Although the effectiveness of mammography for women under the age of 50 years with a family history of breast cancer (FHBC) has not yet been proven, annual screening is being offered to these women to manage breast cancer risk. This study investigates women's awareness and interpretation of their familial risk and knowledge and views about mammographic screening. A total of 2231 women from 21 familial/breast/genetics centres who were assessed as moderate risk (17–30% lifetime risk) or high risk (>30% lifetime risk) completed a questionnaire before their mammographic screening appointment. Most women (70%) believed they were likely, very likely or definitely going to develop breast cancer in their lifetime. Almost all women (97%) understood that the purpose of mammographic screening was to allow the early detection of breast cancer. However, 20% believed that a normal mammogram result meant there was definitely no breast cancer present, and only 4% understood that screening has not been proven to save lives in women under the age of 50 years. Women held positive views on mammography but did not appear to be well informed about the potential disadvantages. These findings suggest that further attention should be paid to improving information provision to women with an FHBC being offered routine screening. In the United Kingdom, as part of the national screening programme, routine mammographic screening is only offered to women aged over 50 years. However, women aged under 50 years who are assessed as having a moderate (17–30% lifetime risk) or high (>30% lifetime risk) risk of developing breast cancer are offered annual mammograms. Some women will be eligible for genetic testing, but the majority of women with a family history of breast cancer (FHBC) will have their risk managed through annual mammographic screening as recommended by management guidelines .It has been increasingly recognised as important that individuals make an informed choice regarding whether or not to participate in screening . For womTo our knowledge, this study is the first large, multicentre UK study to elicit the views and knowledge of women with an FHBC regarding mammographic screening. The following key questions are addressed: (1) What do women know about their level of breast cancer risk? (2) What do women know about the purpose, possible consequences and the effectiveness of mammography? (3) What are women's views about having a mammogram?A total of 3740 women were invited to participate in the study if they were aged 35–49 years and had been accepted on an annual screening programme after they had been assessed at specialist family/breast/genetics clinics as being at moderate or high risk of familial breast cancer. Women were excluded if they had a previous diagnosis of breast cancer, an ovarian only family history or were deemed to be low risk.Familial risk assessment and acceptance on a family history programme followed a similar pattern in the clinics participating in the study. The women were referred to specialist clinics by their general practitioner (GP) or by hospital consultants . All women referred to the clinics were asked to complete a family history questionnaire, which was used to assess risk levels. Assessment into a moderate or high risk category was in accordance with the NICE guidelines published in 2004 . Both moTwenty-one centres running clinics for women with an FHBC throughout the United Kingdom sent questionnaires with a reply paid envelope to women 1 month (range 2 weeks to 4 months) before their scheduled mammogram appointment. Where time permitted, centres sent a reminder to women who did not return their questionnaire within 2 weeks.Women who missed one appointment and failed to contact the clinic within 2 months, or those that missed two or more appointments were classified as non-attenders. These women were sent a brief non-attendance questionnaire to elicit their reasons for not attending.The London Multicentre Research Ethics Committee approved the study.The questionnaire included the following items Socio-demographic measures Age, marital status, ethnicity, educational level, number of biological children and menopausal status.Screening history Women were asked whether they had had previous mammograms or previous recall for further tests.Family history Screening centres categorised women as either moderate or high risk. Women provided information on whether a first-degree family member had died of breast cancer or was currently being treated for breast cancer.Concerns about breast cancer Cancer Worry Scale Revised  and ‘if yes, what were you told your level of risk is?’ (low/moderate/high or please describe in your own terms).Risk perception Perception of likelihood of breast cancer was measured by asking women ‘how likely do you think it is that you will develop breast cancer in your lifetime?’ The question was scored from 1 (definitely) to 5 (no chance). Responses were dichotomised by combining ‘definitely, highly likely and likely’ and ‘unlikely, no chance’ for analysis.Perception of comparative risk of breast cancer was measured by asking women ‘Compared to most other women your age, do you think your own chances of getting breast cancer at some time in you life are?’ The question was scored from 1 (much more) to 5 (much less). Both these questions were developed from previous research .What do you think the main purpose of breast screening (mammography) is? (most of them).Of women who go along for a routine screening mammography about how many do you think will be given a normal result (highly unlikely or unlikely breast cancer is present).If, after a mammogram, a woman is given a normal result what do you think this means? (sometimes).After a mammogram, women may be called back because the appearance of the x-ray suggests further tests are needed. How often do you think this happens? (some or a few).Of the women who are called back for further tests after their mammogram, about how many will turn out to have breast cancer Mammography has been proven to save lives from breast cancer in women under the age of 50 years with a family history like yours  would make me feel that I am doing something positive about my risk of breast cancer’ and four negative statements such as ‘Having breast screening (mammography) would be a frightening experience for me’. Items are scored from 1 to 3 (strongly agree/agree), 4 (neither agree nor disagree) and 5–7 (disagree/strongly disagree). The eight items were factors analysed using principal components analysis, which revealed two components: a positive (Cronbach's α=0.72) and a negative (Cronbach's α=0.54). Responses to the positive component were dichotomised into agree (4–12) and neutral/disagree (13–28) for further analysis. The negative component was not analysed further because of the low Cronbach α-score.Reasons for non-attendance Women were presented with 21 statements of reasons for not attending the clinics plus an option to add their own views and were also asked to identify up to three main reasons for not attending.χ2 test and t-test as appropriate. The Yates continuity correction was used when comparisons were made between dichotomised variables. Age and cancer worry scores  were treated as continuous variables. Owing to the large number of comparisons being made, only results that reached a level of significance of <0.01 were considered statistically significant.A descriptive analysis was conducted to explore women's knowledge and views. Percentages and 95% confidence intervals are presented. Further exploratory analyses to investigate differences between groups were conducted using the After ineligible women were excluded, that is, those who completed the questionnaire after their mammogram or >4 months before their mammogram (244), or did not fulfil the inclusion criteria (222), 2321 women completed the pre-screening questionnaire giving a response rate of 62% (2321 out of 3740). In this study, 52 out of 2321 (2%) who completed the pre-screening questionnaire did not attend their mammogram appointment. The sociodemographic, screening history, family history and psychological variables of the whole sample are listed in Awareness of breast cancer risk Of 439 women participating in the programme for the first time, 38% (95% CI: 33.9–43.2) reported being aware that they were at increased risk >5 years ago. Seventeen per cent (95% CI: 13.9–21.2%) of women reported realising they were at risk <6 months ago.Knowledge of level of breast cancer risk Out of the total cohort, 73% (95% CI: 71–74.7) reported they had been told their risk level and 63% (95% CI: 60.5–64.5) reported what they had been told. Of the 1435 women who reported their risk, compared with clinic-risk level, 69% (95% CI: 66.0–70.9) reported their risk correctly. Of the 782 moderate-risk women, 17% (95% CI: 14.8–20.2) underestimated their risk, 16% (95% CI: 13.4–18.6) overestimated and 67% (95% CI: 63.3–70) reported their risk correctly. Of the 653 high-risk women, 71% (95% CI: 66.9–74.1) correctly reported their risk and 29% (95% CI: 25.9–33.1) underestimated their risk.vs 34%; P<0.000) and significantly less likely to be high risk  than the women who had been told their risk.Of the 1731 women who had been attending a screening programme for more than 1 year, 27% (95% CI: 24.4–28.6) reported they had not been told their risk or that they did not know if they had been told their risk level. These women were significantly less likely to have had higher (college or university) education  of the women reported not knowing. This was significantly related to whether women reported being told their risk  and these women also tended to have lower levels of education  and to be moderate risk .vs 83%; P<0.001). Two per cent (95% CI: 1.8–3.1) of the women believed they would definitely develop cancer. There were no significant differences in whether these women had been assessed as moderate or high risk or whether the women had been told their actual risk level. But as these numbers are very small, these results should be interpreted with caution.Of the 1826 women in the total cohort who believed they did know their likelihood of developing breast cancer, 87% (95% CI: 85.8–88.9) believed they may develop the disease. Comparisons between high-risk and moderate-risk women showed that those at high risk were significantly more sure of the likelihood of developing breast cancer .Women were also asked to rate their own chances of developing breast cancer compared with most other women their age. Of the 2210 women who answered the question, 87% (95% CI: 85.3–88.1) believed that their chances of getting cancer were ‘a little more’ to ‘much more’ than most other women of their age and high-risk women were significantly more sure that their risk was higher than other women  reported that the main purpose of mammography is the early detection of breast cancer. The majority of women  knew that most women would be given a normal result and 77% (95% CI: 75.6–77.1) knew that following a mammogram, women were ‘sometimes’ recalled for further tests. Similar numbers overestimated recall  as underestimated it . Eighty-six per cent (95% CI: 84.5–87.4) of women knew that not all women recalled would be diagnosed with cancer. A small number  thought incorrectly that ‘most’ women recalled would be diagnosed with cancer. Only 4% (95% CI: 3.0–4.6) of women knew that mammography had not been proven to save lives from breast cancer in women under the age of 50 years with a family history and 20% (95% CI: 18.7–22) of women thought that a normal result after a mammogram meant that there was definitely no breast cancer present.Ninety per cent (95% CI: 88.7–91.2) of women felt that having a mammogram would reassure them that everything was OK and 96% (95% CI: 95–96.7) felt that having a mammogram would make them feel they were doing something positive. Eighty-one per cent (95% CI: 79.3–82.5) of women felt that having a mammogram would make them feel less anxious about breast cancer and 78% (95% CI: 76.6–80.1) felt that it would reduce their chances of dying of breast cancer. However, 35% (95% CI: 32.5–36.5) felt that mammograms would be painful, 14% (95% CI: 12.7–15.6) felt that having a mammogram would be frightening, 16% (95% CI: 14.6–17.7) felt that having a mammogram would make them worry about the effects of radiation and 8% (95% CI: 6.5–8.7) felt that having a mammogram would make them worry unnecessarily.P<0.01). But, these women were more distressed . They were also more likely be incorrect about how many women would have a normal result , more likely to be correct about what a