Despite rising breast cancer incidence and mortality rates, breast cancer screening (BCS) rates among women in Qatar remain low. Previous studies indicate the need to better understand the many complex beliefs, values, and attitudes that influence Arab women’s health seeking behavior for the development of culturally appropriate and effective intervention strategies to address breast cancer in the Middle East. This study investigates beliefs, attitudes, and BCS practices of Arabic-speaking women in Qatar.A multicenter, cross-sectional quantitative survey of 1,063 (87.5% response rate) Arabic-speaking female Qatari citizens and non-Qatari residents, 35 years of age or older, was conducted in Qatar from March 2011 to July 2011. Associations between beliefs and BCS practice were estimated using chi-square tests and multivariate logistic regression analyses. Participants who adhered to BCS guidelines (BCS practice = Yes) were compared to those who did not (BCS practice = No).In addition to low levels of awareness and low participation rates in BCS, one quarter of the participants stated their doctors talked to them about breast cancer, and less than half of the women interviewed believed breast cancer can be prevented. Women who engaged in BCS practice were more likely to have a doctor who talked to them about breast cancer, to believe they were in good–excellent health, that cancer can be prevented, or that cancer might be hereditary. The majority wanted to know if they had cancer and felt their health care needs were being met. The main reasons given for not planning BCS were lack of a doctor’s recommendation, fear, and embarrassment.These findings indicate that a variety of channels  should be utilized to create culturally appropriate breast cancer intervention programs and increased awareness of breast cancer, BCS, and the benefits of early detection of breast cancer. Employment of these measures will reduce breast cancer mortality rates among Arabic-speaking women living in the State of Qatar. Qatar, like many other Middle Eastern countries, comprises a traditional, collectivist society. H.H. Sheikha Moza bint Nasser, the most respected and celebrated woman of Qatar, once described Qatar as “a rising homeland that confidently embraces modernization and proudly observes tradition” . Thus, Qatar has the potential to offer the best of the West and the East by offering state-of-the-art medical technology while incorporating social, cultural, and religious principles to address the health care concerns of its two million people. The government of Qatar has made health care research as one of national research priorities; close to 3% of its annual GDP  is allocated to funding research in Qatar. Therefore, health care programs and research aimed at addressing cancer in Qatar can significantly impact the Middle East region and Muslim and Arab women worldwide.Breast cancer is one of the most commonly diagnosed and leading causes of cancer-related deaths among women just after lung cancer ,2. A 201When combined with appropriate treatment, early detection through breast cancer screening (BCS) activities that include breast self examination (BSE), clinical breast examination (CBE), and mammography, has been shown to decrease cancer mortality rates by 25–30% ,13. StudA cancer diagnosis is often accompanied by social stigma in the Middle East, and limited physician disclosures of cancer diagnoses often coincide with social and cultural norms . BecauseStudies indicate that a BCS recommendation from a physician, family member, or friend; awareness of breast cancer and the importance of BCS; a family history of breast cancer; and a higher education level, residence in an urban area, employment, and higher socioeconomic status are important facilitators of BCS behavior -17,25,26Lack of a physician’s recommendation, fear of the BCS procedure and fear of finding cancer, low perceived risk of cancer or effectiveness of BCS, time, cost, preference for a female health professional, accessibility of the health care system, and embarrassment related to the BCS procedure are barriers to clinical breast examination and mammogram practice among Arab women ,14,15,17Despite fear of cancer and low levels of BCS participation, Arab women are eager to learn more about breast cancer and its screening activities -31. To dAccording to Kleinman’s Explanatory Model, “beliefs about sickness … including treatment expectations … affect the way individuals think about and react to sickness and choose among and evaluate the effectiveness of the health care practices available to them” . Thus, iThis paper reports (a) BCS participation rates of Arabic women living in Qatar, and (b) relationships between Arabic women’s BCS practice, their beliefs, values, and attitudes toward BCS, and selected sociodemographic factors. We hypothesize that there is a relationship between Arabic women’s beliefs, values, and attitudes toward BCS and their participation in BCS activities in Qatar.Participant inclusion criteria included being 35 years or older , abilitEthics approval for this research study was obtained from the Hamad Medical Corporation Research Committee , the Qatar Supreme Council of Health (Ethics Assurance No: SCH-A-UCQ-050), and the University of Calgary’s Conjoint Health Research Ethics Board (Ethics ID: E-23551). Consent to participate in this study was obtained from each participant. Prior to conducting an interview, each participant was given an explanation of the study and informed of her rights according to the standard interview guideline. Participants were assured that all information would remain confidential and interview questionnaires were stripped of identifying information to preserve confidentiality. No incentive was given to participants of the survey.Data collection was obtained from interviews using a structured survey questionnaire. Interviews were conducted in Arabic by seven female nurses fluent in Arabic and English. Survey questionnaire items were incorporated from previous peer-reviewed surveys on breast cancer research in the United States and Australia with permission from authors, and further refined after a pilot study field-tested the questionnaire in Qatar -39. ForwDescriptive statistics  and chi-squared tests were performed to determine associations between categorical dependents and categorical predictors. Simultaneous multivariate logistic regression analyses using the “Enter” method was used to further assess the association of preselected factors related to beliefs, values, attitudes, and sociodemographics with binary dependent variables . Multicolinearity for all covariates significant after bivariate analyses was tested before using them in the multivariate logistic regression analyses. Participants assessed with appropriate adherence to BCS recommendations (BCS Practice = Yes) were compared to those who were not (BCS Practice = No). Statistical significance levels were established at alpha = 0.05 , 52% were Qatari nationals, and 47.9% were non-Qatari residents , two-thirds had lived in Qatar for 30+ years, 33.3% had a university education, 36.6% of the married participants’ husbands had a university education, and 65.9% of the participants were unemployed (89.3% of whom were homemakers). Additional analyses found that younger participants were more likely to be university educated than older participants, and the eldest age group (50+ years) was made up of more Qatari nationals than non-Qataris (p < 0.05) , religion 98.2% Muslim), and living area (88.7% in urban areas). Participants’ ages ranged from 35–82 years  Figure .The majority of participants stated that their health status was “good” or “excellent” (76.2%). When asked why people get cancer, participants responded “fate,” “having an unhealthy lifestyle,” “not breastfeeding one’s baby,” or “hereditary factors.” Less than half believed that cancer is preventable (42.8%), and less than one fifth reported that cancer was a punishment from God, bad luck, or that cancer was contagious.The majority of participants reported that they trusted and understood their health care provider (HCP), they felt their health care providers respected them, and that their health care needs were being met. Although only 24.4% of the participants reported that their doctors had talked to them about breast cancer, most said they would make a mammogram appointment if they received a recommendation from their HCP. Most participants said they would want to know if they were diagnosed with cancer (86.6%), and preferred to consult doctors (72.4%) and other HCPs (90.8%) who were female; only 2.1% preferred that a nurse examine them rather than a doctor. Approximately half of the participants had no preference for their HCPs’ language (48.6%) Table .Of the participants who were planning to have a CBE n = 525) or a mammogram , over three quarters reported the following reasons: their own health, their doctor recommended it, or fear of getting cancer. Approximately two thirds said their plan to have a CBE or a mammogram was due to a recommendation from a family member/friend or nurse or from seeing information about breast cancer and its screening in the media or hearing about it in a community health clinic lecture  was because their doctor did not recommend it. Approximately one fifth to one quarter of all participants said their failure to plan a CBE or a mammogram was due to embarrassment related to the procedure, not knowing where to go for a CBE or mammogram, possible pain involved in the mammogram procedure, or fear of cancer being discovered. Fewer participants reported reasons such as it would not do any good, a male might examine them, or fear of gossip. Less than 2% said their avoidance of CBE and mammography was due to their husbands’/male relatives’ disapproval of breast examinations  than younger or older participants. Participants were more likely to practice BCS if they reported their health status to be good or excellent, if they thought that cancer is preventable, or if they thought that cancer is hereditary than participants who did not subscribe to these beliefs. Participants who stated they would want to know if they have cancer were more likely to have had or were planning to have a mammogram. Participants were significantly A higher education level of the participant or the participant’s husband was significantly related to a perceived good-excellent health status, the belief that cancer can be prevented, or the desire to know if cancer was present (p < 0.05). Participants with higher education levels were also more likely to believe that cancer can be hereditary or can arise from an unhealthy lifestyle, whereas less educated participants were more likely to believe that cancer is God’s punishment, bad luck, or contagious (p < 0.05).Participants whose doctors had talked to them about breast cancer and who understood the doctor’s message were significantly more likely to practice BCS. Participants who trusted their doctors and had no gender preference for their HCP were more likely to have had a CBE. Those who preferred to have a doctor rather than a nurse examine them were more likely to have a mammogram than those who preferred a nurse examine them or who had no preference. Language preference for one’s HCP (Arabic or English) was not significantly related to BCS practice Table .Further analyses on age and education differences indicated that older participants (50+ years) and those with lower education levels were more likely to have no preference for the status of HCP (doctor or nurse) that examined them, did not want to know if they had cancer, and believed cancer result from not breastfeeding (p < 0.05).Participants who were planning to have a CBE “for health” were significantly more likely to have had a CBE. Participants were less likely to have had a CBE and less likely to plan to have a future CBE if they perceived a CBE might be