Transcript A reality check for personalised medicine: just a few errors in

A reality check for personalised
medicine: just a few errors in
translation?
Professor Donna Dickenson
Emeritus Professor of Medical Ethics
University of London
This is not a rhetorical question…
• Is genetic personalised (stratified)
medicine a genuine paradigm shift from
a ‘one size fits all’ model towards a
much more powerful and individualised
approach?
• Or are its medical and ethical limitations
much more than a few errors in
translation?
Benefits of pharmacogenetics
• With genetically individuated treatment,
for example in cancer care, patients
might be spared ‘megadose’ regime
that can produce iatrogenic harm
• Patients who are genetically
programmed to respond more quickly to
chemotherapy could get lighter doses
• Lifespan might be extended as well
A recent example
• Two studies on gliomas (Eckel-Passow et al.,
and Cancer Genome Atlas Research Network,
NEJM, June 2015) analysed 1380 tumours,
breaking patients down into five groups,
combinations classified according to three
genetic mutations in tumours
• Current histological approach less effective in
predicting response to treatment and overall
prognosis
Another recent example
• Robinson et al. (Cell, May 2015)
developed genetic map of prostate
cancer in 150 patients, revealing it as
not one disease but several, responsive
to different treatments
• Analysed genetic basis for resistance to
standard treatment, hormone therapy,
as result of specific DNA mutations
(In?)cautious optimism
• At launch in 2010 of NHS initiative to
personalise treatment of up to 6000
patients annually by adjusting their
therapy to genetic mutations of
tumours, Dr Harpal Jumar, chief
executive of Cancer Research UK, said:
‘It’s patently obvious that this is going
to be the way of the future.’
Example of vemurafenib
• 2012: NEJM article reports promising findings
for pharmacogenetic drug used against
aggressive melanoma
• Targets genetic mutation found in tumours of
about half of patients; of those, only about
one-half responded
• The one-quarter who did benefit, however,
gained an extra 7 months lifespan compared
to conventional treatment
But things aren’t always so clear
• At least the figure of one in four who benefit
from this drug is fairly reliable
• But for other tests, predictive value is no
better than tossing a coin (Lee and McLeod
2011)
• Paradox of pharmacogenetics: the more
specific the drug is to particular genetic
subgroups, the harder it becomes to find
enough patients to yield statistically
significant results
An example of serious limitations
• April 2015 study in Science Translational
Medicine of 815 cancer patients: sequencing
tumour genomes for clues to genetic changes
can misdirect individualised treatment in
nearly half of patients, unless first compared
to genetic readout of non-cancerous tissue
• Patients might get wrong targeted therapies
• Two-thirds of genetic changes identified with
tumour-only sequencing were false positives
Two-thirds? Not ‘just a few errors’
• False positive rate might be lessened by
sequencing non-cancerous tissue, but
obviously that increases costs
• Undermines argument that personalised
medicine is cost-effective because only those
patients who would benefit from a therapy
will receive it
• Particularly problematic because many
pharmacogenetic medicines are expensive
Ethical issues must be addressed
• Often assumed that there are no ethical
issues in personalised medicine: that it
is unequivocally what would be called A
Good Thing in 1066 and All That
• But in my 2013 book Me Medicine vs.
We Medicine, I call that assumption into
doubt
The wrong treatment for the wrong
patient at the wrong time?
• Ethos of pharmacogenetics is ‘the right
treatment for the right patient at the
right time’
• A high rate of false positives with
tumour-only sequencing could result in
wrong treatment for ‘right’ patient
• In other cases patients judged ‘wrong’
might be denied treatment altogether
Example of kidney transplants
• Genetic markers can predict probability
of immune system rejection (DionLabrie et al. 2010)
• Level of expression in haematopoietic
cells can forecast incidence of graft
versus host syndrome
• But is it ethical to select potential
recipients on genetic basis?
Again, not a rhetorical question
• Pro: it is both more efficient and more
equitable to use advances in genetic
sequencing to select recipients
• Con: apart of the problem of false negatives,
what cut-off is equitable if the answer is not
black and white?
• Should a patient get a drug even if there is
only a 20 percent chance she will respond?
10 percent? One percent?
Resource allocation: ‘tragic choices’
• Selecting patients on basis of genetic
likelihood of immune system rejection
fits model of allocation by prognosis:
resource should go to those with the
best chance of recovery
• This criterion can be controversial: it
was used to allocate scarce penicillin to
STD sufferers during World War Two,
not to men wounded in battle
Alternative model of allocation
• Resource should be allocated by
diagnosis, to those with most pressing
medical need
• We often favour this second criterion:
for example, we think that dying
patients should receive more time and
care than they ‘deserve’ on basis of
poor prognosis
Application to kidney transplant case
• Where dialysis is too burdensome or is
failing, genetically ‘wrong’ patients
needing a kidney transplant will be
denied their only hope…
• Even if genetic matching improves
overall efficiency…
• And avoids ‘wasting’ scarce resource of
kidney: a genuine ethical dilemma
Colorectal cancer example
• Testing for KRAS gene associated with
colorectal cancer can partially predict
that a ‘wrong’ patient is unlikely to
respond to particular therapy, especially
if cancer has metastasised (Lee and
McLeod 2011)
• Yet sensitivity of KRAS testing is
imperfect, so that many patients
identified as ‘right’ won’t respond either
Cards on the table…
• As a medical ethicist, I would have
concerns about dividing people into
treatment/non-treatment camps based
only on a genetic test, even if there
were no false positives or negatives
• Patients classified as ‘wrong’ might still
want to take their chances on treatment
if there is no alternative
A reality check in times of austerity
• In an era of cost-cutting, it is possible to
envisage a scenario in which genetic testing
is used as a rationale for denying some
patients a therapy
• One systematic review (You 2011) argued
that warfarin management should depend
almost entirely on cost-effectiveness
• Prediction that pharmacogenetics will be used
mainly to rein in patient demand (Sjogren
2010)
Escalating costs in pharmacogenetics
• Because pharmacogenetic drugs typically
treat much smaller populations than old-style
blockbusters, drug firms understandably
argue that they should cost more
• Examples: Kalydeco (ivacaftor) for cystic
fibrosis ($294,000 p.a.)
• Only effective in the four per cent of c.f.
patients who have G551D mutation
‘We Medicine’
• In 19th and early 20th centuries, rich and
poor alike were vulnerable to
contagious diseases such as cholera,
typhus and influenza
• Public health measures such as
sanitation and vaccination served both
social justice and medical progress
‘Me Medicine’
• But when individual conditions such as
cancer and cardiovascular disease
replaced infectious diseases as main
cause of mortality in developed world,
illness was individualised, as was
medicine’s response
• Personalised medicine techniques, such
as pharmacogenetics, take that logic
one step further
Will personalised medicine produce a
more or less fair society?
• That doesn’t mean personalised
medicine is ‘bad’: just that we must
locate it in a wider social context
• We can best advance the cause of
personalised medicine by being properly
sceptical about what it can and can’t do
• …and by insisting on asking the
necessary ethical questions