Expert Opinion - Matching drugs to patients' DNA

Personalised medicines could enable GPs to target drugs to those who will benefit.

Pharmacogenetics, also called personalised medicines, aims to identify an individual's genetic makeup to target drugs to people who will benefit.

Ultimately, a person's genes will tell us how they will respond to medications - both efficacy and side-effects.

This will be significant, especially given the fact that the NHS drug budget amounts to £11 billion and the cost of adverse reactions is estimated at about £466 million, although this is unlikely to take into account the increased costs in primary care consultation time.

The technique involves taking a sample of material to be analysed by the lab. DNA analysis can be for germline mutations (those implicated in Mendelian conditions such as cystic fibrosis, Huntington's chorea, and thalassaemia), or for somatic cell mutations from tumour samples.

There are many research programmes being undertaken in the UK, some funded by the DoH and others by medical charities. In primary care, DNA analysis is likely to be performed using a mouth swab sample, which is quick to take and less invasive than a blood sample but equally effective.

Analysis for somatic cell mutations is being used in oncology departments at the moment. A tissue sample from the tumour is used.

Genetic profiling

The recent ruling on availability of trastuzumab for treatment of early breast cancer (it was previously only available to patients with advanced breast cancer) means that the number of patients tested with this technique will increase substantially in the near future.

Trastuzumab targets an abnormal protein (HER2) which makes tumours grow.

In people who are responsive to the drug, tumours shrink but leave healthy cells intact.

In the future, the same technique might be used in patients with colon cancer to identify those who will benefit from adjuvant chemotherapy (AC).

At present all patients receive AC but only one third will benefit. Genetic profiling will enable the remaining two thirds to avoid the side-effects.

Research is ongoing in the UK for clotting disorders and subgroups of diabetic patients.

In Germany, patients are routinely tested for factor V Leiden. Patients who test positive might have a greater risk of a clotting disorder, and are advised to avoid oral contraceptives and HRT, and to take preventive measures for long-distance travel.

Possible effects

One of the risks associated with pharmacogenetics is that it might split some of the common diseases into sub-groups, imposing a new classification based on the genetic analysis so that the target drug population is smaller.

This makes it less likely that blockbuster drugs will be developed in the future, a prospect that might not be attractive to pharmaceutical companies which are driven by profits but faced with the high cost of drug developments.

The downside for individuals is that there is the double whammy of diagnosis with a life-threatening condition and the possibility that their genetic profile will not complement, match or be susceptible to the drug therapy.

Testing itself can cause anxiety for patients.

Cost

The technique is costly at present but the technology is rapidly becoming cheaper.

There is the prospect of near patient testing, but it is likely that if this moves into primary care the lab will still need to interpret results.

Relevance to GPs

It is increasingly important for GPs to have an overview of genetics.

Cloning, stem cell research, advances in reproductive technologies and forensic genetic profiling feature frequently in the media.

This has raised patient awareness, so GPs might find themselves fielding more questions from patients about inherited or family disease.

Genetics, including pharmacogenetics and reproductive genetics, is a powerful tool which can raise complex medical and ethical issues. This reinforces the need for GPs and other primary care professionals to have a basic knowledge and understanding of genetics because they have in primary care unique opportunities to give information, counsel, refer or reassure patients.

For example, I became involved in pharmacogenetics through a long-standing interest in the development of primary care genetics, which led to the invitation to be a member of the Royal Society pharmacogenetics working group.

In 1995 I ran a multicentre trial on antenatal testing for cystic fibrosis (CF) in primary care. We found that using a mouth wash sample to find out if parents were CF carriers was rapid and effective, and prenatal diagnosis could be completed in the first trimester.

Faster treatments

Genetic analysis gives a lifetime result (except in tumour analysis where mutations are somatic rather than germline).

If pharmacogenetics was routinely used in primary care, GPs would need longer consulting times to take samples, wait for results, interpret results and prescribe.

Primary care computers have no programmes to record genetic analysis in a coded retrievable form which can be searched on for audit or research purposes. At present the information could only be entered as free text.

Medico-legal issues might arise if patients request a pharmaceutical for which their genetic analysis indicates they are non-responders or at risk of adverse reaction.

The positive impact is that, ultimately, some common diseases including diabetes, hypertension and asthma might be reclassified, which would enable prescribers to make a therapeutic choice based on the genetic analysis (and other factors), thus improving efficacy and reducing side-effects.

For me, that is the promise of pharmacogenetics, but we first need very large population studies of pharmacogenetic variability.

The time frame for the introduction of personalised medicines into clinical practice is likely to be 15-20 years, as concluded by the balanced and thoughtful report from the Royal Society's working group.

- Dr Harris is a GP in Manchester and a member of the Royal Society working group on pharmacogenetics. She is an adviser on the Health Technology Assessment research project for haemoglobinopathy screening in primary care, has an interest in the ethical aspects of genetics and worked on the UK Government Human Genetics Commission from 1999 to 2004

KEY POINTS

- Pharmacogenetics aims to identify an individual's genetic make-up to target drugs to the people.

- The technique involves taking a tissue sample (mouth swab or blood sample) and sending it to the lab for analysis for germline mutations or somatic cell mutations from tumour samples.

- Pharmacogenetics may enable a GP to make a therapeutic choice based on a patient's genetic analysis, thereby improving efficacy and reducing side-effects.

- Pharmacogenetics is a powerful tool which can raise complex medical and ethical issues; therefore it is important for GPs to have an overview of genetics.

- If pharmacogenetics were routinely used in primary care, GPs would need longer consulting times.

- It is likely that in 15-20 years, personalised medicines will be available in clinical practice.

For more information visit: www.royalsoc.ac.uk/personalisedmedicines.

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