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Controversies and ethical issues in cancer-genetics clinics Marion Harris, Ingrid Winship, Merle Spriggs
Lancet Oncol 2005; 6: 301–10
Genetic testing is a powerful technology that enables prediction of future health status. Testing for cancerpredisposition genes provides information for both the individual and his or her family. The use of this information reaches beyond the medical sphere to the psychological, social, legal, and ethical. The important issues include informed consent, autonomy, confidentiality, justice, disclosure and non-disclosure, duty to warn, genetic discrimination, predictive genetic testing of children, preimplantation genetic diagnosis, and patenting of cancerpredisposition genes.
Introduction A small but pronounced proportion of all cancers arise in people who carry a germline mutation in a cancerpredisposition gene (figure 1). When a cancerpredisposing mutation has been identified in a family, predictive genetic testing offers an opportunity to practise preventive oncology. Targeted surveillance, chemoprevention, and risk-reducing surgical options can be used just for individuals at risk, sparing those not at risk the need for surveillance measures. A positive genetic-test result has implications for the individual and his or her family. Some members of an extended family will view information that a cancerpredisposition gene is present in the family as useful, whereas others might not welcome the knowledge. Various controversies and ethical issues arise in the routine practice of a cancer-genetics clinic. In some situations, different courses of action are possible and the best course is not readily apparent. This review identifies and describes these issues. Ethics is essentially the use of reasoning to decide which is the best course of action to take. The issues raised in this paper are broadly applicable to a range of genetic disorders but are particularly pertinent to cancer genetics and oncology, because the goal in this specialty is to limit the effect of the cancer by means of prophylactic surgical measures or early detection. Any obstacles or difficulties in achieving this important endpoint are worthy of exploration.
consequent anxiety that a positive test might bring. Such individuals might opt for a programme of surveillance, perhaps deferring testing to a later date (sometimes after having children) or sometimes never. A scarcity of proven measures to reduce cancer risk (as in Li-Fraumeni syndrome) is another reason why some individuals will choose not to be tested. Some people not only decline testing but do not wish to know their family history or risk at all (figure 2). Their reasons could include avoidance of psychological harm and anxiety, as well as fear of stigmatisation and discrimination by employers or insurance companies.2 The 2003 American Society of Clinical Oncology (ASCO) policy statement update on genetic testing for cancer susceptibility defines the basic elements of informed consent for genetic testing for cancer risk.3 The fact that genetic testing is optional and that surveillance advice can be offered on the basis of risk alone without a genetic test, should be discussed in the consultation. The implications of a positive test result, including cancer penetrance (number with the gene change who develop cancer) and expressivity (types of cancer) should be discussed too. The counsellor should
Genetic Health Services Victoria, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria 3050, Australia (M Harris MD, Prof I Winship MBChB, M Spriggs PhD) Correspondence to: Dr Marion Harris, Genetic Health Services Victoria, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria 3050, Australia
[email protected]
Autonomy is the basis of informed consent, a process needed for the protection of the individual’s autonomous choice. To make an informed, autonomous decision a person must have information about the available options and must understand the implications of those options. The decision must be free from coercive influences and based on the individual’s beliefs.1 The decision to accept or decline genetic testing (a decision not to know) can be made autonomously in line with a particular person’s desires and plans. Some people seek clarification of the future risk of cancer for themselves and their offspring and are eager to have testing. Others regard the knowledge provided to be too much of a burden or may dislike the certainty and http://oncology.thelancet.com Vol 6 May 2005
© Alfred Pasieka/Science Photo Library
Informed consent and genetic testing
Figure 1: Germline mutations in cancer-predisposing genes increase the risk of cancer
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emphasise that a negative test result does not mean that no mutation is present unless the test shows the absence of a family-specific mutation, and that the population risk of that cancer type persists. The cost of testing and the psychological implications of both negative and positive results for the individual, the spouse, and any offspring need to be discussed. The provision of predictive testing for others, and options for surveillance and prevention should be outlined. For people to make informed autonomous decisions, such pretest and posttest counselling is mandatory.3
Cost and equity of access to gene testing Genetic testing is expensive; however, long-term cost savings in terms of targeted surveillance measures are probably substantial, as suggested by several analyses of patients with familial breast cancer, hereditary nonpolyposis colorectal cancer, and familial adenomatous polyposis.4–8 Cost savings accrue when individuals potentially at high risk and under surveillance (by regular colonoscopy or mammography) are proven not to have inherited the identified familial mutation and so can discontinue screening measures. In one analysis a group of 48 individuals were offered predictive genetic testing for hereditary non-polyposis colorectal cancer. During the 5 years after genetic testing, the total number of colonoscopies recommended for the group and all
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4 dx 28 Colorectal cancer
Small bowel adenocarcinoma
Figure 2: Family 1 The patient (arrow) was diagnosed as having metastatic adenocarcinoma of the small bowel in her late 20s and had an MSH2 mutation, causing hereditary nonpolyposis colorectal cancer. She died soon after diagnosis. There is a maternal and paternal family history of bowel cancer. Her father does not carry the MSH2 mutation but her brother does. Her mother is estranged from the family but has previously said that she does not wish to know the results of any genetic testing because she finds this too stressful. This woman has siblings, nieces, and nephews.
