Background: There are indications that mortality in breast cancer is related with dietary factors, but no study has been large enough to characterise reliably how, this risk is influenced. To establish a logistic regression equation that would predict breast cancer from factors in the endocrinological and metabolic profile, we studied endocrinological and metabolic risk factors that are modified by the diet, in a population of women with breast cancer in southern Spain.                    Patients and Methods: We carried out a simple a case-control study comparing 204 women with breast cancer  and 250 healthy control subjects. The predictive variables were basal glycaemia, insulin, glycosylated haemoglobin (HbA1c), C-peptide, insulin-like growth factor-I (IGF-I), total cholesterol, triglycerides, high density lipoprotein-c (HDL-C), low density lipoprotein-c (LDL-C), selenium and Quetelet index (BMI).                    Results: The metabolic profile differed between pre- and postmenopausal patients, and metabolic alterations were greater in postmenopausal than in premenopausal women. The differences between healthy subjects and breast cancer patients were clearly significant.                    Conclusions: Our findings have several potential practical applications in the early detection of breast cancer, especially in premenopausal women; in primary prevention; and in the development of a mathematical model of breast carcinogenesis.                     Breast carcinoma includes a heterogeneous group of tumors with variable prognosis. International rates of breast cancer between countries suggests that environmental factors, perhaps dietary, may influence the risk of this disease. We investigated some endocrine and metabolic factors influenced by diet to establish profile of breast cancer. In Spain, incidence of breast cancer increased is 2.26 times the mortality from this tumour  and mortWe have found that although menarche occurs one year later in northern than in southern Spain , mortality from breast cancer is much higher in the former than in the latter part of the country . Women wet al. insulin-like growth factor I (IGF-I) have clearly defined mitogenic effect on mammary cancer cells and it is possible that they promote carcinogene-sis in human mammary tissue, protecting cells from apopto-sis and enhance metastasis   =  70.668; 10 d.f.; chi-squared p  =  0.000; McFadden rho-squared  =  1.000.The variables selected by elimination for inclusion in the linear model proposed to predict the diagnosis of breast cancer were basal blood concentrations of insulin, C-peptide, HbA1c, IGF-I, cholesterol and BMI. The resulting linear mathematical model predicted the diagnosis with a sensitivity of 100% and a specificity of 100%. The model is the following: Diagnost =  Constant + Insulin X1 + C-pep X2+ HbA1c X3 + IGF-I X4 + Chol X5 + BMI X6 . The log likelihood of the constants only model was LL(0) = −33.271 and 2∗[LL(N)-LL(0)]  =  66.533; 6 d.f.; chi-squared p = 0.000; McFadden rho-squared = 1.000.In both cases of pre and postmenopausal women, the model coefficients are the odds ratio calculated by the Systat statistical package; but in this study they would be not significant.To our knowledge this is the first study to develop a linear binary logistic regression model that is highly sensitive and specific in predicting the diagnosis of breast cancer from the subject’s endocrine and metabolic profile. All the variables examined here are clearly modified by the disease and with the exception of selenium, the changes resembling those found in subjects on a hypercaloric diet. The metabolic profile differed clearly in pre- and postmenopausal women: nevertheless we identified some variables that predicted the likelihood of breast cancer in both of these groups. These differences are the reason of two separate models for pre and postmenopausal women.Metabolic alterations were greater in postmenopausal patients, and highly significant differences between healthy control women and patients with breast cancer were found in basal concentrations of glucose, HbA1c, C-peptide, total cholesterol, selenium and in the Quetelet index. The difference between these groups approached significance for insulin, IGF-I and triglycerides concentrations, with a bigger sample size of future study, this shall be corrected.In premenopausal women the difference in basal glucose concentration between patients and controls was not significant; in contrast, significant differences were found for gly-cosylated haemoglobin, serum insulin, C-peptide, IGF-I, total cholesterol and selenium.Elevated glycosylated haemoglobin is a more objective measure of fluctuating glucose levels than is basal glucose concentration, which depends to some extent on the time of day when blood is withdrawn.In postmenopausal women the difference in basal glucose levels between control subjects and patient was significant; however, the difference in insulin levels was not (p = 0.076). We draw attention to the finding that in both pre- and post-menopausal breast cancer patients, C-peptide was significantly elevated; consequently, insulin hyperproduction occurred. However, serum insulin concentrations were lower in both patient subgroups than in their respective control subgroups; the difference was significant in premenopausal women, and approached significance in postmenopausal patients.Our study provides evidence that low serum HDL-C is independently associated with increased postmenopausal breast cancer risk among women with breast cancer. These findings suggest an interaction between metabolic disturbances  in postmenopausal breast carcinogenesis. Probably, after menopause, bioavailable estrogens formed in adipose tissue by the aromatization of androgens are a major stimulus for breast carcinogenesis . BecauseMost recently, in a large cohort of 38.823 women, low serum high density lipoprotein cholesterol, described by the authors as a part of the metabolic syndrome, was associated with increased postmenopausal breast cancer risk .et al. reported an increase in insulin receptors in malignant tumoral tissues [This finding has not been reported in any other situation; the only possible explanation is that the tumoral tissue binds more insulin than do normal tissues. Guastamacchia  tissues . A compr tissues ,35. Thes tissues ,37.et al. reported an interesting finding of a positive relation between the concentration of circulating IGF-I and risk of breast cancer in premenopausal women with respect to hormone-replacement therapy in postmenopausal women [Hankinson al women .The changes in metabolic and endocrine variables in patients with breast cancer simulate the pattern of changes in subjects on a carbohydrate-rich diet, which leads to more or less prolonged increase in postprandial serum glucose concentrations. This would account for the elevated basal serum concentration of glucose in postmenopausal women, and the increased Hb1Ac levels in both pre- and postmenopausal subjects. This relative hyperglycaemia increases pancreatic insulin production, as shown by the increase in C-peptide (secreted at equimolar concentrations with insulin) in both patient subgroups. Excess insulin subsequently disappears from circulation, possibly because of uptake by insulin receptors in the tumoral tissue . InsulinThe increase in serum total cholesterol in our pre- and postmenopausal patients also parallels the increase caused by a hypercaloric diet. In addition, postmenopausal women with breast cancer had a significantly greater BMI than their control subgroup, the difference approaching significance in premenopausal women with and without cancer. One possible explaination for the smaller difference between the latter subgroups is that women who are less overweight may have been physically more active.Serum selenium concentration is thought to reflect dietary selenium intake. Like other authors, we found significantly lower serum levels of this mineral in patients than in controls . We do nTriglyceride levels were higher, and HDL-c, levels lower, in both pre- and postmenopausal patients than in controls; these differences were statistically significant (p<0.05). However, the postmenopausal women with cancer had significantly (p<0.05) higher LDL-c than controls.We have proposed the hypothesis that the metabolic profile can be used to identify clinical cases of breast cancer in the general population (diagnosis). This is of particular importance for premenopausal women, for whom there is no reliable method of early diagnosis. Confirmation of a relationship of breast cancer risk hyperinsulinemia or with plasma IGF-I levels, could open up new perspectives to be used in primary prevention, as a normal reference pattern, moreover, data from the metabolic profile can be used to elaborate a mathematical model of breast carcinogenesis, or the use of certain chemopreventive drugs.In conclusion, our findings, if confirmed, have several practical implications. Many questions remain to be answered and systematic research should be aimed at clarifying the points summarized below 1). We do not yet know whether the metabolic alterations described here precede breast cancer or appear as a consequence of this disease. Moreover, we have yet to determine whether these alterations are reversible 2). It remains to be shown whether metabolic screening and mathematical treatment of the data can detect breast cancer in a high risk population before the disease appears 3). We do not know whether our method is able to rule or diagnose breast cancer in premenopausal women when the results of mammography are inconclusive 4). The effectiveness of our approach needs to be compared with mammography, and the performance of both can be assessed against the gold standard of histological findings 5). The metabolic-endocrine profile could be used to establish normal reference values in dietetic programs of primary prevention. The lack of target values has meant that programs aimed at normalizing the metabolic profile have thus far had only limited success 6). We do not know whether the metabolic alterations induce activation oncogenes and play a role in the growth of breast cancer 7). Identifying the factors which affect these biomarkers is of particular interest as subjects at increased risk could benefit from lifestyle changes, and/or chemoprevention intervention.


