not available at time of printing.

Aim: To establish health related costs and benefits of clinical services for women at increased familial risk of breast cancer.Methods: Analysis of costs and outcomes for one UK regional service, supplemented with data from a multinational collaborative study. Main outcome measures were aggregate costs for regular clinical examination, mammographic screening and further investigations; breast cancer incidence; proportion of cancers detected at "early" or "late" stage, compared with corresponding data for unscreened women of comparable age; survival in relation to stage at diagnosis; itemised and aggregate costs of management for "early" and "late" stage breast cancer; hence direct health care costs per quality adjusted life-year (QALY) gained.Results: The surveillance programme costs 1500 pound ((sic)1600, US$2100) per woman (over 15 years). Breast cancer incidence is close to 6 per thousand examinations; 75% of tumours are detected through screening and 77% are "early" (path stage 1 or 2). Corresponding figures for unscreened women (including relatives of those attending the breast cancer family clinic) indicate that surveillance achieves a beneficial "stage shift", with reduction in treatment costs and improvement in survival, in about 22% of cases.Conclusions: The current clinical service for women at familial risk of breast cancer costs about 4800 pound ((sic)5200, US$6800) per QALY gained. That figure is sensitive to the rate of detection of breast cancer and the degree of beneficial stage shift achieved. Within the realistic range of estimates for these two parameters, the cost per QALY may be as high as 14 pound 000 ((sic)15 300, US$20 000) or as low as 1000 pound ((sic)1100, US$1400).

AIM:To assess the effectiveness of annual ovarian cancer screening (transvaginal ultrasound and serum CA125 estimation) in reducing mortality from ovarian cancer in women at increased genetic risk.PATIENTS AND METHODS:A cohort of 3532 women at increased risk of ovarian cancer was screened at five European centres between January 1991 and March 2007. Survival from diagnosis of ovarian cancer was calculated using Kaplan-Meier analysis and compared for proven BRCA1/2 carriers with non-carriers and whether the cancer was detected at prevalence or post-prevalent scan. Screening was performed by annual transvaginal ultrasound and serum CA125 measurement.RESULTS:64 epithelial ovarian malignancies (59 invasive and 5 borderline), developed in the cohort. 26 tumours were detected at prevalent round; there were 27 incident detected cancers and 11 interval. 65% of cancers were stage 3 or 4, however, stage and survival were little different for prevalent versus post-prevalent cancers. Five year and 10 year survival in 49 BRCA1/2 mutation carriers was 58.6% (95% CI 50.9% to 66.3%) and 36% (95% CI 27% to 45%), which was significantly worse than for 15 non-BRCA carriers (91.8%, 95% CI 84% to 99.6%, both 5 and 10 year survival p = 0.015). However, when borderline tumours were excluded, the difference in survival between carriers and non-carriers was no longer significant.CONCLUSION:Annual surveillance, by transvaginal ultrasound scanning and serum CA125 measurement, in women at increased familial risk of ovarian cancer is ineffective in detecting tumours at a sufficiently early stage to influence substantially survival in BRCA1/2 carriers.

To evaluate current guidelines criteria for inclusion of women in special 'breast cancer family history' surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at 'less than 'moderate' familial risk'. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted 'cutoff' level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45-59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence ('NICE') guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network ('SIGN') in defining 'moderate' familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services.

Background Epidemiological studies have shown that only about 20% of the familial clustering of breast cancer is explained by the known highly penetrant mutations in BRCA1 and BCRA2.We have set out to search for the genes for the remaining 80%.Twin studies indicate a predominant role of shared genes rather than a shared environment; the patterns of occurrence of breast cancer in families are consistent with a major polygenic component.Methods We have assembled a population based set of 5,000 breast cancer cases and 5,000 controls from the East Anglian population.We have simple clinical and epidemiological information, including family history, and samples of blood and paraffin embedded tumour.We have used association studies based on single nucleotide polymorphisms, first with candidate genes and then in a genome-wide scan of 266,000 single nucleotide polymorphisms, to search for the putative predisposing genes.We have as yet searched only for common variants (frequency >5%). ResultsWe have modelled the effects of polygenic predisposition in the East Anglian population, and have shown that the model predicts a wide distribution of individual risk in the population, such that half of all breast cancers may occur in the 12% of women at greatest risk.Both the candidate gene-based and genome-wide scans have provided provisional identification of a number of novel susceptibility genes, and these are currently being confirmed by a world-wide consortium of independent laboratories totalling 20,000-plus cases and controls.No single gene so far identified contributes more than 2% of the total inherited component, consistent with a model in which susceptibility is the result of a large number of individually small genetic effects. S2 Translating breast cancer research into clinical practice -new approaches and better outcomes

