ASCO SPECIAL ARTICLE
American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility
As the leading professional organization representing physicians who are involved in cancer treatment and research, the American Society of Clinical Oncology (ASCO) has long recognized the importance of raising awareness among oncologists and other health care providers about the importance of inherited cancer risk in the practice of oncology and cancer prevention. In 1996, ASCO released its first statement on genetic testing, “Statement of the American Society of Clinical Oncology: Genetic Testing for Cancer Susceptibility,”1 which set forth specific recommendations for oncologists relating to clinical practice and research needs. In 2003, ASCO updated this statement,2 issuing recommendations related to the education of oncologists and other providers, pre- and post-test counseling by health care professionals, informed consent, regulation of laboratories, access, reimbursement, and protection from genetic discrimination. Since 2003, there have been significant developments in the field of genetics that require health care providers, patients, and other consumers of genetic information to think in new ways about these topics. In response, in October 2008, ASCO's Cancer Prevention and Ethics Committees commissioned an update of ASCO's previous statements on genetic testing that would reflect scientific advances and the evolving regulatory and policy environment. This statement update briefly reviews progress in priority areas identified in ASCO's previous statements and addresses how new developments, including the availability of genetic tests of uncertain clinical utility and direct-to-consumer (DTC) genetic testing, impact the practice of oncology and preventive medicine.
Since the first ASCO statement, genetic testing for cancer susceptibility has become an accepted part of oncologic care. Germline testing for inherited predisposition is well established as part of the care of individuals who may be at hereditary risk for cancers of the breast, ovary, colon, stomach, uterus, thyroid, and other primary sites.3,4 Germline genetic testing is distinct from somatic genetic profiling of cancer tissue to predict prognosis or treatment response. Germline testing involves analysis of DNA from blood or saliva for inherited mutations in specific genes that are associated with the type of cancer seen in the individual or family seeking assessment. When identified, such high-penetrance mutations usually result in a significant alteration in the function of the corresponding gene product and are associated with large increases in cancer risk. Other mutations (eg, APC*I1307K, CHEK2*1100delC) result in less dramatic increases in risk (intermediate penetrance). The identification of a high-penetrance mutation often justifies an adjustment of clinical care through the modification of surveillance or through preventive surgery. Germline testing for certain high-penetrance predispositions is now part of clinical guidelines and is reimbursed by most third-party payers.5,6 The impact of intermediate-penetrance mutations on clinical care is less clear.
Although they are clinically relevant, high-penetrance mutations and intermediate-penetrance mutations are uncommon. Most inherited cancer susceptibility arises from a number of DNA sequence variants, each of which, in isolation, confers a limited increase in risk. The genomic locations of a number of these low-penetrance variants (LPVs) have been defined through genome-wide association studies (GWAS). GWAS have identified genetic variations called single nucleotide polymorphisms (SNPs) that, although strongly associated with disease in large case-control studies, are usually not the DNA variations that alter the function of relevant gene products. Instead, the SNPs are located in close proximity to as yet unidentified causative variants. Unlike high- and intermediate-penetrance mutations, SNPs associated with disease risk are generally common (allele frequencies of up to 50% in the populations studied) and confer a modest increase in risk (per-allele odds ratios of < 1.5), although penetrance can vary based on environmental and lifestyle factors. As many as 100 SNPs are currently associated with cancer risk.7 Examples of low-, intermediate-, and high-penetrance genes with mutations and variants associated with increased risk of cancer are listed in Table 1.8–24
|Penetrance||Associated Cancer||Frequency in Population||Relative Risk (to specified age)||Intervention|
|Genes with high-penetrance mutations|
