individuals  allele was found to be slightly increased in breast cancer patients with node-positive status which disagrees with a similar study done in India .Studies explain the importance of gene-environment interaction in carcinogenesis , 13. SmoThe result obtained from the present study indicates that the carriers of 462Val have a significantly higher risk of breast cancer than those are homozygous normal which was outstanding in premenopausal subgroup. Normal homozygote genotypes showed decreased risk of breast cancer. Affected individuals carrying 426Val variant allele do not have distinct clinico-pathological characteristics.


Recently an association between breast cancer and inflammation has emerged as the seventh hallmark of cancer. Chronic inflammation is a key contributor in the development and progression of carcinogenesis. Inflammatory pathways play an important role in the causation of breast cancer. C-reactive protein (CRP) an acute-phase reactant inflammatory protein is synthesized in hepatocytes in response to cytokines that are released from leucocytes within the tumor microenvironment. Several epidemiological studies appraised an association of CRP with breast cancer risk with inconsistent findings. Elevated levels at the time of diagnosis of breast cancer indicate aggressiveness of the tumor. CRP is also a well-established independent prognostic marker. Breast cancer survivors with the state of chronic inflammation are at risk of recurrence and metabolic disturbances. CRP lowering agents along with chemotherapeutic drugs will improve the survival of breast cancer patients. Also, it is a risk predictor for subsequent cardiotoxicity in patients receiving chemotherapy. The present review is aimed at elucidating the role of C-reactive protein, as an inflammatory risk marker and prognostic predictor of breast cancer. It also focuses on conflicting views on the role of CRP in breast cancer and its impact on therapeutic interventions. Worldwide breast cancer is the most frequently diagnosed cancer among women and most common cancer-related death worldwide. According to data reported in 2012, about 1.7 million women were diagnosed with breast cancer and it was the most common cause of cancer-related death (522000 deaths in 2012) [Several etiological factors like age, environmental and genetic factors, endogenous and exogenous endocrine factors have been implicated in the pathogenesis of breast cancer . RecentlState of chronic low-grade inflammation predisposes a person to cancer by building up an inflammatory microenvironment. Histologically, evidence of obvious inflammation is seen rarely in breast cancer. But inflammatory component is there in the microenvironment of tumor cells, which contain white blood cells, macrophages with cytokines, and chemokine, as principal mediators of inflammation. This cancer-related inflammation facilitates promotion and progression of tumor growth . ChronicThe present review is aimed at elucidating the role of C-reactive protein, an inflammatory risk marker and prognostic predictor of breast cancer as well. Also we discussed molecular biology, functions, and limitations of CRP molecule. Streptococcus pneumoniae. It is synthesized by hepatocytes in response to inflammation, trauma, and tissue damage. Also a moderate rise in CRP levels is seen in chronic inflammatory states. CRP has a cyclic pentameric structure with calcium-dependent ligand binding. Five identical noncovalently associated protomers are situated symmetrically around a central pore. Each protomer consists of 206 amino acids residues with ligand binding site having a pocket with two ions of calcium. Calcium ions are required for ligand binding and stability of the molecule CRP [C-reactive protein is a classical acute phase reactant protein from pentraxin family. Tillett and Franscis discovered CRP in 1930 and it was named because of its high binding affinity to C-polysaccharide ofcule CRP .CRP is a prototype of short pentraxin, which represents a systemic response to local inflammation. In human beings, serum amyloid protein is also an additional component of short pentraxin . CRP is CRP is raised in circulation in response to acute inflammation, infection, and tissue damage. The rise in CRP levels is proportional to degree of tissue damage. Its plasma half-life is 19 hours and is catabolized by hepatocytes. Since past decade, with the introduction of high sensitivity assay, it has been evolved as emerging nontraditional novel cardiovascular risk marker because of its confirmed role in initiation and progression of atherosclerosis. It is widely used not only for risk stratification of cardiovascular diseases but also as a predictor of type 2 diabetes mellitus, hypertension, metabolic syndrome, pregnancy-induced