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their offspring was half the number they had undertaken in the previous 5 years, even though some had not adhered to recommended surveillance before genetic testing.5 The cost of complete testing for BRCA1 and BRCA2 genes in Australia is about AUS$2300 (£945), and the cost of a predictive gene test is AUS$250 (£100). In comparison, a lung transplant costs AUS$91 600 (£37 500), the care of a very-low-birthweight baby costs AUS$112 000 (£46 000), and a hip replacement without complications costs AUS$12 500 (£5200).9 In the main, genetic testing is publicly funded in most European countries and in Canada and Australia. In the USA, more testing is offered through private facilities, and guidelines for the insurance industry encourage coverage of the cost of genetic testing and counselling (although federal law does not require such coverage). For people covered by public-health insurance Medicare, coverage for gene testing is decided on a caseby-case basis and varies from state to state in the USA. ASCO supports the principle that individuals with a substantially heightened risk of developing a hereditary cancer should have access to genetic counselling, testing, screening, and surgical interventions, which should be covered by public and private payers.3
Confidentiality and disclosure The confidentiality of the doctor–patient relationship is central to medical practice. By convention, no medical information or gene-test result can be disclosed to any other person or doctor (including insurers and employers) without the consent of the tested individual. When family-specific mutations are identified, individuals are strongly encouraged to share results with other at-risk relatives to facilitate predictive testing, especially when proven surveillance and prophylactic measures are available (eg, for hereditary non-polyposis colorectal cancer). In addition, sharing of this information with other family members might influence reproductive decisions. This disclosure to other relatives can be a burden for the index case, especially since family conflict and estrangement are common.10 Obstacles to disclosure include absence of interest, denial, difficult relationships with family members, reluctance to deliver bad news, and practical barriers to communication (for example, locating family members who have moved to other countries or changed their names). Serious harm can arise when this information is inadvertently (passive non-disclosure) or deliberately (active non-disclosure) withheld from family members (figure 3). Non-disclosure is most serious for genes with high penetrance (as in familial adenomatous polyposis) for which there is strong evidence that surveillance or surgical intervention can prevent or diagnose cancer at an early stage, resulting in a reduction in morbidity and mortality. http://oncology.thelancet.com Vol 6 May 2005
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Passive non-disclosure can be kept to a minimum if the testing team offers to assist and support the proband in this process of disclosure.11 Rare cases of active non-disclosure bring the confidentiality of the index case into direct conflict with the doctor’s duty to warn family members and at-risk family members’ right to know.
B
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Frequency of non-disclosure The frequency of non-disclosure is uncertain. In a survey12 of 800 geneticists, 60% of the 206 respondents had experience of a relative refusing to notify another atrisk relative. Genetic disorders that were not disclosed included Huntington’s disease, familial translocations, and familial cancer syndromes. Reasons cited by the patients for refusals included estranged family relationships, fears of employment or insurance discrimination, and concern about changing family dynamics. 31 of 123 medical geneticists who faced the dilemma of a patient not disclosing thought about disclosure without consent. Four geneticists in seven distinct cases did disclose risk-status information to relatives without consent. Reasons given for not directly disclosing included confidentiality of the doctor–patient relationship, resolution of the difficulty by other means, and concern about legal liability. In a population-based prospective study of genetic professionals’ reports of non-disclosure of genetic-risk information in families in the UK and Australia, 65 cases of non-disclosure were reported representing less than 1% of the genetic clinic consultations in 2000–01.13 In decreasing order of frequency, professionals’ understanding of clients’ reasons for non-disclosure included desire not to cause worry or anxiety, assumptions that the information was irrelevant, belief that family members could not cope with the information, absence of contact with relatives or poor relationships with relatives, belief that it might be better not to know, and reluctance to take on the responsibility. In most instances, professionals took further steps to persuade their clients to disclose, but in no instances was disclosure forced or undertaken without the client’s consent.
