The objective risk information did not directly affect the intention for prophylactic mastectomy. The intention was influenced by perceived risk after counselling , and by the precounselling levels of perceived risk  and breast cancer worry , that is, higher levels of perceived risk and breast cancer worry imply a stronger intention for prophylactic mastectomy. A personal history of breast cancer did not directly influence the intention for prophylactic mastectomy, but affected women who had undergone a mastectomy as surgical treatment were more positively inclined to have a prophylactic mastectomy than women who had had breast-conserving therapy. The impact of objective risk information on the intention for prophylactic mastectomy is limited and is mediated by perceived risk. Important determinants of the intention for prophylactic mastectomy were precounselling levels of breast cancer worry and perceived risk, suggesting that genetic counselling is only one event in the entire process of decision making. Therefore, interventions aimed at improving decision making on prophylactic mastectomy should explicitly address precounselling factors, such as personal beliefs and the psychological impact of the family medical history.Scientific reports suggest that women at risk for familial breast cancer may benefit from prophylactic mastectomy. However, few data are available about how women decide upon this clinical option, and in particular, what role an objective risk assessment plays in this. The purpose of the present study is to assess whether this objective risk information provided in genetic counselling affects the intention for prophylactic mastectomy. Additionally, the (mediating) effects of breast cancer worry and perceived risk are investigated. A total of 241 women completed a questionnaire before and after receiving information about their familial lifetime breast cancer risk in a genetic counselling session. Path analysis showed that the objective risk information had a corrective effect on perceived risk ( It is estimated that 5–10% of breast cancer cases are linked to a breast cancer gene mutation  the objective level of risk as provided in genetic counselling; (2) pre- and postcounselling levels of breast cancer worry and perceived risk; and (3) a personal history of breast cancer. Three features distinguish the present study from other studies of prophylactic surgery decision making, that is, (a) the comparison of a pre- and postcounselling survey; (b) the inclusion of women with a history of breast cancer; and (c) the broad study population inclusive of both low- and high-risk women.Data were collected within the framework of a larger study on risk perception and decision making by women at risk for hereditary breast cancer. For the integrative study, ethical approval was obtained from the hospital's research ethics committee. Participants were at least 18 years of age with a family and/or a personal history of breast cancer who applied for genetic counselling at the Department of Clinical Genetics of the Leiden University Medical Center. Referrals for genetic counselling on breast cancer were based on current national guidelines , surgical procedure to treat breast cancer (i.e. mastectomy or breast-conserving therapy), age, educational level, marital status, and number of children was collected.α=0.66; postcounselling: Cronbach's α=0.73).In both questionnaires, we assessed breast cancer-related worry with two items of the breast cancer worries scale . Larger values on the scale indicated a higher perceived risk.Perceived risk was assessed in both questionnaires with a comprehensive scale that included various aspects of perceived risk: (1) relative perceived lifetime risk of getting breast cancer was measured with the item ‘Compared to the average Dutch woman, my risk of developing breast cancer (again) is 1 ‘very much lower’, through 4 ‘equal to’, to 7 ‘very much higher’, (2) numerical perceived lifetime risk of getting breast cancer was measured with the item ‘My risk of developing breast cancer (again) is … out of 100’, and (3) verbal risk with the item ‘Independent of my actual risk, I feel my risk of developing breast cancer (again) is 1 ‘very low’ to 7 ‘very high’. Perceived risk was measured in both the questionnaires. As the range of items varied, standardised scores of the separate items were used. The precounselling measures of perceived risk were each z-transformed. The postcounselling measures were similarly standardised also using the mean and standard deviation of the corresponding precounselling items. The mean of the three standardised items constituted the perceived risk scale. The scale had an adequate reliability  perceived risk and (b) worry were calculated by subtracting the precounselling value from the postcounselling value. Thus, a positive value indicated increased worry or perceived risk, and a negative value implied decreased worry or perceived risk after the counselling session. These two change scores served as outcome variables. Four predictor variables were used in each analysis: (a) having had a personal history of breast cancer, (b) the objective risk information, and the precounselling measures of (c) perceived risk, and (d) worry. The precounselling measures of perceived risk and worry were included, because the possible range of change is determined by the precounselling values. However, the interpretation of predictive effects of the precounselling measures on the change measures is hampered by the fact that the precounselling measure is a constituent part of the change score. Therefore, we will not describe the relations between the precounselling measures and the corresponding change scores in the path analysis.  and women in the lower risk category (i.e. ⩽30%). The choice for this dichotomy was based on the fact that only women in the highest risk category will be eligible for genetic testing as the chance to harbour a BRCA mutation must be sufficiently high. Two-way interaction variables with risk status (multiplication of centred scores) were included in the analysis .To check whether the observed relations in phases 1–3 would differ between affected and unaffected women, two-way interaction variables with breast cancer history were included in the analyses in a similar way as described above for risk status interactions . In addition, for affected women we examined whether the surgical procedure to treat their breast cancer served as an additional predictor in the phases 1–3 regression analyses.R2), the significance of the explained variance (F-test), and which predictors significantly contributed to this explained variance (β-weights). A P-value <0.05 was considered to indicate statistical significance.For each multiple linear regression analysis, we report the extent of variance in the criterion explained by the regression . Of these 350, 44 women returned their informed consent just at the first counselling session, instead of mailing it beforehand. Therefore, they could not complete the precounselling questionnaire. Another three were excluded from the analysis because they did not return the precounselling questionnaire in time, whereas 13 women did not complete all items of the precounselling questionnaire. Finally, 30 women did not return the postcounselling questionnaire, and 19 women did not complete all items of the postcounselling questionnaire. This left 241 women for our analyses.T-tests and chi square tests showed that the women who did not complete the pre- or the postcounselling questionnaire did not differ from women who did complete all items of both questionnaires on the measures relevant for this study . On only one variable these groups differed. Women who did not complete the pre- or postcounselling questionnaire reported having children more frequently (P=0.025) than women who did complete all items of both questionnaires.n=136) was classified into the highest risk category .Of the 241 women, 168 were healthy and 73 had been treated for breast cancer . In the counselling session, more than half of the women . Most women stated that they almost never or only sometimes worried about developing breast cancer . Similarly, almost all women reported that worries about breast cancer almost never or only sometimes interfered with their daily activities .The perceived risk prior to and after the counselling session was high. The vast majority of the women  thought their risk to be higher than the average Dutch woman's risk. In addition, approximately half of the women  stated that, independent of their actual risk, they felt they had a high risk of developing breast cancer (again). Finally, most of the women perceived their numerical risk to develop breast cancer (again) to be 30% or more .Figure 1Path analysis was applied to examine our research questions. Below, each multiple regression analysis is described separately. Figure 2P=0.53), nor having had a primary breast tumour (P=0.51) was associated with the objective risk information. However, the perceived risk women reported before the consult was positively related to their actual risk . The model was significant in explaining objective risk =2.71, P=0.046, 2R=0.033).Neither the precounselling measure of breast cancer-related worry . As expected, the objective risk information influenced this change in perceived risk . Women with a relatively low objective risk reported a lower perceived risk after counselling, whereas women with a relatively high objective risk remained at a high level of perceived risk after counselling. This means that after counselling women shifted towards a more accurate perceived risk. To illustrate this point, we looked at the numerical risk estimates that women provided. Before the counselling, 83% of the low-risk women overestimated their risk and after counselling 56% overestimated their risk. In contrast, of the high-risk women 89% correctly identified their high-risk status before and after counselling. The change in perceived risk was also predicted by having had breast cancer . Unaffected women showed a stronger decrease in perceived risk after counselling than women with a history of breast cancer. The regression model was significant in explaining the change in perceived risk =29.80, P=0.0001, 2R=0.34).Overall, perceived risk decreased after the counselling session . The objective risk information, as provided in the counselling, did not influence the change in breast cancer worry after counselling (P=0.61). Having had a primary breast tumour  predicted the change in worry. Women who had had a primary breast tumour reported a higher level of breast cancer worry after counselling, whereas unaffected women showed no change in the amount of worry after counselling. The regression model was significant in explaining the change in breast cancer worry =14.35, P=0.0001, 2R=0.20).Overall, breast cancer-related worry slightly increased after the counselling session  and perceived risk  both independently predicted the intention for prophylactic mastectomy. Women who had higher prior levels of breast cancer worry and/or a higher prior perceived risk reported a stronger intention to choose for prophylactic mastectomy. Intention for prophylactic mastectomy was also predicted by the change in perceived risk after the counselling session ; women who shifted towards a lower perceived risk, reported a weaker intention for prophylactic mastectomy. As phase 2a showed, this change in perceived risk was influenced by the objective risk information. Although the objective risk did not have a direct effect on the intention (P=0.78), the objective risk information had an indirect effect by adjusting perceived risk, which in turn affected the intention.Precounselling levels of breast cancer worry (P=0.082). Finally, having had a primary breast tumour had no direct influence on the intention for prophylactic mastectomy (P=0.67). However, as shown in phase 2a, having had breast cancer influenced the change in perceived risk and, consequently, had an indirect effect on the intention for prophylactic mastectomy. The full regression model was significant in explaining the intention for prophylactic mastectomy =10.99, P=0.0001, 2R=0.22).The change in worry after the counselling session did not add to the prediction of the intention for prophylactic mastectomy (Ps>0.102), indicating that the same model applied to low- as well as to high-risk status women.The inclusion of the interaction variables with risk status did not affect the overall model as depicted in No effects are observed for the interaction variables with breast cancer history in the phases 1–3 regression analyses, indicating that the relations depicted in β=0.22; P=0.040): women who had had a mastectomy showed a stronger intention to have a prophylactic mastectomy of the contralateral breast than women who had had breast-conserving surgery. Thus, for affected women the kind of surgical procedure served as an additional predictor, next to the precounselling levels of perceived risk and worry, and the change in perceived risk after counselling.For affected women, the kind of surgical procedure to treat their breast cancer did not predict the objective risk estimate, nor the change in perceived risk or breast cancer worry. However, the intention for prophylactic mastectomy was predicted by the kind of surgical procedure  the relevant, but limited impact of objective risk information on postcounselling deliberations, and (b) the major impact of precounselling factors on these deliberations. Health-care professionals should be aware of the specific limitations of counselling, and of the potential impact of women's personal experiences and beliefs concerning breast cancer. These precounselling factors should be explicitly addressed in the genetic counselling protocol, and should be a guiding element in the process of providing information.


