No large cohort study has examined the risk of endometrial cancer in relation to sun exposure.A population-based cohort study of 29 508 women who answered a questionnaire in 1990–92, of whom 24 098 responded to a follow-up enquiry in 2000–02. They were followed for an average of 15.5 years.Among the 17 822 postmenopausal women included, 166 cases of endometrial cancer were diagnosed. We used a multivariate Cox regression analysis adjusting for age and other selected demographic variables to determine the risk of endometrial cancer. Women using sun beds >3 times per year reduced their hazard risk (HR) by 40%  0.4–0.9) or by 50% when adjusting for body mass index or physical activity , and those women who were sunbathing during summer reduced their risk by 20% (HR 0.8 95% CI 0.5–1.5) compared with women who did not expose themselves to the sun or to artificial sun .Exposure to artificial sun by the use of sun beds >3 times per year was associated with a 40% reduction in the risk of endometrial cancer, probably by improving the vitamin D levels during winter. Excess weight alone is estimated to cause around 50% of all endometrial cancer cases in Europe and the United States . Among tThis prospective cohort study was carried out to assess the potential influence of sun and sun bed exposure on the risk of endometrial cancer.The ethics committee of Lund University (LU-632-03) approved the study. A total of 1000 women from each age group between 25 and 64 years, in all 40 000 women, without prior diagnosis of cancer, were chosen from the general population registry of the South Swedish Health Care Region by computerised random selection. The women were invited to fill out a written questionnaire aiming to identify risk factors for endometrial cancer. Of the women invited, 29 508 (74%) agreed to participate; those who had had a hysterectomy before recruitment were excluded. The initial survey was performed in 1990–92 and a follow-up, similar to the first, in 2000–02. Of the women answering the first questionnaire, 24 098 (82%) also completed the second questionnaire. The initial survey covered reproductive history, hormone use, family history of gynaecological cancer, constitutional factors, marital status, level of education, and lifestyle factors such as level of physical exercise, smoking habits, and sun exposure habits. The follow-up survey covered the past medical history, body mass index (BMI), and present regular exercise.Low-potency oestrogen use and hormone treatment use were classified as previously described  as we found no difference in one, two, or multiparous. Smoking habits were recorded at the inception of the study, categorised as never smokers (reference) or ever smokers. The wording of the sun exposure questions at study inception was: (i) do you sunbathe during summer? ; (ii) do you go abroad on vacation to swim and sunbathe? ; (iii) do you use a sun bed? . The first two questions were dichotomised into yes or no in the final analysis.2)) was calculated on the basis of the present length and weight reported in the second questionnaire. Body mass index was classified into three groups . The level of present physical exercise was also obtained at the second questionnaire, and it was divided into three categories: none, go for a walk one or more times a week, or strenuous exercise weekly.The BMI (weight (kg) per length . Endometrial cancers were identified through the Swedish Cancer Registry , using the ICD9 code numbers 179, 182, and the ICD 10 code number C54. Women with sarcoma of the uterus were excluded. Vital status and the diagnosis of endometrial cancer were determined up until 31 December 2007.P-values <0.05 were considered significant.Only postmenopausal women were included in this analysis, performed with Cox regression using 95% CIs . EndometAt the end of the follow-up in December 2007, 166 of the 17 822 postmenopausal women had developed endometrial cancer, and demographic characteristics in relation to their risks are presented in A novel finding is that women using sun beds had a decreased risk of endometrial cancer, a dose-dependent effect with a 40% reduced risk among those using a sun bed >3 times per year.3 (25-OHVitD) through pre-vitamin D (There is indirect evidence that UV exposure might affect the risk of endometrial cancer, women living at higher latitudes having a lower risk than those at lower latitudes (itamin D . Sun beditamin D . It has itamin D . HoweverThe positive effect of artificial sun exposure through sun bed use also continued when adjusting for potential confounding lifestyle factors such as BMI and physical activity.Overall, physical activity reduced the risk of endometrial cancer by half. Other cohort studies have shown differing results; most have found a decreased risk in physically active women (In our study, smoking women had a decreased risk of endometrial cancer, which is in agreement with other prospective cohort studies (We found that sun bed users were at lower risk of endometrial cancer and there may be an association between vitamin D deficiency and endometrial cancer.


P=0.21) and recent exercise activity (trend P=0.31) were weakly associated with longer survival.We evaluated prediagnosis predictors of breast cancer survival among 717 premenopausal breast cancer patients enrolled in a population-based case–control study and followed for 10.4 years. Using Cox's proportional hazards models, lifetime exercise, weight, and height were not associated with survival. Higher body mass index (trend  Evidence suggests that physical activity reduces the risk of breast cancer , an effect first reported nearly 20 years ago , though As there is currently interest in whether breast cancer risk factors also impact on survival, we have examined these factors in a population-based cohort of breast cancer patients.in situ or invasive breast cancer from 1 July 1983 through 31 December 1989, identified by the University of Southern California Cancer Surveillance Program (CSP), the population-based cancer registry for Los Angeles County.Subjects were breast cancer patients who participated in a population-based case–control study among women aged 40 years or younger  reviewed and approved the study that complied with all applicable federal regulations governing the protection of human subjects. Study subjects were given a detailed explanation of the study including the risk and benefits. All participants provided signed informed consent to participate in the study.In face-to-face interviews, we obtained detailed information about demographics and known or suspected breast cancer risk factors, up to each patient's reference date, defined as 12 months before diagnosis.We asked patients whether they had ever participated at least twice weekly on a competitive athletic team or in dance or exercise classes, or if they jogged or ran one mile at least twice weekly. For those who responded ‘yes’, we recorded for each activity the age started and stopped, the type, and the average number of hours per week of participation. We recorded each episode when activities were started and stopped more than once or when the amount of time spent in the activity changed. We computed the number of hours per week each patient participated in all recreational exercise activities beginning with the year of each woman's first menstrual period and ending at the reference date.2) and weight gain as the difference of weight (kg) at the reference date and weight (kg) at age 18 years. Women with zero or negative weight gain were defined as having a zero weight gain.Details were collected of height and weight at the reference date and weight at age 18 years. Body mass index (BMI) was computed as weight (kg) divided by the square of height  and lymph node involvement (number positive and number examined) were abstracted from the records at the CSP and at the hospital of diagnosis.Details of stage at diagnosis  but then excluded 11 postmenopausal patients, 11 with unknown cancer stage, and five deceased patients with unknown cause of death so that a total of 717 were available for analysis of BMI, weight and height. The first 199 patients enrolled in the case–control study did not receive the detailed assessment about lifetime exercise habits leaving 525 patients available for the exercise analyses. Of the 199 patients without detailed lifetime exercise data, 192 were determined to be otherwise eligible and were included in the analyses of body size and breast cancer survival; for these patients, we created a separate exercise activity code.χ2P-values were used to assess the relationship of patient characteristics at diagnosis with breast cancer survival. Hazard rate ratios (HR) and 95% confidence intervals (95% Cl) were calculated using Cox's proportional hazards methods  were still alive at the date of last follow-up, with a median follow-up time of 10.4 years (Nearly one-half of patients who died of breast cancer were age 35 years or younger at diagnosis compared to just over one-third of those who were alive at the last follow-up or died from other causes (We observed no clear association of lifetime exercise with risk of death from breast cancer, but higher levels of exercise in the year before the reference date were weakly associated with a of reduced risk of breast cancer death (We observed a nearly 25% reduced risk of death among women in the highest quartile of BMI compared to those in the lowest quartile of BMI, a finding that was not statistically significant (Our findings are consistent with the only other study of physical activity and breast cancer survival which found no relation between risk of breast cancer death and total recreational activity performed in the year before diagnosis (As we collected exercise activity data only for those who reported that they had either competed on a sports team, had serious and regular participation in dance, or had run or jogged regularly for at least one mile, some women who were recorded as having not participated in exercise activities may in fact have participated in some activities. The inclusion of these women in the reference category may bias the associations toward the null value, 1.0. However, the intent of the question was to identify the most active women, and activities among women who did not participate in these types of activities are likely to be limited.Our finding of a weak association of BMI with decreased risk of death is somewhat inconsistent with the body of evidence. Approximately two-thirds of studies have reported an increasing risk of death with increasing BMI or weight, and the remaining studies generally reported no association . The womA concern in this as in any follow-up study is loss to follow-up. The patients who were lost to follow-up early on may have differed from those with complete follow-up, leading to bias in the results. However, we were able to follow-up 79% of the patients to the end of the follow-up period and 92% to within 2 years of this point, so it is unlikely that such losses resulted in substantial biases. Another possible limitation is that recall of past exercise activities resulted in some misclassification, particularly those decades before interviews. However, we obtained activity information only from those who indicated that they had participated in serious sports activities or dancing, which allowed us to identify women engaged in strenuous exercise. Although some misclassification undoubtedly occurred, it is likely that our methods resulted in separation of the most active from the least active cohort members. Breast cancer diagnosis may have influenced recall of past exercise activities, but since all patients in the cohort were interviewed after learning their diagnoses, they should all have been similarly affected. All women in the cohort were interviewed prior to the widespread publication of papers indicating that exercise activity was associated with reduced breast cancer risk.It is unclear whether prediagnosis physical activity levels are markers of postdiagnosis activity levels or whether postdiagnosis physical activity influences survival. A recent study reported 24–50% decreases in postdiagnosis compared to prediagnosis physical activity levels of breast cancer patients (Overall, we observe no association of lifetime exercise with breast cancer survival and only a weak association of higher levels of recent exercise with breast cancer survival. In contrast, we find a weak association of higher BMI levels with reduced risk of breast cancer death. It remains unclear whether recent, prediagnosis activity, and body size levels are indicators of postdiagnosis levels. Further examination of physical activity and body size during both pre- and postdiagnosis periods will improve our evaluation of the impact of these factors on breast cancer survival.