Opinions of professional bodies on disclosure In 1998 the American Society of Human Genetics produced a statement on professional disclosure of familial genetic information.2 This statement suggested that patients’ confidentiality should be respected and that the familial implications of any gene-test result should be emphasised to the individual such that disclosure is encouraged but not coerced. Only in exceptional cases should the health professional use a discretionary right to breach confidentiality and only then if certain conditions are met. These conditions include that attempts to encourage disclosure have failed, that harm is serious and foreseeable, that at-risk http://oncology.thelancet.com Vol 6 May 2005
Colorectal cancer Familial adenomatous polyposis dx 36 Ovarian cancer
Breast cancer
Figure 3: Families 2 and 3 The first patient (A; arrow) had rectal bleeding in his early twenties and was diagnosed as having familial adenomatous polyposis. His father had died early of metastatic bowel cancer. 2 years later patient A’s 28-year-old brother presented with a Dukes’ stage C colorectal cancer with profuse polyposis. The patient had intended to inform his brother about his familial adenomatous polyposis, but the pair had drifted apart and had little contact. The second patient (B; arrow) was diagnosed as having breast cancer at age 36 and has a BRCA1 mutation. She has a paternal family history of ovarian cancer. The patient declines to pass information about her mutation to her paternal halfsister. The two women have no contact and parted on bitter terms.
individuals can be identified, and that the disease is preventable or treatable, or early monitoring is medically accepted to reduce risk or avert harm. Furthermore, the harm resulting from non-disclosure should outweigh the harm resulting from disclosure. Various bodies essentially support these recommendations, including the US President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioural Research, the Committee of the Health Council of the Netherlands, the Council of Europe, the Nuffield Council on Bioethics, and WHO.14–18 Groups with a contrary view that confidentiality is absolute include the Norwegian Ministry of Health and Social Affairs, the Swiss Academy of Medical Sciences, and the members of the UK House of Commons Science and Technology Committee.19–21 The American Medical Association suggests that during pretest counselling doctors should inform patients of expectations to notify relatives of information and should assist patients in this undertaking.22 An ASCO policy statement in 2003 suggested that genetic syndromes of cancer predisposition do not justify a 303
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breach of confidentiality, but it encourages voluntary disclosure, concluding that the provider’s obligations (if any) to at-risk relatives are best fulfilled by communication of familial risk to the person undergoing testing.3,23 Ideally, such communication of familial risk should be documented in the medical record.24
Legal precedent, legislation, and disclosure We review three cases of US case law to explore the issue of disclosure. The case of Tarasoff versus Regents of the University of California deals with the concept of general duty to warn. In this case, a psychiatrist was successfully sued when a patient warned of intention to harm a woman whom he subsequently killed. The court judged that the doctor should have breached confidentiality to warn of a foreseeable and serious harm to an identified individual.25 This general example has been distinguished from the situation of warning about a genetic risk since the patient does not directly harm the family members; the mutation is already present (or absent) in the relatives. Instead, the issue is one of a moral duty to inform someone of risks of which they might be unaware. Two other cases deal with physicians being sued for failing to warn of genetic risk from an inherited predisposition to cancer. In Pate versus Threkel, the court judged that a physician had a duty to warn his patient with medullary carcinoma of the thyroid of the risk to her offspring of the same cancer, since this risk could be tested for and the cancer prevented by prophylactic measures. The Californian Supreme court deemed that the physician’s duty was to warn the patient and that direct contact with other family members or offspring would not be practicable and would place unnecessary burden on the doctor.26 The case of Safer versus estate of Pack involved a claim about failure to warn a relative of the risk of familial adenomatous polyposis.27 A court in New Jersey ruled that a doctor’s duty was to take reasonable steps to warn directly immediate family members at risk of harm from an inherited disorder. For doctors who disclose without consent, privacy legislation is a concern. In the USA, a strict rule on privacy of health information, as outlined by the Health Insurance Portability and Accountability Act of 1996, prohibits disclosure of health information unless there is a serious and imminent threat to the health or safety of a person or the public and the physician has the capacity to avert substantial harm.28 Whether a future genetic disease meets these criteria is debatable. Many US states have adopted genetic privacy laws, and in some states these prohibit disclosure of genetic information without written consent from the patient or prevent disclosure in a manner that identifies the individual.24 In Australia, plans are under way to modify federal regulations (Commonwealth Privacy Act 1988) omitting 304