Although it is believed that fish ω-3 fatty acids may decrease breast cancer risk, epidemiological evidence has been inconclusive. This study examined the association between fish and fish ω-3 fatty acids intake with the risk of breast cancer in a case-control study of Korean women.We recruited 358 incident breast cancer patients and 360 controls with no history of malignant neoplasm from the National Cancer Center Hospital between July 2007 and April 2008. The study participants were given a 103-item food intake frequency questionnaire to determine their dietary consumption of fish (fatty and lean fish) and ω-3 fatty acids derived from fish (eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)).p for trend: 0.19 [0.08 to 0.45], p < 0.001 for premenopausal women, 0.27 [0.11 to 0.66], p = 0.005 for postmenopausal women). Similarly, reductions in breast cancer risk were observed among postmenopausal subjects who consumed more than 0.101 g of EPA (OR [95% CI]: 0.38 [0.15 to 0.96]) and 0.213 g of DHA (OR [95% CI]: 0.32 [0.13 to 0.82]) from fish per day compared to the reference group who consumed less than 0.014 g of EPA and 0.037 g of DHA per day. Among premenopausal women, there was a significant reduction in breast cancer risk for the highest intake quartiles of ω-3 fatty acids (ORs [95% CI]: 0.46 [0.22 to 0.96]), compared to the reference group who consumed the lowest quartile of intake.Using a multivariate logistic regression model, high intake of fatty fish was associated with a reduced risk for breast cancer in both pre- and postmenopausal women (OR [95% CI] for highest vs. lowest intake quartiles, These results suggest that high consumption of fatty fish is associated with a reduced risk for breast cancer, and that the intake of ω-3 fatty acids from fish is inversely associated with postmenopausal breast cancer risk. The protective effect of fatty fish intake was observed in both pre- and postmenopausal women.Table Table et al. reported a 9% increase in risk with a 0.1% increase in energy from ω-3 fatty acids in the Nurses' Health Study [The results of studies investigating the association between ω-3 fatty acids and breast cancer risk vary according to the study design. A meta-analysis of biomarker studies based on three cohort and seven case-control studies found a significant protective effect for total ω-3 PUFAs, but only an inverse association with borderline significance for α-linolenic acid in case-control studies. The authors suggested that the findings of cohort studies fit well with the hypotheses of experimental animal studies . Howeverth Study .In addition to study design, ethnic groups have also responded differently in these studies. For instance, a Japanese population demonstrated a significant decrease in postmenopausal breast cancer risk with increased fish intake , and breMany factors may contribute to these discrepant findings in various regions, including sample size, adjustment for potentially confounding variables, the detail and quality of the dietary assessment, unmeasured changes in diet over time, and the stage of cancer at diagnosis . AlternaA study of metastatic mouse mammary carcinoma demonstrated that a diet containing α-linolenic acid-rich linseed oil was very effective in arresting tumor progression in mice . In addiThe present study demonstrated that there were significantly different effects of ω-3 fatty acids from fish on breast cancer risk in pre-and postmenopausal women. Reasons for the stronger associations in postmenopausal women are not yet clear. With respect to the etiologies of pre- and postmenopausal breast cancer, several hypotheses are possible ,46. The The present study is the first to explore the relationship between fish and fish ω-3 fatty acid intake with breast cancer risk in a Korean population. The data were gathered in a detailed face-to-face interview, which enabled the collection of comprehensive information on related lifestyle factors, thus lessening the potential for misclassification and measurement errors. In spite of such strengths, this study also possesses some of the limitations usually inherent to case-control study designs . In particular, the control group was more likely to be highly educated or a professional/office worker, which suggests that participants enrolled from the cancer screening program may over-represent those with healthier habits as opposed to their community-based counterparts. Well-known menstrual risk factors for breast cancer, such as early age at menarche, late age at menopause, or hormone replacement therapy use, did not show definitive associations in the current study population. However, high body mass index and other hormone-related risk factors showed a positive association with breast cancer risk. Cancer patients may differ from controls in their recall of dietary habits. For this reason, the interviewer tried to collect information as soon as possible after diagnosis, which was typically right after surgery. In addition, a wide range of potentially confounding factors, including demographic and lifestyle characteristics, still need to be considered. We were also constrained by our inability to identify other sources of dietary ω-3 fatty acids. The addition of supplements may have enabled us to identify the impact of total ω-3 fatty acids intake. Notably, this study did not include information on fish species , preparation methods , how long the fish was cooked, or how the fish was consumed . These factors may help to elucidate the mechanism whereby fish intake is associated with decreased breast cancer risk. Moreover, further investigations into the dietary intake of halogenated hydrocarbons or heavy metals and genetic factors will be important in clarifying the preventive effect of fish intake on breast cancer.This investigation has identified fish and fish ω-3 fatty acid intake as an important potential protective factor in the nutritional etiology of breast cancer. Our results revealed an inverse relation between breast cancer risk and dietary intake of fatty fish and ω-3 fatty acids from fish. These findings will provide the basis for further studies.The authors declare that they have no competing interests.JK conceived of the study, participated in its design and coordination, and drafted the manuscript. S-YL participated in the coordination of the study and performed the statistical analysis. AS participated in the coordination of the study and helped to draft the manuscript. JR and E-SL participated in the design of the study and revising the manuscript critically for important intellectual content. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/9/216/prepub


P<0.0001), prostate cancer  and bone sarcoma  overall and soft tissue sarcoma in mothers only  were found. There was no excess of any other cancer, including ovarian. High breast cancer risk in relatives was associated with young age at diagnosis in the index . Prospective risk of breast cancer was higher in relatives of index patients who had an affected first degree relative at the time of their diagnosis . These prospective risk estimates are valuable in advising relatives of newly diagnosed breast cancer patients.The cancer experience among relatives of an unselected cohort of 402 breast cancer patients was previously reported. Cases and their first degree relatives were flagged at the National Health Service Central Register for continuous notification of cancer registrations and deaths. More than 10 years of follow-up data have been analysed to update cancer risks overall and to estimate breast cancer risk in relatives prospectively according to family history at the time of breast cancer diagnosis in the index case. Significant excesses of breast cancer  86, 718–722. DOI: 10.1038/sj/bjc/6600106www.bjcancer.comCancer Research UK© 2002  It has been demonstrated that women with a family history of breast cancer are at about twice the risk of developing breast cancer compared with the general population. The magnitude of this risk may vary according to extent of family history. A recent meta-analysis incorporating data from 74 publications on familial breast cancer risk  agreed to be interviewed, where detailed information on the health status (including cancer experience) of their first and second degree relatives was obtained. Further details of methodology are given by Cancers reported at interview were verified by obtaining: pathology reports or other medical records (40.3%) cancer registration details (43.4%), or death certificates (11.8%). It was not possible to confirm reported cancers in nine relatives because they lived abroad. These relatives were excluded from all analyses. All index breast cancer patients and their first degree relatives were flagged at the National Health Service Central Register (NHSCR) for continuous notification of cancer registrations and causes of death. All neoplasms were classified by International Classification of Diseases for Oncology (ICD-O)  morpholoAs index breast cancer cases and their first degree relatives are flagged at NHSCR, it is possible to detect cancers that occurred subsequent to the interview. Expected numbers of cancers were calculated from calendar period-, sex- and age-specific cancer rates for the North West Region supplied by the Office for National Statistics.A person was considered to be at risk from 1 January 1965 (prior to this cancer registration data were less reliable), or date of birth (whichever was later) to date of death, 31 August 1999 for flagged relatives, date of last contact for a small number of unflagged relatives, or 75th birthday (whichever was earliest).In all analyses cancer refers to any malignancy, except for non-melanoma skin cancer, up to age 75 years but all confirmed prostate cancers were included irrespective of age at diagnosis because of the late median age at onset and possible relationship to breast cancer. Multiple primary cancers in the relatives are also included, along with any tumours of the central nervous system whether or not malignant.Relative risks (RR) were calculated by comparing observed numbers of cancers with expected numbers and two-sided Poisson probabilities calculated .For the purpose of the prospective analysis of familial risk of breast cancer we defined two cohorts of women:All female first degree relatives of index cases having at least one first degree relative (in addition to the index case) with confirmed breast cancer diagnosed before the index case (at any time and at any age). These affected first degree relatives were excluded from subsequent analyses of familial risk.All female first degree relatives of index cases with no history of breast cancer in any first degree relative before diagnosis in the index case.Observed breast cancers were compared with the expected (as above) for the two cohorts overall, separately for mothers, daughters and sisters and categorising them by age at diagnosis in the index case . Observed and expected numbers of second malignancies in the index cases were also compared as above. The period of risk was calculated from the date of diagnosis of breast cancer in the index case. Cancers at all ages post-diagnosis were considered.Descriptive data on the 402 cases and their relatives included in the analyses are presented elsewhere , compared with no family history , but both cohorts show a significant excess. This excess of breast cancer in those with no prior family history is greater if the index case was diagnosed before 50 years of age , compared with age 50 or more . Prostate cancer and ovarian cancer risk in first degree relatives was also analysed in the two cohorts. Previous family history of breast cancer did not increase prostate cancer risk compared with no family history . Although there was no overall excess of ovarian cancer, it was thought that prior history of breast cancer in a first degree relative in addition to the index case, might confer a higher risk of ovarian cancer but this was not borne out with only one case of ovarian cancer in the family history cohort.Table 3P=0.640) These figures include eight contralateral breast cancers compared with an expected number of 6.87 . Other second cancers included three colon carcinomas, two carcinoma of vulva, one ovarian carcinoma, four carcinomas of lung, one carcinoma of larynx, one carcinoma of oesophagus, one carcinoma of bladder, one lymphoma, one acute myeloid leukaemia and one multiple myeloma. Younger age at breast cancer diagnosis in the index case did not appear to be predictive of increased risk of a second neoplasm with relative risk of 1.12 for those aged <50 compared with 1.18 for those aged ⩽50 years at diagnosis. Only two of the eight contralateral breast cancers occurred in women whose first breast cancer was diagnosed under age 50 years.There were 24 malignant neoplasms in index cases post-diagnosis of their original breast cancer compared with 26.55 expected  these risk estimates are completely free of any bias. The analyses demonstrated that the breast cancer risk in first degree relatives of index cases, with a previous history of breast cancer, was double that in the relatives of index cases with no prior family history of breast cancer. This is an important finding as this may be masked in analyses which include only retrospective data on first degree relatives . There were 27 families with two cases including the index case. In our previous description of this cohort (It is clear from studies by the Breast Cancer Linkage Consortium (


