D. Eccles

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Summary Background Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. Methods In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. Results 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35–1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32–0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19–0·86, p=0·02) and an IRR of 0·37 (0·18–0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. Interpretation 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. Funding European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort

This multi-centre UK study assesses the impact of predictive testing for breast and ovarian cancer predisposition genes (BRCA1/2) in the clinical context. In the year following predictive testing, 261 adults (59 male) from nine UK genetics centres participated; 91 gene mutation carriers and 170 noncarriers. Self-report questionnaires were completed at baseline (pre-genetic testing) and 1, 4 and 12 months following the genetic test result. Men were assessed for general mental health (by general health questionnaire (GHQ)) and women for general mental health, cancer-related worry, intrusive and avoidant thoughts, perception of risk and risk management behaviour. Main comparisons were between female carriers and noncarriers on all measures and men and women for general mental health. Female noncarriers benefited psychologically, with significant reductions in cancer-related worry following testing (P<0.001). However, younger female carriers (<50 years) showed a rise in cancer-related worry 1 month post-testing (P<0.05). This returned to pre-testing baseline levels 12 months later, but worry remained significantly higher than noncarriers throughout (P<0.01). There were no significant differences in GHQ scores between males and females (both carriers and noncarriers) at any time point. Female carriers engaged in significantly more risk management strategies than noncarriers in the year following testing (e.g. mammograms; 92% carriers vs 30% noncarriers). In the 12 months post-testing, 28% carriers had bilateral risk-reducing mastectomy and 31% oophorectomy. Oophorectomy was confined to older (mean 41u2009yrs) women who already had children. However, worry about cancer was not assuaged by surgery following genetic testing, and this requires further investigation. In all, 20% of female carriers reported insurance problems. The data show persistent worry in younger female gene carriers and confirm changes in risk management consistent with carrier status. Men were not adversely affected by genetic testing in terms of their general mental health.

Guidelines for a genetic risk based approach to advising women with a family history of breast cancer

A family history of breast cancer has long been recognised as a significant risk factor for breast cancer. Quantifying that risk has been approached in publications and practically in a number of different ways. Increasingly regional genetics departments are called upon to help clarify guidelines for referral of women with a family history of breast cancer for genetic testing and to clarify breast cancer risk for women seeking early mammographic screening. This paper represents the current consensus guidelines from the UK Cancer Family Study Group and discusses some of the difficulties surrounding genetic risk estimation.

Predictive testing for BRCA1/2: attributes, risk perception and management in a multi-centre clinical cohort.

The aim of this multi-centre UK study is to examine the attributes of a cohort offered predictive genetic testing for breast/ovarian cancer predisposition. Participants are adults unaffected with cancer from families with a known BRCA1/2 mutation. This is the first large multi-centre study of this population in the UK. The study evaluates mental health, perceived risk of developing cancer, preferred risk management options, and motivation for genetic testing. Participants were assessed when coming forward for genetic counselling prior to proceeding to genetic testing. Three hundred and twelve individuals, 76% of whom are female, from nine UK centres participated in the study. There are no gender differences in rates of psychiatric morbidity. Younger women (<50 years) are more worried about developing cancer than older women. Few women provide accurate figures for the population risk of breast (37%) or ovarian (6%) cancer but most think that they are at higher risk of developing breast (88%) and ovarian (69%) cancer than the average woman. Cancer related worry is not associated with perceived risk or uptake of risk management options except breast self-examination. The findings indicate that younger women may be particularly vulnerable at the time of the offer of a predictive genetic test.

Guidelines for follow-up of women at high risk for inherited breast cancer: consensus statement from the Biomed 2 Demonstration Programme on Inherited Breast Cancer.

BACKGROUNDnSurveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality.nnnMETHODSnData were contributed from seven centres participating in the EU Demonstration Programme on Clinical Services for Familial Breast Cancer. All breast tumours (n = 161) detected prospectively, from the time of enrolment of women in a screening programme, were recorded. Analysis took account of age at diagnosis, whether tumours were screen-detected or not, their pathological stage and outcome by Kaplan-Meier survival plots.nnnRESULTSnMean age at diagnosis was 48.6 years. Overall, 75% of tumours were detected in the course of planned examinations. For women under age 50 at diagnosis, this figure was 68%. Eighteen percent were mammographically negative, (23% in patients under age 50). At first (prevalence) round and at follow-up screening, 16% and 22% of tumours respectively were carcinoma in situ (CIS) while 27% and 22% respectively had evidence of nodal or distant spread (CaN+). Comparison of screen-detected and other tumours showed that the latter were more frequently mammogram-negative and CaN+. Overall five-year survival was 89% and five-year event-free survival 86%. Five-year event-free survival was 100% for CIS, 88% for invasive cancer without nodal or distant spread and 67% for CaN+.nnnCONCLUSIONSnThe majority of cancers arising in women at increased genetic risk of breast cancer can be detected by planned screening, even in those under age 50. Surveillance should include regular expert clinical examination and teaching of breast awareness as well as mammography. Attention to the logistics of screening programmes may improve still further the proportion of tumours that are screen-detected. The trend towards earlier pathological stage in tumours detected during follow-up rounds and the preliminary findings on survival analysis suggest that this approach will prove to be of long-term benefit for breast cancer families.Protocols for activity aiming at early diagnosis and treatment of inherited breast or breast-ovarian cancer have been reported. Available reports on outcome of such programmes are considered here. It is concluded that the ongoing activities should continue with minor modifications. Direct evidence of a survival benefit from breast and ovarian screening is not yet available. On the basis of expert opinion and preliminary results from intervention programmes indicating good detection rates for early breast cancers and 5-year survival concordant with early diagnosis, we propose that women at high risk for inherited breast cancer be offered genetic counselling, education in ‘breast awareness’ and annual mammography and clinical expert examination from around 30 years of age. Mammography every second year may be sufficient from 60 years on. BRCA1 mutation carriers may benefit from more frequent examinations and cancer risk may be reduced by oophorectomy before 40–50 years of age. We strongly advocate that all activities should be organized as multicentre studies subjected to continuous evaluation to measure the effects of the interventions on long-term mortality, to match management options more precisely to individual risks and to prepare the ground for studies on chemoprevention.