Up to 40% of referrals from primary care to 'breast cancer family clinics' prove to be of women whose assessed risk falls below the guidelines' threshold for management in secondary or tertiary care, despite recommendations that they should be screened out at primary care level. A randomised trial, involving 87 such women referred to the Tayside Familial Breast Cancer Service compared two ways of communicating risk information, letter or personal interview. Both were found to be acceptable to referred women and to their family doctors, although the former expressed a slight preference for interview. Only four women returned to their family doctors with continuing concerns about breast cancer. Nevertheless, understanding of information provided by either route was unsatisfactory, with apparent confusion about both absolute and relative risks of breast cancer. Substantial minorities appear to believe that they are at no increased risk at all, or even below the population level of risk, while others remain convinced that their personal risk has been underestimated. Family history record forms, completed by the referred women, preferably with the assistance of relatives, are crucial to full assessment of familial risk but one quarter of women referred to the Tayside Familial Breast Cancer Service currently do not complete and return these forms ahead of their clinic appointment. Further collaboration between primary care and the Breast Cancer Family Service is required to improve provision for concerned women whose risks fall below the threshold for special surveillance and to maximise effective use of the family history record form.

INTRODUCTION Many surgeons, if pressed, would probably maintain that molecular biology, or “molecular medicine”, has had little, if any, impact on their clinical practice. They might even confess to a degree of impatience, sometimes amounting to irritation, with the amount of “hype” given to an area of medical science that has promised much but delivered little in the fty years since the structure of DNA was explained. They are not alone. James LeFanu, general practitioner and medical journalist, savaged molecular genetics in his book The Rise and Fall of Modern Medicine.1 In a BBC interview he said:

Within the past few months, Francis Crick and Maurice Wilkins, two of the three men who won a Nobel Prize for describing the structure of DNA, have died. Their obituaries revisited the famous 1953 Nature papers,1,2 recalling with relish the classic English understatement ‘It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material’. In reality, Crick, at least, was less subdued, bursting in to the Eagle tavern in Cambridge with James Watson and declaiming to the doubtless bemused clientele ‘we have found the secret of life’.3,4

Clinical data and samples from patients diagnosed, more than 10 years previously, with operable node-negative breast cancer (participants in the Scottish Adjuvant Tamoxifen trial), were revisited. Cases with two distinct categories of outcome were selected; more than 10 years disease-free survival (‘good outcome’) or distant relapse within 6 years of diagnosis (‘poor outcome’). An initial set of cases was analysed for a range of putative prognostic markers and a prognostic index, distinguishing the two outcome categories, was calculated. This index was then validated by testing its predictive power on a second, independent set of cases. A combination of histological grade plus immunochemical staining for BCL-2, p27 and Cyclin D1, generated a useful prognostic index for tamoxifen-treated patients but not for those treated by surgery alone. The value of the index was confirmed in a second set of tamoxifen-treated, early stage breast cancers. Overall, it correctly predicted good and poor outcome in 79 and 74% of cases, respectively (odds ratio 11.0). Other markers assessed added little to prediction of outcome. In the case of molecular assays, sensitivity and reliability were compromised by the age of the tissue specimens and the variability of fixation protocols. In selecting patients for adjuvant systemic chemotherapy, the proposed index improves considerably on current international guidelines and matches the performance reported for ‘gene-expression signature’ analysis.