We investigated breast cancer incidence in migrants in the Netherlands in 1988–1998. The standardised incidence ratio for breast cancer in Northwest-Netherlands was statistically significantly reduced for women born in Surinam (0.56), Turkey (0.29) and Morocco (0.22). The proportion of women with advanced stages (III and IV) did not differ significantly between migrants and women born in the Netherlands. Breast cancer, the commonest cancer in women world-wide, has a particularly low incidence in Central- and East-Africa, as well as in East-Asia  and the Comprehensive Cancer Centre West (CCCW), both part of the nation-wide Netherlands Cancer Registry  of the population according to age group, sex and country of birth  for North-Holland and the city of The Hague have been used. For 1988–1994, estimations of Statistics Netherlands for 1992 and 1989–1994 (Surinam and the Netherlands Antilles only) have been used, with extrapolations for the remaining years. North-Holland and The Hague combined represent 18% of the total population of the country, but approximately one-third of the migrant population of the Netherlands.Using the population data by 5-year age group and country of birth and age-specific breast cancer incidence rates from the Netherlands Cancer Registry for 1989–1998, expected numbers of breast cancer (E) for North-Holland and The Hague were calculated for women born in Turkey, Morocco, Surinam, the Netherlands Antilles and Indonesia, as well as for the total female population. The observed numbers (O) of breast cancer were adjusted for cases with unknown country of birth, assuming that the distribution according to country of birth for unknown cases was equal to the distribution of cases with known country of birth. Standardised incidence ratios (SIRs) were calculated as the ratio between the adjusted observed and expected numbers. Exact 95% confidence intervals (CI) based on the Poisson distribution of the adjusted O were calculated using STATA 7.0 .In 1988–1998, a total of 16 499 invasive breast cancers were diagnosed in North-Holland (28% resident in Amsterdam) and 3517 in The Hague .Figure 1The risk of breast cancer among women resident in the Netherlands but born in Surinam, Turkey and Morocco appears to be still close to that in their country of origin. Although no national incidence data are available for these countries, estimates for the year 1990 show incidence rates that were 48, 29 and 35%, respectively, of the Netherlands rate  migrant workers, the percentage of unmarried women without children is negligible . ReproduThe higher incidence in younger (below age 50) than in older women born in Morocco or Turkey, is probably due to a change in risk factors in younger women, such as lower parity. The slightly lower risk for women below the age of 50 born in Indonesia (SIR 0.83) may reflect the fact that older women are mainly of Caucasian (Dutch) origin, while younger women, especially those born after the independence of Indonesia in 1949, are more often of ethnic Indonesian origin.In conclusion, in Northwest-Netherlands, women born in Surinam, Turkey and Morocco have a significantly lower breast cancer risk than women born in the Netherlands. It will be of interest to examine the risk of second-generation migrants in the future.


Exposure to light suppresses melatonin secretion, but to a lesser degree in totally blind persons. Breast cancer was investigated in a cohort of 15 412 Norwegian visually impaired women. The risk among totally blind women was 0.64 , and for those who became blind before age of 65, the SIR was 0.51 (95% CI = 0.11–1.49). Our findings give support to the ‘melatonin hypothesis’. © 2001 Cancer Research Campaign


EHP 116:886–892; Verner et al.][.Persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) are ubiquitous chemical compounds that persist in the environment and bioaccumulate through the food web. Although experiments have shown that POPs stimulate the proliferation of human cancer cell lines, epidemiologic studies of POP-associated cancer risk have yielded inconsistent results, possibly because of the lack of tools for estimating lifetime exposures to these chemicals. Now, however, researchers have developed a new physiologically based pharmacokinetic (PBPK) modeling approach that can potentially be used in epidemiologic studies to simulate lifetime toxicokinetics of POPs in women Previous biological assessments have been limited to measuring POP levels in blood or tissue samples collected around the time of breast cancer diagnosis. However, such assessments may not reflect the body burden during earlier, potentially critical exposure points in a woman’s life such as the fetal, postnatal, and adolescent periods.In contrast, the new model integrates the relevant processes of absorption, distribution, metabolism, and elimination to estimate lifetime blood and tissue exposure and levels during any hypothesized time window of susceptibility in breast cancer development. The model also predicts how various types of relevant lifetime physiologic changes—such as body weight variation, pregnancy, excretion of POPs through lactation, and aging—will influence the kinetics of a compound in a woman throughout her life. The model enables the estimation of interindividual differences in POP exposures through the use of physiologic information obtained from questionnaires in epidemiologic studies.The researchers found that lactation and weight change histories had the greatest impact on the toxicokinetic profile throughout life. According to the model, the longer and later in life lactation occurred, the lower the woman’s blood POP concentration at age 55 . Similarly, variations in body weight throughout life had a greater impact than average body weight on blood POP concentrations, possibly because weight loss is accompanied by unloading of POPs into the blood via lost adipose tissue. This means that quantitative information on both lactation and body weight histories is critical when evaluating past POP exposures.If, as some researchers hypothesize, breast cancer is related to POP exposures at specific time windows of susceptibility during a woman’s lifetime, lactation and body weight histories must be considered in studies of POP exposures and breast cancer risk. Depending on when such physiologic events occur, women having similar POP concentrations at the age of diagnosis may have had completely different internal levels at a time that may be critical to the formation of breast cancer. The proposed PBPK modeling approach therefore could be used in environmental epidemiology research to circumvent limitations inherent in relying on late-life sampling for past exposure assessments.


The association persisted after controlling for fruit and vegetable consumption, or for other flavonoid intake. This inverse association is compatible with and may explain the reported inverse association of breast cancer with consumption of vegetables, particularly leafy vegetables. After controlling for dietary confounding, there was no association of breast cancer risk with flavanones, flavan-3-ols, flavonols, anthocyanidins or isoflavones.Flavonoids have been investigated for possible inverse associations with various chronic degenerative diseases, but there are no epidemiologic data concerning a possible association between several of the main flavonoid categories and breast cancer risk. We have applied recently published data on the flavonoid content of several foods and beverages on dietary information collected in the context of a large case–control study of 820 women with breast cancer and 1548 control women, conducted in Greece. We found a strong, statistically significant inverse association of flavone intake with breast cancer. The odds ratio for an increment equal to one standard deviation of daily flavone intake (i.e. 0.5 mg day Flavonoids are naturally occurring substances in plants . For fivin vitro , parity (parous vs nulliparous), age at first pregnancy , age at menarche , menopausal status  and ethanol intake (<1 glass per month vs ⩾1 glass per month). Exogenous oestrogens were infrequently used in Greece in the late 1980s, as reflected also in our study sample; therefore, exogenous oestrogen use was not controlled for in this analysis  of increase in the intake of the respective compounds. Inverse associations with breast cancer risk were also found for flavonols, flavan-3-ols and anthocyanidins. These associations were sharply attenuated and became nonsignificant, however, when intake of fruits and vegetables or other flavonoids were controlled for. We found no evidence that flavanones had a major effect on breast cancer risk and, for isoflavones, the evidence, if any, was for a positive rather than inverse association.We have found evidence that flavones are inversely related to breast cancer risk. The inverse association of flavone intake with breast cancer was only marginally affected when intake of fruits and vegetables, or other flavonoids was accounted for. The inverse association of flavones with breast cancer is not trivial, since it implies a 13% reduction in breast cancer risk per 1 s.d. (0.5 mg dayVery few studies have examined flavonoids in relation to breast cancer risk. No association between cancer, including breast cancer, and total flavonoids was found in the combined analysis of the 16 cohorts of the Seven Countries Study (As flavones are largely derived from grains and vegetables , and theStrengths of this study are its relatively large study size, the use of a validated food frequency questionnaire and the reliance on generally sound food composition databases . LimitatVarious categories of flavonoids have been reported to inhibit breast cancer cell replication, oestrone sulphatase activity and mammary gland tumorigenesis in experimental analyses (In conclusion, we have found evidence that intake of flavones – but not intake of flavonols, flavan-3-ols, flavanones or anthocyanidins or isoflavones – may be inversely related to breast cancer risk. This inverse association is compatible with and may explain the reported inverse association of breast cancer with consumption of vegetables.