painful/ uncomfortable, if they were afraid cancer might be discovered, or they felt the procedure would embarrass them (p < 0.05) Table .Participants with lower education levels were more likely than those with higher education levels (p < 0.05) to give the following reasons for not planning a CBE: fear of finding cancer, and the belief that a CBE would not be beneficial.Participants 40 years of age or older were significantly less likely to have had a mammogram if they stated the following reasons for not planning a future mammogram: a mammogram might be painful/uncomfortable, fear of knowing they might have cancer, fear of gossip, or embarrassment (p < 0.05) Table .Mammogram practice was not significantly related to participants’ perceptions that a mammogram would not have benefits. However, older participants were more likely to state that their doctors did not recommend having a mammogram, that a mammogram would not do any good, or that they were afraid that cancer might be discovered (p < 0.05). It is important to note that nonsupport of husband or male relatives was not significantly related to participants’ intention to avoid mammography.Table Participants who believed their health status was good–excellent , that cancer could be prevented , or that cancer is hereditary  were twice as likely to practice BSE than those who did not subscribe to these beliefs. Participants who preferred female rather than male HCPs to examine them were half as likely to practice BSE  as those who did not care whether the examining HCP was male or female.Participants who believed cancer could be prevented , who understood their doctor’ message , and believed cancer is hereditary  were more likely to have had a CBE than those who did not. Participants who believed that cancer is God’s punishment  or preferred a female HCP rather than a male HCP to examine them  were approximately half as likely to have had a CBE than those who did not believe cancer is God’s punishment or did not care whether the examining HCP was male or female.Predictors for not planning a CBE included participants’ fear of knowing they might have cancer  and participants’ embarrassment regarding the CBE procedure .Participants (40+ years of age) were more likely to have had a mammogram if they understood their doctor’s message , if they believed cancer could be prevented , or if they believed cancer is hereditary . Participants were half as likely to have had a mammogram if they believed that cancer is God’s punishment  than those who did not have this belief.Fear of knowing one might have cancer  was a significant predictor for not planning to have a mammogram.These findings provide a partial answer to the question of why, despite the availability of health care services and gender-appropriate health care providers in Qatar, less than one third of the women interviewed practiced BCS according to national guidelines. Consistent with Kleinman’s explanatory model of health, illness and disease, this study found that several complex beliefs and attitudes toward breast cancer screening influence BCS uptake among Arabic-speaking women in Qatar. As with Arab or Muslim women living in the West, the women interviewed had low BCS awareness and low screening rates, they overwhelmingly preferred female physicians, and they gave fear or embarrassment as reasons for why they did not plan to have a CBE or mammogram ,41. HoweIt is important to note that fear of cancer is apparently both a facilitator and a barrier to BCS participation, a finding congruent with previous studies in the region ,15,17,30Previous studies indicate that low perceived risk and pessimistic views related to cancer among Arab women can act as barriers to cancer treatment or BCS ,15,43,44Arab patients greatly respect their physicians as experts whose advice is followed . While oMost Qatari women are Muslim and report having a strong faith in God . ModestyIt is difficult to generalize the results of this study to all women living in Qatar because of the non-probability convenience sampling. An attempt to increase generalizability and to reduce potential bias was made by randomly-selecting times to reach every potential participant who met study’s inclusion criteria at all research sites, resulting in a high response rate of 87.5%. Also, data were collected from self-reported interviews, which might be affected by recall or social-desirability response bias. However, the results of this study give insights into breast cancer screening practices of Qatari women that can be applied to women with similar sociocultural backgrounds throughout the Middle East and globally.This study’s findings indicate low levels of awareness of BCS and low participation rates in BCS among women in Qatar. Women who engaged in BCS practice were more likely to have a doctor who talked to them about breast cancer, to believe they were in good–excellent health, to believe that cancer can be prevented, or to believe that cancer might be hereditary. While the majority of participants stated they would want to know if they had cancer and felt their health care needs were being met, their main reasons for not planning BCS were lack of a doctor’s recommendation, fear of being diagnosed with cancer, fear of possible discomfort in the BCS procedures, and embarrassment in undergoing BCS.As women in Qatar become more educated and aware of health and disease, health care providers and policy makers must facilitate Arab women’s desire to know more about the benefits of cancer screening for early detection of this disease. Similar to the findings of a qualitative study of Iraqi women living in the U.S. , the majIf female and male health care professionals would make breast cancer and its screening a mandatory topic of discussion with all gender and age-appropriate women and men, awareness could be raised of culturally-appropriate services available in Qatar. Public health awareness campaigns that highlight these services and regular physician-patient discussions about BCS can be cost-effective and efficient strategies to integrate BCS into the public consciousness while effort is being made to advance national cancer registries and national population based screening programs in Qatar.Ensuring ongoing screening practices requires culturally appropriate community support from respected elders, religious leaders, and breast cancer survivors. Collaboration between researchers, community leaders, health care professionals, and policy makers is important to ensure the appropriateness and success of educational and outreach campaigns aimed at increasing screening uptake and reducing morbidity and mortality related to breast cancer among women in Qatar.BCS: Breast cancer screening; BSE: Breast self examination; CBE: Clinical breast examination; HCP: Health care provider.The authors declare that they do not have any competing interests.DT: Contributed to the conception and design of the study and the acquisition, analysis, and interpretation of data, drafted the manuscript, and gave final approval of the manuscript version submitted for publication. AKA: Contributed to the conception and design of the study and the acquisition of data, revised the manuscript, and gave final approval of the manuscript version submitted for publication. BAS: Contributed to the conception and design of the study and the acquisition of data, revised the manuscript, and gave final approval of the manuscript version submitted for publication. AKM: Contributed to the conception and design of the study and the acquisition of data, reviewed the manuscript critically for content, and gave final approval of the manuscript version submitted for publication. AMN: Contributed to the conception and design of the study and the acquisition of data, revised the manuscript, and gave final approval of the manuscript version submitted for publication. MM: Contributed to the conception and design of the study and the acquisition of data, reviewed the manuscript critically for content, and gave final approval of the manuscript version submitted for publication. SR: Contributed to the conception and design of the study and the acquisition, analysis, and interpretation of data, revised the manuscript, and gave final approval of the manuscript version submitted for publication. CS: Contributed to the analysis and interpretation of data, drafted the manuscript, and gave final approval of the manuscript version submitted for publication. FT: Contributed to the analysis and interpretation of data, revised the manuscript, and gave final approval of the manuscript version submitted for publication. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/13/49/prepub


While there is extensive literature evaluating the impact of phytoestrogen consumption on breast cancer risk, its role on ovarian cancer has received little attention.We conducted a population-based case-control study to evaluate phytoestrogen intake from foods and supplements and epithelial ovarian cancer risk. Cases were identified in six counties in New Jersey through the New Jersey State Cancer Registry. Controls were identified by random digit dialing, CMS (Centers for Medicare and Medicaid Service) lists, and area sampling. A total of 205 cases and 390 controls were included in analyses. Unconditional logistic regression analyses were conducted to examine associations with total phytoestrogens, as well as isoflavones , lignans , and coumestrol.No statistically significant associations were found with any of the phytoestrogens under evaluation. However, there was a suggestion of an inverse association with total phytoestrogen consumption (from foods and supplements), with an odds ratio (OR) of 0.62  for the highest vs. lowest tertile of consumption, after adjusting for reproductive covariates, age, race, education, BMI, and total energy. Further adjustment for smoking and physical activity attenuated risk estimates . There was little evidence of an inverse association for isoflavones, lignans, or coumestrol.This study provided some suggestion that phytoestrogen consumption may decrease ovarian cancer risk, although results did not reach statistical significance. Cancer of the ovary is the second most common gynecologic cancer and the leading cause of death from gynecologic malignancies . While tPhytoestrogens are non-steroidal plant-derived compounds, with a similar structure as endogenous estrogens, and capable of showing both estrogenic and antiestrogenic effects ,10. MainWhile there is an extensive literature evaluating the impact of phytoestrogen consumption on breast cancer risk, its role on ovarian cancer has received little attention . Out of NJ Ovarian Cancer Study, specifically designed to evaluate phytoestrogens and ovarian cancer risk in New Jersey, a population characterized by large ethnic diversity. Consumption of foods high in phytoestrogens not included in the Block food frequency questionnaire (FFQ) (see Appendix 1) was ascertained and a detailed phytoestrogen composition database [We conducted a population-based case-control study, the database  was usedNJ Ovarian Cancer Study has been described in detail elsewhere [The lsewhere . In summlsewhere ,26. We uThe control group was the same as in the EDGE Study, described in detail elsewhere -27. In bInformed consent was obtained from all participants, and the study was approved by the Institutional Review Boards at Robert Wood Johnson Medical School, Memorial Sloan-Kettering Cancer Center, and the New Jersey Department of Health and Senior Services.NJ Ovarian Cancer Study and the EDGE Study to standardize data collection in cases and controls. Interviewers were trained using the same procedures and same training manual. Interviews, conducted by telephone for most respondents, covered established and suspected risk factors for ovarian cancer. In addition to the interview, participants were mailed a package with instructions for providing