|BRCA1||Breast cancer||1/166 to 1/1,000; 1/82 (AJ)||32 (age 40-49 years)||Mammography, MRI screening, risk-reducing surgery|
|MSH2||Colorectal cancer||1/5,800||13.1 (by age 30 years); 9.3 (by age 50 years)||Endoscopy, prophylactic colectomy after diagnosis of malignancy|
|APC||Colorectal adenocarcinoma||1/13,000||19 (L)||Endoscopy, prophylactic colectomy|
|RET||Medullary thyroid cancer||1/200,000||125 (L)||Prophylactic thyroidectomy|
|APC*I1307K||Colon cancer||6/100 (AJ)||1.5-1.7 (L)||None proven|
|CHEK2*1100delC||Breast cancer||1/100-1/500||1.2-2.5 (L)||None proven|
|Low-penetrance variants (SNPs)|
|rs10505477 at 8q24||Colon cancer; prostate cancer||1/2||1.27 (L) for colon cancer; 1.43 (L) for prostate cancer||None proven|
|rs13281615 at 8q24||Breast cancer||2/5||1.21 (L)||None proven|
|rs1219648 at FGFR||Breast cancer||2/5||1.23 (L)||None proven|
Several commercial laboratories currently offer genomic risk assessment, a type of genetic testing for SNPs associated with disease risk. In genomic risk assessment, the SNPs in an individual's genomic profile are identified (or genotyped) and translated into absolute risk estimates through the use of various algorithms. To date, no published studies are known to have established whether these algorithms are well calibrated or whether the risk estimates provided through genomic risk assessment are accurate. Because these tests have uncertain clinical validity, they are not currently considered part of standard oncology or preventive care.
Tests for high-penetrance mutations in appropriate populations have clinical utility, meaning that they inform clinical decision making and facilitate the prevention or amelioration of adverse health outcomes.25 Genetic tests for intermediate-penetrance mutations and genomic profiles of SNPS linked to LPVs are of uncertain clinical utility because the cancer risk associated with the mutation or SNP is generally too small to form an appropriate basis for clinical decision making. For example, a particular LPV (ie, rs13281615) confers a risk of breast cancer equivalent to that of delaying childbearing from age 30 to 35. This level of risk does not warrant changes in recommendations for screening or prevention. However, if not framed appropriately, clinically ambiguous test results could produce unjustified alarm and may lead patients to request unnecessary screening and other preventive care that can cause physical discomfort or harm and increase costs. Alternatively, ambiguous test results or results associated with minimal cancer risk can provide false reassurance that discourages individuals from taking appropriate preventive measures.
Although tests to identify LPVs lack clear clinical utility, some have argued that genomic profiling may be justified on the basis of personal utility.26,27 According to this construct, genetic tests may benefit individuals by providing deeper self-knowledge and motivation to pursue healthy behaviors even if the results do not inform clinical decision making. However, the theoretical benefits of personal utility must be balanced against the risks that may be associated with clinically ambiguous test results. Oncologists and other health care providers may be asked for advice about testing based on personal utility, even though the lack of clinical utility places this choice outside of traditional medical decision making.
Until recently, genetic tests were only ordered by health care providers who served as intermediaries between individuals and the laboratories performing the tests. As intermediaries, health care providers order the tests, receive the results, communicate and explain the results, and coordinate appropriate follow-up care. Test results and subsequent interactions are documented in the medical record. Provider-mediated testing is subject to the ethical principles and legal obligations that are the hallmarks of provider-patient relationships, including truth-telling and confidentiality.28,29
Recently, a number of commercial entities have begun to provide genetic tests and genomic risk profiles directly to consumers, usually through Internet portals.30 The DTC model allows individuals to obtain tests and receive results directly from the company that provides the test, outside of an established provider-patient relationship. Potentially medically relevant DTC tests include tests with accepted clinical utility (eg, BRCA1/2 testing) and with uncertain clinical utility (eg, genomic profiling through SNP genotyping). Genetic tests of no medical relevance are also available but are not the focus of this statement.