P for difference=0.013). The risk of being diagnosed with low histological malignancy grade was higher than high malignancy grade with RR 4.13 (95% CI: 2.43–7.01) and RR 2.17 (95% CI: 1.42–3.30), respectively (P=0.063). For breast cancers with other prognostic characteristics, the risk was increased equally for the favourable and nonfavourable types. Current users of HRT experience a two- to four-fold increased risk of breast cancer with various prognostic characteristics, both the favourable and nonfavourable types. For receptor status, the risk with HRT was statistically significantly higher for hormone receptor-positive breast cancer compared to receptor-negative breast cancer.The aim of this study is to investigate the risk of developing prognostic different types of breast cancer in women using hormone replacement therapy (HRT). A total of 10 874 postmenopausal Danish Nurses were followed since 1993. Incident breast cancer cases and histopathological information were retrieved through the National Danish registries. The follow-up ended on 31 December 1999. Breast cancer developed in 244 women, of whom 172 were invasive ductal carcinomas. Compared to never users, current users of HRT had an increased risk of a hormone receptor-positive breast cancer, but a neutral risk of receptor-negative breast cancer, relative risk (RR) 3.29 : 2.27–4.77) and RR 0.99 (95% CI: 0.42–2.36), respectively ( These findings could partly be explained by the biological influence of exogenous sex hormones on breast tissue as well as surveillance of women using HRT. The latest pooled analysis in 1997 concluded that breast cancers diagnosed in ever users of HRT were less likely to have spread to the regional lymph nodes or more distant sites compared to those developing in women never having used HRT. Furthermore, the excess risk of breast cancer in current or recent users was confined to localised disease. A total of 54% of the pooled studies contributed to this analysis . Recent Increased surveillance of women using HRT may contribute to the findings of apparently more favourable prognostic breast cancer types at the time of diagnosis and some studies find that adjusting for mammographic screening diminishes the magnitude of the effect , the Danish Breast Cancer Group Cooperation (DBCG) register  and the Lands patient Register (LPR) registry . Self-reported information was evaluated together with the data derived from the registries. Information on tumour type, histological malignancy grade, hormone receptor status, axillary lymph status and stage of disease was obtained from the DBCG register. The follow-up started with the questionnaire in 1993, and ended on 31 December 1999.in situ (CIS) of the breast and other invasive cancers, except for non-melanoma skin cancer (n=1086) at baseline. Furthermore, women with missing information on HRT (n=267), premenopausal women (n=5084) and women with a surgical menopause (n=571) were excluded. Also, hysterectomised women (n=2016) were excluded, as information on menopausal status and age at menopause would be missing in these women, which could seriously bias the analyses as described by The cohort comprised a total of 19 898 responders at baseline. We excluded all previously identified breast cancer cases, carcinoma Women were considered postmenopausal if the menstrual bleeding had ceased or they were currently using HRT. The variable on menopausal age was constructed using the age at initiating HRT use or the cessation of menstrual bleeding, whichever event occurred first. The different HRT brands reported in the questionnaire were categorised according to the type and regimens used at baseline, that is, the systemic use of oestrogen only and oestrogen combined cyclically or continuously with progestin. Vaginal applied oestrogen users were considered non-users.Data on prognostic characteristics were available from the DBCG Registry. The following variables were created: tumour size: ⩽2 cm/>2 cm, axillary lymph status: neg/pos, histological malignancy grade: grade 1/grade 2 and 3, oestrogen and progesterone receptor status: pos/neg, histology: invasive ductal/lobular/others. Information on staging was computed: stage according to TNM: stage1/stage 2–4. Nottingham Prognostic Index (NPI) was calculated as (tumour size (cm) × 0.2)+malignancy grade 1–3+lymph nodes 1–3 . The index was grouped into good prognosis (score<3.4)/moderate prognosis (score 3.5–5.4)/poor prognosis (score >5.4)  Model for left-truncated and right-censored data was used in the modelling of time-to-breast-cancer outcomes. The nurse's age was used as an underlying time with the age at study entry as the delayed entry time in the analysis. Women with histologies other than invasive ductal carcinomas were censored at the time of breast cancer diagnosis, as well as breast cancers with missing information on one of the prognostic characteristics. The various prognostic different breast cancer types were considered as single end points. Each prognostic factor was modelled in a multivariate Cox PH model, where relative risk (RR) and their 95% confidence intervals were estimated for HRT-exposure variable, adjusted for only significant risk factors , former benign breast disease (BBD), smoking, night work, body-mass index (BMI), height, physical activity, alcohol intake). Effect modification of HRT by menopausal age or by BBD was tested. Finally, for each of the prognostic factors, the RR estimates for the favourable and nonfavourable breast cancer outcomes in current HRT users were analysed in a competing risks framework using the Wald test. The likelihood ratio test for two competing risks as described in Rosthøj In this population of 10 874 natural postmenopausal women, a total of 2726 women (25.1%) were current users of HRT, 1582 women were past users (14.5%) and 6566 women (60.4%) were never users of HRT at baseline in 1993. Information on the type and regimen of HRT was available for current users.A total of 244 women developed invasive breast cancer during the observation period from baseline in 1993 until 31 December 1999. Histological information was complete for 230 women: 172 invasive ductal carcinomas (74.8%), 36 lobular (15.6%) and 22 ‘other histologies’ such as mucinuous, medullary, tubullary and others (9.6%).n=172). Receptor-positive breast cancer was seen in 79.8%, low histological malignancy grade was found in 37.3%, negative lymph node status in 56.4%, small tumour size in 58.1%, low stage in 40.1% and good prognostic group according to NPI in 39.5%  was increased for current users of HRT, multivariate RR 2.42 (1.81–3.26) compared to never users of HRT. The risk of being diagnosed with invasive ductal carcinomas (n=172) was increased as well, multivariate RR 2.49 (1.76–3.51) compared to never users of HRT  (The risk of being diagnosed with a hormone receptor-positive breast cancer following current use of HRT was significantly increased with an RR of 3.29 (2.27–4.77) compared to the never/past use. The risk of being diagnosed with the prognostic less favourable hormone receptor-negative breast cancer was not increased with the use of HRT; RR 0.99 (0.42–2.36). The difference between these two risk estimates among users of HRT was highly statistically significant (P=0.063).The risk of being diagnosed with a breast cancer of low histological malignancy grade was increased following the current use of HRT compared to the never/past use, with an RR of 4.13 (2.43–7.01). This was nearly twice the risk of developing a breast cancer with a high malignancy grade, RR 2.17 (1.42–3.30), but in the model of competing risks this difference was not statistically significant  are hormone receptor positive, the two prognostic factors somehow resemble each other. A total of 48% of the current HRT users had tumours that were both hormone receptor positive and had low malignancy grade, as opposed to 27% among never users of HRT. Current HRT users diagnosed with tumours of both high histological malignancy grade and negative receptor status comprised 8%, while the corresponding figure for never users was 25%. These rough comparisons indicate that the effect seen for the histological malignancy grade probably is to be explained by receptor status. However, our data do not allow for further statistical comparisons or stratified analyses as numbers are too small and thus additional follow-up time is required.For the other prognostic factors being time-dependent and reflecting the stage and development of the disease, such as lymph node status and tumour size, the risk estimates for the favourable and non-favourable outcomes were equally increased among current users of HRT and past/never users. NPI including both the biological and time-dependent variables showed equally increased risk estimates throughout prognostic groups  for developing a hormone receptor-positive breast cancer among users of HRT. These estimates do not reflect the overall increased incidence of breast cancer with the use of HRT, nor do they reflect the risk of developing the unfavourable type of breast cancer, and thus might be misleading. Hence, it is important to base the analysis on the entire study population, analysing both the favourable and nonfavourable types of breast cancer according to HRT.In the present study, we have furthermore tested whether there was a difference in being diagnosed with a more favourable cancer compared to a nonfavourable cancer in current users of HRT, by a model of competing risks analyses. Similar to our analytic approach, a recent study has analysed the risk of being diagnosed with various types of breast cancer in women attending mammographic screening. The risk of being diagnosed with both favourable and nonfavourable types of breast cancer was increased for users of the combined oestrogen–progestin regimens. Even if no analysis of competing risks was performed, the confidence intervals outline a higher risk of developing an oestrogen receptor-positive rather than a receptor-negative breast cancer in users of HRT for 5 years or more. Furthermore, users of HRT had smaller tumours at the time of diagnosis, which is counterbalanced by a higher rate of false-negative examination results (in vitro study that tibolone does have tumour cell-growth-promoting effects and therefore might be unsuited for women at high risk of breast cancer (It has previously been shown that in this study population there is an increased risk of breast cancer following the use of HRT and that this risk is more pronounced for the combined oestrogen–progestin HRT regimens, especially for the continuous combined HRT regimens (in situ lesions as well as low- and high-stage invasive breast cancer (et al used proxy-variables for HRT type, as it was assumed that women with an intact uterus had used combined oestrogen–progestin regimens and women without a uterus had used oestrogen-only therapy regimens. This might, however, introduce bias when analysing the effect of different HRT regimens.Few other studies have analysed breast cancer prognostic characteristics according to different HRT types and regimen (Observational studies have certain limitations and strengths. As this is a prospective study, there is no recall bias active with respect to exposure information on HRT use. This study comprises a nationwide cohort of Danish nurses and bias by education/social class is therefore not likely to affect the results. The information on HRT types and regimens was available only for current users at baseline, and as in many other prospective cohorts we have no information on updated exposure. Therefore, misclassification might occur over time. However, it has previously been shown that there was a high degree of adherence to therapy regimens among Danish women using HRT, especially with the use of the continuous combined regimens over time . Our datIn conclusion, the current use of HRT increases the risk of being diagnosed with both favourable and nonfavourable breast cancers two- to four-fold. This study shows that, in current users of HRT at baseline, the RR of developing breast cancer with positive hormone receptor status is increased, while the risk of developing a hormone receptor-negative tumour is neutral as compared to the never/past use. This difference is statistically significant. For the other prognostic factors, we find no significant difference in risk estimates for the favourable and nonfavourable prognostic characteristics with the current use of HRT. Concerning different HRT regimens, the risk of breast cancer is increased following the use of any type of HRT, but the highest estimates are seen with the use of the continuous combined oestrogen and progestin HRT regimen.