Epidemiological and experimental evidence indicates that oestrogens are involved in the carcinogenic promotion of human breast cancer. We have undertaken a pilot trial of tamoxifen, an anti-oestrogen, compared to placebo given to 200 women at a high risk of developing breast cancer. The results of this trial show that acute toxicity is low and that accrual and compliance are satisfactory. Furthermore, biochemical monitoring of lipids and clotting factors indicate that tamoxifen may reduce the risk of cardiovascular deaths. At this stage no untoward long-term risks have been identified, and it is therefore proposed that a large multicentre trial should be started.


A subanalysis among 176 036 primiparous women showed a substantial risk reduction if the mother delivered a son , but essentially null if she delivered a daughter . These results suggest that the effect of pre-eclampsia/hypertension may be attributed to factors associated with the particular pregnancy rather than an underlying biological trait of the mother. The stronger risk reduction related to having a son suggests a role for sex-dependent hormones in pregnancy.If the negative association between pre-eclampsia and subsequent breast cancer risk differs by gender, this would strengthen the hypothesis that factors intrinsic to the particular pregnancy may explain the association. The study included 701 006 parous Norwegian women with follow-up for breast cancer through the Cancer Registry of Norway. Breast cancer risk was lower in women with pre-eclampsia/hypertension in their first pregnancy, compared to other women , after adjustment for age at first birth, maternal birth year, length of gestation, marital status, and parity. The risk reduction was slightly greater if the woman delivered a son as opposed to a daughter (relative risks of 0.79  Women who are diagnosed with pre-eclampsia in pregnancy may have a lower risk for breast cancer later in life compared to other parous women  althoughThe influence of pre-eclampsia on subsequent breast cancer risk could be attributed to factors associated with the particular pregnancy, but the effect could also reflect an underlying biological trait in a woman that decreases the risk for developing breast cancer. One approach that may distinguish between these possibilities would be to study whether the association with pre-eclampsia is modified by pregnancy-specific factors, for example offspring gender. If breast cancer risk associated with pre-eclampsia differs according to gender of the offspring the hypothesis that the effect of pre-eclampsia could originate from that particular pregnancy would be strengthened.In a cohort of 701 006 women in Norway, pregnancy-related information from the Medical Birth Registry was linked to the National Cancer Registry. The aim of the study was to compare breast cancer risk in women who had experienced pre-eclampsia or hypertension in their first pregnancy to the risk of women who were normotensive, and to study whether gender of the offspring modifies the association.www.mbr.no). Pre-eclampsia and gestational hypertension were recorded as indicated in the standardised form of the Medical Birth Registry and described elsewhere (www.kreftregisteret.no). Using the unique identification number of Norwegian citizens, we linked all women registered at the Medical Birth Registry to the national Cancer Registry, and identified women who had developed cancer after delivery. A total of 751 581 women were recorded with a singleton first birth in the Medical Birth Registry between 1967 and 1998. Women with missing or improbable combinations of the offspring's sex, gestational age or birth weight in their first delivery were excluded from the analyses (n=48 030). We also excluded women who delivered before 22 weeks of gestation or whose offspring's birth weight was less than 500 g (n=880). Women diagnosed with cancer before the beginning of follow-up (n=1345), and women lost to follow-up (n=320) were also excluded, leaving 701 006 women for analysis. For these women information was available on length of gestation, birth weight, and the offspring's gender. By linkage to the Cancer Registry, we followed these women from the time of delivery (1967–1998) until the diagnosis of cancer, until death from any cause, or to the end of follow-up , whichever occurred first.Data were derived from the Medical Birth Registry of Norway that comprises all births since 1967, and the Norwegian Cancer Registry, which has registered incident cancers since 1953. Midwives and doctors complete a standardised form to notify the Medical Birth Registry about each birth in the country  or term (⩾37 weeks) delivery. In the analysis, we adjusted for potential confounding by the women's year of birth (5 year categories), age at delivery (5 year categories), length of gestation (completed weeks), parity, and marital status, using Cox regression analysis . Precision of the relative risks was estimated by 95% confidence intervals, and the interaction between pre-eclampsia and offspring gender was statistically tested in the regression model.During follow-up, a total of 9160 incident cases of breast cancer were diagnosed among 701 006 women . Among cP=0.06). If pre-eclampsia/hypertension was combined with pre-term delivery, the risk reduction associated with having a son and not a daughter was even greater .In women who delivered a son, the risk reduction was slightly greater  than for women who had a daughter , but the test for interaction was of borderline significance . Further stratification by gestational age (pre-term or term pre-eclampsia) among the primiparous women was not calculated because of the small number of breast cancers in women with pre-term pre-eclampsia.In a subgroup of 176 036 women who remained primiparous throughout the study period, a total of 1916 incident cases of breast cancer were diagnosed during follow-up, and 121 of these cases occurred among the 11 945 women who had pre-eclampsia or hypertension in pregnancy . SimilarWe found that the reduced risk of breast cancer associated with pre-eclampsia or hypertension in first pregnancy was substantial among women who had a son, but essentially null in women who delivered a daughter. Previous studies have also shown an inverse association related to pre-eclampsia , but no Clinical information included in health registries is rarely validated, partly because a gold standard for the diagnosis is not available. Although this may be a weakness of this study, it is equally clear that the diagnosis of pre-eclampsia  in the Medical Birth Registry did not depend on future diagnosis of breast cancer. Consequently, any bias in the association between pre-eclampsia or gestational hypertension and subsequent breast cancer risk is likely to be non-differential, and lead to underestimates of the real effect.In the general population, shorter lengths of gestation appear to reduce the pregnancy-related protection against breast cancer , indicatAn inverse association between pre-eclampsia and breast cancer risk has now been confirmed in a number of studies. It is, however, not clear if the reduction in risk is attributable to long-term effects of the particular pregnancy, or whether women who develop pre-eclampsia exhibit an underlying biological trait that is somehow protective against breast cancer development.A combination of genetic susceptibility and abnormal placentation is thought to constitute the basis for pre-eclampsia, but clinically, the severity of the syndrome depends on degree of hypertension and proteinuria from 20 weeks of gestation and onwards. Pre-eclampsia is characterised by a disturbance in the fundamental balance between steroid and other pregnancy hormones during pregnancy . MaternaOur results suggest that the protective effect associated with pre-eclampsia was restricted to women who delivered a son. This finding may support the hypothesis that a protective effect of pre-eclampsia on breast cancer risk could originate from the particular pregnancy, rather than indicating an underlying biological trait that is protective against breast cancer in women who develop pre-eclampsia.


This report presents information on risk factors for oesophageal cancer in Bulawayo, Zimbabwe. The data analysed were from the Cancer Registry of Bulawayo for the years 1963-77, when all registered patients were interviewed using a standard questionnaire. The age-standardised incidence rates in the urban population of Bulawayo in the first 10 year period were 58.6 per 100,000 in men and 8.1 in women. The distribution of risk factors was assessed in 881 oesophageal cancer cases  and a control group comprising other non-tobacco- and non-alcohol-related cancer (5238) cases. There was a marked geographical gradient in risk in both sexes, which remained after adjustment for lifestyle variables. In men tobacco smoking was significantly associated with risk of oesophageal cancer, with the relative risk rising to 5.7 among smokers of 15 or more g day-1; this effect is independent of alcohol drinking. Among women who had ever smoked tobacco, the relative risk was 4.0 compared with those who had never smoked. Alcohol intake showed no independent effect on risk. Low socioeconomic status  and working as a miner  conferred increased risks in comparison with men of high socioeconomic status.