buccal specimens and waist and hip circumference measurements and the Block 98.2 food frequency questionnaire (FFQ). Participants were instructed to report their usual intake of the food items in the questionnaire during the six months before diagnosis (for cases) or the date of the interview (for controls). Two hundred and five (88%) cases and 398 controls (85%) returned the FFQ. The participants who returned the FFQ tended to be older, but there were no significant differences in education, oral contraceptive use, hormone replacement therapy use, tubal ligation or family history of ovarian cancer (data not shown). Eight of the controls were excluded because both of their ovaries had been removed, placing them at negligible risk of developing ovarian cancer, resulting in 390 controls being included in analyses.We used the same procedures in the The Block 98.2 FFQ  includes 110 food items and was developed using the NHANES  III dietary recall data. It also includes questions on portion size for each food, and pictures are provided to facilitate estimation. The questionnaire includes a variety of foods containing phytoestrogens, such as several kinds of beans, tofu, soymilk, canned tuna fish, meat substitutes , and whole wheat bread. To supplement the list of foods, we added one page with 21 additional food items, based on the LACE questionnaire  and incl2); total energy intake (as a continuous variable), smoking status; alcohol use ; and physical activity in metabolic equivalents (METs) for reported average hours per week of strenuous or moderate recreational activities. We adjusted for total energy intake using the multivariate nutrient density model, by computing nutrient density for each variable expressed in mcg (or mg) per 1000 kcal of intake and including total calories as a continuous variable in the model [We evaluated the association of ovarian cancer risk with total phytoestrogens, as well as with major phytoestrogen groups  and specific phytoestrogens. This included isoflavones , lignans , and coumestrol. Total phytoestrogen consumption was computed by adding total isoflavones, total lignans and coumestrol. Age-adjusted means were compared using ANCOVA. Participants were categorized into tertiles of intake based on the distribution of intake in controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression. Tests for trend were derived by assigning the median value to each tertile. Potential confounding variables considered were age; education ; race; age at menarche (continuous); menopausal status; parity ; oral contraceptive use ; use of hormone replacement therapy (HRT) ; tubal ligation, BMI, calculated as weight (in kg) divided by height . Intake was low in this population and, therefore, we were only able to categorize women into ever vs. never consumers for individual soy foods. There was a suggestion of a decreased risk for tofu and total soy products. However, after including smoking and physical activity in the model with all the other major risk factors, the confidence interval included one. For total soy products, the OR for those consuming more than one cup per month of soy products compared to never users was 0.71 (95% CI: 0.42-1.20).In this study we found a suggestion of an inverse association between phytoestrogen consumption and ovarian cancer risk. However, confidence intervals included the null value after adjusting for covariates, including physical activity and smoking. Estimates were stronger when combined intake from foods and supplements was evaluated. Similarly, there was some suggestion of an inverse association with tofu and combined soy product consumption, but confidence intervals included one.Few epidemiologic studies have evaluated the association between phytoestrogens and ovarian cancer and, to our knowledge, this is the first population-based study to undertake a detailed analysis of lignans, isoflavones, and total phytoestrogens in relation to ovarian cancer risk in the United States, as well as attempting to compute total phytoestrogens from foods and supplements. Total isoflavone intake was previously evaluated in two cohort studies in California  and SwedWe are aware of two other studies reporting on lignan intake and ovarian cancer risk, with conflicting results. The first is a case-control study in Western New York, which evaluated two lignans combined, secoisolariciresinol and matairesinol, and found a strong inverse association with intake . The secSeveral mechanisms have been postulated to explain the potential protective effect of soy and phytoestrogens on ovarian carcinogenesis. They have been shown to inhibit enzymes that synthesize and metabolize estrogens and increase sex hormone-binding globulin synthesis . In addiOur study is subject to the limitations of case-control studies, such as potential recall bias, as cases may report or recall dietary intake in a different way than controls. However, because the relationship of ovarian cancer with soy foods is largely unknown, and lignans are widely distributed in the diet, this is unlikely. The response rate in our study was low. However, it is well known that participation rates in population-based studies have been decreasing over the past years, and rates around 50% are not unusual, particularly among controls . To evalOur sample size was relatively small and we may have lacked power to detect a significant association. Nevertheless, our results were in general agreement with other studies. A major strength of our study is that it was specifically designed to evaluate the association between phytoestrogen intake from foods and supplements and ovarian cancer risk. For example, we expanded the questionnaire to include important sources of these compounds. We also computed all the major phytoestrogens for a detailed assessment.Future studies should conduct a comprehensive assessment by including all major sources of phytoestrogens (including a detailed assessment of phytoestrogens in supplements) and should have sufficient power to evaluate the association, preferably using a prospective design, which avoids the major biases inherent to the case-control approach .Although comparison of results across studies is challenging due to differences in methods and study populations, our findings, together with the few studies published in this area, suggest that soy and phytoestrogen may decrease ovarian cancer risk.The authors declare that they have no competing interests.EVB wrote the first draft of the manuscript. EVB and SHO conceptualized the study design and provided overall supervision for conducting the study. EVB, MK, and UC conducted all the data analyses. LEP implemented case ascertainment. LRR provided clinical expertise. All authors revised the article critically for important intellectual content and approved the final version of the manuscript.Soy yogurtFrozen soy yogurtSoy ice creamSoy cheeseSoy hot dogs/cold cutsOther soy meat substitutesCooked soybeans or edamameRoasted soy nutsTempehMiso soupAlfalfa sproutsSoybean sproutsProtein powders made from soy protein isolateSoy milk Green teaGarbanzo beans, chick peas, ceci beans or hummusDried fruit SeaweedSunflower seedsBlack licoriceThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/11/40/prepub


The association of reproductive factors with hormone receptor (HR)-negative breast tumors remains uncertain.Within the EPIC cohort, Cox proportional hazards models were used to describe the relationships of reproductive factors  with risk of ER-PR- (n = 998) and ER+PR+  breast tumors.ptrend < 0.001 for ER+PR+ tumors; ≥35 vs. ≤19 years HR: 0.93 [95% CI 0.53-1.65] ptrend = 0.96 for ER-PR- tumors; Phet = 0.03). The risk associations of menarcheal age, and time period between menarche and first full-term childbirth with ER-PR-tumors were in the similar direction with risk of ER+PR+ tumors (phet = 0.50), although weaker in magnitude and statistically only borderline significant. Other parity related factors such as ever a full-term birth, number of births, age- and time since last birth were associated only with ER+PR+ malignancies, however no statistical heterogeneity between breast cancer subtypes was observed. Breastfeeding and OC use were generally not associated with breast cancer subtype risk.A later first full-term childbirth was associated with increased risk of ER+PR+ tumors but not with risk of ER-PR- tumors (≥35 vs. ≤19 years HR: 1.47 [95% CI 1.15-1.88] Our study provides possible evidence that age at menarche, and time between menarche and first full-term childbirth may be associated with the etiology of both HR-negative and HR-positive malignancies, although the associations with HR-negative breast cancer were only borderline significant. Breast cancer is a complex and heterogeneous disease with a variety of histo-pathological and molecular subtypes with diverse clinical outcomes and relationships with established risk factors -3. The mFactors that influence the lifetime cumulative exposure to hormones during reproductive life, such as the age at menarche, age at first child-birth, time between age at menarche and first child birth, number of children, use of oral contraceptives (OC) and breastfeeding, have been suggested to be associated with risk of hormone receptor (HR)-positive malignancies (ER-positive or joint ER+PR+),8-11. HoThe incidence of HR-negative disease drops remarkably after menopause  suggestiThe incidence of HR-negative disease drops remarkably after menopause  suggestiThe European Prospective Investigation into Cancer and Nutrition (EPIC) is a multi-center prospective cohort study designed to investigate the relationships between diet, nutrition and metabolic factors and cancer, consisting of approximately 360,000 women and 150,000 men aged mostly between 25–70 years ,17. All a priori if they had a history of cancer prior to recruitment or were missing a diagnosis or censoring date, thus leaving 345,153 participants. At the time of this analysis, three EPIC study centers, , did not provide any information on breast tumor hormone receptor status and therefore were excluded from this analysis . Women were further excluded if they were missing questionnaire data (n = 526) or were missing data on age at menarche, age at menopause, age at first full-term birth, ever use of OCs, number of full-term births, age at last full-term childbirth and duration of breastfeeding . This left a total of 311,097 women with 9,456 first primary invasive breast cancer cases from 10 countries for the present analysis.Of the approximately 360,000 female participants in EPIC, women were excluded The details of standardized procedures for collecting baseline information on the age at first and last menstruation, parity, breastfeeding, exogenous hormone use, and hysterectomy from the general lifestyle questionnaire has been previously reported ,18. BrieWomen were considered postmenopausal at recruitment if they had had no menstrual cycles in the last 12 months, were older than 55 years , or had a bilateral oophorectomy. Women who were aged 46–55 years and had incomplete or were missing questionnaire data on menstrual history were classified with a peri/-or of unknown menopausal status. Women were deemed premenopausal if they reported regular menstrual cycles in the last 12 months or if they were younger than 46 years of age .The details of standardized procedures for measuring height and weight at EPIC study centers has also been previously reported . In mostIn all countries  incident breast cancer cases were identified using record linkage with cancer and pathology registries. In France, Germany and Greece, cancer occurrence was prospectively ascertained through linkage with health insurance records and regular direct contact with participants and their next of kin, and all reported breast cancer cases were then systematically verified against clinical and pathological records. Mortality data were coded according to the 