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.

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: n n• nA small proportion of these cancers (about n5%) are caused by inherited gene mutations nwhich, though comparatively rare, confer very nhigh lifetime risks of developing cancer. In nsome cases these lifetime risks may be as high nas 80%. n• nCancers caused by these high-penetrance ngenes are likely to occur at an earlier age than nsporadic cancers, and 15 – 20% of the cancers ndiagnosed in people under the age of 50 may nbe accounted for by these genetic mutations. n• nCarriers of known genetic mutations which nconfer high lifetime risks of developing nbreast, colorectal or ovarian cancer are also at na somewhat increased risk of developing ncertain other forms of cancer. n• nA further 10 – 20% of breast, colorectal and novarian cancers may be caused by other ninherited predisposition genes which are less npenetrant but which confer some increased nrisk (more than 3 times the general population nrisk). These “medium risk”genes are only nbeginning to be identified.

Management of Hereditary Breast Cancer

D.M. Eccles, P. Simmonds, J. Goddard, M. Coultas, F. Lalloo, G. Evans and N. Haites in collaboration with the European Familial Breast Cancer Collaborative Group Department of Clinical Genetics, Princess Ann Hospital, Coxford Road, Southampton, UK Medical Oncology, Royal South Hants Hospital, Southampton, UK Medical Statistics and Computing, Southampton General Hospital, Southampton, UK Clinical Genetics, St. Mary’s Hospital, Manchester, UK Department of Medical Genetics, Aberdeen Royal Infirmary, Aberdeen, UK

Genetic Testing for Breast Cancer Predisposition in 1999: which Molecular Strategy and which Family Criteria?

The usefulness of genetic testing for risk assessment relies on three parameters: the probability that a given phenotype reflects a genetic trait, the genetic heterogeneity, and the allelic heterogeneity. Concerning breast cancer genetic testing, all these parameters preclude easy genetic diagnosis of a woman with a breast cancer family history and require careful interpretation particularly in the case of a negative result. However, once a mutation has been identified in a family, genetic testing can be offered to the relatives, with a clear positive or negative result. Indeed, as breast cancer is a very common disease, family history may be due to chance without a predisposing gene segregating in the family. However, the probability of a family member being carrier of a predisposing gene can be evaluated taking into account his/her personal and family history (age and affection status for breast and ovarian cancer for all family members) under an established genetic model for breast cancer such as proposed by E. Claus [2,3]. Linkage analyses performed in a large set of families with at least four breast cancer cases, which indicate that BRCA1 and BRCA2 alterations account for the vast majority of familial forms of breast-ovarian cancers (95%) and for 65% of hereditary breast cancer-only cases, provide evidence for the genetic heterogeneity of inherited breast cancers and the probable existence of still unidentified genes [5]. In addition, the BRCAl and BRCA2 genes exhibit high allelic heterogeneity: 1.070 different germline variants of which 664 are inactivating mutations have been reported in the international database for BRCA1 and BRCA2 mutations (the Breast Cancer Information Core (BIC)). Only in a few populations (e.g. Icelandic, Ashkenazi Jewish) is breast cancer predisposition primarily due to a small number of founder mutations. Truncating mutations involving point or small size alteration have been predominantly reported, however, large rearrangements may occur in 10% to 25% of BRCA1 truncating mutations [6,7]. In addition, about 10% of the reported mutations are missense mutations. Except for a few cases, their functional relevance remains to be clarified. The strategy of molecular analysis in women with a breast cancer family history must take into account all these difficulties and relies on: the number of available cases in the family, the choice of the index case, the existence of a founder effect, the nature of the family history. Since the indirect approach by linkage analysis will be applicable in very few families [4] direct analysis for mutation will be performed, generally with a screening method for point or small size mutations initially to save costs. The probability of detecting a point mutation was estimated to be about 63% in large families with disease due to BRCA1 [5]. It must be emphasized that this low detection rate is due to both the incomplete sensitivity of the screening Short Communication

Current Policies for Surveillance and Management in Women at Risk for Breast and Ovarian Cancer: A Survey among 16 European Family Cancer Clinics

The recent isolation of breast cancer predisposing genes (BRCAl and BRCA2) allows for the identification of carriers within affected families. These carriers have a 50– 85% risk of developing breast or ovarian cancer and need careful follow up. The purpose of this study was to evaluate the management and screening protocols implemented in high risk families at various family cancer clinics in Europe.