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Background Irbesartan, a long acting selective angiotensin-1 receptor inhibitor, in Marfan syndrome might reduce aortic dilatation, which is associated with dissection and rupture. We aimed to determine the effects of irbesartan on the rate of aortic dilatation in children and adults with Marfan syndrome. Methods We did a placebo-controlled, double-blind randomised trial at 22 centres in the UK. Individuals aged 6–40 years with clinically confirmed Marfan syndrome were eligible for inclusion. Study participants were all given 75 mg open label irbesartan once daily, then randomly assigned to 150 mg of irbesartan (increased to 300 mg as tolerated) or matching placebo. Aortic diameter was measured by echocardiography at baseline and then annually. All images were analysed by a core laboratory blinded to treatment allocation. The primary endpoint was the rate of aortic root dilatation. This trial is registered with ISRCTN, number ISRCTN90011794. Findings Between March 14, 2012, and May 1, 2015, 192 participants were recruited and randomly assigned to irbesartan (n=104) or placebo (n=88), and all were followed for up to 5 years. Median age at recruitment was 18 years (IQR 12–28), 99 (52%) were female, mean blood pressure was 110/65 mm Hg (SDs 16 and 12), and 108 (56%) were taking β blockers. Mean baseline aortic root diameter was 34·4 mm in the irbesartan group (SD 5·8) and placebo group (5·5). The mean rate of aortic root dilatation was 0·53 mm per year (95% CI 0·39 to 0·67) in the irbesartan group compared with 0·74 mm per year (0·60 to 0·89) in the placebo group, with a difference in means of −0·22 mm per year (−0·41 to −0·02, p=0·030). The rate of change in aortic Z score was also reduced by irbesartan (difference in means −0·10 per year, 95% CI −0·19 to −0·01, p=0·035). Irbesartan was well tolerated with no observed differences in rates of serious adverse events. Interpretation Irbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. Funding British Heart Foundation, the UK Marfan Trust, the UK Marfan Association.

ObjectivesTo assess the feasibility of delivering and evaluating a weight management (WM) programme for overweight patients with a family history (FH) of breast cancer (BC) or colorectal cancer (CRC).Study designA two-arm (intervention vs usual care) randomised controlled trial.SettingNational Health Service (NHS) Tayside and NHS Grampian.ParticipantsPeople with a FH of BC or CRC aged≥18 years and body mass index of ≥25 kg/m2referred to NHS genetic services.InterventionParticipants were randomised to a control (lifestyle booklet) or 12-week intervention arm where they were given one face-to-face counselling session, four telephone consultations and web-based support. A goal of 5% reduction in body weight was set, and a personalised diet and physical activity (PA) programme was provided. Behavioural change techniques (motivational interviewing, action and coping plans and implementation intentions) were used.Primary outcomeFeasibility measures: recruitment, programme implementation, fidelity measures, achieved measurements and retention, participant satisfaction assessed by questionnaire and qualitative interviews.Secondary outcomesMeasured changes in weight and PA and reported diet and psychosocial measures between baseline and 12-week follow-up.ResultsOf 480 patients approached, 196 (41%) expressed interest in the study, and of those, 78 (40%) patients were randomised. Implementation of the programme was challenging within the time allotted and fidelity to the intervention modest (62%). Qualitative findings indicated the programme was well received. Questionnaires and anthropometric data were completed by >98%. Accelerometer data were attained by 84% and 54% at baseline and follow-up, respectively. Retention at 12 weeks was 76%. Overall, 36% of the intervention group (vs 0% in control) achieved 5% weight loss. Favourable increases in PA and reduction in dietary fat were also reported.ConclusionsA lifestyle programme for people with a family history of cancer is feasible to conduct and acceptable to participants, and indicative results suggest favourable outcomes.Trial registration numberISRCTN13123470; Pre-results.