10th Revision of the International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD-10), and cancer incidence data were coded according to the International Classification of Diseases for Oncology (ICD-O-2). Invasive  breast cancer cases were classified as per the International Classification of Diseases for Oncology (Topography C50), second revision (ICD-O-2). Breast tumor receptor status was standardized across EPIC centers using the following criteria for a positive expression: ≥10% cells stained, any ‘plus-system’ description, ≥20 fmol/mg, an Allred score of ≥3, an IRS ≥2, or an H-score ≥10  ptrend = 0.02).When all of the pregnancy related variables were examined together in the same model, risk associations for an increased number of full-term births, and later first and last full-term childbirth with ER-PR- tumors appeared to slightly strengthen; however they remained statistically not significant and had wider confidence intervals Table . When anheterogeneity = 0.002). Among women who had their first full-term childbirth before the age of 25, a longer duration of total breastfeeding showed an indication of a decreased risk association with ER+PR+ tumors . In contrast, among women who had their first full-term childbirth after the age of 25, a longer cumulative duration of breastfeeding was associated with a particular increased risk of ER+PR+ tumors . For ER-PR- tumors, risk estimates in the similar direction to the ER+PR+ tumors were observed, however statistically not significant .Subgroup analyses showed no heterogeneity in most of the risk estimates of the reproductive variables for ER-PR- and ER+PR+ tumors (data not shown), with the exception of the duration of breastfeeding by age at first birth among parous women .Our results showed a significantly heterogeneous risk association for age at first full-term pregnancy by receptor status of the tumor, where later first full-term childbirth was associated with increased risk of ER+PR+ tumors but not with risk of ER-PR- tumors. Menarcheal age and time period between menarche and first full-term childbirth showed suggestively similar risk associations with both ER-PR- and ER+PR+ tumors, however the risk estimates for ER-PR- tumors were generally weaker than for their ER+PR+ counterparts and only borderline significant. Although the heterogeneity between breast cancer subtypes was not statistically significant, other parity related factors  were associated only with ER+PR+ malignancies. Finally, the factors related to breastfeeding and OC use were generally not associated with HR-positive or HR-negative breast cancer risk.Previous prospective studies investigating the association of reproductive factors with HR-positive breast cancer have shown relatively consistent inverse risk associations with increasing menarcheal age, ever having a full-term childbirth and particularly a full-term childbirth at an early age ,9,14,25.We observed for both ER-PR- and ER+PR+ tumors, similar risk associations with increasing menarcheal age and a longer time between menarche and first full-term childbirth. A recent study within the EPIC cohort previously reported on the association of menarche with both ER-PR- and ER+PR+ tumors within the context of childhood growth and earlier sexual maturity . This stWe observed a significantly different risk association for a later age at first full-term childbirth with risk of HR-negative and HR-positive tumors, whereas the associations for parity related factors  appeared to aggregate around HR-positive tumors. The role of a pregnancy with the risk of breast cancer is thought to stem from two major avenues, firstly, hormonal changes before and after pregnancy and secondly , dramatiRecent prospective studies have reported reduced risk associations with breastfeeding with both ER-PR- and ER+PR+ breast cancer ,14. In tOC use has been extensively studied by many epidemiological studies and most studies have found either no association or a moderate increased risk of overall breast cancer, particularly among very young women and recent OC users . More re. Our study does have its limitations. The determination of ER and PR status in breast tumors has become a standard part of breast cancer diagnosis and is used to predict endocrine therapy response [Major strengths of this study are its prospective design and large number of incident cases with receptor information. The large case numbers allowed an in-depth analysis of reproductive-related relative risks, describing risk associations among women of predominantly premenopausal and postmenopausal age. The large case numbers also enabled us to examine subgroup effects such as age at first birth, age at diagnosis, BMI and breastfeeding. To our knowledge, this analysis uses the largest number of incident cases of ER-PR- malignancies, although future prospective studies with a greater number of ER-PR- cases are necessary to characterize the associations, which are of substantially smaller magnitude when compared to their HR-positive counterpartsresponse . While aresponse ,39, the response ,41. In tresponse ,42. In aIn conclusion, our study provides evidence that later age at first full-term childbirth is associated with an increased risk of ER+PR+ tumors but not with ER-PR- tumors. Moreover, age at menarche and time between menarche and first full-term childbirth may be associated with the etiology of both HR-negative and HR-positive malignancies, although associations were only borderline significant for HR-negative tumors. Further studies with more incident cases of ER-PR- tumors are needed to provide more precise risk estimation for reproductive factors with HR-negative tumors.EPIC: European Prospective Investigation into Cancer and Nutrition; ER: Estrogen receptor; PR: Progesterone receptor; HR-positive: Hormone receptor-positive; HR-negative: Hormone receptor-negative; OC: Oral contraception; HR: Hazard ratio; 95% CI: 95% confidence interval; HER2: Human epidermal growth factor-2; BMI: Body mass index.The authors declare they have no competing interests.RR, AL, and RK contributed to the conception of the current analysis and all authors were involved in the design and acquisition of data from the EPIC cohort. RR, AL and RK contributed to the analysis and all authors contributed to the interpretation of the data. RR, KT, AL and RK drafted the manuscript and all authors revised the final draft critically for important critical content. All authors have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/13/584/prepubReproductive factors and risk of ER-positive vs. ER-negative and PR-positive vs. PR-negative breast cancer in all women.Click here for fileReproductive factors and risk of discordant breast cancer subtypes in all women.Click here for file


Sex and growth hormones are positively associated with postmenopausal breast cancer risk. However, few studies have evaluated the influence of multiple hormones simultaneously.We considered the roles of estrone, estradiol, estrone sulfate, testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate and prolactin and, secondarily, insulin-like growth factor 1 (IGF-1) and c-peptide in postmenopausal breast cancer risk among 265 cases and 541 controls in the prospective Nurses' Health Study. We created several hormone scores, including ranking women by the number of hormones above the age- and batch-adjusted geometric mean and weighting hormone values by their individual associations with breast cancer risk.P trend < 0.001) and estrogen receptor (ER)-positive  breast cancer risk. When comparing the top versus bottom quintiles of the score weighted by individual hormone associations, the RR for total breast cancer was 3.0  and the RR for ER-positive disease was 3.9 . The risk further increased when IGF-1 and c-peptide were included in the scores. The results did not change with adjustment for body mass index.Women in the top versus bottom quintile of individual estrogen or androgen levels had approximately a doubling of postmenopausal breast cancer risk. Having seven or eight compared to zero hormones above the geometric mean level was associated with total (RR = 2.7, 95% CI = 1.3 to 5.7, Overall, the results of our study suggest that multiple hormones with high circulating levels substantially increase the risk of breast cancer, particularly ER-positive disease. Additional research should consider the potential impact of developing risk prediction scores that incorporate multiple hormones. Circulating levels of estrogens and androgens are positively associated with the risk of breast cancer in postmenopausal women -4. Furthet al. [Several studies have assessed the joint effects of sex and growth hormones on postmenopausal breast cancer risk ,5,7,8, aet al. . Estroneet al. [To assess this hypothesis and to extend the concept of developing hormone scores, we evaluated the role of multiple hormones on postmenopausal breast cancer risk using data from 265 patients and 541 controls in the prospective Nurses' Health Study (NHS) who had measures of estrone, estradiol, estrone sulfate, testosterone, androstenedione, dehydroepiandrosterone (DHEA), DHEAS and prolactin. We created a hormone score similar to that described by Trichopoulos et al. , as wellThe NHS cohort was established in 1976 among 121,700 US female registered nurses ages 30 to 55 years. All women completed an initial questionnaire and have been followed biennially by questionnaire to update exposure status and disease diagnoses. In 1989 and 1990, 32,826 NHS participants (ages 43 to 69 years) provided blood samples and completed a short questionnaire . BrieflyThe women were diagnosed with breast cancer after blood collection but before 1 June 1998. The follow-up rate was 99% in 1998, and the maximum follow-up time was 8.83 years. We confirmed 320 breast cancer patients who were postmenopausal and not using postmenopausal hormones (PMH) at the time of blood collection. Cases were matched to two controls on age (± 2 years), month of blood collection (± 1 month), time of day of blood draw (± 2 hours) and fasting status. The Institutional Review Board of Brigham and Women's Hospital approved this analysis, and all participants provided their written informed consent.n = 182 cases and n = 370 controls) also had IGF-1 and c-peptide data.Among the potentially eligible 320 cases and 663 controls, 41 cases and 79 controls were missing data for one hormone, 10 cases and 21 controls were missing data for two hormones, and 4 cases and 22 controls were missing data for three or more hormones. In total, 265 cases (147 ER-positive cases) and 541 controls had assay values for all estrogens, androgens and prolactin. A subset , 10 pg/ml estrone (n = 22), 40 pg/ml estrone sulfate (n = 7), 5 ng/dl androstenedione (n = 3), 2 ng/dl testosterone (n = 4), 10 ng/dl DHEA (n = 1), 5 μg/dl DHEAS (n = 5), 0.6 ng/ml prolactin (n = 0), 0.09 ng/ml IGF-1 (n = 0) and 0.02 ng/ml c-peptide (n = 0).Cases and matched controls identified through 1 June 1998 were assayed for estrogens, androgens and prolactin. Cases and matched controls identified through 1 June 1996 were assayed additionally for IGF-1 and c-peptide. Case-control sets were assayed together, ordered randomly and labeled to mask case-control status. The coefficient of variation from blinded replicate samples was less than 15% for all assays. When hormone values were less than the detection limit, we set the value to half this limit. The detection limits of the assays and the number of samples below the limit were 2 pg/ml estradiol , fasting status (yes or no) and time of day of blood draw . All analyses were adjusted for age at menopause (continuous), parity (continuous), family history of breast cancer (yes or no) and personal history of benign breast disease (yes or no). Secondary analyses further adjusted for body mass index (BMI) at the time of blood draw.We estimated the association of each hormone individually with postmenopausal