A case-control study was conducted in Los Angeles County, California, of 163 very young breast-cancer cases  to investigate the role, if any, of oral contraceptives (OC) in the development of the disease. OC use before first full-term pregnancy (FFTP) was associated with an elevated risk, which increased with duration of OC use . This increased risk could not be explained by other risk factors. OC use after FFTP was not associated with any change in risk. A first-trimester abortion before FFTP, whether spontaneous or induced, was associated with a 2.4-fold increase in breast-cancer risk (P < 0.005).


This case-control study aimed to determine critical factors influencing the use of clinical breast examination and mammography among women workers in Monterrey, Mexico.We determined case and control status from survey results. Cases were defined in accordance with the guidelines of the Official Mexican Standard as lack of at least one clinical breast examination during the past year by surveyed women. For women older than 40 years, cases were further defined as lack of at least one mammogram in the previous 2 years and, for women older than 50, lack of a mammogram in the previous year. Controls were defined as adherence by surveyed women to these guidelines. Participants (N = 306 clerks aged 18–60) provided information about their practices, knowledge, and perceptions regarding breast cancer screening. Factors identified by odds ratio analysis as significantly different between cases and controls were analyzed by multivariate logistic regression.Survey participants' knowledge about the utility of breast self-examination , perception that the health care system has enough equipment and personnel for clinical breast examination , and perception that they have enough time to wait for and receive clinical breast examinations  significantly predisposed women to use screening services independent of years of formal education, number of pregnancies, number of living children, hours worked per week, and monthly family income.Perception of organizational and structural factors played a significant role in screening use. Our findings have implications for the general population, provider practices, community interventions, and future development of strategies to increase use of screening services in similar locales. Two decades ago, breast cancer was not a major health concern in the developing world . HoweverWith the goal of formulating recommendations for early detection of breast cancer in developing countries, the 2002 Global Summit Consensus Conference on International Breast Health Care focused on several key issues, including educating and empowering women to adhere to guidelines for breast screening, developing infrastructure for diagnosing and treating breast cancer, and educating primary health care professionals. The 2002 Global Summit also identified social and cultural variables that may be barriers to use of breast cancer screening services, including beliefs that cancer is invariably fatal, spouse/partner lack of acceptance of screening, fear of lack of social support, and preference for traditional medicine .Mexico exemplifies a country caught in this demographic and epidemiologic transition. With socioeconomic development, urbanization, and increased entrance of women into the labor market have come trends linked to increased breast cancer incidence, including obesity, sedentary lifestyle, late parity, nulliparity, and oral contraceptive use ,6. BreasMonterrey, the capital of the state of Nuevo León, is one of many urban areas where chronic diseases such as diabetes, heart disease, and cancer are leading causes of morbidity and mortality . MonterrThe Health Belief Model describes and predicts preventive actions related to cancer by focusing on interactions among health behaviors, practices, and use of services . The modTherefore, we identified and quantified critical factors related to use of breast cancer screening services among women workers in Monterrey, generating novel results for understanding patterns of advanced-stage diagnosis and for modeling strategies to increase early breast cancer detection.This case-control study included formally employed female store clerks working and residing in Monterrey, Mexico. Clerks were selected on the basis of their ability to be surveyed in their place of work away from family and peer influences that could interfere with accurate questionnaire response. The majority of women surveyed (94%) were the only workers present at the place of business; when more than one female worker was present and eligible to be surveyed, we emphasized the importance of each woman responding individually.Women aged 18 years or older were eligible to participate because BSE and CBE are recommended for women starting at this age, and screening at young ages offers an opportunity for women and their doctors or nurses to discuss changes in their breasts, methods of early detection, and factors in the woman's history that might predict future breast cancer. We excluded women with a history of cancer. A minimum sample size of 149 cases and 149 controls was established for 95% confidence in the results and 80% power to detect an odds ratio (OR) of 2.Norma Oficial Mexicana, 041-SSA2-2002) as lack of at least one CBE during the previous year. For women older than 40, we further defined cases as lack of at least one mammogram in the previous 2 years and, for women older than 50, in the previous year. We defined controls as adherence to the Official Mexican Standard guidelines by surveyed women  in Monterrey approved study methodology and protocol measures.We determined case-control status from survey results. Cases were defined in accordance with the Official Mexican Standard  and revised to increase participant comprehension and compliance. The first author (KMW) visited 312 randomly selected businesses throughout Monterrey, accounting for districts of various sizes, and distributed one-third of surveys during each of the three work shifts. Six businesses did not have at least one eligible female clerk on shift. In businesses with eligible participants, the first author explained the purpose of the study and survey, including its anonymous and voluntary nature. The first author left surveys with participants in their place of work and collected them later the same day at a time requested by the participant, usually within 1 hour, to allow for adequate response time during shift breaks or lulls. At collection, respondents were asked if they needed clarification on any of the questions.Of the 379 women asked to participate, 330 (87.1%) agreed and gave informed consent, and 49 (12.9%) declined. Those who declined most frequently cited lack of time (92%), followed by the belief that cancer is invariably fatal, therefore negating the utility of the survey (8%). We excluded the six (1.8%) participants who did not complete at least 80% of the survey.The survey asked about sociodemographic, sociocultural, educational, and organizational and structural factors related to the health care system. Sociodemographic variables included respondent's age, age at first childbirth, number of pregnancies and living children, hours worked per week, and monthly family income. Other variables determined the repeat breast cancer screening practices of the respondents, including the number of BSEs in the previous year and lifetime number of CBEs and mammograms. Response types were 1) open-ended, 2) categorical yes/no, or 3) ranked on a 5-point Likert scale.Sociocultural variables were defined as beliefs and values ingrained in a culture. Respondents provided answers on a 5-point Likert scale (from "very little" to "very much") to the following questions: Are you afraid/feel embarrassed to have your breast examined/receive a mammography from health care personnel? Does your spouse/partner accept that health care personnel examine your breasts/perform a mammography? Do you believe cancer is always fatal?Educational factors included years of formal education and knowledge about breast cancer screening utility and guidelines. Respondents answered the questions: Do you feel BSE/CBE/mammography is important for good health ? Do you know how often you should examine your breasts ? Do you know the screening recommendations for CBE/mammography ?Organizational and structural factors related to the health care system are built into medical encounters that may influence use of services, such as availability of heath resources and quality of care. The survey focused on the respondent's subjective point of view, given that perceptions can be barriers to screening regardless of the objective state of the health care system. Respondents answered the following questions: Did you feel health care personnel and equipment were sufficient for providing CBE/mammography tests ? Did you feel the quality of service provided for CBE/mammography testing was sufficient ? Other structural factors related to the health care system encompass an individual's resources and opportunities to obtain medical attention, such as costs and waiting times. All formally employed persons in Mexico are provided government-funded health insurance covering CBE and mammography screening services, thus removing financial problems as a barrier to screening. Respondents answered how they felt about the waiting time for obtaining CBE and mammography the last time they solicited such services and the waiting time for receiving examinations.We created two education-related indices, each comprising three variables. The first assessed participant knowledge of BSE, CBE, and mammography utility ("screening utility index"). This index coded for accurate versus inaccurate knowledge of the utility of all three detection methods. However, because of an unacceptable level of internal consistency (Cronbach α = 0.48), items could not be combined and were retained in the analysis as separate variables. The second index evaluated participant knowledge of BSE, CBE, and mammography screening guidelines ("screening guidelines index"). This index coded for accurate versus inaccurate knowledge of screening guidelines for all three detection methods. This index reached an acceptable level of internal consistency (Cronbach α = 0.75) and was retained in the analysis along with the individual variables comprising the index.t tests. Univariate OR analysis evaluated the strength of association between participants' knowledge and misperceptions of breast cancer screening and service use. Factors identified as significantly different between cases and controls were entered into multivariate logistic regression models.Survey data were