hypertension, and various types of cancers. It is a sensitive but nonspecific marker of acute and chronic inflammatory conditions like infections, rheumatoid arthritis, and chronic obstructive pulmonary disease. As its concentration is raised in large amount in bacterial infection, it is also useful in differentiating between bacterial and viral infections .Various immunoturbidimetric, nephelometric, and enzyme linked immunosorbent assay methods are available for estimation of serum CRP with detection range of 3 to 8 mg/L. Commercial kits for assay of high sensitivity C-reactive protein (hsCRP) based on immunoturbidimetric, immunonephelometric, and chemiluminescence methods are available with lower detection limit of 0.3 mg/L. Estimation of serum hsCRP is simple, cheap investigation with no diurnal variation. Serum CRP is stable and samples can be stored for long periods at and below −20°C . As it iInflammatory pathways play an important role in the causation of breast cancer. There is a bidirectional link between chronic inflammation and carcinogenesis: tumor originates and progresses at the site of chronic inflammation while tumor cells attract immune cells and promote the production of cytokines and chemokine creating tumor microenvironment. Hence, cancer is associated with the persistent inflammatory state. There is a vicious cycle and complex interplay between cancer and inflammation . So reseEstimation of CRP can be looked at as a simple, cost-effective, easily available screening test to assess future risk of breast cancer.Several epidemiological studies appraised association of CRP with breast cancer risk with inconsistent data findings. So Guo and associates conducted a meta-analysis of 8 cohort and 7 case-control studies to assess the role of CRP in predicting breast cancer risk. Out of 15 studies, two studies had shown negative, statistically insignificant association between one unit change in ln CRP and breast cancer. The remaining studies observed positive association, among which four reported statistically significant positive association. Combined OR per natural unit change in CRP for breast cancer was 1.16 (95% CI: 1.06–1.27) with moderate heterogeneity. They also observed a strong association in retrospective case-control studies compared to cohort studies. Elevated CRP levels significantly increased a risk of breast cancer among postmenopausal women  but not in premenopausal breast cancer . In postmenopausal women, overweight and obesity favor a low-grade chronic inflammatory state that predisposes to breast cancer. Serum hsCRP, a sensitive inflammatory marker, had a stronger association than common CRP. Overall analysis of this meta-analysis reported that a natural log unit rise in CRP level results in 16% increase in breast cancer condition . Meta-anOne of the prospective studies of risk of breast cancer among nondiabetic women observed significantly increased risk in women with hsCRP more than 3 mg/L versus those women with less than 1 mg/L concentration  . Also in2 and history of past smoking were found to have a significant association between CRP and risk of breast cancer. On multivariate analysis, there was no significant association between CRP and other risk factors and characteristics of breast cancer. So the results of this prospective study concluded that CRP is not associated with risk of breast cancer in apparently healthy women [Controversial data has been obtained in several studies assessing the role of CRP as a risk marker. In Women's Health Study, serum CRP levels of 27919 healthy women were assayed and this cohort was followed up for 10 years. 892 women developed invasive breast cancer, which was statistically nonsignificant finding. But women with body mass index above 25 Kg/mhy women . Among ohy women . Similarhy women .Wang and Sun in their systematic review reported no strong evidence between CRP levels and risk of breast cancer . Some reThe exact role of CRP in the pathogenesis of carcinogenesis is uncertain, but evidence from numerous prospective and case-control studies has supported a role of CRP in different aspects of breast cancer. Identification of the role of the molecular pathway in the causation of breast cancer and implementation of anti-inflammatory strategy by therapeutic and lifestyle intervention is important in future to prevent and control incidence of breast cancer.Numerous prospective epidemiological studies have observed the association of CRP at the time of diagnosis of breast cancer with the prognosis of the disease. CRP is synthesized in hepatocytes in response to cytokines, particularly IL-6, released from leucocytes within the tumor microenvironment. IL-6 also helps in binding CRP to phospholipids on tumor cells that results in activation of classic