The aim of the study was to compare psychosocial outcomes for 50 new clinic attendees, referred for cancer genetic counselling to five UK centres. The centres represented England, Scotland and Wales, and were randomly selected from groups ranked by different levels of clinical activity in cancer genetics practice. Questionnaires assessed demographic data, risk perception, mental health and use of health services pre-consultation and at 1 and 12 months follow-up. Satisfaction was measured for attendees and referring doctors at follow-up. A total of 256 unaffected adults fulfilled the study criteria. The five centres varied widely with respect to service organisation and activity, but all had a greater proportion of unaffected attendees with a breast cancer risk (61-91%) than either a bowel cancer risk (0-33%) or ovarian cancer risk (3-25%). There were no significant differences in the psychosocial data between centres pre-counselling. No significant change over time occurred for any of the centres for risk perception or general psychological distress. There were significant differences between centres in reduction of cancer worry from baseline to 12 months and with the number of women who were recommended to have mammographic surveillance who had not received this. Overall, one-third of women for whom mammography had been recommended had not been screened within 1 year of follow-up. Subsequent attendance at the GP, but not at a hospital, was associated with risk level, but differences between centres could not be analysed. Satisfaction differed significantly between centres for 4 : 14 aspects of service provision and with 3 : 17 items concerning communication; satisfaction was high overall. Over 90% of referring doctors were moderately/very satisfied with the service, but 23% were dissatisfied with waiting times and 19% with access to preventive treatment. Results differed significantly between centres for doctor's satisfaction with the provision of referral criteria and prescribing information. In conclusion, there were relatively few significant differences in psychosocial outcomes between centres, considering the wide variation in service organisation and activity. These significant differences were not consistent across the centres, therefore, differences could not be linked to specific aspects of service provision.

There is a need to integrate primary- and secondary-care cancer genetic services, but the most appropriate model of service delivery remains unclear. This study reports patients' expectations of breast cancer genetic services and a comparison of their satisfaction with two service models. In the first model, risk assessment was carried out using mailed family history data. Women estimated as being at high/moderate risk were offered an appointment at the familial breast cancer clinic, and those at low risk were sent a letter of reassurance. In the second model, all women were seen by a genetic nurse specialist, who assessed risk, referred high/moderate-risk women to the above clinic and discharged those at low risk. Over 60% of all women in the study regarded access to breast screening by mammogram and regular check-ups as very important. This underlines the demand for a multidisciplinary service providing both clinical genetic and surgical services. Satisfaction was high with both models of service, although significantly lower among women not at increased cancer risk and thus not offered a clinical check-up and mammography. Increased cancer worry was associated with a greater expressed need for information and for reassurance through follow-up clinical checks and mammography. Better targeting of counselling to the expressed concerns and needs of these women is required to improve the service offered. GPs and patients expressed no clear preference for any specific service location or staffing configuration. The novel community service was less expensive in terms of both staff and patient costs. The potential to decrease health staff/patient contact time and to employ nurse practitioners with both clinical genetic and oncology training should be explored further. The rapidly rising demand for these services suggests that the evaluation of further new models needs to continue to be given priority to guide the development of cancer genetic services.

This study compared the psychological impact of two models of breast cancer genetics services in South East Scotland. One hundred and seventy general practices were randomised to refer patients to the existing standard regional service or the novel community-based service. Participants completed postal questionnaires at baseline (n=373), 4 weeks (n=276) and 6 months (n=263) to assess perceived risk of breast cancer, subjective and objective understanding of genetics and screening issues, general psychological distress, cancer worry and health behaviours. For participants in both arms of the trial, there were improvements in subjective and objective understanding up to 4 weeks which were generally sustained up to 6 months. However, improvements in subjective understanding for the women at low risk of breast cancer (i.e. not at significantly increased risk) in the standard service arm did not reach statistical significance. Cancer worry was significantly reduced at 6 months for participants in both arms of the trial. The two models of cancer genetics services tested were generally comparable in terms of the participants' psychological outcomes. Therefore, decisions regarding the implementation of the novel community-based service should be based on the resources required and client satisfaction with the service.

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 (64% increase compared to a 38% increase in those referred to the regional 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.