normal result means , be more pessimistic about how many recalled women would be diagnosed with cancer  and believe that mammography has not been proven to save lives .Most of the women were positive about mammography. However, 12% (95% CI: 10.9–13.7) of women scored highly on the positive scale, indicating a greater level of disagreement. There were no significant differences between baseline characteristics of these women (cutoff Fifty-four per cent (95% CI: 39.5–67.8) completed a questionnaire on reasons for non-attendance. Most women had been aware of their increased risk for several years before attending the screening programme. Not all women reported that they had been told their risk level and of those who did, the majority reported the level correctly, but a substantial minority reported it incorrectly. Regardless of the level of risk, most women believed that they may develop breast cancer in their lifetime. Women in this cohort were very motivated to attend screening and the majority had positive views about mammographic screening. The women who had less positive views about mammography tended to report higher cancer-specific distress. The majority of women responded correctly to the questions about the purpose and possible consequences of mammography. However, some were incorrect about the sensitivity of mammography, and nearly all were incorrect in believing that mammography had been proven to decrease mortality in women under the age of 50 years. Comparisons of the relationship between views and knowledge showed that the women who were less positive about mammography were more likely to underestimate a good outcome.Even before attending a familial breast clinic, many of the women in this study had been aware that they may be at risk of developing breast cancer for several years, and it has been suggested that obtaining information about personal risk is a primary motivation for attending a familial breast clinic (Of those who stated that they had been told their risk level, 69% accurately reported the same risk level as the clinic assessment. This is similar to rates reported in other studies (Another primary motivation for attending a family history clinic is to be advised on strategies to deal with familial risk . The AgeBecause women with a family history of breast cancer are at greater risk, in the United Kingdom they are recommended to begin annual mammography screening from the age of 40 years. However, there are theoretical concerns that screening may induce breast cancers in these women, as they may have a genetic susceptibility to radiation, for example, women with BRAC mutations are likely to be more sensitive to ionising radiation as BRAC genes are integral in repairing breast cells . They coIn this study, the number of women not attending mammography screening was very small and the main barriers to attendance were practical ones. This reflects the findings in a previous study, which found that once accepted on a family history programme women are highly motivated to attend mammographic screening. Although this study was large and recruited women from throughout the United Kingdom, there is still a possibility of non-response bias, and the results may not be representative of all women offered the option of participating in a mammographic screening programme because of an FHBC. The strength of the study is that it is the first large multicentre UK study to measure knowledge and views about mammography in women with an FHBC.In conclusion, once a woman's increased risk level has been confirmed by health professionals, the only strategy for managing this risk for the majority of women is to participate in an annual mammography screening programme despite the uncertainty at present as to the effectiveness of mammography in this group of women. The results from this study highlight that some women have an overly optimistic view of the role mammography may play in reducing breast cancer mortality. Further attention should be given to providing women with an FHBC information about the potential benefits and limitations of mammographic screening, including its lack of sensitivity. It may also be beneficial if the essence of the debate is communicated to women.


A population-based cohort study of 36 856 women diagnosed with alcoholism in Sweden between 1965 and 1995 found that alcoholic women had only a small 15% increase in breast-cancer incidence compared to the general female population. It is therefore apparent, contrary to expectation, that alcoholism does not increase breast-cancer risk in proportion to presumed ethanol intake. © 2000 Cancer Research Campaign


Sir,et al that as it stands, the model is not easy to use in clinical practice. However, the model is currently being implemented in web-based software that will provide a user-friendly tool for clinical geneticists and oncologists. We disagree however with the premise that the model is particularly hard to understand. The BOADICEA model incorporates the effects of BRCA1, BRCA2 and other genes. Although it has more risk parameters than some other models, it is conceptually quite similar to the The BOADICEA model of genetic susceptibility to breast and ovarian cancer was developed using complex segregation analysis of breast and ovarian cancer . We agreet al question the low breast cancer risk (13% by age 70) estimated for the index woman in Figure 3 of our paper. We agree that this estimate is probably anomalously low, due to imprecision in the BRCA1 and BRCA2 penetrance estimates we used. The average risk of breast cancer in BRCA1 mutation carriers in the first version of the BOADICEA model was estimated to be 35% by age 70 (van Asperen To improve the risk prediction, we have recently refitted the BOADICEA model using additional data from two UK population-based studies of breast cancer (et al question the fact that the presence of ovarian cancer in the family does not affect the breast risk. It is a feature common to BOADICEA and all the other risk prediction models, however, that the risks of breast and ovarian cancer in a family are assumed to be independent given the BRCA1 and BRCA2 genotypes. Thus, the presence of ovarian cancer in the family only affects the breast cancer risk in so far as it affects the BRCA1 and BRCA2 carrier probabilities.van Asperen We agree that the regression model of


The risk estimates and the confidence intervals were extracted from the individual studies, and a mixed effect weighted regression model was used. We identified 22 unique studies on each sex, and the quantitative analysis included 14 studies on men and women, respectively. The summary relative risk estimate was 1.07 (95% CI 1.05–1.09) per unit of increase in BMI (corresponding to 3 kg body weight increase for a subject of average height). We found no evidence of effect modification by sex. Our quantitative summary shows that increased BMI is equally strongly associated with an increased risk of renal cell cancer among men and women. © 2001 Cancer Research Campaignhttp://www.bjcancer.comObesity has been associated with an increased risk of renal cell cancer among women, while the evidence for men is considered weaker. We conducted a quantitative summary analysis to evaluate the existing evidence that obesity increases the risk of renal cell cancer both among men and women. We identified all studies examining body weight in relation to kidney cancer, available in MEDLINE from 1966 to 1998. The quantitative summary analysis was limited to studies assessing obesity as body mass index (BMI, kg m


As part of a cluster randomised trial to assess an alternative model of cancer genetics services, we gathered data on all referrals from general practitioners (GPs) to cancer genetics services in South East Scotland over a 4-year period. The referral rate per 1000 patients rose by 48% from 0.21 in the 2-year period before the trial to 0.31 during the trial. This increase was much greater in the trial group offered the GP clinic service . Thus, the offer of a more local service appeared to have a marked effect on GP management of these women. Referral rates to cancer genetics services from general practices varied widely with higher referral rates from practices with more female partners. There was a negative correlation between referral rates and practice area deprivation scores. However, this was not found during the trial in the group which offered clinics in general practice, the provision of clinic appointments nearer to the homes of more socially deprived women resulting in improved access to women from deprived areas. The interaction with the GP appears to be associated with an inappropriate level of interest in and expectation of the appropriateness of genetic testing. The provision of the clinics within general practice did not result in higher levels of confidence among GPs in managing these women. UK genetic services are based on a network of regional centres offering specialist services  to families at high risk of serious genetic disorders. While links with secondary and tertiary specialists are established in most centres, links with primary care are in the process of development .Family history is known be a significant risk factor for breast cancer. Awareness of the genetic component of certain forms of cancer and therefore the potential importance of a family history is increasing among the population. This, in turn, has resulted in an increasing number of self-referrals to general practitioners (GPs), and subsequently to clinical genetics services , we classified general practices into four groups according to their referral rate during the trial. In each of these four groups, we calculated the proportion of referrals that were estimated to be at high, moderate and low risk based on an assessment of family history information given in the GP referral letter, thus reflecting the information available to the GP at the time of referral. In a few cases, the information in the GP letter was insufficient for an accurate risk assignment and so these women were omitted.Women were asked if they had taken the first step by asking to be referred or if this had been suggested to them by their GP, a hospital doctor or another medical professional. Those who said that they had taken the initiative themselves were asked if this was because of their own concern, the suggestion of another family member, because of something in the press or for another reason.n=125), South West Fife (n=54) and Borders (n=24) National Health Service (NHS) Boards in South East Scotland. A total of 170 practices (84%) agreed to take part, 23 (11%) declined and 10 (5%) did not reply. This meant that 725 of the 828 (88%) GPs in practice across these three NHS Board areas agreed to refer patients into the trial. Practices were randomly assigned to either arm of the trial using a minimisation technique  group completed a family history form and those considered to be at increased genetic risk (i.e. in the ‘moderate-risk’ or ‘high-risk’ categories) received the existing service that comprised an appointment to see a consultant geneticist and breast surgeon at a regional centre. Women referred by the second (‘community clinic’) group were seen at one of several clinics held in a community setting relatively near the woman's own general practice.At the community clinic, the genetics nurse specialist ascertained the woman's family history of cancer and compiled a family tree. This information was compared to published criteria to determine whether she was at increased risk. When an adequate risk assessment could not be made during the appointment, further information and/or confirmation of relatives' diagnoses were obtained from the woman or medical records or from cancer registry data, before the woman was informed of their risk by letter. Women whose risk of breast cancer was estimated not to be increased over that of women of a similar age in the general population (i.e. in the ‘low-risk’ category) were offered information and reassurance and were discharged from the clinic. These women and their GPs were sent a letter reaffirming their low-risk status and summarising the issues discussed at the appointment. Women whose risk was estimated to be increased over that of women of a similar age in the general population were offered an appointment at the regional centre with a consultant breast surgeon and genetics nurse specialist. Further details of the trial interventions are given in a related publication   and the All GPs who referred women during the study period received a questionnaire asking their views about various aspects of the management of women with a family history of breast cancer.