The debate about direct-to-consumer genetic testing has centred on whether consumers are the best judges of their own clinical care. Inthis article, I also examine whether the science of personalized medicine is really as advanced as its proponents
          claim, and how the availability of genetic markers affects decisions on who gets
          and does not get medical treatment

Dickenson, Donna

Canadian Medical Association Journal

English

PubMed

The debate about direct-to-consumer genetic testing has centred on whether consumers are the best judges of their own clinical care. Inthis article, I also examine whether the science of personalized medicine is really as advanced as its proponents claim, and how the availability of genetic markers affects decisions on who gets and does not get medical treatment

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HumanitiesCMAJ©2016  8872147 Canada Inc. or its licensors CMAJ 1“We believe your genetic information should be controlled by you.”1 Under that banner of individual auton-omy, the consumer genetics firm 23andMe conducted personalized genetic testing until it was stopped in November 2013 by the United States Food and Drug Administration (FDA). The FDA ban occasioned a fierce dispute between proponents of appropriate regu-lation and defenders of the libertarian view that the only person deciding whether you should have a genetic test should indeed be you. This debate has centred on whether consumers are the best judges of their own clinical care. In this article, I also examine whether the science of personalized medicine is really as advanced as its proponents claim, and how the availability of genetic markers affects decisions on who gets and does not get medical treatment.In its decision, the FDA cited con-cerns about inaccuracy arising from the limited sample of markers being tested. Researchers have found that test results from different consumer genet-ics companies for common diseases, such as diabetes and prostate cancer, can be radically inconsistent because of the low number of markers tested and the small amounts of genetic vari-ance explained by each marker.2 In fact, genetic tests offered by direct-to-consumer firms only sample a small proportion of single-nucleotide poly-morphisms, (i.e., the points where the genomes of different individuals vary by a single DNA base pair).In October 2015, 23andMe obtained permission from the FDA to resume a limited version of its genetic testing operations. The company previously covered the risk propensity for 254 inherited diseases; however, it is now only allowed to provide nonmedical ancestry tests and carrier data for 36 conditions, which include sickle cell anemia and cystic fibrosis. It is not permitted to perform pharmacogenetic analyses of an individual’s tolerance for a particular drug regimen, such as chemotherapy or warfarin.This final limitation is important, because at the outset, personalized direct-to-consumer genetic testing was widely hailed as the first staging post in the race to develop new forms of medicine that would potentially allow physicians to offer care tailored to the individual’s genome rather than the “one-size-fits-all” model. Variously called precision, personalized or strati-fied medicine, this approach was termed “a true revolution in medicine” by Francis Collins, former co-director of the Human Genome Project, but this assertion is debatable.3Personalized medicine’s claim is arguably strongest in the area of pharma-cogenetics, the relation of heritable varia-tion to individual differences in drug response. Here, the goal is to minimize adverse drug reactions and increase effi-cacy by tailoring the drug regimen to the sequenced genomes of both the patient and the cancer. This double approach is crucial because cancer is frequently het-erogeneous (e.g., after sequencing the genomes of breast cancers in 50 patients, researchers found that only 10% of the tumours had more than three mutations in common).4Recent studies have often confirmed or reconfirmed the value of the pharma-cogenetic approach. An analysis of 1380  gliomas, involving patients who were classified according to three genetic mutations in the tumours, found that the prevalent histologic approach was less effective than a genomic one for predicting response to treatment and overall prognosis.5 A genetic map of prostate cancer in 150 patients, which showed that it comprises several dis-eases responsive to different treat-Medicine and societyEthical qualms about genetic prognosisPiotr Marcinski/iStockCMAJ Podcasts: author interview at https://soundcloud.com/cmajpodcasts/151320-medsoc Early release, published at www.cmaj.ca on March 21, 2016. Subject to revision.Humanities2 CMAJ ©2016  8872147 Canada Inc. or its licensorsments, also analyzed the genetic basis for resistance to the standard therapies as a result of specific DNA mutations.6However, other recent studies have revealed serious clinical and ethical limitations of the pharmacogenetic approach. An analysis involving 815 patients with cancer showed that sequencing tumour genomes for clues to genetic changes can actually misdi-rect individualized treatment in nearly half of patients, unless this sequencing is first compared with a genetic read-out of the patient’s noncancerous tis-sue. Two-thirds of genetic changes iden-tified with tumour-only sequencing were false-positive results, which means patients might be given the wrong tar-geted treatments.7This study undermines the standard argument about resource allocation and personalized medicine: even though pharmacogenetic drugs are frequently more expensive, this form of personal-ized medicine is more