Randomised trial of population-based BRCA testing in Ashkenazi Jews: long-term secondary lifestyle behavioural outcomes.

OBJECTIVE: Ashkenazi-Jewish (AJ) population-based BRCA testing is acceptable, cost-effective and amplifies primary prevention for breast & ovarian cancer. However, data describing lifestyle impact are lacking. We report long-term results of population-based BRCA testing on lifestyle behaviour and cancer risk perception. DESIGN: Two-arm randomised controlled trials (ISRCTN73338115, GCaPPS): (a) population-screening (PS); (b) family history (FH)/clinical criteria testing. SETTING: North London AJ-population. POPULATION/SAMPLE: AJ women/men >18 years. EXCLUSIONS: prior BRCA testing or first-degree relatives of BRCA-carriers. METHODS: Participants were recruited through self-referral. All participants received informed pre-test genetic counselling. The intervention included genetic testing for three AJ BRCA-mutations: 185delAG(c.68_69delAG), 5382insC(c.5266dupC) and 6174delT(c.5946delT). This was undertaken for all participants in the PS arm and participants fulfilling FH/clinical criteria in the FH arm. Patients filled out customised/validated questionnaires at baseline/1-year/2-year/3-year follow-ups. Generalised linear-mixed models adjusted for covariates and appropriate contrast tests were used for between-group/within-group analysis of lifestyle and behavioural outcomes along with evaluating factors associated with these outcomes. Outcomes are adjusted for multiple testing (Bonferroni method), with P < 0.0039 considered significant. OUTCOME MEASURES: Lifestyle/behavioural outcomes at baseline/1-year/2-year/3-year follow-ups. RESULTS: 1034 participants were randomised to PS (n = 530) or FH (n = 504) arms. No significant difference was identified between PS- and FH-based BRCA testing approaches in terms of dietary fruit/vegetable/meat consumption, vitamin intake, alcohol quantity/ frequency, smoking behaviour (frequency/cessation), physical activity/exercise or routine breast mammogram screening behaviour, with outcomes not affected by BRCA test result. Cancer risk perception decreased with time following BRCA testing, with no difference between FH/PS approaches, and the perception of risk was lowest in BRCA-negative participants. Men consumed fewer fruits/vegetables/vitamins and more meat/alcohol than women (P < 0.001). CONCLUSION: Population-based and FH-based AJ BRCA testing have similar long-term lifestyle impacts on smoking, alcohol, dietary fruit/vegetable/meat/vitamin, exercise, breast screening participation and reduced cancer risk perception.

Cluster-randomised non-inferiority trial comparing DVD-assisted and traditional genetic counselling in systematic population testing for BRCA1/2 mutations.

BACKGROUND: Newer approaches to genetic counselling are required for population-based testing. We compare traditional face-to-face genetic counselling with a DVD-assisted approach for population-based BRCA1/2 testing. METHODS: A cluster-randomised non-inferiority trial in the London Ashkenazi Jewish population. INCLUSION CRITERIA: Ashkenazi Jewish men/women >18 years; exclusion criteria: (a) known BRCA1/2 mutation, (b) previous BRCA1/2 testing and (c) first-degree relative of BRCA1/2 carrier. Ashkenazi Jewish men/women underwent pre-test genetic counselling prior to BRCA1/2 testing in the Genetic Cancer Prediction through Population Screening trial (ISRCTN73338115). Genetic counselling clinics (clusters) were randomised to traditional counselling (TC) and DVD-based counselling (DVD-C) approaches. DVD-C involved a DVD presentation followed by shorter face-to-face genetic counselling. Outcome measures included genetic testing uptake, cancer risk perception, increase in knowledge, counselling time and satisfaction (Genetic Counselling Satisfaction Scale). Random-effects models adjusted for covariates compared outcomes between TC and DVD-C groups. One-sided 97.5% CI was used to determine non-inferiority. SECONDARY OUTCOMES: relevance, satisfaction, adequacy, emotional impact and improved understanding with the DVD; cost-minimisation analysis for TC and DVD-C approaches. RESULTS: 936 individuals (clusters=256, mean-size=3.6) were randomised to TC (n=527, clusters=134) and DVD-C (n=409, clusters=122) approaches. Groups were similar at baseline, mean age=53.9 (SD=15) years, women=66.8%, men=33.2%. DVD-C was non-inferior to TC for increase in knowledge (d=-0.07; lower 97.5% CI=-0.41), counselling satisfaction (d=-0.38, 97.5% CI=1.2) and risk perception (d=0.08; upper 97.5% CI=3.1). Group differences and CIs did not cross non-inferiority margins. DVD-C was equivalent to TC for uptake of genetic testing (d=-3%; lower/upper 97.5% CI -7.9%/1.7%) and superior for counselling time (20.4 (CI 18.7 to 22.2) min reduction (p<0.005)). 98% people found the DVD length and information satisfactory. 85-89% felt it improved their understanding of risks/benefits/implications/purpose of genetic testing. 95% would recommend it to others. The cost of genetic counselling for DVD-C=£7787 and TC=£17 307. DVD-C resulted in cost savings=£9520 (£14/volunteer). CONCLUSIONS: DVD-C is an effective, acceptable, non-inferior, time-saving and cost-efficient alternative to TC. TRIAL REGISTRATION NUMBER: ISRCTN 73338115.