χ2 tests were used to compare the distribution of sources of referral before and during the trial, the risk statuses of women who were referred by practices with different referral rates, and the responses of women who had or had not been given information by their GPs. Comparisons were made between referral rates within trial groups using the paired t-test. Comparisons of the number of practice members and female practice members were made using the Spearman rank correlation coefficient since these were not normally distributed. Pearson's correlation coefficients were calculated between locality (Carstairs) deprivation scores and referral rates before and during the trial for all Lothian practices.A total of 203 practices in the Lothian, Borders and South-West Fife regions of Scotland were approached to take part in the study. Some 170 (84%) agreed to take part, 23 (11%) refused and 10 (5%) did not reply.P<0.001).The referral rate  per 1000 patients on the GP lists rose from 0.21 (0.19–0.24) in the 2-year period before the trial to 0.31 (0.28–0.34) during the trial. Thus, there was a 48% increase in referral rate over this period of approximately 2.5 years, a highly significant difference (P< 0.001).Prior to the study, many asymptomatic women with a positive family history were referred to the Edinburgh Breast Unit (symptomatic breast clinic) and then referred on, after receiving a mammogram and an appointment with a breast surgeon, to the cancer genetics clinic. In order to assess if there had been a change in this pattern of referral during the period of the study, we compared the referral sources of this group of asymptomatic women (with a positive family history of breast cancer) before and during the trial. The letter sent out at the start of the trial to all GPs requesting that referrals be directed to cancer genetics services rather than to symptomatic breast services was successful, with the proportion of referrals from the symptomatic breast service falling from 24.6% before the trial to 14.5% during the trial. There was a highly significant difference between the sources of referral before and during the trial  by four strata of general practice referral rates are given in P<0.002; 0.23, P<0.003) and proportion  of female partners in the practice before and during the trial, respectively.Of the practices that had agreed to take part in the study, 15% had no female partners, 67% had one to two female partners and 19% had three or more. Neither referral rate before nor during the trial was correlated with the number of partners or the number of male partners in the practice. However, there is a small but significant correlation between both referral rates and the number . This increase was greater in the community clinic trial group .P<0.01) with referral rates before the trial and −0.13  with referral rates during the trial, suggesting that the tendency for practices serving less deprived areas to have higher referral rates was reduced during the time of the trial. We calculated the correlation between the locality (Carstairs) deprivation score and referral rates before and during the trial for all Lothian practices  to investigate whether general practices serving women who were more socially deprived would have lower referral rates than those serving less socially deprived women. The correlation coefficients were −0.26 .In all, 43% of women indicated that they had asked to be referred . Two-thirds of these women noted that this was based on their own concern with the others requesting referral at the suggestion of another family member. Younger women were more likely to have taken the initiative to request referral  had initiated the referral, only a third stated that they had specifically enquired about their family history of cancer; for over one-half the suggestion of referral had taken place when they had seen the doctor about another matter. There was no significant difference in educational status, perceived level of risk or cancer worry between the two referral groups.Women enrolled in the trial were asked questions about whether any information had been given to them by their GP about their family history of cancer prior to the referral. About 40% of women had received no such information. In total, 50% of those who had received information reported that they found it to be very helpful or helpful. Women were then classified into two groups according to whether or not they had received information.P<0.01). Similarly, 71% of the group who had received information from their GP stated any information from a genetic test would be very important compared with 56% of those who had not received information from their GP, but this difference was not statistically significant.The only statistically significant difference between the two trial groups (after correcting for the number of comparisons made (by the Bonferroni method) related to views on genetic testing. In all, 90% of those who had received information from their GP thought that it was very important or quite important to have genetic testing compared with 73% of those who had not received information from their GP  noted that they were confident or very confident about their women being seen by a genetic nurse specialist or genetic associate rather than by a consultant geneticist. A similar proportion  noted that they were positive or very positive about having genetic clinics in the community. When asked whether they would prefer community clinics run by nurse specialists or regional hospital-based genetic clinics about one-third  favoured the former and one-half  the latter, the remainder being undecided.General practitioners found the structured summary letter the most useful aspect of the service followed by the provision of local community-based clinics . Other items  were rated as useful or very useful by less than a quarter of the GPs. General comments made by GPs included that they had made little use of the service and that women were less likely to default from appointments at community clinics.Specialist outreach clinics in general practice increased throughout the mid-1990s, reflecting a desire within the National Health Service to move towards closer integration of primary and secondary care services , althougThere have only been a limited number of thorough evaluations of outreach services across various disciplines. These have reported improved waiting times, patient satisfaction and convenience to patients but have noted less efficient use of specialist time, limited interaction between primary care and specialist staff and concerns about access to these services not being uniform throughout a region . This found that a GP with an average caseload of 1700 patients would have 140 patients with a family history of breast, colorectal or breast/ovarian cancer, and of these 10 would meet national criteria for referral for risk assessment. Reported referrals to regional services for consultation regarding a family history of breast cancer suggested a referral rate of about 0.25 referrals per 1000 patients per year, consistent with the referral rates found in this study. This is based on referral of patients who presented spontaneously to their GP and not on any form of active surveillance by GPs of family history of cancer within their practice population.We recently carried out a large cross-sectional survey of 13 155 patients registered with GPs in Scotland . Thus, in addition to the underlying general increase in referral rates, the establishment of community clinics resulted in a change in referral behaviour that resulted in a further increase in referral.Despite the increase in referral rates that we recorded over this 3-year period, these rates are considerably lower than those (15 out of 1000 adult women/year) at which women reportedly raise concerns about family history of breast cancer with their GP  suggestiThere was a very wide (more than 30-fold) variation in the annual referral rates. The reasons for this are not clear, but there was a small but significant correlation between referral rates during the trial and the number and proportion of female partners in the practice. Referral rates were greater from those practices with a greater number of female partners and this could be because women with a family history are more likely to seek the advice of a GP, if the GP is female. Thus, if the patient belongs to a practice where it is impossible or more difficult to see a woman, they may be less likely to seek advice. Alternatively, it could be that female GPs are more likely to refer women for genetic counselling about breast cancer risk than male GPs.We postulated that higher referral rates may reflect the use of less rigorous selection criteria by some GPs. For example, this might have occurred because of their knowledge that selection, according to risk, for referral to the breast-screening service would be performed subsequently by the genetic nurse who interviewed the woman at the locality clinic. However, we found no evidence that this had occurred.et al, personal communication). Once the decision to respond to this concern is made by the GP, similar referral criteria are applied. Currently, a more active surveillance of family history of cancer in primary care  is not recommended in national cancer genetics guidelines nor is it supported by GPs (in this survey only 30% agreed that GPs should actively identify those from their lists who might be eligible for genetic counselling).We interpret our finding as follows. Family history of breast cancer is common and many women consulting their GP may mention this at the time of consultation . We founThere is an extensive literature that confirms that people from different socioeconomic groupings consume health care in different ways. This almost invariably shows that more deprived people have worse health and have greater need for health care  falling to −0.01 during the trial. Thus, the tendency for practices serving less deprived areas to have higher referral rates was no longer found where community clinics were held This is consistent with an interpretation that the provision of clinic appointments nearer to the homes of more socially deprived women and staffed by nurses results in GPs more likely to refer and/or women being more willing to attend these clinics than more distant regional clinics staffed by consultants. In addition, GPs commented that women were less likely to default from appointments at community clinics.We found that the interaction with the GP was associated with an inappropriate level of interest in and expectation of the appropriateness of genetic testing, with 90% of those who had received information from their GP considering it important or very important compared to 73% of those who had not received information from their GP. While it is possible that this was due to recall bias, we consider this unlikely and suggest that this is worthy of further investigation. Since genetic testing is only appropriate to a very small percentage of women with very high familial risk, it is important that GPs do not foster this level of expectation.This mismatch in perception about the role of molecular testing between those running cancer genetics clinics and women attending them may need to be addressed specifically in the way clinics are organised in the future and in postgraduate training of GPs.In general, GPs were confident about taking a family history, clinical examination and offering emotional support. They were less confident about risk assessment and deciding if mammographic screening was necessary, and most did not see it as their role to identify those from their lists who might be eligible for genetic counselling. Several commented that they and their staff did not have time to take on additional work of this nature.There were no marked differences between the two trial groups suggesting that the limited number of contacts between the GPs and the genetics nurses who staffed the community clinics were insufficient to alter GP confidence in the management of these women. This was reinforced by the written comments of a number of GPs on the survey questionnaire that they had made little use of the service . It has been noted previously that the limited interaction between primary care and specialist staff jeopardises achievement of one of the central aims of these initiatives – to facilitate integration and overcome barriers between primary and secondary/tertiary care  were rated as useful or very useful by less than a third of the GPs.