C1q complement pathway. Here it acts as opsonin leading to tumor cell lysis . State on = 4502) and compared OS, cancer-specific survival, and DFS in patients with raised and low level of CRP. The pooled hazard ratios (HR) for OS and DFS were significant at 1.62 and 1.81, respectively, and 2.08 for cancer-specific survival predicting poor survival in breast cancer [Moon and associates studied the molecular link between sphingosine-1-phosphate (S1P) and CRP during the invasive process of breast epithelial cells using a xenograft mice tumor model and revealed the molecular basis of S1p-induced transcriptional activation of CRP and its functional significance of invasive phonotype of human breast epithelial cells in an inflammatory environment. S1P upregulates expression of CRP which in turn triggers transcriptional activation of matrix metalloproteinase-9 through reactive oxygen species, calcium ions, and c-fos leading to breast cell invasion . Allin et cancer . Al Murrt cancer .Elevated levels at the time of diagnosis of breast cancer indicate aggressiveness of the tumor. In our case-control study from India, among women with breast cancer, we found a significant correlation of serum hsCRP with stage, size and grade of the tumor, and metastasis . HistoloWith tremendous advances in diagnostic and therapeutic modalities in the field of oncology, the outcome of breast cancer has been improved dramatically. But although highly effective, anticancer drugs are associated with higher risk of incident cardiotoxicity. So monitoring of patients receiving cancer therapy for development of subsequent cardiotoxicity is a great challenge. Biomarkers may help to identify patients at high risk before starting therapy as well as during follow-up. Overweight and obese women at the time of diagnosis or weight gain after diagnosis is associated with elevated levels of inflammatory markers. This causes metabolic disturbances increasing the risk for diabetes mellitus, hypertension, and cardiovascular diseases (CVD) among breast cancer survivors. Thomson et al. evaluated presence of metabolic syndrome and CRP levels as cardiovascular risk factors in breast cancer survivors on adjuvant hormone therapy. They found elevated CRP in 90.5% of the population (mean 5.1 ± 5.3 mg/dL) . RecentlKy et al. compared multiple biomarkers which can predict subsequent cardiotoxicity in breast cancer patients treated with doxorubicin, taxanes, and trastuzumab. They reported a lack of association of CRP levels with cardiotoxicity while troponin I and myeloperoxidase can be used as potential markers of incident cardiac dysfunction in their study participants .HER 2 positive breast cancers are more aggressive with poor survival rate. With the incorporation of monoclonal antibody trastuzumab in their management, significantly reduced mortality, recurrence, and metastasis have been observed with improved DFS. But therapy with adjuvant agent trastuzumab may induce cardiotoxicity. So periodic monitoring for assessment of cardiac function is mandatory because early detection can prevent or reverse this complication by withholding the drug and adding cardiac therapy. In one pilot study, a cohort of 54 HER2 positive women with early breast cancer were prospectively monitored with serum brain natriuretic peptides, hsCRP, and troponin I levels and left ventricular ejection fraction (LVEF) during trastuzumab therapy. Findings on statistical analysis suggested an association of normal hsCRP levels with low future risk of decreased LVEF. This study highlighted the promising role of CRP as a cheap, reproducible, easily available biomarker for identification of trastuzumab-induced cardiotoxicity .Extensive research has also been carried out to evaluate other serum inflammatory markers in breast cancer patients. Various elements of inflammation and enzymes of tissue remodeling are involved in different steps of carcinogenesis and metastasis . CRP andIn cardiovascular diseases, CRP lowering drugs like COX inhibitors, platelet aggregation inhibitors, lipid lowering agents, and angiotensin converting enzyme inhibitors and antioxidants have been found to be promising therapeutic targets. Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively administered COX inhibitors worldwide. These drugs arrest the cell cycle and inhibit the growth of the tumor by inhibiting angiogenesis, neovascularization, and decreasing prostaglandin synthesis. Various clinical trials of NSAIDs showed promising role in reducing the risk of breast cancer .Lipid lowering agent statins also decrease the level of CRP and they have been also found to have an antitumor effect through antiproliferative, antiangiogenic, and antimetastatic properties. But studies have reported inconsistent results for the utility of statin in cancer prevention. The addition of CRP lowering agents along with chemotherapeutic drugs may improve the survival of breast cancer patients.Limitations of CRP Assay. CRP is a sensitive but nonspecific marker of inflammation. Its levels are easily influenced by various physiological and pathological factors like acute and chronic infections and use of anti-infectious agents and anti-inflammatory drugs. Single estimation of CRP level does not help; at least two measurements are needed at the interval of 2 weeks to interpret the risk.In the present review, we intended to evaluate the role of CRP in every aspect of breast cancer, from its usefulness in risk prediction, diagnosis, prognosis, and therapeutics. The microenvironment of tumors rich in inflammatory cells is an essential element in carcinogenesis. Cancer-related inflammation has emerged as an important hallmark of cancer. Chronic inflammation is also an essential player in recurrence of the disease by the promotion of dissemination and growth of metastatic seeds . CRP, anChronic inflammation is a key contributor for breast cancer, right from its causation, initiation, promotion, progression, metastasis, and clinical features. Serum CRP assay is a simple, cheap, and sensitive test available widely. The potential utility of CRP as a risk predictor for breast cancer is questionable in clinical practice. But CRP will have the promising role as an additional prognostic predictor of survival. Also, it is a risk predictor for subsequent cardiotoxicity in patients receiving chemotherapy.Future studies are needed to decide strategy of implementation of anti-inflammatory CRP lowering agents. This may help in prevention, control of breast cancer, and improving outcome in patients with breast cancer. This offers a hope that overall morbidity and mortality can be minimized to a large extent with improved strategies in the management of breast cancer and appropriate interventions aiming towards better patient care.


Familial cancer includes some types of cancer aggregation without a well-defined inheritance pattern. Cancer genetics is an essential component of clinical practice in oncology. In Brazil, breast cancer is the leading cause of death in women. In Maranhão, studies on genetic predisposition are necessary to investigate the incidence and mortality rates. The aim of this study was to investigate familial cancer among relatives of women who died of breast cancer in São Luís, Brazil, constructing a pedigree to identify families with a hereditary predisposition, an important step in the early diagnosis of malignant tumors.The city of São Luís is located on the Island of Maranhão, northeastern Brazil, with a population of 997,098 inhabitants mainly comprising blacks and mulattoes, including descendants of runaway slaves from the Amazon region itself. Data for pedigree construction were obtained from the records of 54 patients seen at the Aldenora Bello Institute of Oncology, São Luís, between 2000 and 2007, as well as by interview with relatives of the patients.The mean patient age at diagnosis was 39.5 years. Most women were mulattoes . A history of cancer was observed in 18 families, with 16 families possessing cases of cancer among first-degree relatives and five among second-degree relatives.A concentration of cancer cases was found in families of patients diagnosed until the age of 40, a finding demonstrating the importance of a family history prior to genetic counseling. Breast cancer is the second most frequent type of cancer in the world and the most common among women. The highest rates are observed in North America and in South American countries such as Brazil and Argentina . In BrazData from the Brazilian Institute of Geography and Statistics (IBGE) showed that life expectancy at birth in Brazil increased from 74.6 to 74.9 years in 2014. The State of Maranhão has a life expectancy of 69.7 years; 66 years for men and 73.7 years for women. In Maranhão, access to health services is still difficult, because of the low economic status of the population and the lack of public policies for the organization of health care [Hereditary cancer comprises diverse syndromes that are relatively rare and of monogenic etiology. These syndromes are estimated to correspond to about 5–10 % of cancer cases in the general population , 5. An eAnalysis of cancer family history may reveal the existence of various other cases of disease with peculiar characteristics, such as relatives affected in three successive generations, two or more first-degree relatives with a premenopausal diagnosis of the disease, cases of bilateral breast cancer, and cases of breast cancer in men .National Institute for Health and Clinical Excellence (NICE) guidelines recommend the use of information