Considerable concerns exist within the medical community about various aspects of DTC genetic testing. For instance, DTC advertising of tests with established clinical utility may promote inappropriate utilization of health care resources.31 There are also concerns regarding the adequacy of counseling and informed consent for tests obtained in this manner. Similarly, there are concerns regarding the safety, effectiveness, and risks associated with DTC provision of tests of uncertain clinical utility. To date, there has been relatively little analysis of the economic, societal, and medical impact of DTC genetic testing. As benefits remain unclear, medical professional societies and other organizations have made recommendations to health care providers, patients, and families about how best to avoid potential harms.1,2,32–35
Early studies suggest that consumers of DTC tests anticipate that they will ask health care providers with whom they have ongoing relationships for advice regarding test interpretation and follow-up care.36 For health care providers, these requests may pose significant challenges. Consumers may have pursued testing without the benefit of pre- or post-test counseling and may be unprepared to receive ambiguous or clinically significant results from tests with established clinical utility.37 Where clinical utility is uncertain, providers face the added challenge of explaining why test results lack clinical consequences. In addition, tests with uncertain clinical validity are not sufficiently reliable to inform clinical decision making. For example, several reports show that the risk calculations for the same conditions derived from DNA samples from the same individual can yield disparate results when analyzed by different DTC laboratories.38–41
As providers of genetic risk assessment to patients and families affected by cancer, it is the role of oncologists and other health care providers to offer genetic tests in a manner that is safe and clinically appropriate. In its previous statements, ASCO recommended that, outside of a research protocol, genetic testing for cancer susceptibility only be offered when the following three criteria are met: the individual being tested has a personal or family history suggestive of genetic cancer susceptibility; the genetic test can be adequately interpreted; and the test results have accepted clinical utility.2 These criteria continue to apply for testing of genetic mutations that cause known cancer susceptibility syndromes. However, for genomic variants of low penetrance, the first of these criteria may require modification. For example, it may be appropriate for oncologists and other health care professionals to support genomic profiling for individuals who do not have a family history of cancer, provided clinical utility is established and results can be adequately interpreted. When genetic tests of high or low penetrance are professionally mediated, health care providers should recommend follow-up care that is justified by the risk level associated with test results. Avoiding unnecessary screening and other medical interventions benefits patients and allows health care providers to serve as responsible stewards of medical resources.42
For tests that are professionally mediated, health care providers are responsible for coordinating post-test follow-up care for their patients. Individuals who order DTC tests of uncertain clinical utility (quadrant 4 of Fig 1) may also ask their health care providers for help interpreting test results and for access to follow-up care.36 This poses significant challenges to the providers, who had no role in initiating or recommending the testing. Further compounding the issue, testing laboratories generally seek to disclaim responsibility for the medical uses of DTC tests, including determining the need for post-test follow-up. If individuals approach providers for guidance after obtaining test results of uncertain utility, it is appropriate for the providers to explain the lack of proven usefulness of the test and base medical follow-up recommendations solely on established cancer risk factors, including family history, possible exposures to cancer-causing substances, and behavioral factors, as well as scientifically validated tests for cancer risks.
When offering genetic and genomic testing, oncologists and other health care providers should continue to be guided by the criteria set out in ASCO's 2003 statement update. Recommendations for follow-up care should be commensurate with the level of risk associated with the genetic variant tested. In circumstances where DTC tests are of uncertain clinical utility, health care providers asked to advise on or recommend follow-up care should base recommendations on established risk factors.
ASCO's educational initiatives in cancer genetics began more than a decade ago and have led to the development of programs and materials intended to provide ASCO members and others with the information needed to deliver high-quality oncology and preventive care.1,2,43,44 Today, education of oncologists remains a key priority. A 2007 survey of 2,000 ASCO members (data unpublished) demonstrated that ASCO members have a continued desire for education in the area of genetic testing. With the emerging availability of tests that identify genetic variants of uncertain clinical utility, forthcoming programs should explain the methodology of GWAS and highlight existing evidentiary gaps in clinical utility. An important resource for practitioners, evidence-based reviews are conducted by the Evaluation of Genomic Applications in Practice and Prevention working group, an advisory group to the Centers for Disease Control and Prevention.45
Because providers other than oncologists may be asked to aid in the interpretation of tests for cancer susceptibility, educational efforts in clinical cancer genetics must reach beyond the oncology community. Providing other health care providers (eg, internists, family practitioners, gynecologists) with information needed to interpret genetic risk assessments for cancer, including genomic profiles of uncertain clinical utility, will benefit patients, particularly as the United States faces an oncology workforce shortage.46 Oncologists and other health care providers also have a role in educating patients and potential consumers of DTC tests about the promise and limitations of genomic risk profiles.