High breast density is associated with increased breast cancer risk. Epidemiologic studies have shown an increase in breast cancer risk in postmenopausal women with high levels of sex steroids. Hence, sex steroids may increase postmenopausal breast cancer risk via an increase of breast density. The objective of the present study was to study the relation between circulating oestrogens and androgens as well as sex hormone binding globulin (SHBG) in relation to breast density.We conducted a cross-sectional study among 775 postmenopausal women, using baseline data of a random sample of the Prospect-EPIC study. Prospect-EPIC is one of two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition, and women were recruited via a breast cancer screening programme. At enrolment a nonfasting blood sample was taken and a mammogram was made. Oestrone, oestradiol, dehydroepiandrosterone sulfate, androstenedione, testosterone and SHBG levels were measured, using double-antibody radioimmunoassays. Concentrations of free oestradiol and free testosterone were calculated from the measured oestradiol, testosterone and SHBG levels Mammographic dense and nondense areas were measured using a semiquantitative computerized method and the percentage breast density was calculated. Mean breast measures for quintiles of hormone or SHBG levels were estimated using linear regression analyses.Both oestrogens and testosterone were inversely related with percent breast density, but these relationships disappeared after adjustment for BMI. None of the sex steroids or SHBG was associated with the absolute measure of breast density, the dense area.The results of our study do not support the hypothesis that sex steroids increase postmenopausal breast cancer risk via an increase in breast density. Dense breast tissues  appear light on a mammogram, while nondense tissue (fat tissue) appears black . Women wIn epidemiologic studies, nulliparity, late age at first child birth and late age of menopause have all been related to increased breast density, indicating that sex steroid levels may influence breast density; it has therefore been hypothesized that breast density may reflect lifetime exposure to sex steroids. Moreover, postmenopausal hormone therapy (HT), and in particular combination therapy of oestrogens and progesterone, increases breast density in most women -7, whereHigher circulating levels of oestrogens and androgens have been clearly established to lead to higher breast cancer risk in postmenopausal women ,13. In tMost of the studies on sex steroids and breast density were small, however , and contained a relatively large percentage of former HT users . It is not known what time period is needed for a complete washout of HT effects on breast tissue, and hence results may be influenced. Furthermore, four of these studies -18, but In the present large, cross-sectional study we set out to investigate the relation between circulating levels of oestrogens, androgens and SHBG, on the one hand, and both measures of breast density (dense area and percentage density), on the other, in a sample of Dutch women, with very few (14%) former HT users.This study included women participating in Prospect-EPIC, one of two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre cohort study with 10 participating European countries. The rationale and design of both the EPIC and Prospect-EPIC have been described in detail elsewhere -21. The An invitation to join the Prospect-EPIC project was mailed to women that were invited for their routine mammography. Those who agreed to participate subsequently received two questionnaires by mail. A general questionnaire was used to gather information on demographic, reproductive and lifestyle factors and on past and current morbidity. To determine the regular dietary intake, a validated extensive self-administered food frequency questionnaire was used containing 178 food items ,23. On tAll participants signed an informed consent and the study was approved by The Institutional Review Board of the University Medical Center Utrecht.n = 1,736) was taken from the total Prospect cohort. Mammograms of 1,595 women could be retrieved from the archives and breast density was successfully measured for 1,516 women. Of these, premenopausal or perimenopausal women or those having an unknown menopausal status (n = 377) were excluded. Women with unknown menopausal status due to hysterectomy were also excluded (n = 257). Women with a hysterectomy after natural menopause (n = 4) and women with ovariectomy on both ovaries were kept in the study (n = 60). None of the 882 remaining women were current HT or oral contraceptive users. For 775 of these women, sex steroid and SHBG levels were available that were used in a previous study [A 10% random sample , testosterone and SHBG were measured using commercially available double-antibody radioimmunoassay kits . The following kits were used: oestrone, DSL-8700; oestradiol, DSL-39100; androstenedione, DSL-4200; DHEAS, DSL-2700; testosterone, DSL-4100; and SHBG, DSL-6300. The intra-assay coefficients of variation were 5.6%, 3.9%, 4.3%, 5.2%, 7.7% and 3.0%, respectively. The inter-assay coefficients of variation were 11.1%, 4.1%, 6.3%, 5.3%, 8.1% and 4.0%, respectively .Concentrations of free oestradiol and free testosterone were calculated from total plasma concentrations of oestradiol, testosterone and SHBG, using theoretical calculations described by Vermeulen and colleagues .The mediolateral oblique mammogram, which is the routine view for breast cancer screening in The Netherlands, was used to assess mammographic density. The proportions of mammographic density on craniocaudal views and mediolateral oblique views and on left and right views have been observed to be very strongly correlated, and representative information on mammographic density is provided in a single view . For eacAfter digitizing the films using a laser film scanner , the mammographic density was quantified using a computer-assisted method based on grey levels of pixels in the digitized mammogram. This computer-assisted method to determine mammographic density has proved very reliable, and the method is described elsewhere in detail . BrieflyTo compute the percentage breast density the dense area of a breast is divided by the total breast area and multiplied by 100. The percentage breast density is used in most publications on breast density. A small-sized breast and a larger-sized breast, however, could have the same percentage breast density, while the absolute amount of glandular and stromal tissue, which is regarded as the target tissue for breast cancer ,28, is hAll mammograms were assessed by one observer in sets composed of 35 randomly ordered films. To assess the reliability of the reader, a library set was created, which consisted of 35 randomly chosen films from our study subjects. This library set was read before the first set, after the last set and at four time points between sets, which were blinded for the reader. The images in the library set were randomly ordered every time they were read to prevent the observer from recognizing this set. In the present study, average intraclass correlation coefficients of 1.00 , of 0.93  and of 0.91  were reached between repeated readings for the total breast area, the dense area and the percentage breast density, respectively.Subjects with plasma sex steroid or SHBG values under the detection limit – which was 1.2 pg/ml, 1 pg/ml, 25 ng/ml, 0.02 ng/ml, 0.05 ng/ml and 5 nmol/l for oestrone, oestradiol, DHEAS, androstenedione, testosterone and SHBG, respectively – were given the value of the detection limit. Six women had an undetectable oestrone level, five women were undetectable for DHEAS, eight women were undetectable for androstenedione, eight women were undetectable for testosterone and 60 women had an undetectable SHBG level. All women had a detectable value for oestradiol. Plasma sex steroid and SHBG levels were log-transformed to normalize the distributions. These transformed values were then used to compute geometric mean levels.All three measures of the breast  were square-root-transformed to normalize their distributions. These transformed values were used in linear regression analyses. For ease of interpretation, the presented means and 95% confidence intervals have been transformed back to the original scale. Means and 95% confidence intervals of breast measures by quintile level of plasma sex steroids or SHBG were estimated with linear regression models using the 'GLM' procedure. To test for linear trends over the quintiles, median values within quintiles were calculated and evaluated as a continuous variable using linear regression analysis. Potential confounding of various factors with known association with sex steroid levels or with breast measures, or with both, was assessed by adding those variables to the crude models.The following characteristics were evaluated for confounding using continuous variables: age, body mass index (BMI), waist circumference, waist–hip ratio (WHR), age at menarche, age at menopause, time since menopause and alcohol consumption. Dichotomous variables were used for ever breast feeding and for family history of breast cancer (mother and/or sister). A variable for ever use of postmenopausal HT combined with time since last use of HT was used with one category for never users and with two categories for ever users – the first of which contained women with a time period since last HT use below the median (5 years), and the second contained women with a time period since last use of the median value or greater. Parity and age at first childbirth were evaluated using a combined variable with one category for nulliparous women and three categories of parous women combined with tertiles of age at birth of the first child . Smoking was evaluated using a variable with three categories, for current smokers, past smokers and never smokers. Variables that changed the crude associations by 5% or more were added to the adjusted models. In a previous study by Aiello and colleagues, different effects were found between HT never users and ever users . We therP values are two-sided, and results were considered significant when below 0.05. All analyses were conducted using the Statistical Analysis System software package .All 2. The age at first childbirth among parous women was 25.4 years on average, and 12.8% (n = 99) of the participants was nulliparous. Women were aged, on average, 48.8 years at menopause, and the average time since menopause was 11.2 years. Only 14.4% (n = 112) of the participants had previously used HT; those previous HT users quit using these compounds on average 7.1 years prior to recruitment . Median values for the percentage density, dense area and nondense area were 21.7% , 25.3 cm2  and 95.1 cm2 , respectively.Table The results of regression analyses for the relation between sex steroids and the percentage breast density, the dense area and the nondense area are presented in Tables The inverse associations of circulating levels of both oestrogens and testosterone with the percentage density were no longer apparent when adjusted for BMI Table . DHEAS aWhen we stratified the analyses according to HT ever use (yes/no), results were highly comparable between the groups.The significant inverse associations between both oestrogens and testosterone with percentage beast density