Selective serotonin reuptake inhibitors (SSRI) decrease platelet-function, which suggests that SSRI use may increase the risk of post-surgical bleeding. Few studies have investigated this potential association.We conducted a population-based study of the risk of re-operation due to post-surgical bleeding within two weeks of primary surgery among Danish women with primary breast cancer. Patients were categorised according to their use of SSRI: never users, current users , and former users . We calculated the risk of re-operation due to post-surgical bleeding within 14 days of initial surgery, and the relative risk (RR) of re-operation comparing SSRI users with never users of SSRI adjusting for potential confounders.389 of 14,464 women (2.7%) were re-operated. 1592 (11%) had a history of SSRI use. Risk of re-operation was 2.6% among never users, 7.0% among current SSRI users, and 2.7% among former users. Current users thus had an increased risk of re-operation due to post-operative bleeding  = 1.4, 3.9) compared with never users. There was no increased risk of re-operation associated with former use of SSRI .Current use of SSRI is associated with an increased risk of re-operation due to bleeding after surgery for breast cancer. Selective Serotonin Reuptake Inhibitors (SSRI) decrease platelet serotonin storage and platelet-function in humans ,2 and arThe prevalence of patients using SSRI is increasing. According to The Danish Medicines Agencys' data, usage has increased from 38.3 Defined Daily Doses/1000 inhabitants in 2004 to 50.3 in 2008 [We therefore conducted a population-based study with prospectively collected administrative data to examine the association between use of SSRI and re-operation due to post-surgical bleeding in a large cohort of Danish women undergoing breast cancer surgery.We conducted this population-based cohort study among residents of Northern Denmark, which has a total population of 1.7 million inhabitants. The Danish National Health Service provides tax-supported healthcare to all residents of the country and refunds part of patient expenditures on a wide range of prescribed drugs, including SSRI. A unique civil personal registration (CPR) number has been assigned to all Danish citizens since 1968 by the Danish Civil Registration System. This number encodes gender and date of birth [All hospitalizations are registered to individual patients in the National Registry of Patients, which has covered all Danish hospitals since 1977. Data from the National Registry of Patients on the inhabitants of Northern Denmark have been merged into a research database at Aarhus University ,11. ThisInformation on re-operation due to post-surgical bleeding within 14 days of primary breast cancer-directed surgery was retrieved from the National Registry of Patients in accordance with the Danish Classification of Surgical Procedures and Therapy . All breast cancer patients were treated with either mastectomy (code KHAC) or breast-conserving surgery (code KHAB).All pharmacies in Northern Denmark use computerised accounting systems connected with the National Health Service to record a customers' CPR number, type and quantity of medication dispensed , and prescription data according to the drug's Anatomical Therapeutic Classification (ATC) . Data on prescriptions for refundable drugs are transferred electronically to the National Health Services and to the research database at Aarhus University, with complete coverage in the region since 1998. In Denmark, anti-depressants are available only by prescription. We identified prescriptions for the following SSRI anti-depressants: Fluoxetine N06AB03, citalopram N06AB04, paroxetine N06AB05, sertraline N06AB06, fluvoxamine N06AB08, and escitalopram N06AB10. Patients were categorised according to their use of SSRI: never users, current users , and former users .To account for factors that may be associated with SSRI anti-depressant prescription and post-surgical bleeding, we obtained data on age at breast cancer surgery and on preoperative use of platelet inhibitors, vitamin K antagonists, oral anti-coagulants, non-steroidal anti-inflammatory drugs (NSAID)  non-SSRFollow-up began at the date of primary breast cancer surgery and continued until fourteen days after the operation or 1 April 2007. We analysed the data first by tabulating contingency tables for the main study variables, from which we calculated the risk of re-operation due to post-surgical bleeding according to use of SSRI. We computed the crude risk difference and risk ratio with their 95% confidence intervals associating SSRI prescription with post-operative bleeding. We then stratified the contingency tables according to each of the possible confounding variables to examine the strength of confounding. We also fitted multiple logistic regression models to the data to compute the odds ratio and associated 95% confidence intervals that controlled for confounding by identified confounders. Given that re-operation for post-surgical bleeding was rare in all combinations of the independent variables, these adjusted odds ratios provide an estimate of the adjusted risk ratios (aRR). In the final model we included variables that changed the exposure odds ratio by 10 percent . All datStudies based on registry data do not require formal ethical approval under Danish law. However, handling of data was approved by the Danish Data-protection Agency.Characteristics of the cohort of 14,464 breast cancer patients according to SSRI prescription are presented in Table Risk of re-operation due to post-surgical bleeding after breast cancer surgery is presented in Table The elevated risk of re-operation among current users of SSRI remained after adjustment for age  when compared with never users. Similarly, the near-null association between former use of SSRIs and re-operation due to post-surgical bleeding remained after adjustment for age . Further adjustment for other medications or the selected potential confounding comorbid diseases did not substantially affect the risk ratio estimates of association.We hypothesized that current use of SSRI would increase the risk of re-operation after breast cancer surgery due to postoperative bleeding, and the results of this investigation were consistent with that hypothesis. While current users of SSRI had almost tripled the risk of re-operation due to postoperative bleeding, the absolute change in risk was only from 2.7% to 7.0%.The present study is population-based with complete prescription and follow-up data. Recall-bias was eliminated by use of prescription records generated before the initial breast cancer surgery date and all data were obtained prospectively from population-based registries that have a completeness approaching 100% . This inOur comparison of post-surgical bleeding risk in SSRI users versus never SSRI users may raise a concern about non-comparability of the baseline risk of post-surgical bleeding related to indications for SSRI use. For example, patients with a history of depression, which is the primary indication for SSRI use, may tend to have a less healthy lifestyle than patients without a history of depression with respect to tobacco use, diet, alcohol use, and exercise ,19. DeprA limitation of the current study is that it includes no information on SSRI prescription compliance. For example, women defined as current users may not have taken the medication up to the day of surgery. Our information on SSRI use relied on registration of dispensed prescriptions and the Danish health care system covers only a proportion of the costs of prescribed medicine. Dispensed prescriptions for which patients must pay part of the cost are likely to be actually used. Furthermore, women on anti-depressant medication with the additional distress of a newly diagnosed breast cancer would be unlikely to stop their anti-depressant medication. Earlier studies on orthopaedic surgery and coronary artery bypass surgery ,6, have The overall risk of re-operation due to postoperative bleeding in breast cancer patients observed in our study was of the same magnitude as that observed in a small single centre cohort (0.8-4.1%) , which aThe clinical relevance of SSRI in relation to bleeding has been discussed for almost two decades ,2,23. BrOur results show overall low risk of re-operation due to post-surgical bleeding among breast cancer patients regardless of whether they are current, former, or never users of SSRI medications. The consequence of stopping SSRI medication used to treat depression in women undergoing treatment for breast cancer may be overwhelming, and may even delay any subsequent cancer-directed treatment. Thus, the potential consequences of stopping the treatment -- taken together with the low overall risk -- suggests that physicians and patients should discuss the risks and benefits of discontinuing treatment with SSRI before breast cancer surgery.Use of SSRI is associated with an increased risk of re-operation due to bleeding after surgery for breast cancer, from about 3% to about 7%. However, the magnitude of the risk difference does not merit pausing antidepressive medicine in psychologically vulnerable patients without a complete discussion of the risks and benefits.(SSRI): Selective serotonin reuptake inhibitors; (CPR): Civil Personal Registration; (ICD): International Statistical Classification of Diseases and Related Health Problems; (NSAIDs): non-steroidal anti-inflammatory drugs; (TCAs): tri-cyclic anti-depressants; (TeCA): tetracyclical anti-depressants; (ATC): Anatomical Therapeutic Chemical.The authors declare that they have no competing interests.RG put forward the hypothesis; made substantial contributions to conception and design and interpretation of the data; and drafted the paper: abstract, introduction, and discussion. DCF was involved in study conception and design; performed the statistical analysis, data interpretation and conclusions; drafted the methods and results section; reviewed and edited the paper. HHH & LP provided the datasets and statistical analysis and support. TLL was involved in revising the manuscript critically for important intellectual content and consistency regarding analysis, interpretation and conclusions. HTS was involved in study conception, design and data collection and revised the manuscript critically for important intellectual content and consistency regarding analysis, interpretation and conclusions. NK supported the development of the hypothesis, helped to draft the paper and was involved in the clinical interpretation of the results and revision of the manuscript for important intellectual content.All authors read and approved the final manuscript.ATC codes for potential confounding drugs:Platelet inhibitors: , dipyridamol B01AC07; clopidogrel B01AC04);Oral anti-coagulants: ;NSAIDs: ;Anti-depressants: Tri-cyclic anti-depressants (TCAs): Desipramine N06AA01; imipramin N06AA02; imipramine oxide N06AA03; clomipramin N06AA04; opipramol N06AA05; trimipramine N06AA06; lofepramine N06AA07; amitriptylin N06AA09; nortriptylin N06AA10; protriptyline N06AA11; doxepin N06AA12; dosulepin N06AA16; amoxapine N06AA17; Tetracyclical anti-depressants (TeCA): Maprotilin N06AA21, Mianserin N06AX03; Other anti-depressants: Duloxetin N06AX21, venlafaxin N06AX16, Mirtazapin N06AX11, Reboxetin N06AX18, Isocarboxazid N06AF01, Moclobemid N06AG02.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2482/10/3/prepub


In this paper, a combined analysis was performed to study the interaction between familial risk and reproductive life factors. In particular, the interaction between familial risk and breast cell mitotic activity (BCMA), as assessed by duration of ovarian activity, was investigated because of the potential importance of mitotic activity on genetically susceptible cells. The present analysis included 3152 cases and 4404 controls in seven case-control studies from four countries. The interaction effect was estimated in each study separately, then combined using two different methods: a multivariate weighted average and a Bayesian random-effects model. The main effects of reproductive life factors on the risk of breast cancer were in agreement with the previous findings. In particular, an increased duration of BCMA before the first childbirth and over life was found to increase the risk of breast cancer (P < 0.001). Slightly increasing but non-significant, familial risks were observed with increasing number of children (P = 0.17), increasing age at first childbirth (P > 0.2) and increasing duration of BCMA (P > 0.2). There was no modification in familial risk with age at menarche and no clear pattern with menopause characteristics. A weak influence of reproductive and menstrual factors on the familial risk emerged from the present study.