Forthcoming educational efforts by ASCO should focus on increasing preparedness among oncologists and other health care providers to administer genetic tests and to recommend appropriate follow-up care. Educational efforts should also raise awareness about recent advances in cancer genetic testing, including the uses and limitations of genomic profiling in assessing cancer risk. These educational efforts should extend beyond the oncology community to other health care providers, patients, and individuals considering DTC tests.
As noted in ASCO's previous statements, prospective clinical trials, large registries, and retrospective reviews are the most accurate methods for deriving relative risks of genetic variants and measuring the response to and effectiveness of clinical interventions based on genetic cancer risk assessment. As tests with uncertain clinical utility become commercially available, establishing an evidence base for the clinically responsible use of these tests is vital for patient safety, as well as effectiveness. Wherever possible, genetic tests with uncertain clinical utility should be administered in the context of clinical trials.
Research is also needed to demonstrate the validity and reproducibility of some commercially available tests, particularly for LPVs defined by SNP genotyping.47 Systematic reviews of genomic variants used in commercial assays show that more than 40% have not been replicated in meta-analyses.48 Because the algorithms used to convert genotypes into absolute risk estimates are empirically derived, prospective research is needed to confirm the calibration of these estimates and to measure the effectiveness of interventions based on individual genomic profiling. Research should include basic studies of the functional significance of the genetic variants linked to disease risk, as well as prospective, randomized controlled trials of individual genomic markers. At a more translational level, it is important to establish criteria for the technologic assessment of genetic and other diagnostic tests.
It is imperative that future research efforts, such as prospective studies of LPVs, include behavioral and psychosocial end points. Research should focus on the interactions between genetic variants; the interactions between variants and environmental or other nongenetic risk factors (eg, drug exposures as part of pharmacogenomic studies); the predictive accuracy of genomic tests compared with traditional risk markers (eg, family history); the psychosocial factors that influence uptake of genetic tests and follow-up actions; the impact of ambiguous test results on the decision to engage in regular prevention activities or demand additional preventive care; and the impact of genomic information in the setting of health and economic disparities worldwide.49–52 Studies to promote effective communication of risk information to patients are important given the challenges of explaining the difference between relative and absolute risks and the minor risks associated with LPVs.50,51 The high demand for multidisciplinary research related to genetic testing is evidenced by recent requests for research on this topic by federal government agencies including the National Institutes of Health, the National Cancer Institute, the Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Quality.51,52 These research programs should be funded for additional cycles and expanded.53–56
Finally, if genetic and genomic tests for cancer risk are going to be offered or justified on the basis of personal utility, an effort should be made to establish an evidence base for these claims. Research should focus on the extent to which personal benefits accrue to individuals who receive tests that have uncertain clinical utility and the appropriate mechanism for measuring personal utility. Establishing an evidence base for personal utility is particularly important for tests that would not be recommended based on clinical utility.48,51
ASCO recommends that genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials. In addition, ASCO supports increased funding for basic and translational research in clinical cancer genetics, including research to demonstrate the clinical validity and reproducibility of risk estimates based on genomic profiles; prospective clinical studies of variants discovered through GWAS and sequencing of individual genomes; multidisciplinary research with clinical, behavioral, and psychosocial end points; and research to investigate an evidence base for claims of personal utility.