from family history, which should be taken into account in assessing risk and deciding whether and when to refer, and when to reassure . Women wThe definition of the form of tracking high-risk women have not yet supported on current scientific evidence and is varied to approach this group in national screening programs. It is recommended that women at high risk of breast cancer have individualized clinical monitoring. The National Institute of Cancer of Brazil (INCA) recommends screening for women at high risk of breast cancer, whose routine should start at age 35 with breast examination and annual mammography .With respect to the histopathological classification of breast tumors, a predominance of infiltrating ductal carcinoma is observed, which accounts for 65.0–85.0 % of these malignant tumors. However, the relationship between histological type and hereditary cancer is still not well established –19.Family health history has long been acknowledged as an important part of the medical examination . In breaPrimary care has an important role in the prevention and early diagnosis of hereditary cancer. Reduction in risk through prevention is a core function of primary care .In Brazil, genetic tests are still not available through the public health service and the construction of pedigrees is therefore important for the investigation of cases of cancer among relatives. The possibility of identifying relatives who are at high risk for the development of cancer permits the application of preventive measures and the early detection of cancer. Patients classified as high risk according to cancer family history could be referred for genetic counseling at other centers of the country.In view of the lack of studies on this subject in the State of Maranhão, the objective of the present investigation was to evaluate the occurrence of malignant tumors in first- and second-degree relatives of patients with a diagnosis of breast cancer who died before the age of 60.An observational, descriptive study divided into two phases was conducted: a retrospective study reviewing the records of 54 patients from São Luís who had died of breast cancer before the age of 60 and had a histopathological exam revealing a malignant breast tumor and a prospective study interviewing relatives for the collection of information about cancer history in these families. Since according to the literature, hereditary cancer syndromes, especially Li-Fraumeni syndrome, affect individuals with one first- or second-degree relative with a typical tumor of this syndrome identified at any age and with another first- or second-degree relative with cancer diagnosed before the age of 60 . Due to The study involved 54 women who lived at São Luís—MA seen at the Aldenora Bello Maranhense Institute of Oncology (IMOAB) between 2000 and 2007. This service is certified as a Reference Center of High Complexity in Oncology (CACON). In the analyzed period, there were 158 deaths due to breast cancer, but were recruited only women’s medical records residing in São Luís, so only 54 were included. This is a convenience sample from the 158 recorded deaths. Because of the difficulty of recruiting relatives of women who resided in the State of Maranhão, only 54 women were included because they lived in São Luis. Family members were invited to participate in the study and after signing an informed consent were included. All family members agreed to participate in the study and there was no loss to follow-up during the period.The following characteristics of morbidity and mortality were analyzed: age at diagnosis and death, overall survival, tumor laterality, tumor stage, associated tumors, and presence of metastases. The presence of other cancer cases in the family, number of affected relatives, degree of kinship, and other types of malignant tumors observed in the family until the third generation were also investigated. The recommendations of the National Comprehensive Cancer Network and of the project Guidelines for Hereditary Cancer were used as criteria of hereditary cancer , 27. ParSociodemographic data, histopathological type, handedness when it comes to breast cancer, staging, overall survival and site-metastatic were obtained by review of medical records.The study was approved by the Research Ethics Committee of the University Hospital, Federal University of Maranhão (No. 362/07). The Statement of Informed Consent Form (ICF) was presented to the families of women who died from breast cancer and signed in obedience for Resolution No. 196/96 and its complementary. The information contained in pedigrees obtained maintains the confidentiality of the study patients and their families.The data were tabulated using the Microsoft Excel 2003 program and analyzed with the Epi-Info 2007 