To test the hypothesis that high levels of endogenous oestrogens increase the risk for developing breast cancer, concentrations of oestrone, oestradiol and oestriol were measured in 24 h urine samples from 1000 women participants in a prospective study of breast cancer on the island of Guernsey. Sixty-nine subjects were diagnosed with breast cancer subsequent to urine collection. Among women who were premenopausal at the time of urine collection, cases excreted less oestrogen than controls; the odds ratios (95% CI) for breast cancer in the middle and upper thirds of the distribution of oestrogen excretion, in comparison with the lower third , were 0.5(0.2-1.2) and 0.4(0.2-1.1) respectively for oestrone, 0.8(0.4-1.8 and 0.4(0.2-1.1) for oestradiol, 0.7(0.3-1.6) and 0.7(0.3-1.6) for oestriol and 0.9(0.4-2.0) and 0.5(0.2-1.3) for total oestrogens. Among women who were post-menopausal at the time of urine collection, the trend was in the opposite direction, with an increase in risk associated with increased oestrogen excretion; the odds ratios were 0.9(0.3-2.2) and 1.1(0.5-2.8) for oestrone, 0.8(0.3-2.3) and 1.9(0.8-4.6) for oestradiol, 1.5(0.6-3.9) and 1.8(0.7-4.6) for oestriol and 0.9(0.4-2.6) and 1.9(0.7-4.7) for total oestrogens. The trends of increasing risk with increasing oestrogen excretion among post-menopausal women were statistically significant for oestradiol (P = 0.022) and for total oestrogens (P = 0.016). We conclude that high levels of endogenous oestrogens in post-menopausal women are associated with increased breast cancer risk, but that the relationship of oestrogens in premenopausal women with risk is unclear.


Using the Swedish Family-Cancer Database, the increased risk of breast cancer in women with relatives with the disease did not vary with paternal/maternal lineage. Familial breast cancer heritable component was 73% and the environmental proportion 27%. Familial aggregation of breast cancer in women below age 51 years is mainly due to heritable causes. Although having a mother or sister diagnosed with breast cancer is known to increase a woman's risk of the disease , the mecTwin and other family studies have consistently shown a familial aggregation of female breast cancer . One estIt is unknown whether breast cancer risk associated with family history differs according to the side of the family of the affected relative. Probably due to lack of reliable data, few studies have investigated this possible difference in risk . HoweverThis population-based study investigated breast cancer risk among women having first- and second-degree relatives with the disease, in order to estimate the heritable and environmental components of familial breast cancer, according to women's age; risk was also examined according to paternal/maternal lineage.in situ breast cancer and alive at the date of the case's diagnosis. Odds ratios (ORs) for invasive breast cancer associated with having an affected relative were estimated, using conditional logistic regression. Analyses were adjusted for mother's and father's year of birth, number of maternal and paternal aunts, and number of sisters. The analyses of familial breast cancer risk associated with second-degree family history according to paternal/maternal lineage were adjusted for the above variables excluding number of sisters. Differences between ORs were evaluated using standard χ2 heterogeneity tests.The Swedish Family-Cancer Database was described in detail previously  compared to a grandmother or an aunt(s), as found in a meta-analysis of 74 studies , indicatFew studies have investigated whether breast cancer risk varies according to paternal/maternal lineage . In the This report uses a novel method to estimate heritable and environmental components of a disease. Although these proportions have mostly been measured using twin data, we used first- and second-degree family history. Overall, familial breast cancer was found to be 73% heritable and 26% environmental, suggesting that familial aggregation in young breast cancers is mainly due to heritable factors. Previous studies have found similar results . The herThe Swedish Family-Cancer Database includes information on most of the Swedish population, providing results, which are generalisable to a population of a similar age to the one discussed. The results presented here suggest that familial aggregation in young breast cancers is mainly due to heritable causes.


Some studies have indicated that reproductive factors affect the risk of histological types of breast cancer differently. The long-term protective effect of a childbirth is preceded by a short-term adverse effect. Few studies have examined whether tumors diagnosed shortly after birth have specific histological characteristics.In the present register-based study, comprising information for 22,867 Norwegian breast cancer cases (20-74 years), we examined whether histological type (9 categories) and grade of tumor (2 combined categories) differed by parity or age at first birth. Associations with time since birth were evaluated among 9709 women diagnosed before age 50 years. Chi-square tests were applied for comparing proportions, whereas odds ratios  were estimated in polytomous and binary logistic regression analyses.Ductal tumors, the most common histological type, accounted for 81.4% of all cases, followed by lobular tumors (6.3%) and unspecified carcinomas (5.5%). Other subtypes accounted for 0.4%-1.5% of the cases each. For all histological types, the proportions differed significantly by age at diagnoses. The proportion of mucinous and tubular tumors decreased with increasing parity, whereas Paget disease and medullary tumors were most common in women of high parity. An increasing trend with increasing age at first birth was most pronounced for lobular tumors and unspecified carcinomas; an association in the opposite direction was seen in relation to medullary and tubular tumors. In age-adjusted analyses, only the proportions of unspecified carcinomas and lobular tumors decreased significantly with increasing time since first and last birth. However, ductal tumors, and malignant sarcomas, mainly phyllodes tumors, seemed to occur at higher frequency in women diagnosed <2 years after first childbirth. The proportions of medullary tumors and Paget disease were particularly high among women diagnosed 2-5 years after last birth. The high proportion of poorly differentiated tumors in women with a recent childbirth was partly explained by young age.Our results support previous observations that reproductive factors affect the risk of histological types of breast cancer differently. Sarcomas, medullary tumors, and possible also Paget disease, may be particularly susceptible to pregnancy-related exposure. Some recent studies have indicated that reproductive factors, as well as other hormone-related risk factors, affect the risk of histological types of breast cancer differently -7, possiThe long-term protective effect of a childbirth on breast cancer risk is preceded by a short term adverse effect ,9. The tIn the present register-based study, we examined associations between histological type and grade of breast cancer tumors and traditional reproductive risk factors, as well as time intervals since first and last (most recent) childbirth. Potential relations with age at diagnosis and family history of breast cancer were also explored.Our study included information on 22,867 Norwegian female breast cancer patients diagnosed at ages 20-74 years (mean 50.8 years) during the period 1955 through 1999. Information on reproductive history, that is date of birth for a woman and all her children, was obtained from the Norwegian Population Registry. Information on reproductive history was regarded as complete for women born in 1925 and later. Since 1953, all cancer diagnoses in the country are by law reported to the Cancer Registry of Norway. Linkage of data from different national registers was possible using the unique personal identification number. The data file that served as basis for the present study was generated as part of a large, population-based prospective study on reproductive factors and cancer risk , includith revision, code 170) were considered. For diagnoses made before 1993, a rather crude classification of histological type was made. The classification system then changed from the 4-digit MoTNaC  to the 6-digit ICD-O-2 . Among 23,039 breast cancer diagnoses in our cohort, histological or morphological code was recorded for 22,867 cases (99.3%). Certain histological codes were combined due to changes in classification system over time, and partly due to the low number of cases of each code. A total of 9 groups were defined for histological type  was performed only for about 15% of cases diagnosed before 1993, but almost 75% of cases diagnosed in 1993 and later had histological grade recorded  or histological grade  differed by age at diagnoses, family history of breast cancer, or reproductive factors. To evaluate which categories had largest impact on the overall test for association, and in what direction, we calculated the cell specific contribution to the chi-square statistic (without squaring). An absolute value of this quantity equal to or above 1.96 corresponds roughly to an independent significant contribution at the 5% level. The corresponding critical value for a nominal significance level of 10% is 1.64. A negative value indicates fewer cases, whereas a positive value indicates more cases than expected by chance.Polytomous logistic regression analysis was applied to examine whether associations between the exposure variables and any specific histological type of breast cancer differed from that seen with ductal tumors, the most common histological type. Odds-ratios (OR) for linear trend through ordered categories of the exposure variables were estimated. An OR-value of 1 indicates that the exposure variable considered is equally associated with the histological types that are compared , indicating a similar risk pattern. If the exposure variable is positively associated with risk, an OR-value >1 indicates a stronger association, whereas an OR-value <1 indicates a less pronounced association than for ductal carcinomas. Binary logistic regression analyses were applied in the analyses of association with histological grade. The OR for observing a poorly differentiated tumor (grade 3-4) rather than a well/moderately differentiated tumor (grade 1-2), with increasing levels of an exposure variable (linear trend), was then estimated.The analyses of time interval since a childbirth were restricted to women diagnosed before age 50 years . Diagnoses during pregnancy (DP), defined as starting 9 months prior to date of birth, and diagnoses before 2 years after delivery, comprised a separate category, whereas subsequent time categories were in 4 or 5 year intervals. The analyses with time interval since birth as main exposure variable were adjusted for age at diagnosis and parity, whereas the analyses of parity and age at first birth were adjusted for age at diagnosis and mutually adjusted for each other.Histological types of breast cancer tumors differed significantly by age at diagnosis Table . The proA significant association between histological type and familial risk was seen, but only in women diagnosed before age 50 years Table . Breast Histological type of breast cancer tumors differed significantly by parity and maternal age at first birth Table . MucinouAmong parous women, the proportion of mucinous tumors decreased with increasing parity; the trend estimates indicated an inverse association with risk stronger than that for ductal tumors Table . A similThe proportion of lobular tumors, and also unspecified carcinomas increased steadily with increasing age at first birth Table . In contAmong women diagnosed before age 50 years, a significant overall association between histological type and time interval since first, as well as last birth was observed Table . The proLobular tumors accounted for 4.7% of all cases diagnosed below 50 years (third most common type). The crude proportion of lobular tumors increased markedly with increasing time interval since birth. However, results from the age-adjusted analyses showed an association in the opposite direction, indicating an inverse association with risk stronger than that for ductal tumors , occurred with a significantly higher proportion in women diagnosed 6-9 years after first birth, and 2-5 years after