cost-effective because only those patients who would benefit from treatment receive it. The ethos of pharmacogenetics is “the right treatment for the right patient at the right time.” However, such a high rate of false-positive results could mean the wrong treatment for the “right” patient.In other cases, genetic testing might result in some patients being denied treat-ment, which raises ethical issues about resource allocation. For example, genetic markers can predict the probability and severity of immune reaction in kidney transplant patients.8 Would it be ethical to select potential kidney recipients primar-ily or solely on a genetic basis? Although individualized genetic testing does not create the ethical dilemma arising from the need to make choices — because of the shortage of donor kidneys — it does not dispel it either.Arguably, it is more efficient and equitable to use advances in genetic sequencing to maximize the chances that the scarce resource of a donated kidney will be put to successful use. But we must also confront the problem of false-negative results, the mirror image of the false-positive problem raised by the study on prostate cancer. Suppose a potential recipient is wrongly identified as genetically more likely to reject the kidney and is disqualified for the trans-plant on that basis. This problem is exacerbated by the probabilistic nature of genetic analysis, which rarely yields black-and-white answers. Should a patient get a kidney, or a drug, if there is only a 20% chance that he or she will respond favourably based on genetic pro-file? Ten per cent? One per cent? Where shall we draw the line?The ethics of resource allocation, that area of “tragic choices”9 in medi-cine, offers two main alternatives for answering such questions. We can select who shall receive a scarce resource on the basis of prognosis: giv-ing the kidney or drug to the patient with the best chance of recovery. Such systems of triage have long been used by medicine, although they are some-times controversial. Choosing on the basis of the genetic likelihood of immune system rejection is a variant of this prognosis-based approach. Of course, in a clinical context, many other factors (e.g., patient age and family history) are also likely to be considered and will probably provide more accu-rate information than personalized genetic screening.10The alternative model of resource allocation is by diagnosis. Here, the argument is that justice demands we should give the resource to those with the most pressing medical need, not the best predicted outcome. We often favour this second criterion. For exam-ple, in palliative care we think that dying patients should receive more medical resources than their terminal prognosis would dictate. Similarly, we might want to give the patient with no other alternative an expensive pharma-cogenetic drug, even if his or her geneti-cally ascertained prognosis for the drug’s likely success is less favourable than in other patients.As a medical ethicist, I would have qualms about dividing patients into treat-ment and nontreatment camps purely on the basis of a genetic prognosis, particu-larly when genetic prognosis is still such an inexact science. A patient who has no other alternative may want to take his or her chances with a pharmaco-genetic drug. Although personalized medicine is framed in the language of individual rights and autonomy, resource allocation decisions are ultimately made by others. Particularly in an era of aus-terity and cost-cutting, the possibility that decision-makers will use genetic testing to limit patients’ “right to choose” is far from remote.Donna Dickenson MSc PhD Emeritus Professor of Medical Ethics and Humanities, University of London, London, UKAuthor of a critical study of personalized medicine, Me Medicine vs. We Medicine (Columbia University Press, 2016)References 1. McGowan ML, Fishman JR, Lambrix MA. Per-sonal genetics and individual identities: motivations and imperatives of early users. New Genet Soc 2010;29:261-90. 2. Kalf RRJ, Mihaescu R, de Knijff P, et al. Risk pre-dictions from direct-to-consumer personal genetic testing: What do consumers really learn about com-mon diseases? Paper presented at the European Society for Human Research and Enbryology (ESHRE) Conference; 2009 May 29–30. 3. Collins FS. The language of life: DNA and the revolution in personalized medicine. New York: Harper Collins, 2010:29. 4. Wadman M. Fifty genome sequences reveal breast cancer’s complexity [online]. Nature 2011 Apr. 2. doi:10.1038/news.2011.203. 5. Eckel-Passow JE, Lachance DH, Molinaro AM, et  al. Glioma groups based on 1p/19q, IDH and TERT promoter mutations in tumours. N Engl J Med 2015;372:2499-508. 6. Robinson D, Van Allen EM, Wu Y-M, et al. Integra-tive clinical genomics of advanced prostate cancer. Cell 2015;161:1215-28. 7. Jones S, Anagnostou V, Lytle K, et al. Personal-ized genomic analysis for cancer mutation discovery and interpretation. Sci Transl Med 2015;7:283ra53. 8. Dion-Labrie M, Fortin MC, Hebert MJ. The use of personalized medicine for patient selection for renal transplantation: physicians’ views on the clinical and ethical implications. BMC Med Ethics 2010;11:5. 9. Calabresi G, Bobbitt P. Tragic choices. New York: WW Norton; 1978.10. Heald B, Edelman E, Eng C. Prospective compari-son of family medical history with personal genome screening for risk assessment of common cancers. Eur J Hum Genet 2012;20:547-51.CMAJ 2016. DOI:10.1503/cmaj.151320

Ethical qualms about genetic prognosis

Donna Dickenson

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Ethical qualms about genetic prognosis

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