the word imminent so that disclosure would be supported in extreme and unusual cases at the physician’s discretion, and as a last resort where a serious threat exists to the health or safety of a person or the public.29 Since the over-riding opinion of most professional bodies on this issue is clear, to clarify the clinician’s duty in this setting there is a view that more legislation is needed. The opposing view is that ways to facilitate and support disclosure by the patient should be explored and that rare examples of active non-disclosure should be dealt with on a case-by-case basis.13
Genetic testing and genetic discrimination A potential drawback of genetic testing is the perception that individuals with cancer-predisposition syndromes can be unjustly discriminated against in employment and in applications for health and life insurance. Such concerns can result in individuals declining genetic testing and, thereby, foregoing prophylactic options.30 Genetic discrimination arises when individuals with no symptoms or signs receive less favourable or adverse treatment because of their genotype. Unjust discrimination takes place when there is no sound actuarial basis for the manner in which individuals are classified.31 The depth of concern about discrimination is shown by one US study,32 in which 163 specialists in cancer genetics responded to a questionnaire about what they would do if they underwent predictive genetic testing for hereditary non-polyposis colorectal cancer and BRCA1 or BRCA2 genes, each with a 50% chance of a positive result. 68% said that they would not bill their insurance companies for the testing because of fear of discrimination, and 26% would use an alias for genetic testing. Evidence of genetic discrimination has been documented in the USA, the UK, and Australia. In one study,33 members of seven UK genetic-support groups returned a questionnaire on genetic discrimination in insurance. A substantial subgroup reported that they had been unfairly treated by insurers, although they did not carry any adverse actuarial risk. This subgroup included individuals with negative predictive-gene tests, carriers of X-linked or autosomal-recessive disorders, and parents of children with a genetic disorder that had arisen as a new mutation.33 This unfair treatment probably reflects a scarcity of genetic knowledge on the part of the insurers involved, but it still amounted to unjust discrimination. In Australia, 48 examples of genetic discrimination in healthy gene-positive individuals were reported in a survey. 23 of these cases involved people who carried an inherited predisposition to cancer. Refusal of life insurance or income-protection insurance, and denial of greater life-insurance cover for those with preexisting policies were all described. Two individuals had genetic testing as part of a job-selection process http://oncology.thelancet.com Vol 6 May 2005
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and three individuals with late-onset neurological disorders were discriminated in the employment setting, with one job loss and two demotions reported.34 In a US study,35 phone interviews with members of different genetic-support groups found that 25% of respondents perceived that they or affected family members had been refused life insurance, 22% had been refused health insurance, and 13% were denied or dismissed from a job because of a genetic disorder in the family. Despite concerns and some evidence, the frequency of genetic discrimination remains uncertain. An Australia-wide study will objectively explore and document the true nature and extent of genetic discrimination in Australia by contact with consumers, third parties (insurers and employers), and the legal system. This study is intended to be one of the most substantial of its kind to investigate genetic discrimination.36 By contrast, another study37 of geneticists, counsellors, actuaries, and insurance agents in seven US states found little or no evidence that health insurers had used or asked for gene-test results in their underwriting. There was no difference between states that had or did not have laws that protect against genetic discrimination for health insurance. This somewhat surprising, though reassuring, finding could reflect the high rate of turnover of individual healthinsurance policies; if people remain in health plans for only a few years, there is little incentive for insurers to appraise the risk of future disease. It also suggests that concerns about discrimination could be exaggerated.