Breast cancer risk is a common indication for referral to clinical genetics services. UK National Institute of Health and Care Excellence (NICE) guidelines use family history (FH) to stratify by 10-year risk of breast cancer from age 40. Patients are stratified into population risk (PR, 10-year risk 8%). Women at increased risk are offered screening at or prior to age 40. To assess the clinical effectiveness of current risk stratification, FH data were obtained for all unaffected women with a FH of breast cancer aged

Colorectal cancer (CRC) risk is well defined for families of patients with classical familial adenomatous polyposis (FAP). However, the risk for those with an attenuated form of FAP is less well characterised. In this study, we estimated CRC risks for carriers of a novel germline mutation in the APC gene that causes attenuated FAP (AFAP). We performed genetic testing on 53 individuals from seven AFAP families harbouring an identical APC:c.288T>A mutation. Using a modified segregation analysis, we estimated relative and absolute CRC risks for mutation carriers. Twenty-three individuals harboured the disease causing mutation. CRC occurred in 28 individuals (mean 61.7 years, range 32–80 years). The estimated CRC relative risks for mutation carriers aged 60–69 and ≥70 years were 19 (95% CI: 1.77–204.08) and 45 (95% CI: 11.32–180.10), respectively, while the absolute CRC lifetime risk for men was 94% (95% CI: 67.5–99.9%), and for women, 84% (95% CI: 50.9–99.0%). This study shows that AFAP can manifest as autosomal dominant late-onset CRC. These findings highlight a subgroup of inherited CRCs that require new criteria for identification and surveillance.

The current work aimed to assess health behaviors, perceived risk and control over breast/colorectal cancer risk and views on lifestyle advice amongst attendees at cancer family history clinics. Participants attending the East of Scotland Genetics Service were invited to complete a questionnaire (demographic data, weight and height, health behaviors and psycho-social measures of risk and perceived control) and to participate in an in-depth interview. The questionnaire was completed by 237 (49 %) of attendees, ranging from 18 to 77 years (mean age 46 (±10) years). Reported smoking rates (11 %) were modest, most (54 %) had a BMI > 25 kg/m2, 55 % had low levels of physical activity, 58 % reported inappropriate alcohol intakes and 90 % had fiber intakes indicative of a low plant diet. Regression analysis indicated that belief in health professional control was associated with higher, and belief in fatalism with poorer health behavior. Qualitative findings highlighted doubts about the link between lifestyle and cancer, and few were familiar with the current evidence. Whilst lifestyle advice was considered interesting in general there was little appetite for non-tailored guidance. In conclusion, current health behaviors are incongruent with cancer risk reduction guidance amongst patients who have actively sought advice on disease risk. There are some indications that lifestyle advice would be welcomed but endorsement requires a sensitive and flexible approach, and the acceptability of lifestyle interventions remains to be explored.

Background: A significant proportion of women are at increased genetic risk of breast cancer. Mutations in high penetrance genes such as BRCA1 and BRCA2 are only responsible in the minority of cases, with low penetrance polymorphisms in other genes expected to account for the majority of the remaining genetic risk. An increasing number of such low penetrance polymorphisms are being identified, but each polymorphism only contributes a small amount to overall risk. Currently, in clinical practice, women who are at increased risk of breast cancer are identified by their family history, and the role of genetic testing for multifactorial risk remains uncertain. We have taken the population frequency and genotype relative risk information for the 18 most established low penetrance breast cancer risk loci and explored the effect of combining information from these loci, with risk derived from family history. Results: Genotyping at these 18 loci could provide significant risk information for an individual. The top 1% of women in the genotype risk distribution would have a risk of breast cancer of 2.11 times the general population. At this level of risk, they would qualify for breast cancer screening from age 40 according to evidence based guidelines issued by the UK National Institute of Clinical Excellence (NICE). In addition, the top 5% of the population are at 1.67 times risk of breast cancer and would have the same risk at age 40 as a 50 year old at population risk who would qualify for breast screening according to UK and US National Screening Guidelines. To investigate whether low penetrance genotype has greater potential if combined with other risk factors, we used a simple multiplicative model to combine family history risk of cancer derived using BOADICEA with genotype information. Our data suggest that genotype would result in a significant reclassification of individual risk. For example, 10% of women who only had a sister affected with breast cancer at 55 would qualify for additional screening under NICE criteria if genotype were taken into account. Extending this approach with 160 complex family histories from the Tayside family history breast clinic, we have shown that genotyping could result in reclassification and change of management for 19.1% of women being assessed in this clinic, with 12.4% of women moving into a higher risk category, and 6.7% of women moving into a lower category. Discussion: These data suggest that genotyping for low penetrance breast cancer risk loci is clinically relevant, and that it will be more powerful if it can be combined with other established risk factors. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-11.

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.