ethics and precision medicine

what is precision medicine?

an approach to healthcare that customises treatment and prevention strategies based on an individual’s unique genetic, environmental, and lifestyle factors - tailored treatment

• prediction and prevention of disease

• precision diagnoses

• personalised (or targeted) interventions

• participatory role for patients - patients will be more compliant with their treatment

stratifying patients - why was precision medicine difficult in the past?

integrating information difficult (records)

less technology = less data

clinical trail process for new drugs - takes lots of time and money - isn’t cost effective if just targeting a small sub-group

importance of precision medicine

everyone is individual

ADRs

some first-line treatments are only 30-60% effective

1 in 17 people have a rare disease

1 in 2 affected by cancer

role of genetics in precision medicine

Sanger sequencing:

• first generation

• accurate and reliable for small-scale sequencing

• expensive and time-consuming

next generation sequencing

• enables whole genome sequencing

• cheaper, time-consuming

• accurate - if there is an error, the next sequence can detect that there was an error

100,000 genomes project aims:

• ethical and transparent programme based on consent

• benefits to patients

• new scientific discovery

prediction and prevention of disease - colorectal polyps and cancer

early prediction and prevention especially in individuals at genetic risk such as for colorectal cancer:

familial adenomatous polyposis (FAP) accounts for 1% of all colorectal cancer in UK each year

polyps aren’t cancerous but they increase the risk of developing colorectal cancer

FAP - rare autosomal dominant inherited disease caused by defects in the APC gene, causes formation of thousands of polyps in the GI tract - 100% lifetime risk of colorectal cancer

can offer treatment before getting the disease

precision diagnosis - neurofibromatosis and proteus syndrome

accurately identify and distinguish between diseases that may have similar clinical features but different underlying causes and treatment strategies. for example:

neurofibromatosis: autosomal dominant condition caused by a mutation in the NF1 gene → dysfunctional neurofibromin → uncontrolled cell growth in nerve tissue, neurofibromas along the nerves of the body

proteus syndrome: caused by mosaic/somatic mutation (mutation in the development of the zygote) in the AKT1 gene → dysfunctional AKT serine/threonine kinase → uncontrolled cell growth → overgrowth of skin, bones, progressive skeletal and vascular malformations - risk of deep vein thrombosis

both diseases show progressive skeletal malformations, benign/malignant tumours, and skin lesions

precision diagnosis confirms NF1 or AKT1 mutations - accurate diagnosis allows for targeted management

personalised (targeted) interventions - Duchenne muscular dystrophy

personalised interventions tailor to the specific mutation type in each patient

Duchenne: X-linked recessive genetic disorder characterised by progressive muscle degeneration - mutations in the gene dystrophin

• Ataluren - reads through stop codons, changes the ribosomes in order to read through the premature stop codons in the dystrophin mRNA - allows for production of full-length dystrophin in patients with nonsense mutations (~10-15% of DMD cases) - requires genetic testing to confirm the nonsense mutation in the DMD gene, only patients with this specific mutation are eligible for ataluren

personalised (targeted) interventions - warfarin

importance of precision dosing

warfarin is an anticoagulant for conditions such as deep vein thrombosis, atrial fibrillation

dosing is highly variable between individuals - too little → risk of clotting, too much → risk of bleeding

requires genetic testing to predict the patient’s sensitivity and metabolism to warfarin

participatory role for patients - diabetes

glucose monitoring devices → better compliance

challenges of precision medicine

ethical

social - educating family as well as patient

legal

interpretation of genetic results

cost - techniques

cost - drugs

ethical considerations

• clinical introduction - how much evidence is needed?

  • scope of estimated benefit - how many people is it likely to benefit

  • existence of alternative treatment - sometimes doesn’t necessarily need to look at genetics

  • nature of potential harm

  • quality of evidence

• patient understanding of precision medicine - not acting in the best for the patient - not informed consent?

• family communication of results

• healthcare disparities

  • genetic variants frequency vary across populations (warfarin)

  • implementing techniques in resource-poor/remote areas

  • availability of testing and knowledge