breast cancer risk. Hormones were modeled in quintiles (based on cutpoints in control women), and RRs compared the top and bottom quintile. Because of the relatively high correlations between sex hormones , the models were unstable when we included multiple estrogens, androgens or all hormones simultaneously in the same multivariate model. As such, a stepwise approach to evaluating the addition of hormones to the statistical model was not feasible. Therefore, we created several scores to combine information about all hormones; these are described below. The primary hormone scores included the three estrogens, four androgens and prolactin. The secondary analyses also included IGF-1 and c-peptide. We calculated each score for estrogens only and androgens only and included the two scores in the same statistical model to evaluate the independent associations of these two important hormone classes. Scores were categorized as indicated in Tables et al. [The first goal of this study was to replicate the analysis by Trichopoulos et al. , thus wem stands for each of the measured h hormones, βm is the coefficient for that hormone modeled linearly on the log2 scale with breast cancer risk and Xm is the value of the hormone. We used β coefficients for hormone levels on the log2 scale modeled continuously that were reported in the literature with the largest sample size evaluating sex hormones [2 scale) and our own data for c-peptide, as a pooled analysis was unavailable. The coefficients used were 0.372 for estrone, 0.255 for estradiol, 0.239 for estrone sulfate, 0.344 for testosterone, 0.293 for androstenedione, 0.215 for DHEA, 0.174 for DHEAS, 0.182 for prolactin, 0.166 for IGF-1 and 0.108 for c-peptide.where hormones , prolacthormones  and IGF-hormones  (Tim Keym) with respect to MCF-7 breast cancer cells, which is a common cell model of breast cancer. We used this metric because biological data were available for all hormones, at physiological concentrations, using this cell line and measuring some marker of proliferation. Since assay metrics that have been published to measure proliferation differed across hormones, we calculated PIm by dividing the cell proliferation results for each hormone by the cell proliferation results for estradiol under the same conditions  and calculated the score by using the following equation:We also were interested in considering the biological influence of the hormones on breast cancer cells and thus created a score that weighted each hormone on the basis of a proliferation index  were 1.0 for estradiol (reference), 0.75 (0.51 to 1.10) for estrone [P values were based on two-sided tests and were considered statistically significant if P ≤ 0.05. The analyses were conducted using SAS version 9.1 software .where  estrone -19, 0.45 estrone , 0.60  and that of controls was 61.8 years (SD = 4.7). A history of benign breast disease was more common in cases than in controls (37.7% vs 30.1%), as was a family history of breast cancer (20.4% vs 15.3%). The mean age at menopause was 50.2 years (SD = 3.6) in cases and 50.8 years (SD = 3.8) in controls. Mean parity was 3.0 (SD = 1.9) in cases and 3.3 (SD = 2.0) in controls.In a multivariate models including standard breast cancer risk factors, women with estrogen or androgen levels in the top versus bottom quintile had approximately a doubling of postmenopausal breast cancer risk (RR range = 1.5 to 2.5) (Table P trend < 0.001) and ER-positive  breast cancer risk (Table P trend < 0.001) for total breast cancer and 3.9  for ER-positive tumors. In the score weighted by the PIm, women in the top versus bottom quintile had a 2.5-fold increased breast cancer risk and a 3.5-fold increased risk of ER-positive disease. Scores developed using the minimum or maximum PIm had similar associations and had a correlation of 0.99 with the score using the mean PIm (data not shown). Adjustment for BMI at the time of blood draw did not substantially change the results (data not shown). For example, the RR comparing the top versus the bottom quintile of the score weighted by individual hormone associations, after adjusting for BMI, was 2.9 (95% CI = 1.7 to 4.8) for total breast cancer and 3.7 (95% CI = 1.9 to 7.2) for ER-positive disease. The three hormone scores were very highly correlated (range = 0.90 between the score summing the number of hormones above the geometric mean and the score weighting by the PIm to 0.98 between the score weighting by the breast cancer association and that weighting by PIm).Increasing numbers of hormones above the age- and batch-adjusted geometric mean level were linearly associated with total  (data not shown). Each score was qualitatively more strongly associated with breast cancer risk among women who had never used PMH versus past users, although none of the interactions were statistically significant (data not shown), likely because one assessment of hormone levels better reflects long-term exposure in women who have never used PMH.The results were similar for invasive breast cancer and when using free estradiol and free testosterone instead of total levels, although the sample size was decreased because of missing SHBG levels (data not shown). The associations between the hormone scores and breast cancer risk also were similar after excluding cases diagnosed in the first two years of follow-up and when stratifying by age (younger than 65 years of age vs age 65 years or older) or BMI (less than 25 kg/mP = 0.52) (Table P trend = 0.005) and that for the androgen score was 1.7  for all breast cancers. The comparable associations for ER-positive disease were 2.4  and 2.0 , respectively. Adjustment for BMI at the time of blood draw did not appreciably change the risk estimates for total breast cancer or ER-positive disease (data not shown). The correlation between the estrogen and androgen scores was 0.41 for the score summing the number of hormones above the geometric mean and 0.47 for the score weighted by the association with breast cancer risk.When a separate score for estrogens and androgens was included in the same statistical model, the association for the estrogen score was slightly stronger than for the corresponding androgen score, although the associations were not statistically significantly different (2) Table . For exaP heterogeneity > 0.33). When we considered women with both estrogen and androgen scores below the 75th percentile (4.7 for the estrogen score and 6.4 for the androgen score) versus those with both scores above the 75th percentile, there was a suggestion of a combined effect for total breast cancer. Compared to women with low estrogen and androgen scores, those with a high estrogen score only had a RR = 1.8 (95% CI = 1.2 to 2.8), those with a high androgen score only had a RR = 1.4 (95% CI = 0.9 to 2.2) and those who had high scores for both hormones had a RR = 2.1 (95% CI = 1.3 to 3.2). The results were similar for ER-positive tumors (data not shown).No interactions were observed between the estrogen and androgen scores  and after adding the IGF-1 and c-peptide scores (RR = 1.53) Table . HoweverWe evaluated the combined influence of multiple sex and growth hormones on the risk of postmenopausal breast cancer on the basis of several scores. The scores ranked women by the number of hormones above the age- and batch-adjusted geometric mean and weighted the hormone values by their individual associations with breast cancer risk or proliferation of MCF-7 breast cancer cells. In each instance, there was a positive linear relationship between the score and risk of breast cancer overall and ER-positive disease. The risks in the highest categories were about double those in which only one hormone at a time was considered. When considering separate scores for estrogens and androgens, the estrogens had a slightly stronger association.et al. [P trend = 0.53). Women with no hormones above the mean had a substantially lower risk of breast cancer compared to all other women , suggesting that sex hormones may act as permissive factors for breast cancer growth. In contrast, our results do not support this hypothesis, as we observed a strong linear trend as the number of hormones above the geometric mean increased, which was more pronounced for ER-positive disease, although we also noted that women with no hormones above the mean versus any had a lower risk of breast cancer (RR = 0.55). Our results are similar regardless of how the hormone score was defined, in part because of the high correlation between the scores. The difference in results between the two studies likely stems from the greater statistical power in our study, since when we created a score using the same hormones as Trichopoulos et al. [P trend = 0.001).Very few studies have evaluated the relationship between multiple hormones simultaneously and breast cancer risk, and those that have considered interactions between two hormones generally have not revealed significant multiplicative interactions ,5,7,8. Het al.  measuredin vitro studies, androgens have been shown to either increase or decrease cell proliferation, depending upon the model system used [Estrogens and prolactin likely influence the risk of breast cancer by inducing cell proliferation and tumor growth through the ER and prolactin receptor, respectively ,33. On ttem used . Biologitem used ,36, but tem used  and DHEAtem used  can incrtem used . These bWe also observed that estrogens may have a slightly stronger influence on breast cancer risk than androgens. Our results are consistent with those of most prior studies -4, whichWhen considering the hormone score counting the number of hormones above the mean, the addition of IGF-1 and c-peptide increased the relative risk for the top category; however, this result was not replicated in the score weighted by individual hormone associations, possibly due to different reference groups. Researchers in two prior studies ,8 observm was based on independent biological data, the score has some limitations. Since there was not a single study comparing all hormones, we drew data from multiple studies that used different metrics of proliferation and may have used different strains of MCF-7 cells. However, we standardized measures for each individual hormone by the comparable assay results for estradiol and averaged results across multiple studies. Also, other metrics, such as apoptosis or binding affinity to ER, would have been of interest but were not available for all hormones. Finally, some potential hormones of interest, such as melatonin and SHBG, either were not measured or had many missing values.This study has several strengths and limitations. First, case-control sets were assayed together, which reduces variability in hormone measures, and the assays had excellent coefficients of variation. Second, we had only one measure of each hormone to reflect long-term exposure; however, the intraclass correlations (ICCs) over two to three years were greater than 0.60  , suggestOverall, this study suggests that having multiple sex and growth hormones with high circulating levels substantially increases the risk of breast cancer, particularly ER-positive disease. It has been hypothesized that the addition of estradiol and/or testosterone levels may improve risk prediction models for breast cancer . Our resBMI: body mass index; DHEA: dehydroepiandrosterone; DHEAS: dehydroepiandrosterone sulfate; ELISA: enzyme-linked immunosorbent assay; ER: estrogen receptor; IGF-1: insulin-like growth factor 1; NHS: Nurses' Health Study; PMH: postmenopausal hormone use; RIA: RIA.The authors declare that they have no competing interests.All authors have made substantive contributions to this study, including its conception (SST and SEH) and design  as well as the acquisition of data (SST and SHE) and the analysis and interpretation of the data , and in the drafting of the manuscript (SST) or revising it critically for important intellectual content .