Five-year disease-specific survival rates of patients at high vs low familial risk were 86 and 90%, respectively. After adjustment, there was no difference in breast cancer mortality in general. A strong family history nonsignificantly increased breast cancer mortality in patients ⩽40 years (adjusted hazard ratio (HR) 4.0, 95% CI 0.8–19.7) and in patients treated without chemotherapy . A strong family history of breast cancer is associated with an increased use of systemic therapy in early-onset patients. Although a strong family history does not seem to affect survival in general, it may impair survival of very young patients and patients treated without adjuvant chemotherapy. Owing to the limited number of patients in this study, these results should be used only to generate hypotheses.This population-based study evaluates the impact of a strong family history of breast cancer on management and survival of women with early-onset disease. We identified all breast cancer patients ⩽50 years, recorded between 1990 and 2001 at the Geneva familial breast cancer registry. We compared patients at high familial risk and low familial risk in terms of tumour characteristics, method of detection, treatment, survival and breast cancer mortality risk. Compared to patients at low familial risk ( One of the most important risk factors for breast cancer is the occurrence of breast or ovarian cancer among family members. Women with one or more first-degree relatives with breast cancer have a 1.8–3.0-fold increased risk of developing the disease . NeverthBRCA1 or BRCA2 genes undergo prophylactic bilateral mastectomy and/or salpingo-oophorectomy to reduce their risk of developing breast and/or ovarian cancer  since 1970. It collects information from various sources and is considered accurate, as attested by its very low percentage (<2%) of cases recorded from death certificates only . All hosIn 1999, the Geneva Cancer Registry set up a Familial Breast Cancer Registry, by extending its data set to the detailed family history of cancer for all women diagnosed with invasive breast cancer in the Geneva population . The high familial risk category included patients who reported one of the following family histories: (1) ⩾1 first-degree relative with breast or ovarian cancer ⩽50 years; (2) ⩾2 first-degree relatives with breast/ovarian cancer at any age; (3) ⩾3 cases of breast/ovarian cancer among first- or second-degree relatives. Patients with other types of family history were classified into the moderate familial risk category.For the purpose of this study, we classified breast cancer patients into three familial risk categories according to the number of relatives diagnosed with breast or ovarian cancer, their age at diagnosis and their degree of kinship (We restricted the current study to women with early-onset breast cancer (⩽50 years). We excluded patients with a moderately increased familial risk in order to maximise the difference in effect of family history. We divided age into two categories . We categorised method of detection as due to symptoms , fortuitously (i.e. during the work-up or treatment of another unrelated illness), breast self-examination and surveillance .Socioeconomic status was based on the woman's last occupation or, for the unemployed, that of the spouse. Four levels were considered as follows: low , middle , high  and unknown. For staging, we used the pathological pTNM (tumour node metastasis) classification system or, when not available, the clinical cTNM classification . Tumoursvs no. Contralateral breast cancer was categorised as ‘synchronous’ if detected within 6 months after diagnosis, and ‘metachronous’ if diagnosed later. Information on BRCA1/BRCA2 status was not routinely available.Locoregional therapy was categorised as breast-conserving surgery followed by radiotherapy, mastectomy, bilateral mastectomy  and other . Use of chemotherapy and hormonotherapy was categorised as yes To compare method of discovery, stage at diagnosis and treatment between patients at high and low familial risk, we used a case–control approach. Cases were breast cancer patients with a strong family history and controls were patients without affected relatives. With unconditional univariate logistic regression analysis, we identified the factors that were significantly associated with a high familial risk. With multivariate analyses, we adjusted the relative risks for all factors significantly associated with family history in univariate analysis.P-value <0.05.We used Kaplan–Meier analysis to calculate breast cancer survival rates for women at high familial risk and those at low familial risk. With univariate Cox proportional hazards analysis, we identified all variables significantly linked to survival. Finally, we calculated breast cancer mortality risk  for patients with a highly increased familial risk compared to those without a family history, adjusting for all other factors significantly linked to survival. To evaluate if the effect of familial risk was different between age groups, we stratified by different age categories  and tested for interaction. We also investigated if the use of chemotherapy changed the effect of a strong family history. Data were analysed with SPSS software and differences were considered significant at a two-sided Between 1990 and 2001, 3709 women were diagnosed with invasive breast cancer in the canton of Geneva. Among them, 824 (22%) were ⩽50 years of age. A total of 58 (7%) patients reported a family history classified as high familial risk, 191 (23%) a moderate familial risk and 575 (70%) reported no first- or second-degree relatives with breast or ovarian cancer. Patients with a moderate familial risk were excluded from further analysis. Details on family history of the patients in the high familial risk category are presented in vs low familial risk. There was no significant difference in age or period of diagnosis. Women with a strong family history had less frequently stage I disease at diagnosis , and more often stage III disease , when compared to low familial risk patients. After adjustment for age, women at high familial risk were significantly more likely to be diagnosed with stage III disease than patients without a family history of breast cancer (adjusted odds ratio (OR) 3.3, 95% CI 1.4–7.8).In vs 43%, respectively), grade 1 tumours  and oestrogen receptor-positive tumours , but these differences were not statistically significant.Women at high familial risk tended to have more frequently axillary lymph node involvement compared to women at low familial risk (53 P=0.051), while the risk to develop metachronous contralateral breast cancer was similar for both groups (median follow-up 5.2 years).The risk of presenting synchronous bilateral breast cancer was increased among patients with a high familial risk : 81% of low familial risk patients vs 23%, respectively), but this result was not significant.vs low familial risk. Bilateral mastectomy for unilateral disease was more common among women with a strong family history .Breast-conserving therapy was performed at a similar rate in patients at high vs 65%, respectively), but this difference was not significant. A higher proportion of women at high familial risk received hormonotherapy . After adjustment for age, stage, oestrogen receptor status, locoregional therapy and chemotherapy, the probability to receive hormonotherapy remained significantly increased among patients at high familial risk .Patients at high familial risk received more often chemotherapy than low familial risk patients . The proportion of women treated with hormonotherapy was also significantly higher , as was the proportion of women treated with both hormonotherapy and chemotherapy . In the group of lymph node-positive patients, high familial risk patients received equally frequently systemic therapy as low familial risk patients , but they were more often treated with both chemotherapy and hormonotherapy .vs 56%, respectively, P=0.020), chemotherapy  and both . In the group of patients with oestrogen receptor-negative tumours, no significant differences in use of systemic therapy were observed.In the group of women with oestrogen receptor-positive tumours, patients at high familial risk received significantly more frequently hormonotherapy when compared to patients at low familial risk . Use of hormonotherapy decreased the breast cancer mortality risk by 40% , but this result was not statistically significant. In univariate analysis, patients with a strong family history did not have an increased risk of dying of breast cancer compared to patients without a family history . After adjustment for all factors significantly linked to survival in univariate analysis (including hormonotherapy), the risk of dying of breast cancer was not significantly different among women at high familial risk compared to those at low familial risk .In the subgroup of patients treated with chemotherapy, a strong family history was not associated with an increased breast cancer mortality risk  . Among pOf the 10 high familial risk women younger than 41 years, two did not receive systemic therapy. Both of them died within 5 years after diagnosis.In the subgroup of patients with poorly differentiated (grade 3) tumours, a strong family history was not associated with a significantly increased mortality risk  (data not shown).Finally, we analysed the survival of the 191 patients at moderate familial risk. Their 5 and 10 years specific survival rates were 93% (95% CI 89–97%) and 85% (95% CI 77–93%), respectively, and not significantly different than those of low familial risk patients. Also, the multiadjusted breast cancer mortality risk of patients with a moderately increased familial risk was not significantly different than that of patients at low familial risk .In this population-based study, we show that breast tumours occurring at an early age among women belonging to high-risk families were neither discovered more frequently by screening or surveillance nor diagnosed at an earlier stage than in patients without a family history of breast cancer. However, after the diagnosis of invasive breast cancer, patients at high familial risk were treated differently compared to patients without a family history, particularly regarding the prescription of systemic therapy. In addition, this study shows that a strong family history of breast and/or ovarian cancer was not associated with a decreased survival after early-onset breast cancer, except, maybe, for very young patients and patients not receiving chemotherapy.BRCA1/BRCA2 germline mutations become increasingly widespread, but vary from one centre to another , this has not been demonstrated for familial cases of breast cancer  and have often been shown to be associated with impaired survival rates , a strong family history might have a negative impact on breast cancer survival. These results are substantiated by a recent study from investigators at the MD Anderson Cancer Center, showing that among very young breast cancer patients (⩽35 years), a family history of ovarian cancer strongly impaired disease-free and overall survival (Based on this study, we conclude that guidelines on screening and management of young women at high familial risk are needed. By better informing the public and primary care physicians on the importance of family history, it should be possible to increase the number of women identified as high risk of developing breast cancer and to propose to these women specific screening and prevention protocols. Finally, additional research is needed to confirm if a strong family history of breast cancer impairs survival of very young patients and those treated without chemotherapy.


