Abstract

The landscape in cancer genetics is changing. The traditional family history (FH) based approach to genetic testing implemented through cancer genetic clinics following intensive face-to-face genetic counselling misses >50% mutation carriers and is being replaced by population-based approaches. A randomised trial (GCaPPS;ISRCTN73338115) of BRCA1/2 testing in the Ashkenazi-Jewish (AJ) population comparing population screening (PS) with standard FH-based testing found no difference in psychological/quality of life consequences between the two approaches. Additionally 60% mutations would be missed by FH-criteria alone. A cost-effectiveness analysis suggests that population screening for BRCA1/BRCA2 mutations in AJ women >30years reduces breast/ovarian cancer(OC) incidence by 0.34%/ 0.62%, saves 0.101 quality-adjusted-life-years (QALYs) leading to 33 days gain in lifeexpectancy and is extremely cost-effective with a discounted incremental cost-effectiveness ratio (ICER) of ‘-£2079/QALY.’ 94% of simulations on probabilistic-sensitivity analysis reconfirm population screening is highly cost-effective at £20,000/QALY threshold. This supports a call to change the clinical paradigm in the AJ population. Efficient, acceptable and more cost-effective ways of counselling/delivering genetic risk information on a population basis are necessary for population testing. A cluster-randomised non-inferiority trial shows that DVD-based approach is an effective, acceptable, non-inferior, time saving and cost-efficient alternative to traditional face-to-face genetic counselling in population testing. Telephone counselling is non-inferior in high-risk women. Alternate models like mainstreaming/use of dedicated nurse specialists are being explored in affected individuals. A population-based case series approach for BRCA1/2 testing is recommended for OC. However, implementation is prevented by lack of funding and awareness. Emergence of improved/sophisticated OC-risk models and validated estimates for new moderate penetrance genes (RAD51C/RAD51D/BRIP1) provides opportunity for population risk stratification and will lead to panel testing. The OC-risk threshold for effective surgical prevention is changing and will facilitate a clinical prevention strategy for moderate-risk women. Advances in high-throughput genetic testing technology, computational analytics and systems medicine approach, provides increasing potential for population testing, risk stratification and cancer prevention. Implementation studies assessing acceptability, clinical validity and cost-effectiveness are needed. Competing interests Investigator on the GCaPPS trial on population based testing Research funding from The Eve Appeal for research into population based testing.