entered directly into SPSS 10.0 for Windows (1999) . Sociodemographic data and quantitative information concerning cancer screening practices were analyzed by descriptive statistics and Significantly more control women than case women had a formal education of high school or more, had at least one pregnancy and at least one living child, and worked 40 hours per week or more . SignifiVariables most strongly associated with use of CBE and mammography were related to educational factors . ControlFour survey variables (data not shown) were not significantly associated with case-control status as determined by OR analysis. These were the belief that cancer is not invariably fatal , spouse/partner acceptance of CBE , spouse/partner acceptance of mammography , and perceptions of reasonable waiting time to receive results of mammography .R2 = 0.292).Variables identified as significantly associated with screening use were entered into multivariate logistic regression analysis . ParticiOur study directly linked the use of breast cancer screening services with years of formal education and accurate knowledge of early detection guidelines. A principal factor for use of screening services was knowledge about BSE screening guidelines, a well-documented indicator in studies of Hispanic women -17. Our Survey participants who perceived that enough equipment and personnel were available for CBE were more inclined to adhere to national screening guidelines for both CBE and mammography. Previous studies indicate the importance of these organizational factors to use of preventive services . Indeed,Social change and epidemiologic transition, especially regarding changes in fertility and breast cancer incidence and awareness in Mexico, also may influence perceptions of the accessibility and quality of medical care concerning sufficient equipment and personnel for CBE. As educational and workforce opportunities improve for women, health awareness and the consequent demand for quality health services increase . HoweverIn addition, participants who perceive they have enough time to wait for and obtain an annual CBE were more inclined to adhere to both CBE and mammography in accordance with national screening guidelines. Structural barriers, such as lack of time, have been described in relation to breast cancer screening, especially the inability of employed women to take work leave or pay child care expenses during an absence . This peFinally, we investigated the influence of fear and embarrassment with regard to CBE and mammography, spouse/partner acceptance of CBE and mammography, and cancer fatality beliefs. Although the sociocultural profile of a population must be considered if a cancer-detection program is to be effective  − and seOur study is subject to information bias because of participants' potential inability to quantitatively recall screening practices and the inaccurate disclosure of personal information such as sexual and reproductive history. To minimize this bias, we surveyed participants away from family and peer influence, assured them of response anonymity, and gave them enough time to carefully consider and answer all questions. Because of these considerations and the high participant response rate, we believe our data are generalizable and have reliably determined critical factors related to use of the breast cancer screening service by this population.We based our study on the assumption that misperceptions can be barriers to screening, regardless of the objective state of the health care system. Therefore, we aimed to determine how users and potential users perceived this system. For example, perceptions of inadequacies in equipment and personnel for CBE may represent actual deficiencies of the system or may result from misconceptions by the general population. The actual state of the breast cancer screening program must be evaluated in terms of these perceptions to determine whether community interventions to increase breast cancer education, screening awareness, and breast health priority are enough or whether macro-level policy interventions aimed at organizational reform of the current system also are necessary.Accurate information and perceptions of the availability of sufficient resources  most strongly determined use of breast cancer screening services. Hypothesized sociocultural factors did not play a significant role. Our findings describing the lack of use of screening services by women workers in Monterrey have implications for the general population, provider practices, community interventions, and future development of strategies to increase use of screening services in similar locales.


Complementary and alternative medicine (CAM) use is well documented among breast cancer patients and survivors, but little evidence is available to describe rates and patterns of use among women at increased genetic risk of breast cancer.BRCA mutation carriers enrolled in a high-risk breast cancer screening study. Participants were asked to report on their use of thirteen therapies within the year prior to enrollment into the study. Logistic regression was used to evaluate the association between various factors and CAM use in this population.A pre-visit telephone interview was conducted to ascertain CAM use among the BRCA1 or BRCA2 mutation-positive (BRCA+) women in this analysis, 78% reported CAM use, with prayer and lifestyle diet being the two most commonly reported modalities. Many subjects used multiple CAM therapies, with 34% reporting use of three or more modalities. The most commonly used modalities were mind-body therapies and biologically-based practices, 61.6% and 51.8%, respectively. High-risk women were more likely to use CAM if they were older, more educated, more worried about ovarian cancer risk, or had a previous cancer diagnosis.Among the 164 BRCA mutation carriers, with frequency of use comparable to that of breast cancer patients and survivors. Given the high prevalence of CAM use in our subjects, especially biologically-based therapies including herbal supplements, whose safety and efficacy in relation to cancer risk are unknown, our study suggests that future research is necessary to clarify these risks, and that it is important for providers to inquire about and to discuss the pros and cons of CAM use with their BRCA+ patients.This study suggests that the prevalence of CAM use is high among  Complementary and alternative medicine (CAM) includes a collection of therapies, practices, and products that are not considered to be part of conventional medical practice . The NatThe 2002 National Health Interview Survey (NHIS) of 31,044 US adults, of whom more than 17,000 were women, provides the most recent CAM use data for the general population. In that survey, CAM use was greater among women than men, with sixty-nine percent of women reporting CAM use within the 12 months prior to survey completion. Prayer was the most commonly used modality. When prayer for health reasons was excluded, the prevalence of CAM use among women decreased to 40%. Higher levels of CAM use were associated with increased education, higher income, and poorer health status. In general, women between 50–59 years of age comprised the sub-group with the highest rates of use for most CAM modalities, except for prayer, which continued to increase with advancing age [Several studies have shown that cancer patients and survivors are more likely to use CAM than unaffected individuals in the general population, with up to 83% reporting CAM use -8. FurthBRCA1/2 genes, cancer survivors reported significantly more CAM use than unaffected women [BRCA+ women were more likely to be using CAM one year after disclosure of their genetic test result, compared with usage rates prior to genetic testing [While there is an extensive literature regarding CAM use among breast cancer patients, much less is known about its use among women at high genetic risk of developing breast cancer. In a previous study of CAM use within a cohort of women undergoing genetic counseling and testing for germline mutations in ed women . A follo testing .BRCA1 or BRCA2 mutations enrolled in a high-risk breast cancer screening study.Women at increased genetic risk of breast and ovarian cancer face difficult decisions when choosing the optimal strategy to manage their cancer risk. Their decisions are often based on personal beliefs, attitudes, and experiences, as expressed by their cancer risk perception and worry -20. FurtBRCA1 or BRCA2 mutation, or were first- or second-degree relatives of a known BRCA mutation-positive family member. Women younger than 25, but within 5 years of the age at diagnosis of the youngest family member with a hereditary breast-ovarian cancer syndrome-associated tumor, were also eligible.The Clinical Genetics Branch Breast Imaging Screening Study in Women at High Genetic Risk of Breast Cancer: Annual Follow-up Study (NCI protocol 01-C-0009) is aimed at evaluating breast cancer screening modalities among women who are genetically predisposed to developing breast cancer. The study consists of four consecutive annual evaluations including mammogram, breast MRI, clinical breast examination, transvaginal ultrasound, CA-125 and breast ductal lavage. As part of this protocol, participants were asked to complete a self-administered questionnaire and a telephone questionnaire prior to their first study visit. Participants were eligible for the study if they were between 25 and 56 years of age, had a known in situ (DCIS), Stage I, or Stage IIA breast cancer were eligible provided that at least 6 months had elapsed since completing primary therapy . Other exclusion criteria included a personal history of ovarian cancer (any stage); breast cancer (stage IIB or higher); DCIS, Stage I or Stage IIA breast cancer with a relapse after primary treatment; or any other invasive cancer except non-melanoma skin cancer or cervical carcinoma in situ, unless relapse-free for 5 years prior to the time of enrollment. Informed consent was obtained from all participants, and a total of 200 women were enrolled onto 01-C-0009 between June 2002 and February 2007. A secondary study objective of the study was to determine the rates of CAM use in high-risk women enrolled in this breast cancer screening study related to various participant characteristics and screening behaviors. Of the participants in the Breast Imaging Screening Study, 164 women who know their BRCA+ status and completed their CAM questionnaire were included in this analysis.Exclusion criteria included pregnancy or lactation within 6 months of enrollment, abnormal CA-125 level, bilateral breast cancer, previous bilateral mastectomy or bilateral radiation