The incidence of adenocarcinoma of the oesophagus in British women is among the highest in the world. To investigate its aetiology, we conducted a multi-centre, population based case–control study in four regions in England and Scotland. We included 74 incident cases in women with histologically confirmed diagnoses of adenocarcinoma of the oesophagus, and 74 female controls matched by age and general practice. High body mass index (BMI) around the age of 20 years  = 6.04, 95% confidence interval (CI) 1.28–28.52) and low consumption of fruit  were associated with increases in risk. Breastfeeding by women was associated with reduced risk of their subsequently developing this cancer  and there was a significant dose–response effect with total duration of breastfeeding. The summary population attributable risk from these three factors was 96% (90% if breastfeeding is excluded). We conclude that high BMI in early adulthood and low consumption of fruit are important risk factors for adenocarcinoma of the oesophagus. Breastfeeding may confer a protective effect but this needs confirmation. This cancer is a largely preventable disease in women. © 2000 Cancer Research Campaign


Correlation between circulating sex steroid levels and breast cancer has been controversial, with measurement of free, or bioavailable hormone rarely available. Salivary hormone levels represent the bioavailable fraction. To further elucidate the role of endogenous hormones in breast cancer, we aimed to assess correlation between salivary sex steroid levels and breast cancer prevalence.Salivary hormone levels of testosterone (T), Estradiol (E2), Progesterone (P), Estriol (E3), Estrone (E1), DHEAS and Cortisol (C) were measured by Enzyme Immunoassay (EIA) in 357 women with histologically verified breast cancer and 184 age-matched control women.Salivary T and DHEAS levels were significantly lower in breast cancer cases vs. controls . E2 and E1 levels were elevated and E3 levels were lowered in cases vs. controls.Salivary T levels, representing the bioavailable hormone, are significantly lower in women with breast cancer compared to age-matched control women. These findings support the protective role of biovailable testosterone in counteracting the proliferative effects of estrogens on mammary tissue. The risk of developing breast cancer is related to events of reproductive life and lifestyle factors that modify levels of endogenous sex hormones. Soon after the discovery of sex hormones, it was suggested that breast cancer risk was related to endogenous estrogen levels. Recent large prospective cohort studies on postmenopausal women make it clear that high levels of estrogens increase mammary gland proliferation and are associated with increased breast cancer risk .Interestingly, several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. In cell cultures and animal experiments, androgens have been shown to exert anti-proliferative effects . It has Our aim was to examine whether salivary testosterone levels were lower in breast cancer patients compared to the general population. Hypotheses of whether elevated testosterone levels are associated with elevated estrogen levels were also investigated. To address this issue a case-control study was designed. Immunoassay has been used for the measurement of hormones in saliva, given the sensitivity, reliability, and serum saliva correlations for these assays ,8.Salivary hormone levels were collected in 357 newly diagnosed breast cancer patients between 2001 and 2004. Breast cancer diagnosis was categorized according to histological reports to: IDC , DCIS , ILC (infiltrating lobular carcinoma) and LCIS . All patients were in a single surgical practice of one of us (RG).Salivary hormone levels were also collected in a group of 184 controls. These were women who presented with benign breast disease  in the same practice (RG), during the same time period. Patients with atypical ductal hyperplasia were excluded from the study.The two groups (patients and controls) were matched for breast cancer risk factors such as age, menopause status, family history of breast cancer, use of hormone therapy, age at menarche and age at first birth Table . Breast Salivary testosterone (T), Estradiol E2), Progesterone (P), Estriol (E3), Estrone (E1), dehydroepiandrosterone sulfate (DHEAS) and cortisol (C) levels were measured in all women and compared between the two groups  was collected in polypropylene tubes in the morning upon rising and before breakfast (7-9 a.m.). Food and beverages (except water) were avoided 2 h prior to saliva collection. Women on hormone replacement therapy (HRT) had discontinued therapy at least one month prior to salivary hormone collection. Saliva samples were shipped within 24 h for laboratory analysis.Saliva was processed by adding 50 μl of 0.14 mg/ml dithiothreitol (DTT) per ml of saliva to break up mucins that interfere with saliva extraction. Steroids were then extracted from 1.5 ml of saliva by C-18 column chromatography. Samples were gently pulled through the columns by vacuum. Control and calibrator samples were prepared from Biorad Lyphocheck diluted 1/100 in phosphate-buffered saline (PBS) buffer containing DTT. The C-18 columns were washed twice with PBS buffer, vacuum dried, and the steroids eluted with 100% ethanol. The eluted solvent containing the steroids was dried under nitrogen and then reconstituted 2× in PBS buffer containing 0.1% T904 detergent and 0.05% Proclin antimicrobial (assay buffer).Steroids in the extracted/reconstituted saliva were quantified by enzyme immunoassay (EIA) with commercial kits from DRG, Germany. Standards were prepared in assay buffer from a concentrated stock of each hormone with serial dilution. Inter- and intra-assay coefficients of variation for low and high controls for all steroids tested were 10% or less. Ranges were based on gender, age, menstrual status  from greater than 1000 women in each category.Univariate statistical analysis was performed to address the questions stated before.Normality of the data was checked using graphical investigation (histograms and q-q plots) as well as the Kolmogorov Smirnov test (results not shown). Student's t-test was used to compare the mean hormone levels while chi-square tests were performed when comparing frequencies. A simple linear regression was used to illustrate graphically the correlation between testosterone and E1, E2 levels. Also, multivariate analysis was performed to assess the dependency of testosterone levels on a set of independent variables. All statistical analysis were performed in an alpha = 5% level.Table Menopausal women had, on average, reduced T and DHEAS levels when compared with premenopausal in both groups (data not shown). Comparison of salivary hormone levels according to menopausal status Table  showed tRatios of testosterone over E1 and E2 were also computed overall as well as in pre and post menopausal women ] or ductal carcinoma in situ (DCIS). Results are shown in Table To assess whether breast cancer patients with higher testosterone levels have corresponding higher E1 levels, a scatter plot was created. In Figure A multivariate linear model was used to assess the dependency of Testosterone levels on a set of independent variables Table . It was This study has shown for the first time that endogenous bioavailable testosterone levels are lower in women with breast cancer vs. relevant control women. Although saliva has not yet become a mainstream sample source for hormone analysis, it is a valuable research tool offering a non-invasive and stress-free alternative to plasma and serum. It has proven to be reliable and in some cases superior to other body fluids demonstrating a very close correlation with free testosterone levels in serum . Saliva Our findings that estrogens are related to individual breast cancer risk both premenopausally and postmenopausally are generally consistent with former studies -16. In lThere are conflicting data on the association between androgen levels and breast cancer risk . Some reEvidence suggests that the fall in androgen production begins as early as the third decade in women, with a gradual decline thereafter . We founOne may argue that there are some breast cancer patients in our study with high androgen levels and some healthy individuals with low levels. We believe that higher testosterone levels are generally associated with higher estrogen levels since androgens are the substrate for conversion to estrogens. This could explain the positive association in some studies between breast cancer and testosterone where, this association was no longer significant after adjusting for estrogens ,24. In oIt is has also been suggested that the balance between the stimulatory effect of estrogens and the inhibitory effect of androgens is the critical factor that regulates mammary cell proliferation both in normal and in cancer tissues . In suppUnlike other studies ,28, no cA major weakness of the present study is that body mass index (BMI) was not reported. However, the relationship of adiposity with breast cancer especially in postmenopausal women could be partially explained by the increases in endogenous estrogens , and notOur findings are in agreement with clinical and experimental observations suggesting that androgens counteract the proliferative effects of estrogens on the mammary gland and are considered to be protective against estrogenic carcinogenesis ,4,31,32.Salivary testosterone levels are significantly lower in breast cancer patients compared to controls. These differences are more profound in postmenopausal women. Salivary E1 and E2 levels were elevated in cases leading to a lower T/E1 ratio in breast cancer patients comparing to healthy individuals.Our results support a correlation between endogenous androgen and estrogen levels and breast cancer risk. Breast cancer patients appear to have a relative imbalance of sex steroid hormones in favor of estrogens. Higher biovailable testosterone may counteract the proliferative effects of estrogens on mammary tissue and may exert a protective role to the breast, inhibiting cancer development and/or tumor growth.DHEAS: Dehydroepiandrosterone Sulfate; FSH: Follicular Stimulating Hormone; SHBG:Sex Hormone Binding Globulin; T:Testosterone; E1:Estrone; E2: Estradiol; E3: Estriol; P:Progesterone; C:Cortisol; EIA:Enzyme ImunoAssay; DTT:Dithiothreitol; PBS:Phosphate-buffered saline; IDC:Infiltrating Ductal Carcinoma; ILC:Infiltrating; Lobular Carcinoma; DCIS:Ductal Carcinoma in situ; LCIS:Lobular Carcinoma in situ; HRT:Hormone Replacement Therapy; BMI:Body Mass Index; pg/ml: picograms per mililiter; ng/ml: nanograms per mililiter.The authors declare that they have no competing interests.CD participated in supervising, analyzing data, writing and literature search, DZ made the lab analysis, SM made the statistics, AT participated in literature search and writing, AA participated in editing the ms, RG had the conception of the study and recruited participants. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/547/prepub