Some studies have suggested that night work may be associated with an increased risk of breast cancer in nurses. We aimed to explore the role of circadian gene polymorphisms in the susceptibility to night work-related breast cancer risk.We conducted a nested case-control study of Norwegian nurses comprising 563 breast cancer cases and 619 controls within a cohort of 49,402 Norwegian nurses ages 35 to 74 years. We studied 60 single-nucleotide polymorphisms (SNPs) in 17 genes involved in the regulation of the circadian rhythm in cases and controls. The data were analyzed in relation to the two exposure variables "maximum number of consecutive night shifts ever worked" and "maximum number of consecutive night shifts worked for at least 5 years." The odds of breast cancer associated with each SNP was calculated in the main effects analysis and in relation to night shift work. The statistically significant odds ratios were tested for noteworthiness using two Bayesian tests: false positive report probability (FPRP) and Bayesian false discovery probability (BFDP).AANAT gene had increased risk of breast cancer, whereas TT carriers of BMAL1 rs2278749 and TT carriers of CLOCK rs3749474 had reduced risk. The associations were found to be noteworthy using both the FPRP and BFDP tests. With regard to the effect of polymorphisms and night work, several significant associations were observed. After applying FPRP and BFDP in women with at least four night shifts, an increased risk of breast cancer was associated with variant alleles of SNPs in the genes AANAT , BMAL1  and ROR-b (rs3750420). In women with three consecutive night shifts, a reduced risk of breast cancer was associated with carriage of variant alleles of SNPs in CLOCK (rs3749474), BMAL1 (rs2278749), BMAL2 (rs2306074), CSNK1E (rs5757037), NPAS2 (rs17024926), ROR-b , MTNR1A (rs131113549) and PER3 (rs1012477).In the main effects analysis, CC carriers of rs4238989 and GG carriers of rs3760138 in the Significant and noteworthy associations between several polymorphisms in circadian genes, night work and breast cancer risk were found among nurses who had worked at least three consecutive night shifts. BRCA1 and BRCA2), more moderate susceptibility variants  and several as yet unidentified common susceptibility variants associated with low to moderate increased risk [Breast cancer in women is the second leading cause of mortality . The etised risk ,5.At present, there is not sufficient evidence for any occupational exposure to be classified as carcinogenic in relation to breast cancer. However, night work is a potential risk factor that has been found in many studies to be associated with an elevated risk of breast cancer -12. A reN-acetyltransferase (AANAT) protein or melatonin receptors MTNR1A (MT1) and MTNR1B (MT2) and possibly the retinoic acid-related orphan receptors ROR-a and ROR-b [+) human breast cancer cells, melatonin suppresses both ER mRNA expression and estrogen-induced transcriptional activity of the ER [Night work was classified as a Group 2A carcinogen by the International Agency for Research on Cancer (IARC) in 2007 ,18. The nd ROR-b . An antif the ER ,26. Melaf the ER  and to rf the ER ,29. Othef the ER , althougf the ER ,32.The circadian clock is regulated by several proteins, such as aryl hydrocarbon receptor nuclear translocator-likes  also known as Mop3, circadian locomotor output cycle kaput (CLOCK), neuronal PAS domain protein 2 (NPAS2), periods , cryptochromes (CRY1 and CRY2), TIMELESS, ROR-a and ROR-b, that interact with each other in various transcriptional and translational feedback loops . The maiPER1 may be downregulated in tumors and tumor cell lines compared to normal cells [PER2 gene has been shown to induce apoptosis through upregulation of the tumor suppressor gene TP53 and the proapoptotic gene Bax [PER2 gene mutation (S662G) also leads to enhanced resistance to X-ray-induced apoptosis and increased RAS-mediated oncogenic transformation, and it affects tumorigenesis in mice [The circadian genes may affect cancer susceptibility through effects on biological pathways that regulate DNA damage and repair, carcinogen metabolism and/or detoxification, cell growth and cell death . It has al cells . The PERgene Bax . A PER2  in mice .To date, there are no genetic susceptibility biomarkers identifying women who are particularly susceptible to breast cancer related to exposure to night work. In particular, knowledge of how night work, together with common genetic variants in genes regulating the circadian rhythm, may affect breast cancer risk is limited . The aimet al. [n = 1,132), were alive as of February 2009 (n = 943), consented to be interviewed (n = 706) and had an occupational history as a nurse of at least 1 year (n = 699). The controls were frequency-matched to cases by year of diagnosis and in 5-year age groups. They were all cancer-free at and prior to the year of diagnosis of the case, were alive as of February 2009 , had consented to an interview (n = 900) and worked as nurses for minimum of 1 year (n = 895). Breast cancer cases were identified by linkage to the Cancer Registry of Norway by personal identification number given to all Norwegians alive since 1960. The Cancer Registry of Norway has virtually complete records of all cancer cases in the Norwegian population since January 1953 [The details of study design, data collection, recruitment of cases and controls have been described previously by Lie et al. ,9. Briefary 1953 . Both canight work in this study includes working periods from rotating as well as permanent night schedules. A "night shift" was defined as a shift including work between 12 a.m. and 6 a.m. For each job, we assessed information gathered for the year of start and end, workplace , proportion of full job and work schedule . If the job included night shifts, we also asked about the number of night shifts per month, and number of consecutive night shifts. Two surrogate measures for night work were applied: maximum number of consecutive night shifts in all jobs  and maximum number of consecutive night shifts the nurse had worked during a minimum of 5 years .Full details on the exposure assessment were described in a recent study . BrieflyWe focused our analysis on the variable consecutive night shift because, in our previous analysis , the conDNA from 563 saliva samples taken from cases and 619 samples obtained from controls were isolated using the Oragene·DNA isolation kit  as instructed by the manufacturer, with some modifications. Briefly, 1 ml of saliva was transferred to an Eppendorf tube, and reagents provided by the supplier were added. DNA was successfully extracted from all saliva samples that were received.r2 ≥ 0.80 and minor allele frequency (MAF) ≥ 5%, and location in the relevant circadian, melatonin and light signaling pathways. Because of the constraint of the project budget, and hence limitations on the number of polymorphisms that could be placed on the chip, 60 SNPs were successfully designed and genotyped  and one SNP in the MTNR1A gene (rs2119882) were in Hardy-Weinberg equilibrium. Two previously reported SNPs, rs35670208 in the ARNTL2/BMAL2 gene and rs28936679 in the AANAT gene, respectively, were found to be nonpolymorphic in this population. Genotyping was performed using the iPLEX genotyping assay  at the Centre for Integrative Genetics (CIGENE) genotyping core facility at the University for Environment and Biosciences, Ås, Norway.The single-nucleotide polymorphism (SNP) selection strategy was based primarily on a candidate gene approach using information from a search of relevant studies published by 2009. We searched the literature for polymorphisms in the core circadian genes and melatonin biosynthesis and/or bioavailability that had been investigated for an association with cancer risk. Since there were few polymorphisms that had been investigated by 2009, we also included polymorphisms using one or more of the following criteria: assumed functionality , cancer genetic marker of susceptibility (CGEMS) for breast cancer in epidemiological studies (candidate gene or genome-wide association studies (GWASs)), candidate tag SNP with 2 test was used to assess case-control differences in the frequency distribution of categorical variables, and a nonparametric Mann-Whitney test was used to assess differences in median age between cases and controls. On the basis of existing knowledge of factors associated with breast cancer, the following factors were regarded as potential confounders: age at time of diagnosis (as a continuous variable in 5-years age groups), period of diagnosis (1996 to 1999 and 2000 to 2007), parity , family history of breast cancer in mother and/or sister (no or yes), use of hormone treatment during the 2 years before the reference year  and frequency of alcohol consumption at time of diagnosis (less than twice weekly or at least twice per week). These variables were included in the final logistic regression model to obtain adjusted odds ratios (ORs) for developing breast cancer associated with the frequency of polymorphisms alone , the polymorphisms and night work (stratified by number of consecutive night shifts). On the basis of the results of our previous study showing associations between intensity of night work and breast cancer risk, we examined the simultaneous effects of polymorphisms and night work by comparing the frequency of genotypes of each polymorphism in cases and controls who had worked either at least four and three consecutive night shifts with a reference group who had worked only day shifts or a maximum of two consecutive night shifts. We compared the frequency of SNPs in subgroups defined by both intensity (number of consecutive nights) and duration (number of years) of night work. In our previous study [P values (P interaction) are reported for the joint effects of shift work and genotype. All reported P values are two-sided. P < 0.05 was considered statistically significant. All statistical analyses were carried out using SPSS release 21 software .Pearson's χet al. [To evaluate the possibility of false-positives due to multiple testing, we applied two Bayesian statistical tests, false positive report probability (FPRP) and the Bayesian false discovery probability (BFDP), that have been used frequently to test noteworthiness of findings in genetic association studies -43. The et al.  as a meaet al. . We perfet al. ,42. We cet al. .et al. [P values and genotyping rates are given in Additional File The study design is a nested case-control study  and GG carriers of AANAT rs3760138 with an OR of 1.42  had increased risk of breast cancer. The carriers of variant TT genotype of SNP rs2278749 in the BMAL1 gene with an OR of 0.45  and the homozygote genotype TT of rs3749474 in the CLOCK gene with an OR of 0.64  had reduced risk of breast cancer. All of these associations were found to be noteworthy for both FPRP (<0.2) and BFDP (<0.8).The analysis of main effects, without regard to night work , ROR-b rs3903529 , two SNPs in the AANAT gene  and rs4238989 ) and MTNR1B-rs10830963  were associated with increased risk of breast cancer. In the same group, two SNPs in the CRY2 gene, rs11038689  and rs1401417 , were associated with reduced risk. In the group with three night shifts, a reduced risk of breast cancer was associated with the presence of one variant allele (heterozygote) or two variant alleles (homozygote) for SNPs in CLOCK rs11133373 , CLOCK rs3749474 ; ROR-b rs3903529 , ROR-b rs7022435 ; ROR-b rs7022435 ; ROR-b rs3750420  and MTNR1A rs 13113549 .Compared to the reference group Table , in the BMAL1  and rs969485 ) and ROR-b , rs3903529 ) and MTNR1B rs10830963 . In the group with three consecutive night shifts, the SNP rs11695472 in the PER2 gene  was associated with increased risk of breast cancer. The SNPs BMAL1 rs2278749 , BMAL2 rs2306074 , CLOCK rs3749474 , CSNK1E , rs5757037 ), NPAS2 rs17024926 ; PER3 rs1012477 , ROR-b , rs3750420 ) and MTNR1A rs131113549  were associated with decreased breast cancer risk , ROR-b  and MTNR1A (rs131113549) were found noteworthy. With respect to both intensity and duration of night shift work for at least 5 yr  and ROR-b (rs3750420). In the subjects with three