program, version 3.4.3.A total of 158 deaths due to breast cancer were observed among women aged 60 years or younger between 2000 and 2007. Fifty-four women with breast cancer who lived in São Luís—MA were studied.The age of these women at the diagnosis ranged from a minimum of 22 years to a maximum of 60. The mean age was 39 years and 6 months, with a standard deviation of 7.52 and the average (age of) death of 41.98 years, with a standard deviation of 7.91 age. The demographic data presented in Table The most common histological type was infiltrating ductal carcinoma (83.3 %), followed by the association of infiltrating ductal carcinoma/infiltrating lobular carcinoma (7.4 %). One patient (1.9 %) had lobular carcinoma and another (1.9 %) had comedocarcinoma. The right breast was the most affected . The left breast was affected in 21 (38.8 %) patients and 7 (12.9 %) presented a bilateral tumor. In the cases studied, there were no cases of family history in bilateral cancer, with no information being available for two (3.7 %) patients. Lymph node involvement was observed in 36 (66.7 %) women and all of them developed distant metastases, except for one patient. The most frequent metastatic sites were bone , lungs , and liver  . Stage II was observed in 13 (24.0 %) women and stage IV in 14 (25.93 %)  and only one had to 240 months. A relationship was observed between tumor stage and overall survival, with 85.7 % of the patients with initial tumor stage IV and 22.2 % with stage III presenting survival less than 12 months  were observed in another index case. Malignant tumors also occurred sporadically in second-degree relatives, with the observation of lung cancer in two families and a case of prostate cancer in another. The distribution of multiple cases of cancer is shown in Table An association of breast and ovarian cancer (breast-ovarian syndrome) was observed in two women 11.1 %, 2/18) and association of breast and colorectal cancer  in a woman , and other cases . Figure /18 and aBreast cancer mortality rates continue to be high in Brazil, because in most cases the diagnosis is made during a late stage of the disease. According to Abreu and Koifman , stages Variations in the incidence of breast cancer among young women are reported in the literature. In the study of Silva , 22.3 % Eisenberg , followiSeveral studies have demonstrated a relationship between breast cancer and other cancer cases in the family, with the prevalence of cancer cases ranging from 5 to 10.0 % , 31, 32.In studies designed to evaluate the relationship between a certain type of cancer and a family history of this disease, some confounding factors may impair the analysis such as a small number of affected subjects and difficulties in the confirmation of family history . In the In the study of Vieira , the tumTwo index cases call attention because of the particularities of their evolution. The first was an association with pregnancy in a 29-year-old woman. According to the patient, nodules arose in her right breast by the sixth month of gestation but no appropriate investigation was performed. During the puerperium, after treatment for mastitis without an adequate response, the diagnosis of a malignant breast neoplasm was established. However, distant disseminated tumor cells were detected and the patient died after only 2 months. The family history of this index case showed a case of cervical cancer.Breast cancer is the second most frequent tumor associated with pregnancy and hypertrophy and breast engorgement during this period may contribute to a delay in diagnosis. However, the disease itself does not indicate a poor prognosis. In a series of 15 cases of pregnancy-associated breast cancer most patients had locally advanced disease at diagnosis but progressed satisfactorily and were free of the disease . We founAnother woman aged 50 years at the time of diagnosis of breast cancer presented a history of melanoma. The patient had been treated but recurrence was observed 1 year later, after the diagnosis of breast cancer had been made. The stage of the breast tumor was IIa and the patient died at 52 years, with survival of 25 months. Only lymph node involvement was demonstrated.Limitations of this study are the small number of included cases, large account of the women reside in the interior of state of Maranhão; Absence of a control group of to compare if there was a greater risk of family cancer in women who have had breast cancer.In conclusion, the evaluation of family history of breast cancer by pedigree construction permitted the identification of family groups with an elevated risk of familial cancer. This finding demonstrates the relevance of this strategy for primary prevention and early detection of breast cancer in the Maranhão population.