therapy, weight over 136 kg, or allergy to gadolinium. Individuals with a personal history of ductal carcinoma Demographic information, including age, race , marital status , number of children , education , and personal cancer history, was obtained through the pre-visit questionnaires.Complementary and alternative medicine data were obtained through the pre-visit telephone interview, which was completed prior to the first study visit. Participants were asked to answer "yes" or "no" to the use of each of thirteen CAM therapies  within the previous year. No standard examples of these modalities were provided by the interviewer, and no further details regarding frequency, duration, or purpose of use were elicited. Participants were also given the opportunity to report the use of additional therapies. For data analysis purposes, the individual CAM therapies were further grouped by the defined NCCAM domains: biologically-based practices ; mind-body medicine ; energy healing, manipulative and body-based practices (massage therapy); and alternative medical systems .breast/ovarian cancer in your lifetime?" Participants responded with categorical options: "Much less," "A little less," "About the same," "A little more" or "Much more," coded on a 1–5 scale. For the current analysis, responses were dichotomized to average or below average (codes 1–3) and above average  risk perceptions [Perceived breast and ovarian cancer risk was assessed for each cancer with the survey question: "In your opinion, compared to other women your age, what are your chances of getting ceptions . Individbreast/ovarian cancer; how often have thoughts about your chances of getting breast/ovarian cancer affected your mood; how often have thoughts about breast/ovarian cancer affected your ability to perform your daily activities?" Participants responded with categorical options: "Not at all or Rarely," "Sometimes," "Often," "A lot," coded on a 1–4 scale. The average score was calculated for each cancer to determine their level of cancer worry. Individuals who chose not to answer the questions were excluded from the cancer worry analysis.Cancer worry was determined using three validated questions from the Lerman Cancer Worry Scale ,24, relaDepression was measured using the 20 question Center for Epidemiologic Studies Depression (CES-D) Scale, a short self-report instrument designed to measure depressive symptoms in the general population, emphasizing depressed mood, the major affective component of depression . Each quParticipants provided detailed information on how frequently they performed cancer screening activities before study enrollment. For mammography and transvaginal ultrasound (TVU), we dichotomized participants as either "following" or "not following" appropriate screening guidelines (monthly breast self exam (BSE), annual mammography, annual TVU) based on self-reported screening frequency ,27. The For comparison between CAM users and non-users, Chi-square and Fisher's Exact tests were used as appropriate for categorical variables, and Wilcoxon rank-sum test was used for continuous variables. We used logistic regression to evaluate the association between various factors and CAM use. Factors with a p-value of ≤ 0.20 in the univariate analysis were included in the final multivariate logistic regression model. Factors with a two-tailed p-value of ≤0.05 in the multivariate model were considered to be statistically significant. All statistical analyses were conducted using SPSS 15.0.BRCA+ women who knew their mutation status prior to enrolling in the Breast Imaging Screening Study, 164 answered the pre-visit telephone CAM questionnaire and were included in this analysis. The cohort was highly-educated (92.7% attending college); predominately white (97.6%); most were married (72%); over half reported having children (54.3%); and 17.7% had a personal history of cancer prior to study entry.Of 165 BRCA+ population was 78% (128/164), with an average of 2.3 CAM therapies used per person. Thirty-four percent of the cohort reported having used three or more CAM therapies within the past year. As shown in Figure BRCA+ women reported prayer as the sole CAM therapy used. If spiritual healing/prayer are excluded, 68.9% of participants had used CAM in the previous year. Spiritual healing/prayer and lifestyle diet were the most commonly reported modalities . Figure The overall CAM use rate in our There were significant positive associations between CAM use and several demographic, health-related, and psychosocial variables Tables  and 2. HFactors with p ≤ 0.20  were included in the multivariate logistic regression model. Odds ratios and 95% confidence intervals are presented in Table BRCA+ women were included in the analysis.Since a previous cancer diagnosis was highly-associated with CAM use in our population, a finding previously-reported in the general population literature, we repeated our analyses after excluding the women with a previous cancer diagnosis. The overall patterns of the CAM therapies used remained unchanged (data not shown), with the exception of lifestyle diet being more commonly used than spiritual healing/prayer  compared with 48.2% and 48.8%, respectively in the previous analysis. When spiritual healing/prayer was excluded, overall CAM use was 65.2% compared to 68.9% when all Age, education, previous cancer diagnosis, ovarian cancer worry, breast cancer worry, and BSE all had p ≤ 0.20 in the univariate analyses again and were included in the multivariate logistic regression model. Ovarian cancer risk perception was also included in the multivariate analyses with p = 0.15. As was the case with the previous analysis, age, higher education, ovarian cancer worry, and BSE remained statistically significantly associated with CAM use (p ≤ 0.05), with similar odds ratios. Ovarian cancer risk perception was no longer statistically significant.BRCA mutation carriers who are at increased genetic risk of breast and ovarian cancer, and who had undergone risk assessment and counseling prior to enrollment. Compared with data from women in the general population [BRCA+ women in our study [Our study provides the largest, most comprehensive descriptive analysis of CAM use among pulation , the higpulation -8. When ur study . TherefoBRCA+ population, consistent with reports based on general population samples [CAM use in our cohort was associated with older age, higher education level, and higher levels of ovarian cancer worry. A previous cancer diagnosis showed the strongest association with increased CAM use in our  samples -8. In a  samples . Since oPrevious studies have reported conflicting evidence for the association between age and CAM use both in the general population and in breast cancer patients and survivors ,6,28,29,BRCA mutation-positive; have chosen breast cancer screening rather than prophylactic mastectomy to manage their risk; and, for the majority, have not developed a BRCA-related malignancy. These characteristics, in the aggregate, may yield a group of women which is less worried about developing cancer than the more heterogeneous groups of high-risk women who have been studied previously.This study showed no association between CAM use and perceived cancer risk (breast and ovarian) or breast cancer worry. CAM users tended to be more worried about ovarian cancer, but overall the reported levels of breast and ovarian cancer worry were low. Higher rates of CAM use have been associated with increased levels of depression in cancer survivors and individuals with chronic illness in some studies ,13,31, aPrior reports have suggested that high-risk women report better health maintenance practices than do women from the general population ,16. TherBRCA mutation carriers, since it was comprised of research volunteers who were almost exclusively white and highly-educated, both characteristics that are associated with higher rates of CAM use in the general population.Limitations to our study include the reliance on self-reported data regarding CAM use. Participants were not provided examples for each of the thirteen modalities, and thus may have interpreted modalities such as lifestyle diet differently. Furthermore, we did not collect data on duration and frequency of use for each CAM, nor did we elicit information regarding specific motives for CAM use such as cancer prevention. Such data might have provided further insight into the lifestyle choices that our subjects have made in their efforts to prevent breast and ovarian cancer, and cope with the increased stress related to knowing that they are at high risk of malignancy. Another limitation of the study is a relatively small sample size both overall and of cancer survivors, providing for minimal statistical power for some analyses. Finally, our study population should not be considered representative of all BRCA+ women, most of whom have never developed cancer, are roughly equivalent to the rates reported for women being treated for, or having survived, breast cancer, and seem to be higher than the rates reported for women from the general population. Further investigation will be required to better understand the intensity of, and motivations for, CAM use, as well as the relationships between CAM use, conventional screening practices, and cancer risk and worry in BRCA+ women. Data from a more representative sample of all mutation carriers would likely be very informative as well. However, given the high prevalence of CAM use in our subjects, especially the predominance of biologically-based therapies, which might pose a greater risk of unanticipated adverse effects, our study suggests that it is important for providers to inquire about, and to discuss the pros and cons of CAM use, with their BRCA+ patients [We have documented that the rates of CAM use in our cohort of patients .in situ: DCIS; Center for Epidemiologic Studies Depression: CES-D; transvaginal ultrasound: TVU.Complementary and alternative medicine: CAM; National Center for Complementary and Alternative Medicine: NCCAM; National Health Interview Survey: NHIS; ductal carcinoma The authors declare that they have no competing interests.CMM, PLM, and JB performed the statistical analysis. CM was the primary author and wrote the final manuscript. All authors helped to conceive the study, participated in its design and coordination, and contributed to drafting the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Radiologically dense breast tissue (mammographic density) is strongly associated with risk of breast cancer, but the biological basis for this association is unknown. In this study we have examined the association of circulating levels of hormones and growth