night shifts, SNPs in BMAL1 (rs2278749), BMAL2 (rs2306074), CSNK1E (rs5757037), NPAS2 (rs17024926), PER3 (rs1012477) and MTNR1A (rs131113549) were associated with decreased breast cancer risk. Haplotype analysis of the polymorphisms localized on the same chromosome did not result in any significant associations (data not shown).After applying FPRP and BFDP tests, in subjects with four or more night shifts Table , increasBMAL1 and CLOCK were associated with risk of breast cancer. There are no functional data to explain how each SNP in each of the genes may affect the risk for breast cancer. SNPs may change transcription binding affinity of the BMAL1/CLOCK complex that is necessary for expression of the target genes. For example, a reduced affinity of BMAL1/CLOCK to CLOCK promoter due to polymorphisms in these genes may lead to lower expression of CLOCK proteins. A reduction in the levels of another core circadian protein (CRY2) in breast epithelial cells in culture has been shown to lead to higher accumulation of DNA damage after exposure to chemical mutagens [In the main effects analysis, two SNPs in mutagens ,49. Downmutagens .BMAL1  and ROR-b  had a noteworthy increased risk of breast cancer. Although not noteworthy, there was also a 2.75 increased risk of breast cancer in women who had worked four or more night shifts and carrying two variant G alleles of CLOCK rs111133373 compared to women with the same genotype in the reference group. Interestingly, women with three successive night shifts and carrying the same SNPs and genotypes had a reduced risk of breast cancer, indicating a protective role for these genetic variants. In addition, women in this exposure group carrying at least one variant allele of several SNPs in the other core circadian genes such as BMAL2, CSNK1E, NPAS2 and PER3 had a noteworthy reduced risk of breast cancer. For comparison, only two SNPs in the CRY2 gene (rs11038689 and rs1401417) had protective effects in women with four or more night shifts, though this effect was not noteworthy.Several SNPs in the core circadian genes had noteworthy associations with breast cancer risk. Women with the highest number of successive night shifts and carrying at least one variant allele of SNPs in the two core circadian genes PER3 (rs1012477), CSNK1E (rs1534891) and CLOCK , are novel in relation to breast risk but may not be specific to breast cancer, because they have also been found to be associated with prostate and colorectal cancer risk [BMAL1, CLOCK, CRY1, CRY2, PER1, PER2 and PER3 gene expression levels in peripheral blood leukocytes [BMAL1 (rs2279287), CLOCK (rs1801260), PER1 (rs2735611), PER2 (rs2304672), PER3 (rs10462020), CRY1 (rs8192440) and CRY2  were not found to be different between shift workers and day-only workers [Many of the associations, such as R3 rs10127, CSNK1Ecer risk . It mighukocytes . In the SNK1E rs14891 and et al. [NPAS2 gene was found to be associated with reduced breast cancer risk in women with less than 2 yr of shift work. We were not able to confirm such an association in our study; however, for another SNP, rs17024926 in the NPAS2 gene, we found a reduced risk of breast cancer in shift workers who had worked three night shifts for at least 5 yr , whereas women with three night shifts and carrying a homozygote variant of rs7022435 and rs3750420 had reduced risk. The three SNPs are located in intron 1 downstream of the exon 1 in the ROR-b transcripts. These SNPs are part of a haplotype block that spans the region containing the promoter region and the exon 1 (55 kb upstream to 6 kb downstream) of the gene. This haplotype has also been associated with an increased risk of human bipolar syndrome [ROR-b gene. The ROR proteins are involved in regulation of circadian rhythms by activating transcription of the core circadian BMAL1 gene [Increased risk of breast cancer in women with four or more night shifts was associated with AL1 gene .CRY2 gene (rs11038689 and rs1401417) had protective effects in women with four or more night shifts. The biological functions of these SNPs are not known. These polymorphisms have been found to be associated with postmenopausal breast cancer risk, with significant effect modification by menopausal status where this association was evident only in women with ER- and/or PR-negative breast tumors but not ER- and/or PR-positive tumors [et al. [BMAL1 rs2278749 TT genotypes had more pregnancies and miscarriages, whereas NPAS2 rs11673746 T carriers had fewer miscarriages, indicating a possible role of these polymorphisms affecting age at first birth and also number of children, both of which are established risk factors for breast cancer [Two polymorphisms in the e tumors . This ma [et al.  showed tt cancer .AANAT) or melatonin receptors (MTNR1A and MTNR1B), several SNPs were associated with increased risk of breast cancer. In the main effects analysis, the variant genotypes of both of the AANAT polymorphisms were associated with increased breast cancer risk. However, the risk associated with the rs3760138 GG genotype was 40% higher in the most exposed group with four or more night shifts (1.82 vs 1.42). These two SNPs are located in the regulatory regions of the AANAT gene which could potentially affect the expression of the AANAT gene. The AANAT gene product is an acetyltransferase that regulates melatonin biosynthesis during night and day periods by pineal gland. Polymorphisms in this gene have also been associated with sleep disorders, but there are no data on the association between these polymorphisms and breast cancer risk. The levels of melatonin may also be affected by variants in the genes that encode melatonin receptors 1A and 1B. The MTNR1B rs10830963 was associated with increased risk in the high-level exposed group of women carrying two variant alleles, without being noteworthy by FPRP and BFDP. The variant alleles of MTNR1A rs113113549 polymorphisms were associated with decreased risk of breast cancer in the women with three consecutive night shifts. Night shift workers have been shown to have substantially reduced melatonin levels during night work and daytime sleep, and levels remain low even when a night shift worker sleeps at night [In the genes controlling melatonin biosynthesis  is warranted. The selection of genes and polymorphisms differs from other studies as well and may have affected the outcomes. Finally, although we set very low prior probabilities for multiple testing, it is still possible that some associations may not be true positive or negative findings.We have found a number of polymorphisms in a number of core circadian or melatonin biosynthesis and/or bioavailability pathway genes that could be associated with breast cancer risk in shift workers. The associations seem biologically plausible because many of the polymorphisms may alter gene expression, mRNA stability or protein function. Future studies investigating the genetic and epigenetic functionality of these SNPs, as well as epigenetic changes in the shift workers, are warranted to understand exact biological mechanisms.N-acetyltransferase; ARNTL: Aryl hydrocarbon receptor nuclear translocator-like; CGEMS: Cancer genetic marker of susceptibility; CIGENE: Centre for Integrative Genetics; CLOCK: Circadian locomotor output cycle kaput; CRY: Cryptochrome; CSNK1E: Casein kinase 1; ER: Estrogen receptor; GWAS: Genome-wide association study; H-W: Hardy-Weinberg; LAN: Light at night; MAF: Minor allele frequency; MTNR: Melatonin receptor; NPAS2: Neuronal PAS domain protein 2; PER: Period; ROR: RAR-related orphan receptor; SNP: Single-nucleotide polymorphismAANAT: Arylalkylamine The authors declare that they have no competing interests.SZ, AH and KHA were involved in designing and conducting the genetic studies, genotyping and data analysis and wrote the first and revised drafts of the manuscript. JASL, HK and KK were responsible for the design, coordination and execution of the case-control study and were also involved in revising the manuscript. All authors read and approved the final manuscript.Legend to Supplementary Figure 1: The flow-chart showing study design.Click here for fileSupplementary Tables S1-Table S2. Supplementary Table S1: Full name of the circadian genes and their protein functions. Supplementary Table S2: The circadian genes, SNPs, base change, MAF/GMAF, Hardy-Weinberg values and genotyping rateClick here for file


In England, guidance from National Institute for Clinical Excellence (NICE) states women with a family history of breast cancer presenting to primary care should be reassured or referred.We reviewed the evidence for interventions that might be applied in primary care and conducted an audit of whether low risk women are correctly advised and flagged.We conducted a literature review to identify modifiable risk factors. We extracted routinely collected data from the computerised medical record systems of 6 general practices ; of the variables identified in the guidance. We implemented a quality improvement (QI) intervention called audit-based education (ABE) comparing participant practices with guidelines and each other before and after; we report odds ratios (OR) of any change in data recording.The review revealed evidence for advising on: diet, weight control, physical exercise, and alcohol. The proportion of patients with recordings of family history of: disease, neoplasms, and breast cancer were: 39.3%, 5.1% and 1.3% respectively. There was no significant change in the recording of family history of disease or cancer; OR 1.02 (95% CI 0.98-1.06); and 1.08 (95% CI 0.99-1.17) respectively. Recording of alcohol consumption and smoking both increased significantly; OR 1.36 (95% CI 1.30-1.43); and 1.42 (95% CI 1.27-1.60) respectively. Recording lifestyle advice fell; OR 0.84 (95% CI 0.81-0.88).The study informs about current data recording and willingness to engage in ABE. Recording of risk factors improved after the intervention. Further QI is needed to achieve adherence to current guidance. Breast cancer is the most common cancer in women and accounts for over 30% of new cancers in females, in the UK  each year with concern over breast cancer risk. 40–50 people with a positive family history of breast, ovarian or bowel cancer are found on a GPs list of 2000 patients . Women wAudit, seeks to improve patient care and outcomes through a systematic review of care against explicit criteria and is an established method of promoting quality improvement in the care of patients. The Royal College of Physicians report “Teams without Walls” calls for greater use of audit as a means of continuous improvement . EnglishWe carried out this study to determine whether an audit-based education improved risk factor management in women who have a low risk of breast cancer; using improved recording of family history and its risk factors in primary care computerised medical record systems as our audit criteria. The focus on the audit was to record family history and record risk factors where there was evidence that intervention in primary care affects outcome.This is a before and after study of audit-based education (ABE), a non-judgemental quality improvement intervention to explore concordance with guidance in the management of people with a family history of breast cancer in primary care. The study consisted of two phases: (1) A literature review to identify the lifestyle factors that may reduce the risk of breast cancer, which might form part of a quality improvement (QI) initiative in this domain. The objective of the literature review was to inform what elements of the NICE guidance might be amenable to interventions carried out in primary care; (2) Piloting the audit-based education process developed in the first phase in six volunteer practices.The literature review was conducted to identify the risk factors associated with breast cancer. A comprehensive search of numerous databases was carried out. The searches were limited to human subjects, English language and studies from the last ten years. The searches identified 1119 articles including 312 reviews. The initial search identified articles prior to 1/1/2010, and was used to inform the components of the audit based education programme. It has subsequently been reviewed to include major literature published since the start of the study.Inclusion criteria;•Data representative of the general population.