disappeared after adjustment for BMI. No relationships were found between sex steroids and the absolute measure of mammographic density, the dense area. High levels of SHBG were associated with high percentage density and a low nondense area. These relations disappeared after corrections for BMI and for WHR.r = 0.84 and r = 0.76, respectively) [An advantage of the present study is its size – with 775 participants, our study is larger than all previous studies -17 excepctively) . If miscTo our best knowledge, seven previous studies on sex steroids and breast density have been published -18,31,32In the present study, crude models show both oestrone and oestradiol to be inversely related to the percentage density. After correction for BMI these relations were no longer apparent. Associations with free oestradiol were in the same direction and were somewhat stronger. Three other studies also found the crude inverse relation between oestradiol and percentage density, but only in the study by Boyd and colleagues did this association remain statistically significant after adjustments for confounders, although only with free oestradiol ,18. ThisOur result of a positive association between circulating SHBG levels and the percentage breast density are in line with four previous studies ,15,17,18Studying so many associations raises the question of whether multiple testing has resulted in false positive results. The positive crude relations between both oestrogens and testosterone and the nondense area, however, were expected. After menopause, circulating oestrogen levels reflect the conversion of androgens to oestrogens in adipose tissue. Most of the circulating testosterone is also converted in the adipose tissue from androstenedione . OestrogCirculating progesterone levels were not available in the present study. As combined oestrogen and progesterone HT use exerts stronger effects on breast density than oestrogen alone treatment -37, progAfter studying our results and the results of five previous studies on sex steroids and postmenopausal breast density, we conclude that there is no major proof for such associations in postmenopausal women, at least not to the same extent as the associations between sex steroid levels and breast cancer risk. Some of the previous studies were relatively small, but the study by Warren and colleagues  as well BMI = body mass index; DHEAS = dehydroepiandrosterone sulfate; EPIC = European Prospective Investigation into Cancer and Nutrition; HT = hormone therapy; SHBG = sex hormone binding globulin; WHR = waist–hip ratio.The authors declare that they have no competing interests.MV participated in the design of the study, performed the statistical analyses and drafted the manuscript. PHMP conceived of the study, participated in the design of the study and helped to draft the manuscript. PAHvN participated in the design of the study and helped to draft the manuscript. YTvdS conceived of the study, participated in the design and coordination of the study and helped to draft the manuscript. DEG conceived of the study, participated in the design of the study and helped to draft the manuscript. CHvG conceived of the study, participated in the design and coordination of the study, helped to perform the statistical analyses and helped to draft the manuscript. All authors read and approved the final manuscript.


Ptrend=0.47) or AIDS-relative time (Ptrend=0.14) or after adjustment for established cancer risk factors. However, it increased significantly between 1980 and 2002 (Ptrend=0.003), approaching the risk of the general population. We conclude that the cancer deficit reflected direct or indirect effects of HIV/AIDS and that anti-HIV therapy reduced these effects.By linking HIV/AIDS and cancer surveillance data in 12 US regions, breast and reproductive cancer risks with AIDS were compared to those in the general population. Trends in standardized incidence ratios (SIRs) were assessed by CD4 count, AIDS-relative time, and calendar time. Standardized incidence ratios were indirectly adjusted for cancer risk factors using data from AIDS cohort participants and the general population. With AIDS, 313 women developed breast cancer  0.62–0.77), 42 developed ovary cancer , and 31 developed uterine corpus cancer . Uterine cancer risk was reduced significantly after age 50 (SIR 0.33). Breast cancer risk was reduced significantly both before (SIR 0.71) and after (SIR 0.66) age 50, and was lower for local or regional (SIR 0.54) than distant (SIR 0.89) disease. Breast cancer risk varied little by CD4 count ( Increasing numbers of women have been infected with human immunodeficiency virus (HIV) and now are living with the acquired immunodeficiency syndrome (AIDS). The effects of AIDS on women, particularly in the era of highly active antiretroviral therapy (HAART), are not well defined. In the era before HAART, the risks of developing Kaposi sarcoma, anal cancer, and perhaps lymphoma were lower for women than for men with AIDS . Other tBreast cancer may occur less often in women with AIDS than in the general population  in 12 regions of the US to identify cancers arising among PWA , and analysed by site using the Surveillance, Epidemiology and End Results program's ‘Site recode with KS and mesothelioma’ , which is the ratio of observed to expected cancers derived from contemporaneous, racial/ethnic ancestry-, age-, and registry-specific population-based incidence rates . For an We used Poisson modeling and a two-sided score test (n=24 898) and 2000 (n=24 503) National Health Interview Surveys (NHIS) (n=483) or the Women's Interagency HIV Study   . For womFor breast cancer, we adjusted for the effects of age at first live birth or nulliparity and BMI with age-specific relative risks (RRs) . We did In linkages performed during 2003–2005 in 12 regions of the US with population-based cancer ascertainment, 85 268 women were followed for 665 987 person-years, measured from 5 years before to 10 years after an initial AIDS diagnosis. There were 51 616 women of African ancestry (61%), 17 705 women of Hispanic ancestry (21%), 15 019 non-Hispanic women of European ancestry (18%), and 928 women of other or missing ancestry (1%). At AIDS diagnosis, median age of the women was 36 years (interquartile range 31–43 years); 90% of the women were age 50 years or younger.The incidence of breast and uterine corpus cancers, but not of ovary cancer, was significantly lower than in the general population. Specifically, linkage to the cancer registries revealed 313 cases of breast cancer , 31 cases of uterine corpus cancer , and 42 cases of ovary cancer  among women with AIDS. Breast cancer SIR was reduced in all groups defined by age at AIDS onset, including those with AIDS onset before age 35 (SIR 0.69). As shown in Ptrend=0.14, Ptrend=0.72 and 0.94, respectively, data not presented). As with the AIDS-relative time analyses, CD4 lymphocyte count at AIDS onset was not significantly associated with SIR for breast cancer .We examined trends in SIR with respect to time relative to AIDS onset and CD4 count, as measures of immune deficiency . Near thvs 4.7 expected) in the cohort with AIDS onset in 1980–1989, whereas the SIR was 0.38 with AIDS onset in 1990–1995, and the SIR was 0.83 with AIDS onset in 1996–2002 (Ptrend=0.002). Excluding the 1980–1989 cohort that had no cases, the SIR still increased significantly (P=0.01) from the 1990–1995 to the 1996–2002 cohort. The significant increase in breast cancer SIR also was found using single calendar years in a Poisson regression model  but data were sparse.Calendar time was used as a surrogate for availability of anti-HIV therapy – little or none pre-1990, single and dual reverse transcriptase inhibitors in 1990–1995, and HAART after 1995. As shown in adj 0.72 vs 0.69 unadjusted). For uterine corpus cancer overall, there was little effect with indirect adjustment for parity and smoking (SIRadj 0.59) or for BMI (SIRadj 0.56) compared to the unadjusted estimate (SIR 0.57). Among postmenopausal women, the SIR for uterine corpus cancer was modestly attenuated with adjustment for parity and smoking (SIRadj 0.39) and for BMI .Indirect adjustment for age at first live birth, nulliparity and BMI had little effect on the breast cancer SIR estimate (SIRWomen with AIDS had a low incidence of locally invasive and regionally disseminated breast cancer, but this cancer deficit attenuated over time to approach the incidence in the general population. Ovary cancer incidence did not differ with AIDS, but a uterine corpus cancer deficit was large and statistically significant among postmenopausal women. Although women with HIV/AIDS had lower fertility and BMI in the pre-HAART era (μl−1, total estradiol and testosterone levels were at the low end of the normal range (Cancer risk with HIV/AIDS might reflect differences in hormonal balance or cycling. In the general population, high levels of serum estrogens and testosterone have been linked with an increased risk of breast cancer in postmenopausal women , suggestSince the 1980s, HIV/AIDS patients have had marked changes in body composition that may have affected their endogenous hormone levels and risk of cancer. In the early 1990s, before availability of HAART and the current obesity epidemic (Perhaps the deficit in breast cancer reflects the ability of HIV to infect, replicate in, and impair proliferation of breast cells . EpithelBias is an important concern for our study. Women with HIV/AIDS may have been screened infrequently and had conditions that diverted attention from breast masses or vaginal bleeding (From 1980 to 2002, women with AIDS had significantly reduced risk of breast and postmenopausal uterine corpus cancers, but not of ovary cancer. The cancer deficits were unrelated to immune deficiency or selected risk factors. We offer two hypotheses for the breast cancer deficit. First, women with HIV/AIDS had alterations of reproductive and perhaps other hormones tied to breast cancer (


Sir,et al were added to our models.In a recent interesting study by P trend=0.03). This is contrary to the findings of Monroe et al, who observed a significant increase in risk of breast cancer with greater consumption of grapefruit in this subgroup.Stratification by BMI did not alter the breast cancer risk with either grapefruit or grapefruit juice intake. However, stratification by hormone therapy showed a significant decrease in risk of breast cancer with greater intake of grapefruit in women who never used hormone therapy .Furthermore, the association between grapefruit (not grapefruit juice) intake and breast cancer risk differed significantly by oestrogen and progesterone receptor status of the tumours. No association was observed in women with oestrogen and progesterone receptor positive cancers. However, in women with oestrogen and progesterone receptor negative cancers, there was a significant decrease in breast cancer risk with increased consumption of grapefruit , oestrone , or oestrone sulphate .We also examined cross-sectionally the relationship between consumption of grapefruit and grapefruit juice and plasma levels of oestrogens among 701 postmenopausal women not using hormone replacement. No significant correlation was observed  for plasma oestradiol (Our findings do not support an adverse effect of consumption of grapefruit or grapefruit juice on risk of breast cancer or on endogenous hormone levels.