Employment discrimination To work is a basic human right, and in the USA many individuals obtain group health insurance through their work. Many people without work have no health insurance, unless it is purchased privately or is publicly covered by Medicare or Medicaid. Employers might seek to choose employees without genetic disorders to reduce compensation claims, reduce sick leave, or to boost productivity. This possibility is especially important in the USA where an employer pays for the health insurance of employees in proportion to the number of claims made. In 2000, US President Bill Clinton signed the first executive order of the 21st century, prohibiting the US federal government from using genetic information in hiring, promoting, and all other employment-related decisions.38 32 US states have enacted laws to ban collection of genetic information by employers and discrimination on this basis;39 other legislation just prohibits discrimination. In 2003, in the USA act s1053, The Genetic Information Non Discrimination Act was passed by the US senate. A further vote in the US House of Representatives is still needed, but if passed it will become a law that prohibits genetic http://oncology.thelancet.com Vol 6 May 2005
discrimination by all health-insurance providers and employers based on an individual’s inherited susceptibility to disease, including cancer. In 1989, the European parliament decreed that there should be no storage of genetic data on employees and that employees should have the right to refuse genetic testing without consequences.40 Similarly, a German commission suggested that collection or use of genetic information should be prohibited, and the Health Council of the Netherlands rejected genetic tests as part of job-selection procedures.15,41 The Nuffield Council of Bioethics suggested that genetic testing for employment purposes should be done only when it is directly relevant to the individual’s work.42 A review29 in Australia suggested that employers should not be allowed to request or gather genetic information in relation to job applicants or employees except when the aim is to ensure that a person can meet the inherent requirements of a job in relation to occupational health and safety issues. Thus, the general consensus is that genetic testing should be done or the results used only when the test is directly related to a job and there is a good medical reason to know the result.43
Health insurance and genetic discrimination Health insurance determines access to healthcare. Many countries (including European countries and Australia) have government-sponsored healthcare systems such as the UK National Health Service, with private health insurance as an optional extra. Concerns about genetic discrimination in health insurance relate to insurance obtained through employment-based or the private health-insurance system and are therefore especially relevant in the USA. Some degree of protection for US citizens is provided by the federal Health Insurance Portability and Accountability Act of 1996.28 This law prevents group health-insurance plans from using genetic information in underwriting health insurance (but not from obtaining this information) and allows employees to maintain their level of insurance cover if they change or leave jobs (ensuring that genetic information is not regarded as a pre-existing disorder). The Americans with Disabilities Act protects individuals subject to discrimination on the basis of genetic information; however, the amount of protection is uncertain.44 More than 40 US states have laws that ban health-insurance discrimination on the basis of genetic test results or information; however, the definition of genetic information and the degree of protection varies from state to state.37,45
Life insurance and genetic discrimination Many people do not have life insurance, but in some countries such insurance is necessary to obtain a home loan. Life insurance is sold to individuals as a commercial contract in which the insurer agrees to pay a 305
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death benefit in exchange for a premium proportional to the mortality risk of the individual.46 In most countries, life insurance or applications for disability income protection are rated by risk and the individual pays according to the risk brought to the insurance pool. Applicants must disclose all information known that could be relevant to permit accurate underwriting (risk assessment) of the policy by the insurer. Participating individuals are assessed according to age, sex, family history, and past medical history.29 Once obtained, the life-insurance policy is fixed. Controversy arises when insurers seek to use genetic information, particularly results of predictive DNA gene tests, in underwriting life-insurance policies for healthy people when they or their close relatives carry an identified inherited predisposition to cancer (such as a BRCA1 mutation). Many cancer-predisposition syndromes result in a heightened rather than a certain risk of cancer. Such uncertainty needs to be factored into the actuarial assessment of mortality risk. In some instances the relation between a gene-test result and subsequent mortality rate is uncertain. Most insurers argue that this genetic information, where known, should be disclosed in a life-insurance application. In most countries, laws on insurance contracts require individuals to disclose all relevant information for this purpose even when the information is not specifically requested.29,31 Failure to disclose means the insurer can resign from the