last birth. These time periods frequently overlap, since most women deliver their subsequent children within a few years. However, the age-adjusted trend estimate showed a significant increase rather than decrease in the proportion of medullary tumors with increasing time since birth Table . The posUnspecified adenocarcinomas/carcinomas , occurred with a significantly higher proportion in women diagnosed <2 years after last birth. A significant decreasing trend was seen both with time interval since first and last birth Table . SarcomaPaget disease (1.2%) appeared to be more common in women diagnosed 2-5 years after last birth compared to any other time period since birth Table . The numThe proportion of poorly differentiated tumors decreased steadily with increasing age Table . This agNo significant overall association was found with family history of breast cancer Table . Among nNo overall significant difference in the proportion of high-grade tumors was seen between nulliparous and parous women Table . Among pAmong women diagnosed before age 50 years, the proportion of poorly differentiated tumors decreased steadily with increasing time since first and last birth Table . The assIn this large register-based study of breast cancer cases, histological type and grade of tumors were found to differ significantly by age, parity, and maternal age at first birth. The difference between nulliparous and parous women by histological type was most pronounced among women at pre- and perimenopausal ages. Ductal tumors represented the most common histological type in all subgroups defined by time interval since birth. Nevertheless, certain histological types appeared to be more susceptible to an adverse effect of a pregnancy. Further knowledge on this issue may provide important information in the treatment of women diagnosed with breast cancer shortly after a childbirth.The results from this study need to be interpreted with some caution. Our study comprised information on breast cancer cases diagnosed in Norway in the period 1955-99. The histological classification system and procedures have varied over time, and may also have varied at the individual as well as institutional level. Still, the distribution of histological types across the two main calendar periods considered (before/after 1993), was roughly the same. Moreover, the observed age distribution of histological types appeared to be rather similar to that reported by others ,29, exceEstablished associations between reproductive factors and the risk of breast cancer will mostly reflect associations with ductal tumors, which comprise about 80% of all breast cancer cases. A complete risk analysis of each subtype, in particular when considering time-related effects of a pregnancy, is difficult due to the low number of cases of certain histological types. However, the population at risk for each histological type in our cohort is the same, and information from the present study with respect to contrasting histological types, is thus comparable to the few previous studies that have calculated risk estimates specific to histological type, despite different measures of effect. Most of these studies, however, have focused on traditional reproductive factors, rather than time-related effects of a childbirth.Consistent with results from previous studies ,7, our rResults from some previous studies have indicated that lobular tumors may be more strongly associated with age at first birth than other histological types of breast cancer -3,7. OurThe transient increase in risk of breast cancer shortly after a childbirth is assumed to be related to a growth enhancing effect of pregnancy-related factors on pre-malignant breast cells ,21. BiolThe proportion of ductal tumors seemed to be particularly high among women diagnosed <2 year after first childbirth, but no clear trend with time since birth was seen. In one previous study of breast cancer diagnosed during pregnancy , all tumThe crude proportion of lobular tumors increased with increasing time since birth, but the age-adjusted trend estimate indicated an association in the opposite direction, with a decreasing trend in risk stronger than for ductal tumors. Lobular tumors have been found to be particularly sensitive to hormonal exposure ,5, and mMedullary tumors occurred with significantly higher frequency 2-5 years after last birth in our study. The unadjusted trend estimate indicated a decrease in the proportions of medullary tumors with increasing time since birth. The age-adjusted analyses, however, suggested an association in the opposite direction. The observed non-linear pattern with time since birth, with a peak 2-5 years after last birth, made interpretation of estimated linear trends somewhat difficult though. Thus, our data may indicate that medullary tumors are particularly susceptible to pregnancy-related exposure. Medullary tumors have previously been noted to progress rapidly from a pre-clinical to a clinically detectable phase . The tumResults from the present study also suggested that a pregnancy may have particular impact on the development of Paget disease. As far as we know, no previous studies have reported that this disease may be more common in the first years following a childbirth. Consistent with previous suggestions ,46, mostThe proportion of unspecified carcinomas decreased significantly with increasing time since birth in our study, both in unadjusted and adjusted analyses. The rather high proportion of unspecified carcinomas in women diagnosed shortly after birth, however, may reflect difficulties with classification of the tumor. About half the tumors within this subgroup were poorly differentiated.The present finding that younger women, and women with recent childbirths more often have poorly differentiated tumors, is consistent with results from previous studies ,50. ResuConsistent with results from two previous studies ,51, we oConsistent with findings from previous studies that have calculated risk estimates specific to histological subgroups, our results indicate that the associations between reproductive factors and the risk of breast cancer differ by histological type of the tumor. The overall protective effect of a pregnancy seemed to be particularly pronounced in relation to mucinous and tubular tumors. Differentiation of breast cells after a full-term pregnancy, but also a long-term reduction in prolactin levels, have been suggested to explain the protective effect of a childbirth on the risk of breast cancer. It is difficult to draw a final conclusion whether any of these hypotheses are more likely to explain associations with the risk of developing specific histological types of breast cancer tumors.Certain histological types occurred with a significantly higher proportion in women diagnosed shortly after a childbirth, indicating a higher susceptibility to an unfavorable effect of pregnancy-related factors. Both hormonal and non-hormonal mechanisms have been suggested to explain the short-term adverse effect of pregnancy on breast cancer risk. Results from our multivariate regression analysis indicated that lobular tumors, presumably the most hormone-sensitive tumor type, occurred with higher frequency than expected shortly after a childbirth. The number of such tumors during this time period was very low though, making results from the multivariate analyses very imprecise. In view of findings from previous studies, the significantly higher proportion of women diagnosed with Paget disease in the first years following a childbirth, gives support to the hypothesis that an inflammation process in connection with pregnancy and lactation may contribute to progression of breast cancer disease. The higher frequency of women with Paget disease with increasing number of births may reflect a higher susceptibility to an inflammation in multiparous women.The observed higher proportion of sarcomas and medullary tumors among women with a recent childbirth may be related to young age of the women, since we cannot rule out the possibility of residual confounding. The higher frequency of medullary tumors among multiparous women, however, is consistent with an unfavorable effect of a pregnancy on this particular histological type of breast cancer. Additional studies with more detailed information on histological type of tumor are needed to further explore these issues. Improved knowledge may have implications both for prevention and treatment of breast cancer disease.The authors declare that they have no competing interests.GA initiated the study, conducted statistical analyses and prepared initial draft and revisions of manuscript. IH contributed on methodological issues and ST contributed on medical issues. All authors contributed to the scientific content of the manuscript, commented on revisions and read and approved the final version.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/10/226/prepub


Obesity and physical activity are modifiable risk factors in the development of post-menopausal breast cancer. The aim of this study was to assess the level of awareness and prevalence of these factors in women attending family history clinics.Women attending the breast cancer family history clinic from 2004 to 2006 completed a questionnaire (SP15 format) about their knowledge of and exposure to various diet and lifestyle factors. All women had been counselled by a Consultant Cancer Geneticist and were given verbal and written information on the effect of life style on breast cancer risk. Responses were analysed using SPSS™ software.The response rate was 70% and two thirds of women were post-menopausal. The prevalence of obesity in post-menopausal women was 37% with 40% being overweight. The majority of women consumed a healthy balanced diet. Only 15% of post-menopausal women exercised for more than 4 hours per week. Two-thirds of women correctly stated that obesity increases their breast cancer risk and 73% of these were overweight or obese. Over 87% were correctly aware of the role of family history, 68% of a high fat diet, and 57% of hormone replacement therapy in the development of breast cancer.Women attending family history clinics lead a high risk lifestyle for the development of breast cancer with high prevalence of obesity and low levels of physical activity. A campaign of patient education is needed to promote healthy lifestyle choices, especially physical activity, in these high-risk women. Breast cancer is the most common cancer in women in the UK and is twice as frequent as any other female cancer . Women wThe aim of this study was to assess the level of awareness of and prevalence of life-style related risk factors, such as obesity, physical activity and high fat diet, in women attending breast cancer family history clinics.This cross-sectional survey was carried out at a large teaching hospital in the West Midlands, England. All women who had attended the Breast Cancer Family History clinics between 2004 and 2006 were invited to participate in order to allow comparison between pre- and post-menopausal women. The questionnaires were in SP15 format.The patients were handed questionnaires at the family history clinic (FHC) visit or the questionnaires were sent to them through the post. Data on height and weight were used to calculate BMI. The women were questioned on their lifestyle choices such as smoking habits (cigarettes per day), alcohol intake (units per week), level of physical activity (hours per week) and dietary habits. Questions were also asked about their knowledge of conventional risk factors such as reproductive, contraceptive and hormone replacement therapy. For the purpose of this study, post-menopausal status was defined as 50 years of age or above. Women who had previously had a hysterectomy were categorised as post-menopausal.Responses were analysed with frequencies, single variable and multiple response analyses using SPSS software programme™.Of the 130 women who were approached, 92 returned their questionnaire (response rate 71%), although not all women answered all questions and two questionnaires were excluded due to lack of data.The mode age group was over 60 years (26%), whilst 6% women were 35 years or younger. Seventy-two women responded to the question on ethnicity and the majority (93%), described their ethnicity as white, British, with the remaining 5 describing themselves as Afrocaribbean. Of the 90 women who responded to the question on menopausal status, sixty were post-menopausal.The