•Articles which discuss modifiable risk factors at population level risk.•Articles only related to breast cancer and not breast cancer-associated problems (e.g. lymphedema in breast cancer patients).•Studies of risk assessments with confidence intervals or at least P values.Exclusion criteria:•Small sample size (n) less than 50.•Articles in relation to other issues such as familial risk factors and diagnostic tests (e.g. mammography).http://www.clininf.eu/fhbc).The outputs of the searches were sorted based on title and abstract into those to be definitely excluded and those to retain. Findings from about 66 full texts which included systematic reviews and primary articles were used for the literature review.  intervention to support this process , a data extraction method sponsored by the Department of Health of England. We processed these data using SPSS Version 18) for statistical analysis . We repo8 for staWe collected initial data from six volunteer practices in South London and fed back these data to representatives of the pilot practices. The practices developed an action plan. This involved them deciding how they might raise general awareness of family history recording, and recording of lifestyle factors by feeding back the presentations from the baseline meeting, as well as discussing the workshop outputs at meetings held at general practices. The key points from the workshop were noted down and lead GPs who agreed to disseminate through their usual practice business processes. We then conducted a second data collection process with these practices, and then fed this data back to complete the audit cycle.The data are reported as two cross-sections at two time periods, approximately 6 months apart. We used two cross sections at two different time points so that the data included recording of lifestyle factors about new patients who registered during the audit period. We hypothesised that a practice responding to the intervention might be most likely to ask new patients about any family history of breast disease.We used Altman’s method to assess any differences between before and after readings; this method is designed to be used to compare two cross sections measured at different time points . We havehttp://www.clininf.eu/fhbc.A baseline data collection (round 1) was made to investigate the extent to which NICE guidance was being followed in terms of the provision of lifestyle advice to women with a low risk of breast cancer who can be reassured and managed in general practice. We planned a data quality workshop (DQW) which is probably the most important component of the QI process; it is an interactive process involving representatives of each practice. The objective of the DQW was twofold: (1) To share baseline levels of recording between general practices and their general practitioners; (2) To recognise the value of recording family history and implementing an action plan for improved recording and management. The second data collection (round 2) served to measure any change in the quality of data recording after six months. An Example of a DQW presentation is available online at: This intervention meets the National Patient Safety Agency (NPSA) and National Research Ethics Service (NRES) descriptions of clinical audit . Hence eAlthough there are many risk factors associated with a family history of breast cancer; there is a much more limited number where intervention is known to affect outcome, which we included in the audit. Whilst recording of the numbers of cases of a family history of breast cancer did not increase, the odds ratio of recording risk factors where interventions might affect outcome did. However, practitioners felt they lacked knowledge of how best to record. Also they felt that their computer system did not readily support recording of family history.The broad consensus from the literature review about risk factors associated with breast cancer is summarised below. These formed the “long-list” of potential variables that might be included in our audit–based education, quality improvement intervention.Oral contraceptive pills (OCP). There is evidence of an increase in the risk of breast cancer during use of OCP with higher dosage being related to higher risk [1. her risk -29. Afteher risk ,27.Hormone replacement therapy (HRT). Long term HRT apparently increases breast cancer risk especially when used from 50 years of age [5 is less than 25 kg/m2. According to the recommendation by the British Menopause Society, HRT may be given for symptom relief in the short term (up to 5 years) but long term use needs to be assessed individually at regular intervals [2. s of age . The riss of age ,31,32 ans of age ,34. Thisntervals .Breastfeeding. Breastfeeding is reported to be protective for breast cancer [3. t cancer ,37. Decrt cancer ,39. Riskt cancer .Alcohol. It is reported that there is about a 10% increased risk of breast cancer for each additional unit (10–12 g) of alcohol per day [4.  per day . Risk ap per day -44. Cons per day -47. Ther per day .Obesity. Increased weight from younger to older ages is reported to be associated with statistically significant increased risk of breast cancer for pre- and post-menopausal women [2) post-menopausal women have 31% excess risk compared to those whose BMI is less than 25 kg/m2 [5. al women -53. A st25 kg/m2 . Moreove25 kg/m2 . There a25 kg/m2 .Diet. Studies report that high consumption of fruit and vegetables may offer significant protection against breast cancer [6. t cancer -60. Meatt cancer -63, thout cancer ,65. A ret cancer . Polyunst cancer -69. HowePhysical activity. Increased total activity and recreational physical activity especially after menarche may decrease risk of breast cancer in postmenopausal women [7. al women ,71. Betwal women . A studyal women .Smoking. There is evidence that smoking especially during the period between menarche and first childbirth may increase the risk of breast cancer [8. t cancer . The inct cancer ,76.Reproductive factors. Overall risk of breast cancer in both pre- and post-menopausal women seems to increase with increasing age of first childbirth or first full term pregnancy, as well as with low parity and a nulliparous state [9. us state ,77. Womeus state ,79. Eachus state . Severe lifetime events. One study found that after adjustment for age, menopause and other potential confounders, severe life events increase the risk of breast cancer by 11 times [10. 11 times . Chemicals and radiation. High exposure to polycyclic aromatic hydrocarbons may increase breast cancer risk by 50% [11. k by 50% . Long tek by 50% . Medium k by 50% -86. Expok by 50% . Healthy lifestyle index. A recent case control study demonstrated that healthy lifestyle significantly reduces the odds of having breast cancer in both pre and post-menopausal women. Healthy lifestyle index was considered as the combined effect of moderate and/or vigorous-intensity physical activity, low consumption of fat, processed foods, refined cereals, complex sugars, and the avoidance of tobacco smoking and alcohol consumption [12. sumption .Our final list of variables for inclusion into the audit-based education programme is those where change may reduce the risk of breast cancer; they include: weight control, dietary change, physical activity and reduction of alcohol intake. These are all variables readily extracted from primary care computer systems.Weight control. Reduction in body weight is reported to reduce breast cancer risk, especially in postmenopausal women [1. al women ,89.Diet. The evidence for effectiveness of dietary change in reducing breast cancer risk is relatively limited. A randomised trial in women with early stage breast cancer reported that a reduction in the amount of dietary fat of 18–19 g per day was associated with a decreased risk of breast cancer recurrence [2. currence .Physical activity. A minimum of 150 minutes and up to 420 minutes per week of moderate to vigorous intensity physical activity may decrease the risk of breast cancer [3. t cancer .Alcohol intake reduction. There is evidence that decreasing (by one drink or less per day) or stopping alcohol consumption altogether may reduce breast cancer risk in post-menopausal women [4. al women ,89.The practices were drawn from across London, they were largely in mixed areas with a social class distribution approximating to or just below the national average; two practices could be described as inner city, and one practice was located in a more affluent area. The practice population had a population younger than the national average, with an excess of younger women Figure ; The meaThe baseline data collection of lifestyle factors took place as planned with the exception of the technical problems reported above. The focus of the practices action plan was on improving quality of data recording at new patient medicals.We extracted a dataset that would provide insight into whether the elements of a family history of breast cancer identified in the literature review were recorded. Only 1.3% of the female adult population had a history of breast or bowel cancer recorded. This increased to 1.8% in the after group, with this history being recorded for 2.8% of new patients  rather than disease specific codes. In addition, there was very little use of negative codes (e.g. no family history of breast cancer.) The computerised records factors included reporting differences in where in the system family history was recorded, inconsistency in the information requested (for example some systems asked which family member), and inconsistencies in the coding system ). There are also family history codes in different parts of the coding hierarchy; practitioners did not like the codes that displayed an asterisk  in six practices; and it has provided insight into the level of data recording, and that improved assessment of family history and other risk factors is most easily improved at the time of new patient appointments. However, more needs to be done to improve assessment across practice populations.There was no significant change in the recording of family history of disease or cancer after the audit, though the recording of risk factors improved.The study provided insight into variation and issues with current data recording, the willingness of practitioners to collaborate and rate of change achieved by audit and feedback. Whilst recording of risk factors improved with audit-based education further interventions are needed to raise data quality and care to standards where people with a small increased risk are adequately flagged in primary care records.The authors declare that they have no competing interests.IR conceived the audit design with SdeL, secured the funding, presented the intervention, wrote the first draft document and responded to further drafts. SC carried out the breast cancer risk literature review and contributed to all drafts of the paper. TC carried out the data analysis and was involved in the writing of the early draft documents and contributed to all drafts of the paper. IJ developed the final paper and assisted with the revision of the final paper. AT recruited practices to take part in the audit and contributed to all drafts of the paper. SdeL conceived the audit design with IR., worked with colleagues to develop the audit package, led the informatics aspects of the study, wrote the first version of the complete paper from draft documents supplied by IR, SC, and TC, and contributed to all drafts of the paper. SdeL also wrote the first revision post peer review. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/14/105/prepubBox S1. Epidemiology of breast cancer in the UK. Box S2. Audit-based education (ABE) – a quality improvement method. The quality improvement strategy developed by the Primary Care Data Quality Programme (PCDQ). Table S1. Age-sex profiles of participating practices. Table S2. Growth in practice populations between first and second data collections. Table S3. Availability of key data fields in first and second data collections.Click here for file