Michael Steel

The impact of genetic counselling about breast cancer risk on women’s risk perceptions and levels of distress

SummaryWomen referred to a familial breast cancer clinic completed questionnaires before and after counselling and at annual follow-up to assess their risk estimate and psychological characteristics. The aims were to determine whether those who attended the clinic overestimated their risk or were highly anxious and whether counselling influenced risk estimates and levels of distress. Women (n = 450) at this clinic were more likely to underestimate (39%) than overestimate (14%) their risk. Mean trait anxiety scores were higher than general population data (t = 4.9, n = 1059, P < 0.001) but not significantly different from published data from other screening samples. Overestimators (z = 5.69, P < 0.0001) and underestimators (z = –8.01, P < 0.0001) reported significantly different risk estimates (i.e. increased accuracy) after counselling, but significant inaccuracies persisted. Over- (n = 12) and underestimators (n = 60) were still inaccurate in their risk estimates by a factor of 2 after counselling. Thirty per cent of the sample scored above the cut-off (5/6) for case identification on a screening measure for psychological distress, the General Health Questionnaire (GHQ). GHQ scores were significantly lower after counselling (t = 3.6, d.f. = 384, P = 0.0004) with no evidence of increasing risk estimate causing increased distress. The risk of distress after counselling was greater for younger women and those who were more distressed at first presentation. The counselling offered was effective in increasing the accuracy of risk perceptions without causing distress to those who initially underestimated their risk. It is worrying that inaccuracies persisted, particularly as the demand for service has since reduced the consultation time offered in this clinic. Further work is needed to evaluate alternative models of service delivery using more sophisticated methods of assessing understanding of risk.

Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers

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.

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BackgroundA gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients.MethodsFifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action.ResultsGaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds).ConclusionThrough recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care.

Patient satisfaction with two different models of cancer genetic services in south-east Scotland

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.

Slimming on the Internet.

Summary The first 50 websites identified on searching the Internet for ‘weight loss diets’ were assessed systematically and their content compared with published clinical guidelines for management of obesity. The relevance and quality of the sites varied enormously. Only 3 confined themselves to sound dietary advice. Most promoted dietary supplements or other ‘slimming aids’, often of uncertain composition and based on dubious physiological principles. Potential hazards—for example, those of very low calorie diets—were rarely highlighted and certain regimens on offer were potentially dangerous.

Referrals of women with a family history of breast cancer from primary care to cancer genetics services in South East Scotland

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.

Utilisation of prophylactic mastectomy in 10 European centres.

Increasingly women at high risk of breast cancer are opting for prophylactic surgery to reduce their risks. Data from 10 European centres that offer a risk counselling and screening service to women at risk show different approaches to the option of preventive surgery, although most centres adhere to a protocol including at least two risk counselling sessions and a psychological assessment. Thus far the combined centres have data on 174 women who have undergone prophylactic mastectomy with in excess of 400 women years of follow up. Operations were carried out on women with lifetime risks of 25–80%, with an average annual expected incidence rate of 1% per women. No breast cancers have occurred in this cohort. Long term follow up on an extended group of women will be necessary to truly address the risk of subsequent breast cancer and the psychological sequelae.

Ethical, social and economic issues in familial breast cancer: a compilation of views from the E.C. Biomed II Demonstration Project.