factors with mammographic density. A total of 382 subjects, 193 premenopausal and 189 postmenopausal, without previous breast cancer or current hormone use, were selected in each of five categories of breast density from mammography units. Risk factor information, anthropometric measures, and blood samples were obtained, and oestradiol, progesterone, sex hormone binding globulin, growth hormone, insulin-like growth factor-I and its principal binding protein, and prolactin measured. Mammograms were digitised and measured using a computer-assisted method. After adjustment for other risk factors, we found in premenopausal women that serum insulin-like growth factor-I levels, and in postmenopausal women, serum levels of prolactin, were both significantly and positively associated with per cent density. Total oestradiol and progesterone levels were unrelated to per cent density in both groups. In postmenopausal women, free oestradiol (negatively), and sex hormone binding globulin (positively), were significantly related to per cent density. These data show an association between blood levels of breast mitogens and mammographic density, and suggest a biological basis for the associated risk of breast cancer.British Journal of Cancer (2002) 87, 876–882. doi:10.1038/sj.bjc.6600537www.bjcancer.comCancer Research UK© 2002  Differences between individuals of the same age in the radiological appearance of the breast reflect differences in tissue composition. Epithelial and stromal tissues attenuate X-rays more than does fat, and appear light on a mammogram, while fat appears dark . ExtensiThe biological basis for inter-individual variations in breast tissue composition, and for the association of these variations with risk of breast cancer is, however, unknown, although several factors are known to influence the radiographic appearance of the breast. Mammographic density decreases with greater parity, greater body weight, greater age , growth hormone, insulin like growth factor-I (IGF-I), its principal binding protein - insulin-like growth factor binding protein-3 (IGFBP-3), and prolactin.The general method employed was to select pre- and postmenopausal women without breast cancer but with different degrees of mammographic density, to collect information from them about risk factors, and to measure hormones and growth factors in blood samples obtained under standardised conditions. We determined the total area of the breast, and the area of dense tissue on mammography, using a previously described computer assisted method , that was recorded by radiologists during film reporting. We wished to ensure that we recruited women with as wide a range of mammographic density as possible. The number of subjects in each of the five radiological categories of density that were actually recruited were as follows: <10% Breast density was subsequently definitively classified as a continuous variable by quantitative methods that are described below. On hundred and fifty-five subjects (41%) fell in the same category according to the two methods of classification, and 317 (83%) were within one category on both methods. , agreed to take part in the study, and the rate of participation did not vary according to the extent of mammographic density.Subjects who agreed to enter the study were then visited in their homes by the study research assistant. These visits took place in the morning after subjects had fasted for at least 12 h. All measurements in premenopausal women were made when subjects were in the luteal phase of the menstrual cycle (between days 20–24). Blood was refrigerated immediately after collection, spun and serum separated within 1–2 h of collection, and stored at −70°C until analysis. The mammogram closest to the time of the blood draw was used, and the average time interval between the mammogram and the blood draw was 32 weeks. The phase of the menstrual cycle at which mammograms were obtained is, however, not known because subjects were recruited into the present study after the mammograms had been taken.Information about epidemiologic risk factors for breast cancer, and other factors, was collected using a questionnaire, developed for this purpose, that included questions about menstrual and reproductive history, and family history of breast and other cancer.Each subject was weighed on a balance scale and measured for height. Skinfold thickness in the triceps, sub-scapular, and iliac crest areas was measured using Lange calipers, and waist and hip circumferences were measured with a tape measure. The research assistant who made these measurements was trained and certified by the Department of Athletics and Recreation, University of Toronto.Serum oestradiol  and progesterone levels were measured using radioimmunassays kits purchased from Orion Diagnostica , and the inter-assay performance was monitored using controls provided by the kit manufacturer. Oestradiol in serum from postmenopausal women was measured by Esoterix Laboratories, California, USA by radioimmunoassay after extraction.Serum SHBG levels were determined using an established steroid-binding capacity assay using reference serum samples to control for inter-assay performance . The perIGF-I, IGFBP-3 and growth hormone were all measured by Esoterix, California, USA, IGF-I and IGFBP-3 using a competitive binding radioimmunoassay, and growth hormone with a two site immunometric assay. Prolactin was measured by radioimmunoassay in the Wellesley Hospital in Toronto. The per cent coefficient of variation within assays was less than 7% for all (except progesterone which was 8.7%), and between assays was less than 10% for all (except progesterone which was 11.9%).The measurements that are the subject of the analyses that follow were made using a randomly selected, craniocaudal mammographic view of one breast from each subject.2 per pixel). Images were analysed using a computer assisted method  which were representative of radiographically dense tissue. We then calculated the histogram of pixel values within these boundaries, and calculated the size of the projected area of the breast in the image, and of the area of density. The percentage of radiographic density is the area of dense tissue divided by the entire projected area of the breast and multiplied by 100.A subset of duplicate images were included as a check on reliability. Reliability of the measurements made in the present study was high with a test-retest correlation of at least 0.9.Data analysis was carried out using the SAS statistical software package . Data we−1, the lower limit of sensitivity for the assay. An additional 22 observations had missing growth hormone information . There was, however, no relationship between mammographic density and whether growth hormone could be detected.Values for growth hormone were undetectable in 128 of the 382 subjects (34%) and for purposes of analysis were assigned the value of 0.2 ng lTo examine the relationships between hormones, growth factors and mammographic measures we carried out a series of multiple regression analyses that adjusted sequentially for other factors that could be confounding or modifying variables. For two variables, IGF-I and total oestrogen, their respective binding proteins, IGFBP-3 and SHBG, are known to determine the amount of free and biologically active growth factor or hormone, and were introduced into the regression analyses before the other variables. Among the other factors examined, that included other risk factors for breast cancer , measures of body size, and blood levels of other hormones or growth factors, only age and measures of body size had a substantial influence on the results. Among the measures of body size examined, that included height, weight, body mass index, waist and hip circumference and their ratio, and skinfold thickness measurements, the waist measurement was the most strongly correlated with mammographic density, and was the measure of body size used in these analyses. In all of these analyses both mammographic measures, and blood levels of hormones and growth factors, were treated as continuous variables.Table 1n=13, and 28.5, n=180) and postmenopausal subjects .Sixty subjects had previously taken hormone replacement therapy (HRT), stopping an average of 5 years before the date of the mammogram. After adjustment for age, the mean per cent density was similar in those who had previously used HRT and in those who had not, in both premenopausal . Free oestradiol, calculated from SHBG levels, showed negative associations with per cent density that remained statistically significant after adjustment only in the postmenopausal.Progesterone was significantly and positively associated with per cent density in both pre and postmenopausal women, but became non-significant in both groups after adjustment for age and the waist measure. , suggesting that, after allowance has been made for the difference in mean level, the menstrual cycle was not a major source of variation in per cent density in premenopausal subjects.These results in part confirm the findings of a cross-sectional study in the Nurses Health Study (NHS) by The associations of IGF-I and prolactin with risk of breast cancer in the NHS, respectively in pre and postmenopausal women, are thus similar to the associations with mammographic densities according to menopausal status seen in the present study. The average age of the premenopausal women studied here was 45 years, and some may have been perimenopausal. The association of growth factors and hormones at earlier ages is at present unknown but it is known that blood levels of IGF-I peak in adolescence . Some of the observed features may be explained by the actions of growth hormone. IGF-I is produced in the liver and other tissues, including the breast, in response to growth hormone , and bloAn alternative potential explanation for these findings may lie in the known actions of oestrogen. Oestrogen is involved in the control of the secretion of both growth hormone (These findings suggest novel potential approaches to breast cancer prevention, directed at modulation of the growth hormone-IGF-I axis and prolactin. Furthermore, unexpected relationships between the determinants of serum free oestradiol levels and mammographic densities suggest that manipulation of SHBG levels or function could also be beneficial. There is clearly a need for an improved understanding of the genetic and environmental factors that influence levels of these hormones and growth factors, and in particular the relationship between these factors and other known influences on risk of breast cancer, including familial, menstrual and reproductive risk factors, and ovarian hormones.