Helicobacter pylori infection. A positive history of stomach cancer in one or more first-degree relatives was associated with an increased risk of the disease in women, but not in men after controlling for H. pylori infection and other confounding variables. Women with both a family history and H. pylori infection were associated with more than five-fold increased risk of the disease  compared to those without these factors. These results suggest the existence of inherited susceptibility to the disease in women, and that measurements of H. pylori infection together with the family history allow meaningful evaluation of risk beyond that provided by either factor alone.We used 202 cases of stomach cancer and 394 controls nested within the Japan Collaborative Cohort Study For Evaluation of Cancer Risk (JACC study) to investigate whether family history has an independent effect on the risk of stomach cancer after controlling for the  Helicobacter pylori (H. pylori) , a nation-wide multicenter collaborative study to evaluate prospectively various risks or protective factors on cancer mortality and incidence. Details of the study design were reported previously (n=39 293) also donated a residual serum sample (about 2 ml) used for the general health checkup. It was partitioned into 0.3–0.5 ml aliquots and stored at −80°C until laboratory analyses.At the time of recruitment, baseline characteristics were gathered by self-administered questionnaires, which covered the medical history and included lifestyle-related items such as drinking and smoking, level of education, and family history of several medical conditions including cancer. About one-third of the cohort members (n=65 184) and coded according to the tenth revision of International Classification of Diseases and the second edition of International Classification of Diseases for Oncology. These data were collected at the central office of the Research Committee.Vital statuses of the participants were checked annually by each regional research centre, with permission to review their population-register sheets from the Ministry of Public Management, Home Affairs, Post and Telecommunications. Incidence of cancer was ascertained in 24 study areas (n=10) contained only one control; a total of 394 controls was available for the present analysis. As information on the location of cancer within the stomach or the histological type was not available in all cases, we did not use it to classify cases.We first restricted the subjects to those who lived in the study areas where cancer incidence was ascertained. We then excluded 857 participants with a self-reported history of cancer at any site. Among the remaining 64 327 subjects, diagnosis of stomach cancer 12 or more months after cohort recruitment was documented in 804 cases until the end of 1997. Serum had been obtained from 218 out of the initial 804 cases. However, seven cases without enough serum for laboratory analysis, and one case without an eligible control subject were excluded. In addition, one of the 24 study areas where family history was not assessed was excluded from the analysis. Thus, the study reported here included 202 cases (105 men and 97 women) in total. Lag time between blood sampling and stomach cancer diagnosis varied between 12 and 113 months (median 50 months). Each of these subjects was matched with two control subjects for gender, age at recruitment (as near as possible), and study area, who had also provided an adequate baseline blood sample and who were alive and remained free of confirmed cancer as of the end of 1997. Owing to a lack of eligible subjects, a few sets  with antigen from Japanese (J-HM-CAP), and the serum titer of immunoglobulin G antibodies 2.3 or greater was defined as positive infection.Serum samples from each case and matched controls were retrieved from storage and shipped on dry ice to a single laboratory for the assay. None of the samples had been previously defrosted. H. pylori infection were collected at the baseline, using a self-administered questionnaire. A drinking habit was first categorised into three statuses . If present, it was further categorised into two levels by weekly consumption , that is, daily alcohol consumption times days of drinking per week. Smoking status was classified into three levels . Consumption frequency of vegetables, citrus fruits, and green tea was initially assessed in five levels . For the present analysis, the former two and the latter three categories were combined. Salty-food preference was categorised into three levels . Information on educational level was measured as the age of formal schooling completed and was classified into two categories: ⩽15 years old (corresponds to ⩽9 years of schooling) and ⩾16 years old (corresponds to ⩾10 years of schooling). Missing values in each variable were treated as an additional category in the variable, and were included in the analyses.Family history of stomach cancer was defined as when the subject had at least one first-degree relative with a history of stomach cancer. Risk factors that could potentially confound the relation between family history and stomach cancer other than χ2 tests for categorical variables. We then performed logistic regression analysis, conditioned on the matching variables of gender, age, and study area, and presented the odds ratios (ORs) that represent the risk associated with a positive family history of stomach cancer. Adjusted estimates of risk were obtained with multivariate models that controlled for H. pylori infection, and other covariates listed above. To assess the joint effect of family history and H. pylori infection on the risk of stomach cancer, four categories were created by the combination of these two factors. Another logistic regression analysis was performed taking a category with no family history and no H. pylori infection as a reference. The 95% confidence intervals (95% CIs) are presented for all ORs. All reported P-values are two-sided. All analyses were performed separately for men and women with SPSS statistical package for windows version 11.5.We compared the baseline characteristics of case subjects and control subjects by one-way analysis of variance for continuous variables and P-values for the χ2 test were 0.87 in men, 0.054 in women; case vs control). The proportion of individuals infected with H. pylori was high even in control subjects . However, it was higher in cases with stomach cancer in men and especially in women. Cases and controls did not differ significantly in terms of smoking status, alcohol intake, or other diet-related items for both sexes. The proportion of women with a higher educational level seemed to be higher in controls compared to that in cases.H. pylori infection or other potentially confounding variables. A family history of stomach cancer did not seem to be related to the risk of the disease incidence in men in the present dataset.H. pylori infection in men with a family history was 81.6%, against 82.2% in men without such a history .The prevalence of H. pylori infection, significantly increased risk  was observed in women with a family history of stomach cancer and H. pylori infection compared with those without these risk factors. In men, however, no significant associations were observed.In another logistic regression analysis comparing the risk of the disease among the four subgroups created by the combination of presence or absence of a family history and H. pylori infection. Women with both a family history and H. pylori infection had a greater than five-fold increased risk of the disease compared to those without these factors. The combined effect of these factors on the final risk of stomach cancer is approximately equivalent to the multiplicative product of the risks from the separate factors. Some biologic interaction between these two factors has been reported previously . However, other studies did not necessarily find the effect restricted to women  (Unexpectedly, family history of stomach cancer and serological prevalence of H. pylori infection were associated with a greater than five-fold increased risk of the disease compared to those without these risk factors. Measurements of H. pylori infection together with the family history allow meaningful refinement of risk stratification beyond that provided by either factor alone. The study thereby partly confirms and extends the still quite limited empirical evidence on an issue that might well be relevant for potential screening strategies at least in women.In conclusion, a family history of stomach cancer was associated with an increased risk of the disease in women. In addition, we observed that women with both a family history and


Epidemiological evidence indicates that mammographic dysplasia is associated with an increased risk of breast cancer, particularly in premenopausal women. To examine biochemical associations with mammographic dysplasia we have compared premenopausal women with different patterns of the breast parenchyma on mammography. One group had extensive radiological dysplasia (n = 30) and the other no dysplasia (n = 16). Both groups were recruited from mammographic units in the same way and then compared according to epidemiological risk factors, anthropometric measures, nutrient intake and plasma levels of oestradiol, progesterone and prolactin obtained in both follicular and luteal phases of the menstrual cycle as well as total plasma cholesterol and lipid fractions. Women with mammographic dysplasia were found to be leaner, more often nulliparous and to consume more alcohol than women without these radiological changes. Mammographic dysplasia and a family history of breast cancer were found to be independently associated with significantly higher levels of high density lipoprotein cholesterol (HDL-C) after taking into account the possible confounding effects of percentage body fat, parity and consumption of alcohol and dietary fat. Triglyceride levels were also independently associated with a family history of breast cancer. We conclude that further investigation is warranted of the role of plasma lipids in relation to breast cancer risk.


A number of genes are known to be involved in inherited susceptibility to breast and/or ovarian cancer. In the context of high-risk families the most important genes are BRCA1 on chromosome 17q, which is associated with a high penetrance of both breast and ovarian cancer, and BRCA2 on chromosome 13q, which causes a high risk of breast cancer but a lower risk of ovarian cancer. Other high-risk cancer genes that confer increased risks of breast or ovarian cancer in addition to other cancers include the hereditary non-polyposis colorectal cancer genes and the TP53 gene, which causes breast cancer as part of the Li-Fraumeni syndrome. The predisposing mutations in these genes are relatively rare in the population. More common genes which are associated with an increased, but lower, risk of breast cancer are the ataxiatelangiectasia gene and the HRAS1 gene. This paper reviews recent progress in mapping and cloning of these susceptibility genes, and provides estimates of the cancer risks associated with each gene and the frequency of predisposing mutations.


IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls  comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the  The insulin-like growth factor-I (IGF-I) signaling pathway stimulates cell proliferation and inhibits apoptosis IGF1, IGFBP1, and IGFBP3 in relation to breast cancer risk. The most extensively examined polymorphisms in IGF1 has been the 5′ simple tandem repeat that lies 1-kb upstream from the IGF1 gene transcription start site  and an A/C polymorphism 5′ to IGFBP3 at nucleotide −202 (rs2854744) IGF polymorphisms modestly affect circulating levels of IGF-I and IGFBP-3 IGF1, IGFBP1, and IGFBP3 genes were conducted in two prospective cohorts Previous epidemiologic studies have suggested that high circulating levels of IGF-I and low levels of IGFBP-3 are associated with increased risk of premenopausal breast cancer IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk, we conducted a haplotype-based analysis in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) To comprehensively examine the role of common genetic variation in the The BPC3 has been described in detail elsewhere Cases were initially identified in each cohort by self-report and subsequently verified from medical records or tumor registries and/or linkage with population-based cancer registries. In all cohorts, questionnaire data were collected prospectively before the cancer diagnosis. Controls were matched to cases by age, ethnicity (except in PLCO), and in some cohorts additional matching criteria were utilized (e.g. date of blood draw).IGF1, IGFBP1 and IGFBP3 characterization and selection of haplotype-tagging SNPs (htSNPs) have been described elsewhere IGF1, IGFBP1, and IGFBP3 were sequenced in a panel of 95 advanced breast cancer cases from the MEC . SNPs were also selected from public databases to capture the genetic diversity of regions from ∼20 kb upstream to ∼10 kb downstream of each gene. Haplotype blocks (regions of strong linkage disequilibrium) were defined using the method of Gabriel et al. h2>0.80.The details of IGF1, 154 SNPs were genotyped a multiethnic panel of 349 individuals with no history of cancer (18). Of the 154 SNPs genotyped, 53 were identified as monomorphic and 37 had poor genotyping results —these 90 SNPs were eliminated from further analysis. The remaining 64 SNPs were used for genetic characterization and had an average density of one SNP for every 2.4 kb over a 156-kb region. Fourteen htSNPs were selected using the expectation-maximization algorithm h2>0.85). For genetic characterization of IGFBP1 and IGFBP3 (which are located contiguously in a 35kb region of chromosome 7), 56 SNPs were genotyped in the multiethnic panel (18). Of the 56 SNPs genotyped, 17 were identified as monomorphic and 3 had poor genotyping results (as discussed above)—these 20 SNPs were eliminated from analysis. The remaining 36 SNPs were used for genetic characterization, having an average density of one SNP for every 2 kb over a 71-kb region. Twelve htSNPs were selected to predict the common haplotypes among Caucasians (rh2>0.99). Additionally, two genic SNPs in IGFBP3 that were not part of a haplotype block were examined , and two additional IGFBP3 SNPs  were included. Thus, a total of 16 SNPs across IGFBP1 and IGFBP3 were evaluated. Genotyping of breast cancer cases and controls was performed in four laboratories  using a fluorescent 5′ endonuclease assay and the ABI-PRISM 7900 for sequence detection (Taqman). Initial quality control checks of the SNP assays were done at the manufacturer ; an additional 500 test reactions were run by the BPC3. Assay characteristics for the IGF1, IGFBP1, and IGFBP3 htSNPs are available on a public website (http://www.uscnorris.com/mecgenetics/CohortGCKView.aspx). To assess interlaboratory variation, each genotyping center ran assays on a designated set of 94 samples from the Coriell Biorepository  (22). The completion and concordance rates were each >99%For genetic characterization of IGF-I and IGFBP-3 levels were measured by enzyme-linked immunosorbent assays among non-users of postmenopausal hormones . Detailed laboratory methods for these studies have been previously reported IGF1 and IGFBP3 SNPs were calculated using linear regression analysis while adjusting for age at blood draw, assay laboratory and batch for circulating IGFs, BMI, race/ethnicity, and country within EPIC cohort. Additional regression analyses were conducted simultaneously adjusted for all other IGF1 and IGFBP SNPs to determine the best fit model of circulating levels.In our hormone analyses, circulating IGF-I and IGFBP-3 values were naturally log-transformed to provide approximate normal distributions. Geometric mean levels of IGF-I and IGFBP-3 for In our breast cancer analysis, we examined both single SNP and haplotype effects on breast cancer risk. For single SNP analyses, we used conditional multivariate logistic regression to estimate odds ratios (ORs) for breast cancer using a linear (log-odds additive) scoring for 0, 1 or 2 copies of the minor allele of each SNP. For the haplotype analyses, we calculated haplotype frequencies and subject-specific expected haplotype counts separately for each cohort, by country within EPIC, and by ethnicity within the MEC. An expectation-substitution approach was used to assign expected haplotype counts based on unphased genotype data and to account for uncertainty in assignment IGF1, IGFBP1, or IGFBP3 haplotypes and risk of breast cancer (or subtypes defined by receptor status), we used a likelihood ratio test comparing a model with additive effects for each common haplotype (treating the most common haplotype as the referent) to the intercept-only model. To test for heterogeneity across cohorts and ethnic groups, we used the Wald X2 for the htSNPs and a likelihood ratio test for the haplotypes.To test the global null hypothesis of no association between variation in IGF1, IGFBP1, or IGFBP3 htSNPs or haplotypes and breast cancer differed by menopausal status , stage  or hormone receptor (ER and PR) status.We considered conditional models both without and with adjustment for known breast cancer risk factors. These included menopausal status , age at menopause , BMI , parity , use of postmenopausal hormones , first-degree family history of breast cancer , age at menarche , and use of oral contraceptives . Because results remained virtually unchanged regardless of the model used, we present results from the conditional models adjusting for matching factors only. We also evaluated BMI, family history of breast cancer, and use of postmenopausal hormones for possible interaction effects using likelihood ratio testing (LRT). Models with the main effect of genotype and the covariate of interest were compared to models with the main effects of genotype and the covariate of interest, plus a multiplicative interaction term of the two variables. We also examined whether the associations between Lastly, this analysis includes a portion of the previously published data from the MEC IGF1 is shown in IGFBP1 and IGFBP3 is shown in IGF1 locus was characterized into four haplotype blocks. IGFBP1 and IGFBP3 loci are 19kb apart and were characterized by three haplotype blocks. The genotyping success rate was ≥95% for all SNPs at each genotyping center. No deviation from Hardy-Weinberg equilibrium was observed among the controls overall (at the p<0.01 level). The frequencies of individual SNPs and common haplotypes within each LD block were consistent across all cohorts (data not shown).The genomic structure of Study characteristics of each cohort (except PLCO) have been published previously IGF1 . However, these SNPs (wild type vs. variant homozygote) individually accounted for less than a 5% change in mean IGF-I levels. Results did not differ after simultaneously adjusting for all other IGF1 and IGFBP SNPs in the regression analysis (data not shown). The strongest relationships for IGFBP-3 were observed with five SNPs in IGFBP3 block 3: rs3110697, rs2854746, rs2854744, rs2132570, rs2960436 . Rs2854746 remained significantly associated with IGFBP-3 levels (p<0.0001) after adjusting for all other IGF1 and IGFBP SNPs simultaneously in the regression analysis. These SNP associations account for a change in mean circulating IGFBP-3 levels ranging from 6% (rs2132570) to 12% (rs2854746).SNPs in IGF1  and IGFB , nor were other SNPs or haplotypes consistently associated with risk. When examining these associations among invasive breast cancer only, by stage, or by hormone-receptor status, we did not observe any associations between variation in these genes and disease risk (data not shown). Results did not differ when examining associations separately for pre- and post-menopausal women or when restricting the analysis to only white women (data not shown). No consistent interactions were observed among variants in the IGF1, IGFBP1, and IGFBP3 genes with any of the following: first-degree family history of breast cancer, ever oral contraceptive use, use of postmenopausal hormones, and BMI . We observed no interactions resulting in sub-group associations with disease risk (data not shown).None of the Across all statistical tests performed in relation to disease status, we observed fewer significant findings than those expected by chance alone . None of these findings provided clear evidence for main effect or subgroup associations for any of the SNPs or common haplotypes. Thus we believe these sporadic associations may reflect chance. Finally, we repeated all analyses excluding subjects from the MEC and EPIC cohorts, and found no meaningful differences in associations when compared to overall findings (data not shown).IGF1, IGFBP1, and IGFBP3 genes in relation to both circulating IGF-I and IGFBP-3 levels and breast cancer risk. Several genetic variants in IGF1 and IGFBP3 predicted circulating levels of IGF-I and IGFBP-3, respectively, but no associations between these variants and breast cancer, overall or in subgroups, were seen. It is thus unlikely that these polymorphisms and their associated hormone levels substantially affect breast cancer risk. There was also no evidence of effect modification by selected breast cancer risk factors or subgroup effects, including menopausal status. While some previous epidemiologic studies have shown stronger support for a role of the IGF-I signaling pathway in premenopausal breast cancer Our study is by far the largest to examine genetic variation in the IGF1, IGFBP1, and IGFBP3 genetic variation in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk IGF1, IGFBP1, or IGFBP3 in relation to breast cancer with mixed results IGF1 is the (CA)n repeat polymorphism that lies 1-kb upstream of the IGF1 transcriptional start site IGF1 (CA) n polymorphism, we used data from a prior study Our findings are consistent with two previous studies that comprehensively examined the role of IGFBP3 (rs2854744), and located in haplotype block 3, has been the most extensively examined polymorphism in the IGF binding proteinsIGFBP3 gene) nor the haplotype block were associated with breast cancer risk in our data.The A/C polymorphism at nucleotide −202 in IGF1, IGFBP1, and IGFBP3 loci. The latter allows our analysis to provide powerful null evidence against a main effect association between breast cancer risk and variants in these genes that are common among Caucasian women as well as in defined subgroups of the study population.Strengths of the BPC3 include its size and the comprehensive characterization of variation around the IGF1 and IGFBP3 genes significantly influence circulating levels of IGF-I and IGFBP-3, respectively, but have no measurable effect on breast cancer risk. Given the large size of our study, it is unlikely that these loci contribute substantially to breast cancer risk among white, primarily postmenopausal, women, at the population level.In summary, results from this large collaborative study support previous evidence that specific genetic variants in