Demand for clinical services for familial breast cancer is continuing to rise across Europe. Service provision is far from uniform and, in most centres, its evolution has been determined by local conditions, specifically by local research interests, rather than by central planning. However, in a number of countries there is evidence of progress towards co-ordinated development and audit of clinics providing risk assessment, counselling, screening and, in some cases, prophylactic intervention. Much important information should emerge from continued observation and comparative assessment of these developments. In most countries for which relevant data are available, there is a distinct bias towards higher social class among those who avail themselves of clinic facilities (in line with findings from many other health-promotion initiatives). This should be addressed when considering future organisation of clinical services. Molecular genetic studies designed to identify the underlying mutations responsible for familial breast cancer are not generally regarded as part of the clinical service and are funded through research grants (if at all). Economic considerations suggest that there is a case for keeping this policy under review. Familial cancers throw into sharp relief certain ethical and legal issues that have received much recent attention from government advisory bodies, patients’ representatives, professional commentators and the popular media. Two are of particular importance; first, the right to gain access to medical records of relatives, in order to provide accurate risk assessment for a given family member, versus the right to privacy in respect of personal medical information and, second, the obligation (or otherwise) to inform family members of their risk status if they have not actively sought that knowledge. The legal position seems to vary from country to country and, in many cases, is unclear. In view of pressures to establish uniform approaches to medical confidentiality across the EC, it is important to evaluate the experience of participants in this Demonstration Programme and to apply the principle of “non-malfeasance” in formulating regu-lations that should govern future practice in this field. Data on economic aspects of familial breast cancer are remarkably sparse and outdated. As evidence accrues on the influence of screening and intervention programmes on morbidity and mortality, there is a strong case for evaluating the cost-effectiveness of different models of service provision.

Oral Contraceptive Use and BRCA Penetrance: A Case-Only Study

Background: Women with deleterious mutations in BRCA genes are at increased risk of breast cancer. However, the penetrance of the genetic trait may be regulated through environmental factors. This multinational case-only study tested the interaction between oral contraceptive use and genetic susceptibility in the occurrence of breast cancer. Methods: We recruited 3,123 patients diagnosed with breast cancer before the age of 45 years. Participants were classified according to their probability of carrying a BRCA mutation on the basis of their family history of breast and ovarian cancer. According to a case-only approach, the frequency of relevant exposures among breast cancer cases with high probability of BRCA mutation (“genetic cases”) was compared with the frequency of the same exposures among breast cancer cases with a low probability of BRCA mutation (“sporadic cases”). The interaction odds ratios (OR) and 95% confidence intervals (CI) for oral contraceptive use were estimated by unconditional logistic regression, after controlling for potentially confounding variables. Results: The analysis was carried out comparing 382 “genetic” and 1,333 “sporadic” cases. We found a borderline significant interaction between genetic breast cancer and oral contraceptive use for ever users compared with never users (OR, 1.3; 95% CI, 1.0-1.7). The greatest interaction OR was found for women who started using pill at 18 to 20 years (OR, 1.6; 95% CI, 1.1-2.3). Conclusion: These results suggest that BRCA mutation carriers, as well as women with a significant family history of breast and ovarian cancer are more vulnerable to exogenous hormones in oral contraceptives. (Cancer Epidemiol Biomarkers Prev 2009;18(7):2107–13)

Cancer genetics services in Europe

It has long been recognised that some very rare forms of cancer predisposition, such as retinoblastoma, are caused by inherited gene mutations [7]. It is only within the last decade or so, however, that rapid progress has been made in understanding the role that inherited mutations also play in determining a proportion of the more common cancers, including breast, colorectal and ovarian cancer [1,2,3,4,6,8,9,10]. Although there is still uncertainty about the precise contribution of inherited predisposition genes to the incidence of these cancers, the available evidence suggests that breast, colorectal and ovarian cancer have a number of common genetic features: • A small proportion of these cancers (about 5%) are caused by inherited gene mutations which, though comparatively rare, confer very high lifetime risks of developing cancer. In some cases these lifetime risks may be as high as 80%. • Cancers caused by these high-penetrance genes are likely to occur at an earlier age than sporadic cancers, and 15 – 20% of the cancers diagnosed in people under the age of 50 may be accounted for by these genetic mutations. • Carriers of known genetic mutations which confer high lifetime risks of developing breast, colorectal or ovarian cancer are also at a somewhat increased risk of developing certain other forms of cancer. • A further 10 – 20% of breast, colorectal and ovarian cancers may be caused by other inherited predisposition genes which are less penetrant but which confer some increased risk (more than 3 times the general population risk). These “medium risk”genes are only beginning to be identified.