prevalence of obesity among the post-menopausal women was 36% (21/59) with a further 41% (24/59) in the overweight range. In the pre-menopausal group, less than half of the women (14/29) were categorised as overweight or obese.Eighty-eight women stated their alcohol consumption and all but one of the post-menopausal women drank within recommended national limits. Seven of the nine women who smoked were post-menopausal and all nine women stated that they thought smoking increased their risk of breast cancer.Eighty-nine women answered these questions. Most women (60%) met the Department of Health guideline of eating five portions of fruit and vegetables each day, whilst over a quarter (30%) stated that they never ate any fried food and over half (58%) that they occasionally did. Sixty two percent of women stated that they "occasionally" ate fast foods and 42% ate red meat on a weekly basis. The results for the women in the post-menopausal group are shown in figure Eighty-eight women responded to questions relating to their exercise levels. Nearly a quarter 21/88) of all women stated they did no exercise at all and over three-quarters (16/21) of these women were post-menopausal. Only 15% (9/59) of the post-menopausal women compared to 35% (10/29) of pre-menopausal women exercised for more than 4 hours per week (figure 1/88 of aFamily history (91%) and smoking (86%) were the strongest risk factors thought to increase the risk of developing breast cancer. Sixty-seven per cent of post-menopausal women correctly stated that obesity could increase their risk of developing the disease. However, 73% of women who recognised that obesity is a risk factor for developing breast cancer were either overweight or obese. Seventy-three per cent of pre-menopausal women incorrectly stated that obesity increased their individual risk of developing breast cancer.There is a high prevalence of obesity and being overweight amongst high-risk women attending breast cancer family history clinics. This is particularly the case for post-menopausal women in whom obesity is a risk factor for the development of the disease. The prevalence of obesity in the study population was fairly representative of the UK population, as statistics released by the WHO in 2006 stated 30–40% of women in the post-menopausal age group in the UK were overweight and 25–31% were obese . In the Ecological studies have shown national per capita fat consumption correlates highly with breast cancer mortality rates . Most re2) and actively encouraged and supported to achieve this.Evidence suggests that lowering a woman's lifetime exposure to oestrogens may reduce the risk developing breast cancer. The only practical strategy in achieving this is through changes in lifestyle, which aim to reduce obesity after the menopause. Post-menopausal women, particularly those in higher risk groups, should be educated on the benefits of maintaining a healthy body weight (BMI between 18.5 and 24.9 kg/mMost women recognised that a positive family history was a risk factor for development of the disease. The reason this figure was not 100% could be due to a lack of awareness or incorrect response ticked on the part of the patient, or inadequate explanation on the part of healthcare professionals. The high level of knowledge of smoking as a risk factor for cancer in general can be credited to the recent campaigns to raise public awareness and could explain the low rates of smoking in these women. This highlights the potential benefit that interventions may have if women are actively educated about the contribution of obesity in the development of post-menopausal breast cancer. Most women attending the family history clinics identify themselves as being at high risk and may be more amenable to engage in health promoting behaviours that are perceived to be risk reducing in nature. Evidence from studies suggests that reducing levels of obesity can reduce the number of breast cancer cases by one tenth [Obesity is a potentially modifiable risk factor in the development of breast cancer in post-menopausal women. The prevalence of obesity and being overweight in postmenopausal women with a positive family history are high. There is still a degree of uncertainty amongst women as to the role of obesity in the risk of developing breast cancer. Lack of physical activity appears to be a key area for intervention. This study identifies that there is scope for patient education and weight management by increased physical activity in women attending the family history clinics for breast cancer. Increased physical activity has the potential to decrease breast cancer in post-menopausal women. A campaign of patient education is particularly needed to promote healthy lifestyle choices in this group of patients already at a higher risk of breast cancer due to a positive family history.The authors declare that they have no competing interests.ARC conceived the idea and supervised PB to design the study and statistical analyses. CR participated in writing up the manuscript. All authors read and approved the final manuscript.


POT1, TEP1, TERF1, TERF2 and TERT were genotyped. We did not identify any significant associations between individual SNPs or haplotypes and breast cancer risk; however, data suggested that three correlated SNPs in TERT  may be associated with reduced risk of breast cancer among individuals with a family history of breast cancer . In conclusion, our data do not support substantial overall associations between SNPs in telomere pathway genes and breast cancer risk. Intriguing associations with variants in TERT among women with a family history of breast cancer warrant follow-up in independent studies.Telomeres, consisting of TTAGGG nucleotide repeats and a protein complex at chromosome ends, are critical for maintaining chromosomal stability. Genomic instability, following telomere crisis, may contribute to breast cancer pathogenesis. Many genes critical in telomere biology have limited nucleotide diversity, thus, single nucleotide polymorphisms (SNPs) in this pathway could contribute to breast cancer risk. In a population-based study of 1995 breast cancer cases and 2296 controls from Poland, 24 SNPs representing common variation in  An estimated 90% of eligible cases were identified through a rapid identification system at five participating hospitals. Information from Cancer Registries was used to identify the remaining 10% of eligible breast cancer cases. Eligible control subjects were residents of Warsaw and Łódź who did not have a history of breast cancer at enrollment. Controls were randomly selected from population lists, and frequency-matched to breast cancer cases by city and 5-year age groups. Women provided a personal interview on known and suspected risk factors. Venous blood samples were collected by a trained nurse. The study protocol was reviewed and approved by local and National Cancer Institute (NCI) Institutional Review Boards. All participants provided written informed consent. Of the 3037 eligible cases and 3639 eligible controls identified, 2386 (79%) cases and 2502 (69%) controls agreed to participate in the personal interview. The present study is limited to women with blood DNA samples: 1995 cases (6% in situ) and 2296 controls, which represented 84 and 94%, respectively, of the study population.The design of this population-based breast cancer case–control study has been described . If an rs number has not yet been assigned, an E number (e.g. E3675_301) is provided, based on nomenclature from the SNP500Cancer project . Twenty-four SNPs in ics, NCI . Assay c project .TERF1 IVS9-163T>C  and TERT Ex2-659G>A . Genotypes were called for >98% of all SNPs. Genotype frequencies for all loci were in Hardy–Weinberg equilibrium among controls.A total of 100 duplicate DNA pairs were ⩾98% concordant for each SNP with the exception of n=31), even spacing across the gene, SNPs with potential functional implications and/or patterns of nucleotide diversity and linkage disequilibrium (LD) previously determined through extensive re-sequence analysis (http://tagzilla.nci.nih.gov/). R2H was the pairwise correlation coefficient between SNPs determined by these programs. SNPs with R2H ⩾0.8 were considered highly correlated.Initial SNP selection criteria included MAF greater than 5% in Caucasians from SNP500 Cancer ) has minimal LD and eight common SNPs in the 31 SNP500 Caucasians. The five TEP1 SNPs genotyped  has very limited nucleotide diversity with only four common SNPs in SNP500 Caucasians between introns 7 and 9  has only four common SNPs between introns 1 and 8 and a very small common haplotype block between introns 6 and 7  (R2H>0.8), but did not cover the SNP in intron 1 , which only had a MAF of 5% in SNP500 Caucasians. Studies of genetic variation in TERT  are complex due to low nucleotide diversity and limited LD  due to lack of assay availability, which would have increased the R2H to 0.83; however, we did genotype Ex16+203C>T (rs2853690), which was only 1776 bp 3′ of TERT Ex14+7C>T. The four SNPs genotyped in POT1  spanned 73.1 kbp (−1386G>A through IVS13-98T>G), a region with strong LD and 11 common SNPs in SNP500 Caucasians  and 95% confidence intervals (CI) from logistic regression models with dummy variables for matching factors (age in 5-year categories and study site (Warsaw or Łódź)) were used to estimate relative risks for the genotypes examined. The association between genotypes and breast cancer risk was tested using a 2 degrees of freedom (df) likelihood ratio test and a trend test. Heterogeneity of genotype ORs among groups of women defined by age categories and family history of breast cancer in first-degree relatives were evaluated by introducing interaction terms in logistic regression models. A positive family history was defined for women reporting one or more first-degree relatives diagnosed with breast cancer in the study questionnaire. An additive genetic model was assumed in interaction analyses. Age was considered as a continuous variable in tests for genotype–age interactions. Haplotypes were constructed for cases and controls using PHASE v2.1  and HaplMost cases (74%) and controls (69%) in the study were postmenopausal, and cases were diagnosed at an average age (standard deviation) of 56 (±10) years. The established risk factors were associated with breast cancer risk in comparable direction with similar estimates of magnitude reported by others  and TERT Ex2-659G>A (A305A)  (TERT Ex2-659G>A (A305A) and two other linked TERT SNPs appeared to be limited to individuals with a family history of breast cancer in first-degree female relatives, −1381C>T , −244C>T , and Ex2-659G>A (A305A)   . The inv39–0.84) . These STERT and for each of the two major haplotype blocks in TERT . There were no significant associations for haplotypes in the primary case–control analysis (data not shown). However, a block 1 haplotype (ATCCA) in TERT was associated with protection from breast cancer when only individuals with a family history of breast cancer were studied .Haplotype analyses were performed for all SNPs studied in TERF2 IVS-42T>C variant alleles and breast cancer risk . No other associations were significantly modified by family history of breast cancer  and breast cancer risk. The SNPs genotyped were representative of common genetic variation across the genomic region of interest, and showed no significant overall associations with breast cancer risk. However, data suggested association between variants in TERT among women with a positive family history of breast cancer.To our knowledge, this is the first study to investigate genetic variation within genes important in telomere biology  suggested longer telomere length in with TT homozygotes compared with CC  was also associated with a reduced risk of breast cancer in individuals with a family history of breast cancer, however, the functional significance of the SNP is unknown. It does not appear to affect an intron–exon splice site , and could be related to breast cancer risk based on the role suggested for telomere biology in this disease (TERT −1381C>T, −244C>T, Ex2-659G>A and the corresponding haplotype in individuals with a family history of breast cancer are intriguing and warrant follow-up in independent studies.The SNPs evaluated in this study were chosen based on previous knowledge of common genetic variation resulting from re-sequence analysis, captured most of the common variation in the five studied genes (i.e.