Although it has been demonstrated in previous studies that tubal ligation can have widespread effects on ovarian function, including a decrease in the risk of subsequent ovarian cancer, few studies have evaluated effects on breast cancer risk. In a population-based case–control study of breast cancer among women 20–54 years of age conducted in three geographic areas, previous tubal ligations were reported by 25.3% of the 2173 cases and 25.8% of the 1990 controls. Initially it appeared that tubal ligations might impart a slight reduction in risk, particularly among women undergoing the procedure at young ages (< 25 years). However, women were more likely to have had the procedure if they were black, less educated, young when they bore their first child, or multiparous. After accounting for these factors, tubal ligations were unrelated to breast cancer risk (relative risk (RR) = 1.09, 95% confidence interval (CI) 0.9–1.3), with no variation in risk by age at, interval since, or calendar year of the procedure. The relationship of tubal ligations to risk did not vary according to the presence of a number of other risk factors, including menopausal status or screening history. Furthermore, effects of tubal ligation were similar for all stages at breast cancer diagnosis. Further studies would be worthwhile given the biologic plausibility of an association. However, future investigations should include information on type of procedure performed (since this may relate to biologic effects) as well as other breast cancer risk factors. © 2000 Cancer Research Campaign


It is well established that parity and use of oral contraceptives reduce the risk of ovarian cancer, but the associations with other reproductive variables are less clear.We examined the associations of oral contraceptive use and reproductive factors with ovarian cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 327 396 eligible women, 878 developed ovarian cancer over an average of 9 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models stratified by centre and age, and adjusted for smoking status, body mass index, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, and mutually adjusted for age at menarche, age at menopause, number of full-term pregnancies and duration of oral contraceptive use.P-trend, <0.01). Compared with nulliparous women, parous women had a 29%  lower risk, with an 8% reduction in risk for each additional pregnancy. A high age at menopause was associated with a higher risk of ovarian cancer . Age at menarche, age at first full-term pregnancy, incomplete pregnancies and breastfeeding were not associated with risk.Women who used oral contraceptives for 10 or more years had a significant 45%  lower risk compared with users of 1 year or less (This study shows a strong protective association of oral contraceptives and parity with ovarian cancer risk, a higher risk with a late age at menopause, and no association with other reproductive factors. In developed countries, ovarian cancer is the sixth most common malignancy and cause of cancer death in women . Some reThe aim of this study was to evaluate the association between oral contraceptive use and reproductive factors with ovarian cancer risk in a large prospective European study. A secondary aim was to examine whether these associations differed by participant characteristics such as age at enrolment, body mass index (BMI) and other factors.The European Prospective Investigation into Cancer and Nutrition (EPIC) includes approximately 370 000 women and 150 000 men and was designed to investigate dietary and lifestyle determinants of cancer. The participants were recruited between 1992 and 2000 in 23 centres in 10 European countries . The cohort population and data collection procedures have been described in detail elsewhere , if they had incomplete follow-up data (n=2205), if they had a bilateral ovariectomy (n=10 500), if they did not return the baseline questionnaire (n=509), if they never menstruated (n=61), if they had missing information on oral contraceptive use and all reproductive history variables (n=7589), or if they were diagnosed with a non-epithelial ovarian cancer (n=26). Of the final analytic cohort of 327 396 women, 878 developed epithelial ovarian cancer from the date of recruitment until the end of follow-up . The cancer diagnosis was confirmed by histology for 77.6% of the cases, by clinical examination for 13.8% and the remaining 8.6% by self-report, autopsy or death certificate. In all, 47% of tumours were of a serous histology, 10% were mucinous, 10% endometrioid, 4% clear cell and 1% undifferentiated; the remaining 28% had missing, undefined or not otherwise specified histologies. Of the 878 cases, 70 were of low malignant potential (borderline tumours); exclusion of these cases did not change the risk estimates, and they were therefore included in the final analysis.Of the approximately 370 000 women enrolled in the cohort, women were excluded if they had prevalent cancer , incomplete pregnancies (defined as induced or spontaneous abortions) and age at the first full-term pregnancy was also collected. Information on breastfeeding was collected for the first three full-term pregnancies and the last one. The duration of breastfeeding was calculated as the sum for all pregnancies for which we had information. For women with more than four pregnancies and who had breastfed for all the pregnancies for which we had information, the duration of breastfeeding was taken to be the number of pregnancies multiplied by the mean of breastfeeding duration of each child. Menopausal status was defined according to information on menstruation status, hysterectomy, ovariectomy, use of exogenous hormones and age, details of which are provided elsewhere  and unilateral ovariectomy status was also collected from the baseline questionnaire. Weight and height were measured at recruitment, except for part of the Oxford cohort, the Norwegian cohort, and approximately two-thirds of the French cohort, among whom weight and height were self-reported. Body mass index was calculated as weight in kilograms divided by height in metres squared. A combined physical activity index was calculated, which incorporated occupational and recreational activities.Hazard ratios (HRs) and their 95% confidence intervals (CIs) for ovarian cancer were estimated using Cox proportional hazards models with age as the underlying time scale. Entry and exit time was defined as the woman's age at recruitment and age at ovarian cancer diagnosis or censoring , respectively. All models were stratified by EPIC recruitment centre and age at enrolment . The proportionality of hazards was verified based on the slope of the Schoenfeld residuals over time, which is equivalent to testing that the log HR function is constant over time . Linear All models were adjusted for potential risk factors for ovarian cancer, including tobacco smoking status , BMI (continuous), unilateral ovariectomy , simple hysterectomy , menopausal hormone therapy , and further mutually adjusted for age at menarche , age at menopause , number of full-term pregnancies  and duration of oral contraceptive use , as applicable. Only the fully adjusted statistical models are presented in the text, because the centre and age-stratified models yielded almost identical estimates. For each covariate, missing values were assigned to separate categories, where appropriate; an analysis that excluded individuals with missing values for these covariates produced similar results and is not presented here. Further adjustments for physical activity, diabetes mellitus and education yielded almost identical results and are not presented.To examine whether the oestrogen dose in oral contraceptive formulations influenced the risk, the analyses were stratified by calendar year of first oral contraceptive use. The oral contraceptives prescribed before 1970 were typically high-dose preparations, whereas those prescribed between 1970 and 1980 were typically medium dose and by 1980 most prescriptions were for low-dose preparations (vs ⩾50), BMI , smoking status (ever vs never), parity (parous vs nulliparous), menopausal status  and menopausal hormone therapy at recruitment (ever vs never use and current vs never use). Tests for interaction were carried out by using the relevant exposure variables, indicator variables for the potentially modifying factors, and product terms of the two variables. Sensitivity analyses were run after excluding ovarian cancer cases that developed in the first 2 years of follow-up or after excluding participants with a history of simple hysterectomy and/or unilateral ovariectomy at baseline. The statistical significance of the interaction terms was evaluated by the Wald test. All P-values (P) were two-sided and all analyses were performed using STATA version 11 .Analyses were also performed by ovarian cancer histology, EPIC-participating country and according to other factors including: age at recruitment . There was no association between age at first use of oral contraceptives and risk of ovarian cancer , and that remained very similar after additional adjustment for smoking status, BMI, unilateral ovariectomy, simple hysterectomy, menopausal hormone therapy, age at menarche, age at menopause and number of full-term pregnancies , with a stronger inverse association in women with a BMI <24 kg m−2  compared with women with a BMI of 24 kg m−2 or more . This association was also stronger in pre/perimenopausal women  than in postmenopausal women .The reduced risk of ovarian cancer associated with ever use of oral contraceptives was similar within each category of calendar year of first use . The risk associated with increasing duration of oral contraceptive use did not vary significantly by ovarian cancer histology, country, age at recruitment, smoking status or parity (data not shown). However, there was some evidence that this association varied by BMI . Compared with nulliparous women, women with four or more full-term pregnancies had a 38% lower risk . Age at first full-term pregnancy, ever having had an incomplete pregnancy and breastfeeding were not associated with risk  lower risk of ovarian cancer , with a ith risk .vs ⩽45 years: HR, 1.46; 95% CI, 1.06–1.99). The estimated cumulative duration of menstrual cycles was also associated with a higher risk . A one-year increase in menstrual lifespan corresponded to a 2% higher risk . However, when women who were diagnosed