Sir,post hoc genotyping. In their collection of French families in which one or more child is affected by AT, d'Almeida and co-workers have shown how potential biases, introduced by late genotyping of relatives with certain outcomes, can be addressed by various analytical approaches. They then compare and discuss the results.Thank you for the opportunity to comment on this interesting letter, which addresses some important methodological issues in studies of risk factors with ATM allele are at increased risk for breast cancer and perhaps other potentially deadly diseases, we considered that we could not backdate the result of the gene testing, that is, reallocate the person-years at risk from the start of follow-up of these relatives, without running the risk of introducing differential misclassification. As the date of testing was not available for all relatives, we decided not to change the gene probability scores of the tested persons but only to change the scores of their ancestors. We thus chose to retain some random gene exposure misclassification due to the initial allocation of carrier probability, defined by location in a family, rather than risk introducing non-random misclassification, which can lead to overestimation of risks.In the Nordic study, genotyping of probands and parents was generally completed during the diagnostic work-up of the AT patients, that is, at the date of start of follow-up for subsequent breast and other cancers. Supplementary genotyping of other family members was usually conducted years or decades later, either among survivors who were willing to participate or among relatives who had died from breast cancer and for whom tissue blocks were available. As the study hypothesis was that carriers of an It is reassuring that d'Almeira and co-workers report in their letter that some, limited variation in breast cancer risk estimates was found with each of the three approaches in the French material, and that the mothers in this study – as in the Nordic study – clearly showed a very high risk for breast cancer. In the Nordic study, we concluded that our data did not convincingly point to a trend of increasing risk with each increment in the probability of being a gene carrier, indicating that we should consider other mechanisms than a genetic one as the cause of breast cancer in these families. We nevertheless reported a significantly increased risk for breast cancer among female relatives below the age of 55 years who had an estimated gene carrier probability of 0.25, and we acknowledged that the estimated trend in breast cancer risk by increasing gene carrier probability was based on a very limited number of outcomes. As pointed out by d'Almeira and co-workers, international collaboration is the only means of addressing this problem in an epidemiological design.


P value for linear trend=0.008). A protective effect of long gestational duration and an increased risk for high birth weight were found for seminomas. Non-seminomas were associated with short gestational duration, particularly among those with low birth order  and high maternal age . No significant differences were found in tests for heterogeneity between the two histological groups. Our data support the hypothesis that intrauterine environment affects the risk for germ-cell testicular cancer. Seminomas and non-seminomas seemed to have similar risk patterns, although they are not entirely congruent.We aimed to investigate the role of perinatal determinants on the risk for germ-cell testicular cancer, with respect to the aetiological heterogeneity between seminomas and non-seminomas. A case–control study of 628 case patients with testicular cancer (308 seminomas and 320 non-seminomas) and 2309 individually matched controls was nested within a cohort of boys born from 1920 to 1980 in two Swedish regions . Cases were diagnosed from 1958 to 1998 and were identified through the Swedish National Cancer Registry. Perinatal information on cases and controls was collected through charts available at maternity wards. Gestational duration, categorised in three categories , was negatively associated with the risk for testicular cancer  87, 545–550. doi:10.1038/sj.bjc.6600470www.bjcancer.comCancer Research UK© 2002  Testicular cancer is the most common neoplasm among young adults, with a peak of occurrence among males aged 30 years. The incidence varies 10-fold between countries  were identified through the National Cancer Registry, that includes all newly diagnosed malignant neoplasms in Sweden from January 1958. They were diagnosed from 1958 to 1996, with the exception of subjects born in Uppsala-Örebro Health Care Region, for whom the period of follow-up ended in 1994.Patients are listed in the Cancer Registry according to the national registration number (NRN) that was assigned to all residents in Sweden since 1947. NRN is a unique personal identifier containing information on date and county of birth for subjects born 1947 onwards, or county of residence at 1947 for those born before that .We collected information available at different maternity wards and their archives. A standardised chart to record information about newborns and their parents was introduced in Sweden in 1973. Hospitals included in the study were selected because they used similar charts before 1973, but the number of available variables varied over different hospitals and different time periods. However, the maternity charts were usually carefully filled in and missing values rarely occurred once a variable was included in the chart.Variables used in the analysis included maternal age at delivery, socio-economic status of the mother according to educational and/or occupational level, maternal parity (defined as number of births including the present birth), pre-eclampsia or eclampsia during pregnancy, gestational duration and weight at birth, neonatal jaundice and medical problems of the newborn. Other recorded variables were not used either because of a large number of missing values  or because they were not judged to be biologically plausible risk indicators.Small- and large-for-gestational-age were computed on the basis of both weight at birth and gestational duration, according to the intrauterine growth curves reported by We estimated odds ratios (ORs) with corresponding 95% confidence interval (CI) using conditional logistic regression  availablTable 1controls . A missicontrols .Most of the analyses were conducted separately for seminomas  and non-seminomas . Heterogeneity of results between the two histological types was tested by comparing the likelihood of the model with interaction term between histological group and determinant of exposure with the same parameter derived from the model without interaction term (likelihood ratio test). Variables were included in the models if they were independent determinants and/or substantial confounders.The effect of individual and joint exposure indicators  was also assessed. In this analysis maternal age was categorised into two groups according to the median value of the control distribution: young mothers (<28 years old) and old mothers (28+ years old).P for linear trend: 0.008), as well as a significant elevated risk for high birth weight.Characteristics of cases and individually matched controls are shown in In Table 2As foetal growth and gestational duration are highly interdependent, we evaluated the joint effect of these variables in a separate model (data not shown in tables). As compared with those born normal-for-gestational-age at term, infants born both preterm  and large-for-gestational-age had a three-fold risk for testicular seminomas .Table 3Among boys born preterm, high maternal age as well as low birth order further increased the risk for non-seminomas .The present study is one of the largest to investigate the effect of different indicators of intrauterine exposures on the risk for germ-cell testicular cancer.The study was an enlargement of a previous analysis that indicated etiological heterogeneity between the two major histological groups of testicular cancer  and birth weight (u-shaped trend) from this study can be interpreted both in terms of oestrogen exposure and of foetal growth retardation or placental malfunction. Some previous studies found similar results for at least one of the two variables (One of the most frequently reported findings in previous studies is the increased risk of testicular cancer among firstborn infants (In our previous study jaundice was found to be associated with an increased risk for testicular cancer, in particular for non-seminomas (The classification of germ-cell testicular cancer into seminoma and non-seminoma has a well established prognostic relevance. Despite the two histological types differing by about 10 years in the mean age at diagnosis, they show similar trends in incidence. Thus, it has been suggested that the aetiological heterogeneity is unlikely to be large , althougSome case–control studies conducted analysis separated by seminomas and non-seminomas (In spite of the size of our enlarged study we could not find any statistically significant heterogeneity between seminomas and non-seminomas. However, tests for heterogeneity imply a multiplicative model and ruling out differences on the base of a formal test would be excessively conservative . FurtherWe investigated the effect of the interaction between different perinatal factors in analysis separated by the two histological groups. Seminomas were associated with high birth weight, in particular among preterm boys, and we found an additive effect between maternal age and birth order. These results are consistent with some previous studies that indicated at least one of the latter two variables as risk factors confined to seminomas  study obSince variables that we examined in our study are only indicators of some unknown risk factors, possibly hormonal, any hypothesis on the underlying aetiological mechanism is tentative. Indicators for high levels of maternal oestrogens during pregnancy, such as high birth weight (In conclusion, our results support the hypothesis that the intrauterine environment affects the risk for germ-cell testicular cancer. Seminomas and non-seminomas seemed to have similar risk patterns, although different patterns appear for the two histological groups with respect to interaction between different perinatal exposures.