Among 288 breast cancer patients , we identified 26 families with a history of breast cancer, including a minimum of three first- or second-degree relatives. Complete pedigrees with verified malignancy data from the Finnish cancer registry were constructed for 22 families. The median age at breast cancer diagnosis of the young probands (< 40 years of age) was 35 years and of bilateral probands was 54 years. The relatives of the young probands were diagnosed with breast cancer at a younger age (median age 54 years) than the relatives of the older  probands (median age 60 years). Standard life-table methods were used to compare the risk of breast cancer in the family members with that of the general population. Among the relatives of the young probands, the increased breast cancer risk occurred in the early post-menopausal period, whereas the risk estimate for the relatives of the bilateral probands closely followed that of the general population. In both groups, however, those family members reaching the age of 80 years had a cumulative probability of over 50% of developing breast cancer. The standard life-table method proved useful when assessing the age-specific risk for familial breast cancer, taking into account numerous family members as well as their age at disease onset. This kind of analysis can be performed in populations for which reliable cancer registry data are available. It provides a useful tool for selecting individuals for imaging and mutation screening, counselling and experimental chemoprevention programmes.


The overall risk for cancer among 19 856 parents of schizophrenic patients in Denmark was not increased; however, a 30% increased risk for lung cancer was observed in mothers , suggesting an indirect effect on cancer risk mediated by life-style factors. The belief that psychological stress causes cancer has a long history, but scientific evidence remains contradictory to date .A son or daughter with severe mental illness, such as schizophrenia, is associated with significant grief, sorrow and feeling of loss constituting psychological distress among family members . We inveFrom the nationwide Danish Central Population Register (CPR) we identified all 2 013 848 parents born in Denmark, alive on 1 April 1969 whose children were born after 1935 and were living between 1 April 1969 and 1 January 1983. Only parents whose children were over the age of 15 years at the termination of follow-up on 31 December 1997 were included since less than 1.5% of schizophrenia cases develop before that age  among parents with schizophrenic offspring relative to parents without schizophrenic offspring was estimated by log-linear Poisson regression with the GENMOD procedure in SAS 8.01. The RRs were calculated by sex, adjusted for age and calendar period (in 5-year categories) and number of children. All covariates were treated as time-dependent variables using the categories with the largest number of cases as the references. The parents were classified as exposed only from the date of schizophrenia diagnosis in the offspring and thus, parents contributed person-years at risk to the nonexposed group until schizophrenia is diagnosed in the offspring. From that date onwards the parents were contributing person-years as exposed.There were 19 856 parents in the exposed cohort and 1 979 216 parents in the unexposed cohort. The 1 999 072 cohort members had an average follow-up time of 24.2 years and contributed 48 343 429 person-years at risk.The overall risk for cancer among parents whose offspring were diagnosed with schizophrenia was 1.00  for fathers and 0.97  for mothers (We found no evidence that schizophrenia in an offspring was associated with an increased risk of overall cancer in the parents. There was an excess risk for lung cancer in mothers to schizophrenic offspring but this was not observed in fathers.Our study has the advantage of access to nationwide registries with complete coverage (Our study is in line with previous studies, suggesting that increased overall cancer risk attributable to stressful life events is small if any at all (Taken together the evidence from this analysis provides no support for a direct effect of psychological stress on cancer aetiology.


The impact of the screening process on generic health status did not differ between risk categories. Relatively more women reported mammography as quite to very painful (30.1%) compared to MRI. Anxiety was experienced by 37% of the women undergoing MRI. We conclude that screening for breast cancer in high-risk women does not have an unfavourable impact on short-term generic health-related quality of life and general distress. In this study, high-risk women who opted for regular breast cancer screening had a better health status than women from the general population.The effectiveness of intensive surveillance in women at high risk for breast cancer due to a familial or genetic predisposition is uncertain and is currently being evaluated in a Dutch magnetic resonance imaging (MRI) screening (MRISC) study, in which annual imaging consists of mammography and MRI. Unfavourable side effects on health-related quality of life may arise from this screening process. We examined the short-term effects of screening for breast cancer in high-risk women on generic health-related quality of life and distress. A total of 519 participants in the MRISC study were asked to complete generic health-status questionnaires  as well as additional questionnaires for distress and items relating to breast cancer screening, at three different time points around screening. The study population showed significantly better generic health-related quality of life scores compared to age-/sex-adjusted reference scores from the general population. Neither generic health-related quality of life scores nor distress scores among the study sample ( Women in Western countries have a 8–10% average lifetime risk of developing breast cancer. One of the risk-increasing factors is a family history of breast cancer .The effectiveness of intensive surveillance in women at high risk for breast cancer is yet uncertain, although preliminary results have been reported  Does the screening process have any impact, negative or positive, on generic health-related quality of life and distress among high-risk women? (2) Do high-risk women who opt for regular screening differ from the general population with respect to generic health-related quality of life?The MRISC study, activated at six family cancer clinics in the Netherlands, is an ongoing prospective observational study for women at increased risk for breast cancer due to a familial or genetic predisposition  . In addiFinally, the questionnaire contained items on sociodemographic characteristics , parity, educational level and employment status) and cancer-related characteristics  of cancer in the past and family history (mother and/or sister(s) affected with breast cancer)).Participating women were divided into subgroups according to three criteria. The first was their cumulative lifetime risk (CLTR) for developing breast cancer, based on the tables of Claus , Student's t-test or ANOVA  and by nonparametric procedures . Age- and sex-adjusted reference scores for the SF-36 and EQ-5D were assigned to participating women at T0, based on their age at T0. The one-sample t-test was used to test whether the difference between the reference and the observed health-related quality of life scores differed systematically from zero. As only sex- and no age-adjusted reference scores for the SOM scale were available, we analysed the differences between observed SOM scale scores and sex-adjusted reference scores by means of a t-test for two independent samples allowing for unequal variances.Differences in distribution of background variables between the different subgroups were analysed by means of the P⩽0.10) difference in distribution between the relevant subgroups as covariates in the model, and then by removing covariates that did not show a significant (P⩽0.05) confounding effect on any of the outcome scores between the subgroups. In all models, we used a compound symmetry covariance structure. The parameters of these covariance matrices were allowed to differ between groups in the models that included one of the three group factors, as this provided for better fitting models.To evaluate changes over time in generic health-related quality of life scores (SF-36 and EQ-5D) and in SOM scale scores for the total group of women, we used a repeated measures ANOVA model with time as the only main effect. Differences in health-related quality of life and SOM scale scores between the various subgroups, including differences over time, were also examined with repeated measures ANOVA models. Three models were fitted, each including the main effect for time, and one of the three factors: risk category (model A), screening modality (model B) and additional diagnostic evaluation (model C); all models included the interaction effect for time with one of the three factors. For each model, selection of relevant confounders was done by initially including age and those background variables  or the MIXED procedure of SAS .All From September 2000 to November 2002, 519 women were approached for the health-status study; 69.6% consented to participate . At NoveP⩽0.01) between the three risk categories. Of the total study sample, 1.6% just started with regular surveillance. Most of the women (88.6%) had (had) a mother and/or sister(s) affected with breast cancer.Sociodemographic and cancer-related background characteristics of the total study sample and the different subgroups are given in P=0.38) and CLTR of developing breast cancer (P=0.36) were found between the study sample (n=334) and the women who refrained from participation in the health-status study (n=109). There were also no significant differences with regard to sociodemographic and cancer-related background characteristics and baseline SF-36, EQ-5D and SOM scale scores between the 288 women with a usable T2 questionnaire and the 46 women (334–288) without a usable T2 questionnaire, except for the vitality score of the SF-36, which was lower for the women without a usable T2 questionnaire .No significant differences with regard to age (P⩽0.01) but small change in visual analogue scale (VAS) scores over time. A post hoc analysis revealed that the mean VAS score at T0 (81.9) differed significantly (P⩽0.01) from the mean T1 score (79.0), which in itself differed significantly (P⩽0.05) from the mean T2 score (80.7). All