An investigation of routes to cancer diagnosis in 10 international jurisdictions, as part of the International Cancer Benchmarking Partnership: survey development and implementation.

OBJECTIVES: This paper describes the methods used in the International Cancer Benchmarking Partnership Module 4 Survey (ICBPM4) which examines time intervals and routes to cancer diagnosis in 10 jurisdictions. We present the study design with defining and measuring time intervals, identifying patients with cancer, questionnaire development, data management and analyses. DESIGN AND SETTING: Recruitment of participants to the ICBPM4 survey is based on cancer registries in each jurisdiction. Questionnaires draw on previous instruments and have been through a process of cognitive testing and piloting in three jurisdictions followed by standardised translation and adaptation. Data analysis focuses on comparing differences in time intervals and routes to diagnosis in the jurisdictions. PARTICIPANTS: Our target is 200 patients with symptomatic breast, lung, colorectal and ovarian cancer in each jurisdiction. Patients are approached directly or via their primary care physician (PCP). Patients' PCPs and cancer treatment specialists (CTSs) are surveyed, and 'data rules' are applied to combine and reconcile conflicting information. Where CTS information is unavailable, audit information is sought from treatment records and databases. MAIN OUTCOMES: Reliability testing of the patient questionnaire showed that agreement was complete (κ=1) in four items and substantial (κ=0.8, 95% CI 0.333 to 1) in one item. The identification of eligible patients is sufficient to meet the targets for breast, lung and colorectal cancer. Initial patient and PCP survey response rates from the UK and Sweden are comparable with similar published surveys. Data collection was completed in early 2016 for all cancer types. CONCLUSION: An international questionnaire-based survey of patients with cancer, PCPs and CTSs has been developed and launched in 10 jurisdictions. ICBPM4 will help to further understand international differences in cancer survival by comparing time intervals and routes to cancer diagnosis.

Population testing for cancer predisposing BRCA1/BRCA2 mutations in the Ashkenazi-Jewish community: a randomized controlled trial.

BACKGROUND: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)-based testing. METHODS: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided. RESULTS: One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%. CONCLUSION: Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn't adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers.

Cost-effectiveness of population screening for BRCA mutations in Ashkenazi jewish women compared with family history-based testing.

BACKGROUND: Population-based testing for BRCA1/2 mutations detects the high proportion of carriers not identified by cancer family history (FH)-based testing. We compared the cost-effectiveness of population-based BRCA testing with the standard FH-based approach in Ashkenazi Jewish (AJ) women. METHODS: A decision-analytic model was developed to compare lifetime costs and effects amongst AJ women in the UK of BRCA founder-mutation testing amongst: 1) all women in the population age 30 years or older and 2) just those with a strong FH (≥10% mutation risk). The model assumes that BRCA carriers are offered risk-reducing salpingo-oophorectomy and annual MRI/mammography screening or risk-reducing mastectomy. Model probabilities utilize the Genetic Cancer Prediction through Population Screening trial/published literature to estimate total costs, effects in terms of quality-adjusted life-years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER), and population impact. Costs are reported at 2010 prices. Costs/outcomes were discounted at 3.5%. We used deterministic/probabilistic sensitivity analysis (PSA) to evaluate model uncertainty. RESULTS: Compared with FH-based testing, population-screening saved 0.090 more life-years and 0.101 more QALYs resulting in 33 days' gain in life expectancy. Population screening was found to be cost saving with a baseline-discounted ICER of -£2079/QALY. Population-based screening lowered ovarian and breast cancer incidence by 0.34% and 0.62%. Assuming 71% testing uptake, this leads to 276 fewer ovarian and 508 fewer breast cancer cases. Overall, reduction in treatment costs led to a discounted cost savings of £3.7 million. Deterministic sensitivity analysis and 94% of simulations on PSA (threshold £20000) indicated that population screening is cost-effective, compared with current NHS policy. CONCLUSION: Population-based screening for BRCA mutations is highly cost-effective compared with an FH-based approach in AJ women age 30 years and older.