contract. Such a disclosure can result in the application being refused, accepted on standard terms, or accepted on nonstandard terms (premium-loaded, exclusions, reducedsum payout, or restricted periods of coverage). The premium might not change from the insurer’s previous assessment if the individual’s family history is already substantial, and should be reduced in the event of a negative predictive gene test. Disclosure is required by the insurance industry because of concerns about adverse selection,47 which involves disproportionate purchase of insurance by highrisk individuals when premiums are not adjusted for risk. In this setting, since claims are high, premiums rise and those at low risk leave the system. At an extreme, this can threaten the viability of the industry. At the moment, the insurance industry could withstand restricted adverse selection; however, it might not be able to in future years. Although results of genetic tests previously done should be disclosed, there is no standard requirement by insurers for genetic testing to be done before needed insurance cover is provided. Such forced testing would be a violation of autonomy and a person’s wish not to know. In some countries, notably the UK and Australia, the insurance industry has adopted codes of practice. These codes stipulate that insurers will not ask applicants to have genetic testing.48 Therefore, industry codes rather than legislation determine standard 306
practice. Similarly, protection against genetic discrimination for people seeking life insurance is not enshrined in US law.49 The UK has adopted a two-tier system for the use of genetic tests in underwriting life-insurance policies. A moratorium has been placed on the use of the results of genetic tests by insurance companies for policies up to £500 000 for mortgage or term life insurance and £300 000 for critical illness, long-term care, and incomeprotection insurance; this moratorium lasts until the end of 2006. For people seeking policies beyond these financial limits, gene test results can be used by insurers only if the test has been approved by the UK Genetics and Insurance Committee. By January, 2005, the only gene test approved by the Genetics and Insurance Committee was that for Huntington’s disease, but applications for the use of positive predictive-gene tests for BRCA1 and BRCA2 are expected in 2005.50 Some UK insurance companies have announced that they will not seek or use such information.51 Similarly, federal legislation in the Netherlands prohibits insurers from asking for results of previous gene tests for a lifeinsurance contract below a predetermined amount.31 Some European countries have banned insurance companies from accessing genetic information altogether. The French insurance industry has imposed a voluntary moratorium on access to genetic information.43 A ban on insurers requiring or obtaining results of previous testing was supported by the European parliament in 1989 and a WHO statement in 1997, although neither of these bodies has binding force.49 The ban and the WHO statement are supported by the European Privacy directive that was enacted in 1998 and covers all 15 member countries of the European Union. These countries are required to enact privacy legislation to prohibit data collection or processing of health information as well as other data. This directive has made privacy a fundamental human right.52 There are four suggested ways to change the status of genetic testing and life-insurance applications. Some people believe that a total ban denying the insuranceindustry access to gene-test results is appropriate because insurers should have no access to confidential genetic information. A second approach is that all countries should provide a basic level of life insurance cover below which no disclosure of genetic information is required (as in the UK and the Netherlands). A third suggestion is that a new type of genetic-insurance product could be created for individuals with positive gene-test results. Such products could include a policy that excludes death or disability caused by the genetic factor identified.53 Finally, in most countries, insuranceindustry codes rather than legislation prohibit insurers from requiring genetic testing and DNA results; because the enforceability of industry codes can be questioned, some people believe that legislative re-enforcement is needed as soon as possible. http://oncology.thelancet.com Vol 6 May 2005
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Patents on genes that predispose to cancer Patents are intellectual property rights that are granted by a government to the inventor of a new product or process and give the inventor the right to stop others from exploiting the invention for a defined period (commonly 20 years). They are commercial tools, and patent holders are remunerated by issuing patent licenses to others for a fee. The aim of patents is to encourage and reward inventiveness. They might encourage the development of new clinically useful genetic tests.54 Criteria for patentability include novelty, inventiveness, and industrial application. Concerns have been expressed that gene patents hinder provision of medical genetic testing to the broader community and might cause a rise in the cost of testing by monopoly control. Financial effects can be substantial if government-funded genetic services are compelled to pay licensing fees or royalties. Further concerns are that patents hinder genetic research and innovation, when patent holders do not exploit inventions or adopt restrictive licensing practices. Patent holders are