Obesity increases the risk of uterine cancer, but results by histological type have differed.We followed 36 755 women for 17.8 years for uterine cancers.−2) compared with lean (BMI: 20–24 kg m−2) women, was 11.1 .Body mass index (BMI) was positively associated with uterine cancers as a whole, particularly for endometrioid adenocarcinomas, for which the relative risk for very obese women (BMI: ⩾40 kg m The obesity epidemic contributes to a steadily increasing incidence of endometrial cancer for which obese women may have a six-fold higher risk compared with lean women .Two population-based studies have addressed the issue of whether obesity is differentially associated with histological subtypes of uterine cancer, but with inconsistent results. In one study, there was a stronger positive association with endometrioid adenocarcinoma (type I tumours) than for other subtypes , as well as a weaker association for sarcomas and mixed endothelial and mesenchymal tumours .In this prospective study of 36 755 women, we have compared the association of BMI with the risk of uterine cancer as a single entity, with all endometrial cancers, and with the risk of endometrioid adenocarcinomas.Between 1984 and 1986, all inhabitants aged 20 years and older in the Nord-Trøndelag County in Norway were invited to participate in a study (the HUNT-I Study), in which standardised measurements of height and weight were made. A detailed description of the HUNT Study is given elsewhere  were identified by the linkage of HUNT Study participants to the Norwegian Cancer Registry, using the unique 11-digit identity number of Norwegian citizens. Follow-up time was calculated as person-years from the HUNT baseline until the date of diagnosis of uterine cancer or any other cancer , emigration, death or the end of follow-up, 31 December 2005, whichever occurred first.The histological diagnoses are based on mandatory reporting to the Norwegian Cancer Registry from all pathological laboratories in Norway. Cancers diagnosed before 1993 were classified according to MOTNAC . After 1993, tumours were classified according to ICD-O-2, a 6-digit code for morphology and grade of differentiation. According to the WHO classification , tumours−2), and categorised as <20, 20–24, 25–29, 30–34, 35–39 and 40 kg m−2 and higher. Information on prevalent diabetes (yes/no) and smoking status  was obtained through self-administered baseline questionnaires. Information on recreational physical activity  included the frequency (five categories), duration (four categories) and intensity (three categories) of the activity.Body mass index was calculated as weight divided by height squared (kg mWe estimated age-adjusted relative risks (as hazard ratios) associated with BMI for different categories of uterine cancer using Cox regression analysis . In three separate analyses, the following classifications were used all uterine cancers, all endometrial cancers and endometrioid adenocarcinomas. To estimate the log-linear trends of BMI, we included BMI as a continuous variable. In a separate analysis, we assessed BMI and the risk of uterine cancers other than endometrioid adenocarcinomas.This study was approved by the Regional Committee for Ethics in Medical Research and by the Norwegian Data Inspectorate.n=44/20%) or mesenchymal tumours (n=14/6%).We followed up 36 755 women  for an average of 17.8 years (range: 0–21). During follow-up, 263 histologically verified uterine cancers were diagnosed, and 224 of them (85%) were classified as endometrial cancers. Among the latter, 166 (74%) were classified as endometrioid adenocarcinomas . In totaP for trend, <0.001) that was also present for endometrial cancers and for endometrioid adenocarcinomas . The relative risks across the categories of BMI were higher for endometrial cancers than for all uterine cancers, but confidence intervals (CIs) overlapped. Compared with the reference (BMI: 20–24 kg m−2), the age-adjusted relative risk for BMI ⩾40 kg m−2 was 8.3 (95% CI: 4.1–16.7) for endometrial cancer, 6.7 (95% CI: 3.4–13.4) for all uterine cancers and 11.1 (95% CI: 5.2–23.8) for endometrioid adenocarcinomas. For uterine cancers other than endometrioid adenocarcinomas (n=97), compared with the reference group (BMI: 20–24), there was an increased risk associated with a BMI of ⩾35 (age-adjusted relative risk 4.67 (95% CI: 2.4–9.2)), but there were no associations for the other BMI categories.For uterine cancers as a whole, there was a strongly positive association with BMI .In this prospective study of 36 755 women, there was a strongly positive and linear association of BMI with the risk of cancer of the uterine corpus. Separate analyses showed that a stronger association of BMI with the risk of endometrioid adenocarcinomas than for uterine cancers as a whole. Previous studies have shown a two- to six-fold higher risk of uterine cancer among obese women compared with lean women. Most studies have used all uterine cancers as a single entity as the endpoint .n=166) of all endometrial cancers were classified as endometrioid adenocarcinomas, which accords with the literature  of the endometrioid adenocarcinomas were diagnosed after 1993, when the classification distinctly differentiated between type I, type II and other tumours of the endometrium. In our study, 74% (terature . AnotherThe increased risk associated with obesity has been attributed to higher concentrations of endogenous oestrogen hormones. Oestrogens produced in the adipose tissue have a direct mitogenic effect on endometrial cells, and it is assumed that this effect is not counterbalanced by progesterone because of chronic anovulation accompanied by reduced progesterone synthesis. However, weight-related increase in endometrial growth factors .Our results suggest a positive association of BMI with all subtypes of uterine cancer, but the association was strongest for endometrioid adenocarcinomas. However, the moderate precision of the estimates warrants that future studies assess how obesity is related to different subtypes of uterine cancer.


P<0.001), screening and management with unaffected women (P=0.01) and breast cancer prevention with younger women (P=0.01). Prophylactic mastectomy was discussed more frequently with women with medical and allied health training (P=0.02), and prophylactic oophorectomy with women affected with breast cancer (P=0.03), those in non-professional occupations (P=0.04) and with a family history of breast and ovarian cancer (P<0.001). Consultants used significantly more behaviours to facilitate understanding with women who were in non-professional occupations (P=0.04); facilitated active patient involvement more with women affected with breast cancer (P<0.001) and used more supportive and counselling behaviours with affected women (P=0.02). This study showed that patient demographics were more likely to predict consultants' communication behaviours than the woman's psychological status. Methods to facilitate assessment of psychological morbidity are needed to allow more tailored communication.This multicentre study examined the influence of patient demographic, disease status and psychological variables on clinical geneticists/genetic counsellors (consultants) behaviours in initial consultations with women from high-risk breast cancer families. One hundred and fifty-eight women completed a pre-clinic self-report questionnaire. The consultations were audiotaped, transcribed verbatim and coded. Consultants did not vary their behaviour according to women's expectations. However, significantly more aspects of genetic testing were discussed with women who were affected with breast cancer  87, 502–508. doi:10.1038/sj.bjc.6600484www.bjcancer.comCancer Research UK© 2002  Previous research has documented consultants' reports of the cancer genetic services typically provided to women from high-risk breast cancer families. These include cancer risk assessment and education, facilitation of genetic testing, pre- and post-test counselling, provision of personally tailored cancer risk management recommendations, and psychosocial counselling and support services .A recent survey of Australian clinical geneticists and genetic counsellors identified the provision of individualised care as the single most important goal of genetic counselling  or psychological variables influence consultant communication.Women assessed to be at potentially high risk for the development of breast cancer because of their family history, and who were attending their first consultation in any one of 10 familial cancer clinics in four Australian States , were included in the study. Women were quota-sampled according to whether or not they had previously had breast cancer. Women were considered ineligible for participation if they were unable to give informed consent, that is, if they were younger than 18 years or showed evidence of a severe mental illness. Individuals with limited literacy in English were also excluded because data collection was based on self-administered questionnaire.A sample size of 158 women is sufficient to detect an association between patient characteristics and consultants' behaviours of a magnitude of 0.3, that is a small to medium effect size, at a 0.05 level of significance with a power of 80%.This study is one component of a larger randomised controlled trial of providing women with an audiotape of their genetic counselling consultation, the results of which will be reported separately. Staff at each of the participating clinics invited women to participate in the study when they telephoned to make their appointment. If verbal agreement was obtained, women were mailed a self-administered questionnaire prior to their genetic consultation that they returned in a pre-paid envelope. The consultations were audiotaped and copies of the audiotape were retained for analysis. Ethics approval from 10 different ethics committees responsible for each of the participating clinics was sought and obtained prior to data collection.Women were asked to provide details on age, education, occupation, marital status, language spoken at home, parents' country of birth, marital status, medical or allied health training, religious affiliation or spiritual belief and the number of biological children and sex and age of each child.Number of first- and second-degree relatives who had developed and/or died of breast or ovarian cancer were collected from study participants as a measure of ‘cancer burden’.An eight-item true–false measure assessed knowledge about breast cancer genetics. The scale is a revised version of a measure previously used in a study on the psychological impact of BRCA1 testing  of breast cancer  by choosing between seven response options ranging from 1–100%. A decision was made to code women's risk accuracy within categories, as risk estimates vary widely and often only a general risk category  is given in the genetic counselling session. Participants' numerical estimate of life time risk was converted to a category according to the figures given in the Australian National Health and Medical Research Council Guidelines e.g. a potentially high risk category 25–80%; a medium risk category 12–25% and a low risk category 9–12% .This was determined by the figure given by the consultants in the consultation or the post consultation summary letter . Participants' responses were deemed accurate if their risk estimate fitted within the risk category given by the consultant. If women were inaccurate it was determined whether they had under-estimated or over-estimated their risk of breast cancer.r=0.80  breast cancer genetics; (ii) genetic testing; (iii) family history and risk; (iv) prophylactic surgery; (v) breast cancer prevention; (vi) screening