other generic health-related quality of life scores (SF-36 and EQ-5D utility) and SOM scale scores did not show any significant change over time.The mean score results from the SF-36, EQ-5D and SOM scale at different time points around screening  are shown in P⩽0.01/P⩽0.05) higher SF-36 scores on most scales as compared to the age- and sex-adjusted SF-36 reference scores from the Dutch (P⩽0.01) more favourable compared to the age- and sex-adjusted EQ-5D utility reference scores from the Swedish general population (P⩽0.01) compared to the age- and sex-adjusted reference scores from the Swedish general population , educational level (model B), number of years adhering to regular surveillance (models A and B), frequency of BSE (model A) and mother and/or sister(s) affected with breast cancer (models A and B).P-value range 0.16–0.73) for any of the SF-36, EQ-5D and SOM scales. For none of these scales there was a significant main effect of risk category . The same holds for model B: there were no significant interaction effects between screening modality and time , and no significant main effect of screening modality  for any of the outcome scales. Only for the VAS, there was a significant (P⩽0.01) interaction between additional diagnostic evaluation and time (model C). Women without additional diagnostic evaluation after scheduled screening had higher VAS scores at baseline than those undergoing additional diagnostic procedures , but this difference disappeared at T1 and T2. For the other scales, no significant interaction effects between additional diagnostic evaluation and time  were seen. There was no significant main effect of additional diagnostic evaluation  for any of the outcome scales.The analyses with model A revealed no significant interaction between risk category and time  higher educational level compared to Dutch women aged 15–64 years  as compared to the age-/sex-adjusted reference scores. It seems that high-risk women who choose for regular screening have a better health status than women from the general population. Most of the women opt for intensive surveillance voluntarily, and this may result in a selection of healthy and well-coping women. This was also seen in the Rotterdam screening trial for prostate cancer, where health status among the voluntary attenders was better than among the general population  compared to CBE or MRI, while a large proportion of the women experienced any discomfort during mammography (69.2%) and MRI (45.3%). The documented incidence of pain associated with screening mammography varies from 1 to 62% .We did not investigate the impact of additional diagnostic work-up on generic health-related quality of life during recall. There is evidence that recall after a false-positive mammogram causes elevated levels of anxiety and breast cancer worries, even after receiving reassurance that all is well (Besides intensive surveillance, prophylactic mastectomy is an alternative risk reducing strategy, especially for BRCA 1/2 mutation carriers (We conclude that the screening process does not have an unfavourable impact on short-term generic health-related quality of life and general distress in women at high risk for breast cancer. In this study, high-risk women who opted for regular breast cancer screening had a better health status than women from the general population, which may partly be due to difference in educational level.


Histologic and genetic evidence suggests that at least some columnar cell lesions (CCL) of the breast represent precursor lesions in the low-grade breast neoplasia pathway. However, the risk of subsequent breast cancer associated with the presence of CCL in a benign breast biopsy is poorly understood.The authors examined the association between the presence of CCL and subsequent breast cancer risk in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies . Benign breast biopsy slides were reviewed by pathologists and CCL presence assessed. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the association between CCL and breast cancer risk.P for interaction between CCL presence and BBD category = 0.77).Women with CCL  had an increased risk of breast cancer compared with those without CCL , although this was attenuated and became non-significant after adjustment for the histologic category of BBD . CCL presence was associated with the greatest risk of breast cancer for those with nonproliferative BBD  and the lowest risk for those with atypical hyperplasia (AH) ; however, this apparent heterogeneity in risk across BBD categories was not significant (These results provide evidence that CCL may be an important marker of breast cancer risk in women with BBD but suggest that CCL do not increase breast cancer risk independently of concurrent proliferative changes in the breast. In fact, these lesions have been reported to be present in nearly half of biopsies performed for mammographic microcalcifications and have been identified as the source of three-quarters of biopsy-detected microcalcifications . CCL is u (DCIS) . Althougu (DCIS) ,4, "clinu (DCIS) ,6, "coluu (DCIS) , "atypicu (DCIS) , "atypicu (DCIS) -10, and u (DCIS) . The incu (DCIS)  is facilSome of the earliest evidence suggesting that CCL may be premalignant was their frequent detection near known precancerous and cancerous changes in the breast. Several studies have reported a high frequency of CCL and low-grade DCIS in the same breast ,8,12, wiMounting histopathologic and molecular evidence indicates that CCL may indeed be early precursors to low-grade invasive breast carcinomas. CCL have been proposed as breast cancer precursors largely because of the cytologic and architectural similarities of more advanced CCL to atypical hyperplasia (AH), a suspected precancerous abnormality, and DCIS, a well-established precursor to invasive carcinoma ,8,10. Inet al. did find some suggestion of an increased risk of breast cancer subsequent to CCL, as 9 out of 63 participants with advanced CCL (14.3%) developed subsequent infiltrating carcinomas after eight years of follow-up [et al. found that none of 84 patients with advanced CCL alone developed subsequent breast cancer over a 10-year follow-up [et al. [Descriptive studies among patients with advanced CCL, although unable to quantify the elevation in breast cancer risk associated with CCL, suggest that CCL are unlikely to be a strong risk factor for subsequent breast cancer. While Martel ollow-up , most otollow-up . Similarollow-up  or amongThe very limited epidemiologic evidence on CCL suggests that CCL may be markers for concurrent atypical proliferative changes in the breast rather than breast cancer precursors -27. GiveThe NHS is an ongoing prospective cohort study that began in 1976, when 121,700 female registered nurses between ages 30 and 55 years completed a mailed, self-administered questionnaire regarding their health behaviors, lifestyle factors, and medical histories. Follow-up questionnaires have been sent to participants every two years to obtain updated information. The biennial questionnaires have assessed a variety of known and suspected risk factors for breast cancer, including history of BBD. On the 1976, 1978, and 1980 questionnaires, participants were asked if they had ever been diagnosed with fibrocystic or other BBD and whether this diagnosis had required hospitalization; from 1982 onward, the questionnaires have inquired specifically about BBD confirmed by biopsy. Deaths are reported by family members and the postal service, and regular searches of the computerized National Death Index are also conducted . The NHSin situ were included in the study. Eligible controls were women who completed the questionnaire for the same year that the breast cancer case was reported and had a previous diagnosis of biopsy-confirmed BBD, but were free from breast cancer; within each NHS cohort, they were matched to breast cancer cases on year of birth and year of diagnosis of BBD. We attempted to identify four matched controls for each case, but this was not always possible for logistical reasons. Informed consent was obtained from all participants. The study was approved by the Human Research Committee of Brigham and Women's Hospital, Boston, Massachusetts.We conducted a nested case-control study to assess morphological changes in benign breast lesions and breast cancer risk among participants in the NHS and NHS II who had reported a previous diagnosis of BBD that was confirmed by biopsy. Within this subcohort, eligible cases were women who reported a first diagnosis of breast cancer between 1976 and the return of the 1996 questionnaire in the NHS or between 1989 and return of the 1995 questionnaire in the NHS II. Self-reported breast cancers were confirmed by review of medical records, and both invasive breast cancer and carcinoma et al. [in situ or invasive carcinoma, invalid dates of diagnosis, or insufficient information on laterality, there were a total of 395 cases and 1,610 controls [Eligible cases and controls were contacted for permission to obtain their BBD pathology records and biopsy specimens, and specimens then were obtained from hospital pathology departments when possible. These methods have been described in detail elsewhere ,30. Brieet al. ,32, whicet al. ,33,34. Acontrols ,30. AlthDuring histologic review of benign breast biopsies for breast cancer cases reported in the 1976 through 1996 questionnaires in the NHS and in the 1991 through 1995 questionnaires in the NHS II and for matched controls, the presence of CCL was recorded on the pathology worksheets as "columnar alteration of lobules." At the time these benign breast biopsies were reviewed, CCL were not considered to be of particular interest and were usually not further stratified; thus, the categorization of these lesions as "columnar alteration of lobules" was in keeping with the standard of practice of the time. For the 42 cases and 116 controls from the NHS 1996 questionnaire cycle, presence of CCL subtypes  was assessed rather than the overall presence of CCL. These women with only subtype information were re-categorized by presence or absence of CCL to allow their inclusion in analyses. After exclusion of five subjects having lesions without adjacent tissue for evaluation, the final sample for this analysis included 394 cases and 1,606 controls. Given the small number of cases and controls in which CCL were further classified with regard to the presence or absence of atypia, CCL were considered as a single group for these analyses.The distributions of breast cancer risk factors were examined according to CCL presence among the controls, adjusting for age at benign biopsy when appropriate. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk according to CCL presence. Unconditional rather than conditional logistic regression was used because this analytic approach allowed us to use all cases and controls for whom we had histologic information. We first adjusted only for the matching factors, which were age at breast cancer diagnosis or index date , year of benign breast biopsy , and time since benign biopsy . In another set of models, additional adjustment was made for histologic category of BBD , which is a strong predictor of breast cancer risk . We also2), postmenopausal hormone use , and oral contraceptive use . Because BMI at age 18 appeared to be more strongly related to breast cancer risk than current BMI, we chose to consider adjustment for BMI at age 18 and change in weight since age 18 rather than current BMI. Individual adjustment for these covariates did not change the estimated OR substantially, nor did simultaneous adjustment for the four factors having the strongest influence on the OR . We examined relationships between CCL and estrogen receptor (ER) status, grade, and ipsilaterality in additional unconditional logistic regression models. All statistical analyses were performed using the SAS software package . All tests were two-sided, with P < 0.05 indicating statistical significance.The following covariates were considered as potential confounding factors: first-degree family history of breast cancer , age at menarche , menopausal status , jointly classified parity and age at first birth , BMI at age 18 . We also assessed breast cancer risk factors by case-control status and found that established breast cancer risk factors were associated with breast cancer in our study population, although most of these associations were non-significant. Compared with controls, cases had a higher prevalence of family history of breast cancer, lower mean parity and older mean age at first birth among parous women, higher mean alcohol consumption, and a higher prevalence of postmenopausal hormone use , and the mean time since biopsy was 10.0 years (SD = 7.2 years). Compared with women with no CCL, women with CCL were older at the time of their biopsy and had less time since their biopsies  or when proliferative disease without atypia and AH were collapsed into a single category (P = 0.93).When women were jointly classified according to histologic category and CCL presence, all groups had an elevated breast cancer risk compared with the reference category, nonproliferative BBD and no CCL. Women with both AH and CCL were at highest risk , but this risk was not significantly different from that among those with AH without CCL. Within all BBD histologic categories, breast cancer risk was elevated for women with CCL, with the risk higher for those with less severe BBD . However, there was no evidence of an interaction between CCL and BBD histologic category when either three histologic categories were used , although this analysis excluded those with AH, who have been shown to be at highest risk of subsequent breast cancer. Given the strong correlation between CCL and concurrent AH found by Boulos et al. (P < 0.0005), it is possible that the relative risk for presence of CCL would have been somewhat higher had women with AH been included in the main analysis. As in our study, Boulos et al. found that the elevated risk of breast cancer among those with AH was not further increased among those who additionally had CCL, suggesting that CCL are not an independent breast cancer risk factor among women with AH [et al. that assessed subsequent breast cancer risk from a broad range of benign breast lesions found a non-significantly elevated risk of breast cancer among a small number of women with multiple CCL compared with those with non-proliferative disease and no breast pathology , although no increased risk was found for focal CCL  [et al. because this study used a different pathologic classification scheme in which CCL were considered a proliferative disease rather than a separate entity that could exist in conjunction with either nonproliferative or proliferative BBD.Few previous epidemiologic analyses have evaluated the risk of subsequent breast cancer following detection of CCL, but the magnitude of risk associated with the presence of CCL found in our study is consistent with that reported by Boulos  with AH . Anotherto 1.39) . HoweverOur study is the largest nested case-control study of CCL and breast cancer to date and therefore yields important clues into the relationship between presence of CCL and breast cancer risk. However, given the heterogeneity of CCL, it is possible that assessing risk of breast cancer for all CCL subtypes combined masks an effect of advanced CCL subtypes, which are less common. Histopathologic and molecular evidence suggests that CCL displaying low-grade cytologic atypia, recently termed "flat epithelial atypia" (FEA) by the World Health Organization Working Group on the Pathology and Genetics of Tumors of the Breast , may be However, the malignant potential of FEA remains equivocal, as descriptive and epidemiologic studies fail to support molecular findings, just as they do for overall CCL risk. Most descriptive follow-up studies among women with what would now be classified as FEA, including one with an average follow-up of nearly 20 years, have found progression to invasive carcinoma to be uncommon ,11,23,24et al., only 52 biopsies contained FEA without AH [Although we considered performing a CCL subtype-specific analysis, information on subtype  was collected for only 157 women whose breast cancer or index date was reported on the 1996 NHS questionnaire. We chose not to re-review the biopsy slides for the presence of FEA, as prevalence of FEA appeared very low from the 1996 questionnaire cycle, with only 4 of the women out of 53 with CCL from this cycle having FEA. Because FEA is a rare occurrence, many thousands of breast biopsies would be needed for adequate power to study its relationship with subsequent breast cancer. Moreover, to study the association between FEA and breast cancer independent of AH, an adequate number of women with FEA but not AH would be required. This would only be possible in an extremely large study, as FEA commonly occurs in conjunction with AH. Even in the largest previous epidemiologic study of CCL by Boulos thout AH .The strengths of the study include its prospective design, the confirmation of breast cancer cases through review of medical records, the centralized pathology review of specimens from benign biopsies before the development of breast cancer, and the detailed information on other breast cancer risk factors. Furthermore, ours is the first observational study to compare the risk of subsequent breast cancer by BBD histologic category. Although power was limited to test for heterogeneity by histologic category, our findings suggest that CCL may be a marker of increased risk among those with non-proliferative disease. Such a differential effect of CCL on breast cancer risk across BBD categories could have important implications for clinical management of patients with CCL, especially given that women with non-proliferative disease are typically considered to be at no elevated risk for breast cancer compared with women from the general population.In light of these findings, large epidemiologic studies assessing CCL subtype-specific risks are needed to inform clinical guidelines for the management of CCL. In particular, better understanding is needed as to whether CCL with atypia in the absence of more advanced lesions require treatment similar to that for DCIS. Additionally, adequately powered epidemiologic studies might help elucidate whether CCL are of concern only among women without proliferative disease. Regardless of whether particular CCL subtypes are simply markers for premalignant changes in the breast or precancerous histologic changes themselves, recognition of these lesions is nevertheless important, as detection of CCL via biopsy should prompt additional scrutiny for other pathologic changes in breast tissue that may signal the early development of DCIS or invasive carcinoma.in situ; ER: estrogen receptor; FEA: flat epithelial atypia; NHS: Nurses' Health Study; OR: odds ratio.AH: atypical hyperplasia; BBD: benign breast disease; BMI: body mass index; CCL: columnar cell lesions; CI: confidence interval; DCIS: ductal carcinoma The authors declare that they have no competing interests.SA participated in the study design, data analysis and interpretation, and manuscript drafting. LC participated in the study design, data collection, and manuscript revision. SS and JC reviewed the BBD biopsy slides and participated in the study design and manuscript revision. GC participated in the study design, data collection, and manuscript revision. RT participated in study design, data collection, manuscript revision, and study supervision. All authors read and approved the final manuscript.Supplementary table S1. A Word document containing a table that lists the means and percentages of characteristics by case-control status among participants with benign breast disease (BBD).Click here for file


Risk factors for male breast cancer were investigated in a case-control study of 21 cases and 82 controls admitted to hospital for acute, non-neoplastic, non-hormone-related diseases in the Greater Milan area between 1988 and 1994. More educated men tended to be at higher risk of breast cancer, with a multivariate odds ratio (OR) of 2.6 [95% confidence interval (CI) 0.7-9.4]. The OR was 3.2 (95% CI 1.1-9.6) for those in the higher social class. Men with no offspring were at higher risk than fathers, with an OR of 5.5 (95% CI 1.8-16.7). A history of breast cancer in female relatives was reported by two cases and one control, giving an OR of 8.5 (95% CI 1.1-69.0). Cases were somewhat heavier than controls, and significantly taller, with an OR of 5.7 (95% CI 1.6-19.9) for subjects taller than 170 cm vs shorter ones. The association with weight, however, decreased after allowance for height, and no difference was observed for body mass index. Socioeconomic correlates and family history are similar to well-assessed risk factors for female breast cancer. The associations with anthropometric measures and childlessness may find an explanation in chromosomal abnormalities, such as Klinefelter's syndrome, or other hormone-related disorders.