under no obligation to attempt development of gene therapies but can block others from doing so, thereby hindering future therapeutic advances.54 Some argue that patents on gene sequences should never have been granted since a genetic sequence is not an invention. Several organisations around the world have been reviewing the legal, ethical, and social implications of gene patents.54–56 There have been calls for reform of patent law. Options include use of compulsory licensing provisions of various patent acts to ensure access to patented genetic materials and technologies. In the future, some people believe that exclusive licensing of gene patents should be discouraged.56 There is growing consensus that gene patents relating to the provision of healthcare should be broadly licensed.57 Others believe that although continuous monitoring is necessary there has, to date, been no adverse effect of gene patenting on research or healthcare.55 Myriad (Salt Lake City, UT, USA) holds patents to the sequences of BRCA1 and BRCA2 in many countries and has a monopoly on testing for these genes in the USA. Controversy ensued when Myriad attempted to enforce these patents in Canada in 2001. The company advised provincial Canadian governments of its exclusive rights to gene testing of BRCA1 and BRCA2 and requested that all tests be sent to its centre in Utah at a cost three times higher than the cost of local testing. Ontario elected to continue BRCA testing, disputing that Myriad had the right to control where and how the testing should be done. British Columbia suspended BRCA-gene testing but reintroduced it in 2003.58 In May, 2004, the European Patent Office overturned one of Myriad’s three European patents on BRCA1 since the patent’s original submission contained sequence errors; by the time the errors were revised the correct http://oncology.thelancet.com Vol 6 May 2005
sequence had already been published so the work was not novel and not patentable. The scope of the remaining two patents was substantially cut in January, 2005. The bodies opposing the Myriad patents included Institut Curie, a cancer research centre in Paris with support from other French institutions, most European genetics societies, and the European parliament. They charged that the patents impeded healthcare and scientific discovery.59 In Europe, Myriad’s BRCA2 patent was also revoked in 2004. Cancer Research UK now has a Europe-wide patent on BRCA2 and will permit publicly owned laboratories and hospitals to use the gene free of charge for research and clinical purposes.60 An Australian biotechnology firm (Genetic Technologies Limited) caused concern when it became Myriad’s exclusive agent in Australia and New Zealand. There was concern that the company might enforce Myriad BRCA patents, charging costly fees for licences for BRCA testing, or force closure of genetic testing laboratories in public hospitals. The company has since publicly stated that it will not enforce these patents.61 However, Genetic Technologies Ltd is selling licences to its worldwide gene patents on non-coding DNA to research groups and biotechnology companies. This action could have substantial future implications for genetic testing related to cancer and to other genetic disorders, such as cystic fibrosis and Duchenne muscular dystrophy, because non-coding DNA (intronic or intervening sequences) covers much of the human genome. Concerns again centre on the fear of aggressive enforcement of patents with restriction of access to testing, rising costs of testing, and possible closure of public-testing laboratories. Other biotechnology companies and organisations hold patents on cancer-predisposition genes. Genzyme Molecular Oncology, a division of Genzyme corporation, holds US patent rights to MSH2, APC, and the TP53 genes. The Massachusetts Eye and Ear infirmary and the Whitehead Institute hold a US patent on the retinoblastoma tumour-suppressor gene.
Genetic testing of children Testing for cancer-predisposition genes in children is indicated if malignant disease can develop in childhood and if evidence-based-risk-reduction strategies exist and should be implemented in childhood. Examples include retinoblastoma-gene testing (to avoid eye examinations under anaesthesia every 3 months), RET-gene testing for multiple endocrine neoplasia 2 (to guide the need for thyroidectomy), and APC-gene testing for familial adenomatous polyposis (to guide the need for sigmoidoscopy). The American Society of Human Genetics, the Clinical Genetics Society in the UK, and the Human Genetics Society of Australasia have developed guidelines advising that if there is no cancer risk in childhood, testing should be deferred until adulthood.62–65 307
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uncertainty and anxiety in parents and children could be reduced, that testing might result in better psychosocial adjustment in the child, that professional paternalism is avoided, and that parental authority over minors is respected.64 The aim is to work out what is in the child’s best interests. Each family needs to be counselled on an individual basis.
Prenatal diagnosis or preimplantation genetic diagnosis for cancer-predisposition genes dx 30
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Sarcoma Breast cancer Adrenocortical carcinoma
Figure 4: Family 4 The patient (arrow) died from metastatic breast cancer in her early thirties. Her family had Li-Fraumeni syndrome and carried a germline-TP53 mutation. Shortly after his wife’s death her husband came to discuss predictive gene testing for his children aged 2 years and 4 years.