with ovarian cancer within the first 2 years of follow-up were excluded from the analysis (194 cases), the associations of age at menopause  and menstrual lifespan  with risk of ovarian cancer were attenuated.The risk of ovarian cancer was not associated with age at menarche or menopausal status , althougNone of the associations between reproductive factors and risk of ovarian cancer differed by ovarian cancer histology, country, age, BMI, smoking status, menopausal status or menopausal hormone therapy (data not shown). In addition, sensitivity analyses that excluded participants with a history of simple hysterectomy and/or unilateral ovariectomy at recruitment yielded almost identical estimates.This large prospective study confirms the strong protective association of oral contraceptive use and parity on risk of ovarian cancer. No significant associations with risk were found for age at menarche, age at first full-term pregnancy, incomplete pregnancies or breastfeeding.vs never users of oral contraceptives  of a magnitude similar to our findings. The pooled analysis also showed that, although the risk is attenuated with increasing time since last use, the protective effect of oral contraceptives on ovarian cancer remains for many years after cessation of use  reported a relative risk of 0.73  for ever A protective as sociation between parity and ovarian cancer risk has been observed in most previous studies (Breastfeeding was not significantly associated with ovarian cancer risk in this study population, and although this is consistent with several studies (The exact mechanisms through which oral contraceptives and parity may reduce risk are not known, although several hypotheses have been proposed. These include inhibition of ovulation , exposurStrengths of the present study include its prospective design and the wide distribution of oral contraceptive use and reproductive variables in different European studies. However, although EPIC is one of the largest studies to date to examine reproductive factors with ovarian cancer risk, there was limited statistical power to detect differences by histological subtypes of ovarian cancer. All analyses were adjusted for potential risk factors of ovarian cancer and further mutually adjusted for menstrual and reproductive variables, and which made little difference to the risk estimates suggesting that residual confounding is unlikely to influence our results. In particular, we lacked information on tubal ligation in EPIC but given the low prevalence of this procedure in Europe (In conclusion, this study shows a strong protective association of oral contraceptive use and parity with risk of ovarian cancer, a higher risk with a late age at menopause, and no association with other reproductive factors in this large cohort of European women.


Despite available demographic data on the factors that contribute to breast cancer mortality in large population datasets, local patterns are often overlooked. Such local information could provide a valuable metric by which regional community health resources can be allocated to reduce breast cancer mortality. We used national and statewide datasets to assess geographical distribution of breast cancer mortality rates and known risk factors influencing breast cancer mortality in middle Tennessee. Each county in middle Tennessee, and each ZIP code within metropolitan Davidson County, was scored for risk factor prevalence and assigned quartile scores that were used as a metric to identify geographic areas of need. While breast cancer mortality often correlated with age and incidence, geographic areas were identified in which breast cancer mortality rates did not correlate with age and incidence, but correlated with additional risk factors, such as mammography screening and socioeconomic status. Geographical variability in specific risk factors was evident, demonstrating the utility of this approach to identify local areas of risk. This method revealed local patterns in breast cancer mortality that might otherwise be overlooked in a more broadly based analysis. Our data suggest that understanding the geographic distribution of breast cancer mortality, and the distribution of risk factors that contribute to breast cancer mortality, will not only identify communities with the greatest need of support, but will identify the types of resources that would provide the most benefit to reduce breast cancer mortality in the community. Despite advances in breast cancer prevention, early detection, and treatment, not all segments of the population benefit equally from these gains. For example, patients lacking health insurance have higher breast cancer mortality rates than other populations Large nationwide studies have established a strong correlation between risk factors and breast cancer mortality. These risk factors include ethnicity, income, health insurance coverage, education, obesity, and screening . Many of these risk factors are demographically inter-related. For example, lower income often correlates directly with lack of health insurance coverage. Importantly, many of these risk factors also track geographically, such that there are geographic areas with high poverty rates, decreased education levels, an aging population, or a large African American population. While recent efforts have focused on identifying patterns in U.S. breast cancer mortality, mapping mortality rates alongside risk factors in a local, geographic context, or how previously identified risk factors may relate to breast cancer mortality within a local area The overall goal of this study was to determine if existing demographic data could be mined to uncover spatial patterns of breast cancer at the local level, which could then be applied to community health resource allocation. In order to address this hypothesis, we compared known breast cancer risk factors (listed below) with the endpoint of mortality across an 11-county area that encompasses urban, suburban, and rural communities, including the metropolitan Nashville area. Counties included Cheatham, Davidson, Dickson, Maury, Montgomery, Robertson, Rutherford, Sumner, Trousdale, Williamson, and Wilson. Each specific variable was examined for statistically significant correlations with mortality at both the county level and, within Metropolitan Nashville, at the ZIP code level.Demographic data from free, publically available national  and statewide  datasets were queried for breast cancer mortality, incidence, age of female populations, number of Stage IV diagnoses, mammographic non-screening rates, females covered by insurance health insurance, median household income, education level, and ethnicity of the female population. These values were clustered for each county in Middle Tennessee and used to generate a community breast cancer profile for Middle Tennessee area. The variables assessed were selected based on known associations with breast cancer risk. The geographic boundary information was gained from the United States Census Bureau Maps and Cartographic Resources (2000), which are also publically available and free. The data were analyzed anonymously and not linked to any patient identifying information, thus alleviating privacy concerns.http://www.R-project.org.].To assess potential correlations between breast cancer mortality with other risk factors within each middle Tennessee county or within the entire Middle Tennessee affiliate, population data and risk factors were clustered according to the ZIP codes geographically occupying each county. Correlations were examined by Pearson correlation test. Spearman’s tests were applied for examining the correlation between ranking of risk factors in individual counties. The risk factors were ranked in ascending order, from the county exhibiting the lowest risk factor measurement to the county exhibiting the highest risk factor measurement. All graphics and analyses were performed by R version 2.11.1. .For example, higher mortality rates in rural counties  overlap with lower SES, including education, suggesting that educational resources coupled with greater access to care could benefit these populations. Access to information and educational materials may benefit specific population identified at the local level. Indeed, a recent study reported that Latinas exposed to cancer education were more likely to be up to date on Pap and mammography screening than community members who did not receive these materials A common factor that overlapped with elevated mortality rates in urban Davidson County and rural Trousdale, Dickson, and Maury counties was a lack of medical insurance coverage, suggesting that this may be a critical barrier to breast cancer survival for several distinct populations in the Middle Tennessee area and an opportunity for intervention. Local resources, including public health departments, health care professionals, and local affiliates of national foundations , can provide resources in order to promote screening, increase breast cancer awareness in targeted communities , and by making mammographic screening more readily available to an uninsured population.Early detection relies on awareness of breast health, self-exams, and routine mammography. We therefore examined the non-screening rates in each of the eleven counties . In spitA critical barrier to successfully implementing such programs at the community level is identifying populations with the greatest need and/or the greatest risks, understanding where resources might have the greatest impact, and identifying which resources would be most effective. This is particularly important in the current economic environment in which donations and government services tend to diminish, leaving foundations and community health programs with more limited resources. Our community profile data suggest that the geographic distribution of breast cancer mortality in relation to known risk factors is a valuable tool for effective resource allocation. We demonstrate through our study that analyses of known risk factors can be undertaken with existing data to map potential targets for intervention, which could serve as a model for community health resource allocation. This model could serve to not only identifies communities with the greatest need of support, but also mortality-associated risk factor disparities within any given location community, thereby identifying modifiable targets that will provide the most benefit to the local area.