BRCA1 and BRCA2 are responsible for most of the known causes of HBOC, while mutations in mismatch repair genes and several genes of moderate penetrance are responsible for the remaining known hereditary risk. Women with a history of familial ovarian cancer or with known germline mutations in highly penetrant genes are offered the option of risk-reducing surgery that involves the removal of the ovaries and fallopian tubes . Growing evidence now supports the fallopian tube epithelia as an etiological site for the development of HGSC and consequently, salpingectomy alone is emerging as a prophylactic option. This review discusses the site of origin of EOC, the rationale for risk-reducing salpingectomy in the high-risk population, and opportunities for salpingectomy in the low-risk population.High-grade serous carcinoma (HGSC) is the most common and aggressive histotype of epithelial ovarian cancer (EOC), and it is the predominant histotype associated with hereditary breast and ovarian cancer syndrome (HBOC). Mutations in  BRCA1 or BRCA2.In 2015, approximately 22,000 women in the United States were diagnosed with ovarian cancer and 14,000 died from this devastating disease . MoleculBRCA1 or BRCA2. The lifetime risk of developing ovarian cancer with germline mutations in BRCA1 and BRCA2 is 40–60 and 11–27%, respectively  compared with African-American women (32%). Of interest, Hispanic women (43%) and Asian women 52%) have higher survival rates. It is estimated that about 1 in 500 Americans have a mutation in 2% have hectively . The burutations , 11. Thepatients . These dOvarian cancer incidence and mortality among US women has declined in those aged 35–59 years due to earlier detection methods or changes in risk  as womenScreening methods with CA-125 and transvaginal ultrasound have proved mostly ineffective in decreasing mortality for sporadic HGSC and ovarian cancer in general , 16. Earin situ carcinoma in the distal end of the fallopian tube of women undergoing prophylactic surgery, the ovary was thought to be the etiological site of high-grade serous ovarian cancer. Now, there are two candidates for the cell of origin, namely, the fallopian tube epithelium (FTE) and the ovarian surface epithelium (OSE). Both share common mesodermal embryological origin and close anatomic proximity. The fallopian tube, along with the uterus, uterine endocervix, and superior aspect of the vagina are derived from an invagination of the celom known as the Mullerian or paramesonephric ducts. The OSE is derived from the mesothelial celomic epithelium that lines the primitive ovary  observed in the ovary. These events, along with proliferation of the OSE, promote metaplastic changes leading to neoplastic transformation   –31, promons (6%) , 32–34, ons (6%) , 36. OveBRCA mutation carriers undergoing risk-reducing surgery led to the discovery of putative cancer precursor lesions in the fallopian tube referred to as serous tubal intraepithelial carcinoma (STIC)   –40. STICs (RRSO) , 41. Thes (RRSO) .TP53 mutations, which are ubiquitous in HGSC, are usually concomitantly found in STIC and HGSC , and secretory cell outgrowths (SCOUTS) . These land HGSC , 44. Oveand HGSC . HoweverMany studies have now reported the incidence of non-invasive neoplastic lesions (STIC) in the distal end of the fallopian tube. It is estimated that occult invasive and STIC are identified in 0.9–8.5% of women undergoing RRSOs , 46–63 . The frePowell and colleagues reported that in a long-term follow-up study of women diagnosed with non-invasive serous tubal epithelial carcinoma who underwent RRSO, 6% (1/17) recurred 43 months after risk-reducing surgery compared to 43% of women who had unsuspected invasive carcinoma at time of surgery . There iEpidemiological data show that oral contraceptives, aspirin, and other non-steroidal anti-inflammatory drugs reduce the risk of ovarian cancer. In a meta-analysis as a primary prevention mechanism by Havrilesky et al., oral contraceptive pills use reduced ovarian cancer risk by 50% if used for more than 10 years . RecentlTubal ligation  has been shown to reduce ovarian cancer risk that theoretically is spread through retrograde menstrual flow –70. In pBRCA1 or BRCA2 mutations by as much as 96%   .BRCA1 and BRCA2) and moderate to lower penetrant genes such as PTEN, PALB2, CHEK2, ATM, and BRIP1. The removal of the fallopian tubes alone is referred to as risk-reducing salpingectomy (RRS). In young women identified with a BRCA1 or BRCA2 mutation, RRS is performed in an effort to reduce ovarian cancer risk while maintaining adequate hormonal levels to avoid the effects of early menopause. This latter approach, however, is not restricted to women at high risk for serous ovarian cancer, as it will also have a beneficial impact on reducing the risk of development of endometriosis-associated clear cell and endometrioid ovarian cancer  consider opportunistic salpingectomy during hysterectomy, (2) consider excisional bilateral salpingectomy rather than tubal ligation for sterilization, and (3) refer all HGSC patients for BRCA1/2 germline testing (Opportunistic salpingectomy refers to removal of the fallopian tubes in women who are  testing . Interim testing . The autThe caveat to opportunistic salpingectomy is that even if implemented on a large scale, the true impact of ovarian cancer reduction will take years to be realized . It is aThere is categorical evidence that RRSO reduces ovarian and breast cancer death and all-cause mortality , 79. TheSG wrote and conceptualized. RG researched references and made figure. BS wrote and conceptualized.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.