Barriers and facilitating factors for implementation of genetic services Martina Cornel Professor of Community Genetics and Public Health Genomics VU University Medical Center, Amsterdam EUPHA 11 November 2016 Round table "Bridging the gap between knowledge and practice in public health genomics"

Role in the Project – Domain 4 Our role NOT in identification of biomarkers, rather in later translational issues (WHO, WHAT, WHERE)

2000: genome sequence published Bill Clinton: We are here to celebrate the completion of the first survey of the entire human genome … With this profound new knowledge, humankind is on the verge of gaining immense, new power to heal. Genome science will have a real impact on all our lives -- and even more, on the lives of our children. It will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases. Vlnr Venter Clinton Collins Collins FS (Right at photo). Nature 2010 & © AP PHOTO/RON EDMONDS

Analysis of DNA cheaper every year, Moore’s law from bioinformatics: 18 months 0,5x price http://www.genome.gov/images/content/cost_per_megabase2.jpg

Collins, 10 years later (Nature 2010;464:674-5) Has the revolution arrived? The consequences for clinical medicine, however, have thus far been modest. Those who somehow expected dramatic results overnight may be disappointed, but should remember that genomics obeys the First Law of Technology: we invariably overestimate the short-term impacts of new technologies and underestimate their longer-term effects.

What to prioritize? considerations of medical benefit, health need and costs evidence of benefit in terms of clinical benefit, benefit of information for important life decisions, benefit for other people apart from the person tested and the patient specific likelihood of being affected by the condition tested for Severin et al. European Journal of Human Genetics (2015) 23, 729–735

Barriers? Lack of genetic knowledge relevant for every day care in other sectors of medicine Lack of HTA for application of genetics Lack of translational research in terms of translation “from bench to bedside” (unlike translational research “from mice to man”) How to integrate in daily practice? Guidelines, funding, access, programmatic approach Commercial offers direct-to-consumers (DTC) of tests with low predictive value – undermining trust

What to prioritize… criteria? VUmc Basispresentatie What to prioritize… criteria? Penetrance The likelihood of symptoms in a person with the mutation High predictive value 60-80% breastcancer risk in BRCA1&2 (lifetime risk) Interventions available Oöphorectomy, Mammography or mastectomy Clinical utility More healthy years Figure: Hartman 2016 NEJM

What to prioritize… criteria? Breast cancer in the family at a young age Potentially high risk Interventions available "I CARRY A “FAULTY” GENE, BRCA1, WHICH SHARPLY INCREASES MY RISK OF DEVELOPING BREAST CANCER AND OVARIAN CANCER. [...] ONCE I KNEW THAT THIS WAS MY REALITY, I DECIDED TO BE PROACTIVE AND TO MINIMIZE THE RISK AS MUCH I COULD. I MADE A DECISION TO HAVE A PREVENTIVE DOUBLE MASTECTOMY. I STARTED WITH THE BREASTS, AS MY RISK OF BREAST CANCER IS HIGHER THAN MY RISK OF OVARIAN CANCER, AND THE SURGERY IS MORE COMPLEX. [...] I CAN TELL MY CHILDREN THAT THEY DON’T NEED TO FEAR THEY WILL LOSE ME TO BREAST CANCER."

Colon cancer? FAP, Lynch (HNPCC) Colonoscopy Aspirine decreases cancer risk in Lynch syndrome (CAPP3 trial)

Screening? Cascade screening! VUmc Basispresentatie Screening? Cascade screening! After identification of an index patient, invite all first degree relatives (parents, brothers, sisters, children)

Screening? Cascade screening! VUmc Basispresentatie Screening? Cascade screening! father brother If some of the first degree relatives test positive, invite their first degree relatives.

Beyond BRCA and Lynch Cardiogenetics Oncogenetics Diabetes LQTS, HCM, ARVC/ARVD, etc Oncogenetics BRCA 1&2 Lynch syndrome (hereditary non-polyposis colorectal cancer) Familial adenomatous polyposis multiple endocrine neoplasia (MEN1, MEN2A, MEN2B, …) Diabetes Monogenic subtypes (MODY) such as GCK MODY (mild, but risk of perinatal death) HNF1A and HNF4A MODY manage well on a low dose of sulfonylureas © Lectrr Borry Matthijs

Service stratified according to profile? http://www.nature.com/nrg/journal/v17/n7/fig_tab/nrg.2016.27_F2.html

Service stratified according to profile? http://www.nature.com/nrg/journal/v17/n7/fig_tab/nrg.2016.27_F5.html

Beyond “monogenic” Testing increasingly with “(onco)panels” in clinical genetics services BRCA1/2/CHEK2 46 “well known” syndromes >100 genes if many different cancers Which gene(variant) to be added next? PALB2 – rare but similar impact as BRCA1/2 “multifactorial” gene set to tailor breast cancer screening? Some women start at 25 years of age (high risk surveillance) Some start at 40 years of age (moderate risk surveillance) Some start at 50 and come only once every 5 years Some don’t need mammography Testing with polygenic risk models? Not yet in services, first pilots ongoing

Who takes the initiative? Government in Familial Hypercholesterolaemia in The Netherlands until recently (2013)? Public health for national screening programmes? Clinical geneticist for family members of index? Oncologist for cancer patient? Pathologist for MSI testing or immunohistochemistry (Lynch)? Primary care physician to inform or alert family members? …..

Public health: work to be done! Genetic education HTA, prioritization Integration of genetics in screening Stratification according to risk (genetic & other) Collaboration, coordination, attunement between stakeholders Access, funding, programmatic approach

Conclusion