and management; and (b) Process behaviours: (vii) facilitating patient involvement; (viii) understanding; (ix) patient centredness and partnership building; and (x) supportive and counselling behaviours. These categories were based on (i) the National Health and Medical Research Council's Guidelines on the Familial Aspects of Cancer: A Guide to Clinical Practice (The transcripts were coded to capture 10 aspects of the genetic counselling that encompassed (a) Practice , (ii) anGenetic Testing has eight component behaviours that were summed to provide a total score.Under each of these categories the content or behaviours that characterised that issue were identified. The presence or absence of each component was coded. Whether the woman or the genetic counsellor/geneticist initiated the content was noted and finally, the actual words used were recorded. An example of coding for an information giving behaviour is shown in Table 1 and aThree coders (including EL) were trained. Two coders re-coded a random 10% of their own consultation transcripts and 10% of the other coder's consultation transcripts to determine intra-and inter-rater reliability. There were 274 content coding variables for each consultation. The average inter-rater reliability over the 274 codes was 93% (range 67–100%) and the average intra-rater reliability was 92% (range 65–100%). The areas of highest agreement were information-giving categories: risk (96–100%); screening (89–99%); genetic testing (84–99%); prevention (91–100%); and there were lower levels of agreement on some consultant communication facilitation behaviours: facilitating communication (67–87%) and discussing psycho-social issues (69–76%). Thus interpretation of findings on these latter variables must be made with some caution.Descriptive statistics  were used to summarise most of the data, including demographics and psychological status. Frequencies were calculated for each consultant behaviour. Total scores for the 10 pre-defined counselling categories were calculated by summing the component behaviours.t-tests and Pearson's correlations) if the category total score was normally distributed and non-parametric statistics (Mann–Whitney U and Spearman's correlations) if the category total score was non-normally distributed. Some individual consultation behaviours are analysed by chi square analyses. Variables associated with the outcomes at P<0.25  questionnaires, for whom there was an audible audiotape of their consultation for verbatim transcription.n=158), 89 women were unaffected with breast cancer (56%) and 69 were affected (44%). The majority had a family history of breast cancer (77%) and almost a quarter had a family history of breast and ovarian cancer (23%). The median age of participants was 42 (range 19–79) s.d.=11.9. The majority of women were married or in a de facto relationship (76%). Over half the women were educated above year 12 (55%) and 57% were in professional or semi-professional occupations while 33% had some form of medical or allied health training.Of the final sample  and women in professional occupations  gave more correct answers.Prior to the clinic visit, women gave a mean of five correct answers on the eight breast cancer genetics knowledge scale. Areas where fewer women gave correct answers concerned the role of male inheritance, the presence of more than one breast cancer pre-disposition gene and the effectiveness of bilateral mastectomy in reducing breast cancer risk. Multivariate analysis showed that women younger than 42 years .Just under half of unaffected women estimated their risk of breast cancer accurately. Of the women who were inaccurate, half underestimated and half overestimated their risk. Accuracy of risk perception prior to counselling was significantly associated with a higher educational level with 67% of women educated above year 12 being accurate compared to 33% of women educated below year 12  prior to counselling. A small sub group of unaffected (10%) and affected (19%) women showed significant stress responses. Almost one-fifth of unaffected and affected women were clinically anxious and 18% of unaffected women and 28% of affected women were ‘borderline’ clinically anxious. Five per cent (5%) of both unaffected and affected women were clinically depressed and 8% of unaffected and 16% of affected women were ‘borderline’ clinically depressed. These results are not dissimilar to others reported for affected and unaffected women  expected a genetic test, while just under half the sample expected to discuss prophylactic surgery. About half the women expected to discuss their feelings and receive reassurance.not expect this information also received it, as these topics appeared to be standard components of the genetic counselling consultation. Univariate statistical testing showed no relationship between baseline expectations concerning these topics and consultant behaviour. Similarly, there were no relationships between baseline expectations for discussion of feelings and reassurance, or for a genetic test, and consultant behaviours.Table 321=6.3, P<0.01). Very few women expected or received information about IVF. A larger number (38) expected to discuss the impact of breast cancer risk on child bearing decisions, and those with this expectation were more likely to discuss it .About half of the women who wanted information about hormone replacement therapy (HRT) and the oral contraceptive pill (OCP) received it, while about a third of the group who did not expect these topics to be covered nevertheless discussed them. Univariate tests revealed a significant relationship between expectations and consultation behaviour concerning OCP , with a trend towards using more behaviours if the woman was anxious (median 5.3 compared to 4.9), . They used more behaviours to facilitate active patient involvement with women who were affected with breast cancer (median 3.0) compared to unaffected women (median 2.0), .A summary of the significant findings of predictors of consultants' communication behaviours is shown in Table 4123=−2.375, P=0.02).Women's breast cancer status was found to be a significant predictor of supportive behaviours with consultants using more such behaviours with affected women (mean 4.0) than unaffected women (mean 3.1), , while the reverse was true for information on screening and management (median of 4.2 issues discussed with unaffected women versus 3.2 with affected women) . Non-medical strategies to prevent breast cancer (such as diet) were discussed more frequently with younger women aged 42 years or less, (median 2.0 behaviours) compared to older women (median 1.5) (P=0.01).More aspects of genetic testing were discussed with affected women (median 5) than with unaffected women (median 4) , and less with women who underestimated their breast cancer risk . Prophylactic oophorectomy was discussed more with women who were affected with breast cancer , worked in non-professional occupations , and who had a family history of breast and ovarian cancer .Prophylactic surgery was discussed in half of the consultations, but its discussion was initiated by the consultant in only a third of these consultations. Multivariate analyses showed that prophylactic mastectomy was more likely to be discussed with women who had some form of medical training  most women received what they expected. However, women who were not expecting these facts were also likely to receive them, suggesting that consultants gave this information in a standard, rather than tailored manner. For example, half of women who had not expected to discuss their breast cancer risk did so.Where expectations were not well matched  the majority of women did not receive what they expected, and their expectations did not influence consultants' behaviour. However, women did appear more successful in communicating their expectations of fertility topics, with consultants appearing more responsive to their expectations. If women's expectations are unrealistic , it may be beneficial to discuss this when they make their genetic counselling appointment, to avoid unrealistic expectations. The impact of meeting women's expectations on their satisfaction with the encounter will be explored in another paper.This study found that breast cancer status was a significant predictor of consultants' behaviours. For example, consultants used significantly more supportive and counselling behaviours with women who were affected with breast cancer and facilitated more active patient involvement with such women. Women with breast cancer are faced with an uncertain prognosis and many experience clinically significant levels of depression and anxiety  with women who were in non-professional occupations, and there was a trend for consultants using more of these behaviours if the woman was anxious. This suggests they were responding appropriately to women whose understanding might be expected to be poorer. However, levels of knowledge and risk accuracy prior to counselling were not related to the level of detail provided about genetics, risk and screening, suggesting that these were not easy to assess within the consultation. As with emotional status, routine assessment of these features before the consultation, fed back to the consultant, might provide useful cues to the consultant on the level of detail required by each person. Several instruments to assess understanding are currently available (for example the measure used in the current study) that might prove useful for this purpose.Consultants were also more likely to discuss genetic testing and prophylactic oophorectomy with affected women, and screening and management issues with unaffected women. Since mutation detection in Australia is initiated in affected women and unaffected relatives are only offered predictive testing once a family-specific mutation has been identified, it is not surprising that genetic testing is more frequently discussed with affected women. Nor is it surprising that prophylactic oophorectomy is more frequently discussed with affected women (even if their mutation status is unknown), since it is very likely that they are carriers of a mutation that may also increase their risk of ovarian cancer. By contrast, an unaffected woman with unknown mutation status has a less than one in two chance of being a carrier and thus her a priori risk of developing ovarian cancer is considerably lower. On the other hand, screening and preventive strategies, such as taking tamoxifen, are more relevant to unaffected women, and appropriately discussed more frequently with them.The woman's occupation  were also significant predictors of consultant behaviours, in particular, discussion of prophylactic surgery. Prophylactic surgery was most commonly raised by the woman herself, and it may be that those with medical training were more aware of mastectomy as an option, and therefore initiated the discussion.Finally, consultants facilitated more active involvement in affected women. There may be a perception that affected women are more experienced in the medical encounter, and more familiar with decision making, and these women certainly have more decisions to make.This study has concluded that consultants tailor their information giving according to clinical factors, such as breast cancer status, but that many other features, such as women's expectations, their psychological state and knowledge, do not influence consultant behaviour. It is likely that these features are not easy to assess in the consultation, and strategies to more directly assess these features, such as through questionnaire or clinical questioning, will be required if consultants wish to tailor their consultation accordingly.