The reasoning behind this advice is to protect the child’s future autonomy and right not to know, to ensure that the child is not treated differently by the parents and is not stigmatised with limited education, marriage, and reproduction opportunities.65 However, some people argue that the idea of the child’s best interests includes more than medical interests; predictive testing in children can have important psychosocial benefits such as self knowledge and planning.65,66 When children have a risk of developing a malignant disease in childhood, in the absence of validated riskreducing strategies, testing is especially controversial (figure 4). Childhood surveillance for Li-Fraumeni syndrome consists of a yearly review (history and examination) by an oncologist with the optional use of abdominal ultrasonography to screen for abdominal tumours such as adrenocortical carcinoma. In some cases, parents want children to be tested for adult-onset cancer-predisposition syndromes. ASCO guidelines suggest that if conflict occurs, parental authority should be respected and should supersede.3 Arguments in favour of such testing include that 308
Prenatal diagnosis involves identification of a familyspecific mutation in a cancer-predisposition gene and collection of a fetal sample by chorionic-villus sampling or amniocentesis to find out whether or not the fetus is affected. Such testing provides the option to terminate the pregnancy if the fetus is affected. Preimplantation genetic diagnosis involves the use of in-vitro fertilisation to create several embryos. By day 3, the embryos consist of six to ten cells and one or two are removed for analysis. PCR is used to amplify DNA to detect singlegene diseases.67 Only unaffected embryos are reimplanted. This technique has been used for a range of genetic disorders in which family-specific mutations have been identified, including Huntington’s disease, cystic fibrosis, and Duchenne muscular dystrophy. Prenatal testing for adult-onset cancer-predisposition syndromes remains controversial because people can live for 40 years or longer before developing a cancer and owing to incomplete disease penetrance, some gene-positive individuals might never be affected by cancer (as for those with a BRCA mutation). Furthermore, in many disorders prophylactic or surveillance measures can largely prevent cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer) or favourably affect the individual’s course with early diagnosis. Hope for better future screening and prevention options, as well as gene therapies, is strong. Other objections to prenatal diagnosis and preimplantation genetic diagnosis include debate about abortion and the moral status of the embryo, as well as the selection process itself, with some embryos selected and others discarded because of genetic composition. Risks of greatly expanded future selection of embryos and children raise concerns of a eugenic world of designer children, although testing and selection for features, such as intelligence, height, and beauty, are not practicable at present. Many view preimplantation genetic diagnosis as ethically acceptable when it is done to produce offspring free from serious genetic disease.68 Some families (particularly those with familial adenomatous polyposis and BRCA mutations) are determined to cut the line and have unaffected children to ensure that both the next and future generations avoid the familial cancer burden, suffering, and need for surveillance. In the UK, the Human Fertilisation and Embryology Authority controls whether a clinic is licensed for http://oncology.thelancet.com Vol 6 May 2005
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Search strategy and selection criteria Data for this paper were identified from MEDLINE with the search terms “genetic testing”, “genetic counselling”, “genetic screening”, “disclosure”, “non-disclosure”, “duty to warn”, “genetic discrimination”, “insurance”, “insurance selection bias”, “genetic privacy”, “preimplantation genetic diagnosis”, “gene patents”, and “cancer”. Papers published in English from 1996 onwards were included. The report Essentially Yours, Protection of Human Genetic Information in Australia, March, 2003, produced by the Australian Law Reform Commission, National Health and Medical Research Council, and the Australian Health Ethics Committee was also accessed.
preimplantation genetic diagnosis and for what indications. In the USA, there is no such comparable regulatory body and the indications for preimplantation genetic diagnosis are left to providers and their clients.69 More than 1000 children have been born after testing for preimplantation genetic diagnosis.69 Preimplantation diagnosis has a 97% accuracy rate; however, many centres recommend confirmatory antenatal testing for a continuing pregnancy to exclude the small chance of genetic misdiagnosis. Pregnancy outcomes are similar to those of other in-vitro fertilisation populations.67 To date, preimplantation genetic diagnosis has successfully produced healthy children without familial adenomatous polyposis, retinoblastoma, Von Hippel-Lindau syndrome, BRCA1 and BRCA2 mutations, Li-Fraumeni syndrome, neurofibromatosis types I and II, and familial posteriorfossa brain-tumour syndromes.70
Conclusion Genetic testing aims to predict future health and to facilitate the practice of preventive oncology for the individual and for family members. The task of regulating the use and protection of genetic information is essential to ensure that the most good and the least harm comes to all. Conflicts of interest We declare no conflicts of interest. References 1 Beauchamp T, Childress J. Principles of biomedical ethics, 5th edn. New York: Oxford University Press, 2001: 57–58, 77–78. 2 The American Society of Human Genetics social issues subcommittee on familial disclosure ASHG statement: professional disclosure of familial genetic information. Am J Hum Genet 1998; 62: 474–83. 3 Offit K, Bertagnoli M, Bombard A, et al. American Society of Oncology Policy Statement Update: genetic testing for cancer susceptibility. J Clin Oncol 2003; 21: 2397–424. 4 Vasen H, van Ballegooijen M, Buskens E, et al. A cost effectiveness analysis of colorectal screening of hereditary non polyposis colorectal carcinoma gene carriers. Cancer 1998; 82: 1632–37. 5 Stanley A, Gaff C, Aittomaki A, et al. Value of predictive genetic testing in management of hereditary non-polyposis colorectal cancer. Med J Aust 2000; 172: 313–16.
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