As in its previous statements, ASCO recommends that genetic testing only be conducted in the setting of pre- and post-test counseling. Pretest counseling allows for advance consideration of medical options and the impact test results may have on family members. Post-test counseling provides a valuable opportunity for health care providers to interpret test results, recommend appropriate follow-up, and emphasize the importance of continuing regular prevention activities. Not all DTC testing companies offer counseling, and they may only offer counseling to consumers who pay additional fees. Where counseling is provided, there is some concern that advice offered by counselors employed by testing companies may be biased in favor of testing.57
ASCO reiterates its recommendation that all genetic testing and genomic risk assessment, including genomic profiling for LPVs of uncertain clinical utility, be conducted in the setting of pre- and post-test counseling by experienced health care professionals. ASCO recommends that DTC testing companies provide pre- and post-test counseling or refer consumers to independent providers of these services.
ASCO has consistently underscored the importance of informed consent for genetic testing in its policy statements and other educational offerings. In its 2003 statement update, ASCO outlined the basic elements of informed consent for genetic testing for cancer risk.2 This established framework remains relevant today, subject to minor updates that address issues raised by the availability of genetic and genomic tests with uncertain clinical utility and DTC tests. These updates are listed in Table 2.
Abbreviation: DTC, direct to consumer.
For professionally mediated genetic and genomic tests, health care providers and patients engage in the process of informed consent, often as a component of pre- and post-test counseling. In the absence of genetic counseling by their health care providers, it is necessary for individuals seeking DTC testing to proactively obtain information they need to make informed decisions. The basic elements of consent identified by ASCO can serve as a framework for gathering this information. Awareness of laboratory privacy policies and practices related to data security, laboratory compliance with applicable licensing requirements, the availability and cost of genetic counseling, and the possible use of DNA testing samples in future company research may be relevant to an individual's decision to pursue genetic or genomic testing. Companies offering DTC tests should make this information clearly and easily available to the public, preferably as part of a consent form that must be acknowledged by the individual undergoing testing before testing is completed. Laboratories intending to conduct research using DNA samples submitted for testing should obtain consent to use these samples. The consent form should explain whether and how samples will be identified, stored, and destroyed, and whether genetic risks found through future research will be reported back to individuals who allow their samples to be used. Testing should not be contingent on allowing DNA samples to be used in future research.
Patients and health care providers should engage in the informed consent process before cancer susceptibility testing in accordance with the basic elements of consent updated in Table 2. Individuals considering DTC testing are advised to gather information that will help them make informed decisions about pursuing genetic or genomic testing. Testing laboratories should make information about data privacy, data security, laboratory licensure, the availability of genetic counseling or cancer genetic risk assessment, and any potential for future use of DNA samples submitted for testing clearly and easily available to the public.
ASCO has previously called for increased access to genetic testing and coverage of genetic testing services by third-party payers. Considerable progress in this area has been achieved; genetic risk assessment and genetic counseling for most cancer predisposition syndromes are covered by major third-party carriers. ASCO reiterates its call for coverage of genetic and genomic testing services that keeps pace with proven scientific advances in testing and preventive care.2,44 As data emerge and are replicated, it will be vital to include evidence-based genomic risk profiles and pharmacogenomic tests in existing third-party reimbursement policies. In addition, the importance of making genetic and genomic tests available to populations who have been historically underserved by the US health care system cannot be overstated; without improvements in access, the health disparities faced by these groups will continue to grow. Providing coverage under Medicare and Medicaid for a broader range of genetic testing and related services with demonstrated clinical utility would help minimize gaps in access.58 The exploration of novel, culturally sensitive approaches may also improve uptake and effectiveness of genetic testing among underserved groups.59–61
ASCO supports continued expansion of third-party reimbursement of genetic and genomic tests and preventive care with accepted clinical utility in keeping with the rapid pace of scientific advances. ASCO also recommends that steps be taken to ensure access to testing for historically underserved groups, including increased coverage by Medicare and Medicaid, and the exploration of novel, culturally sensitive approaches to increasing the uptake and effectiveness of testing.
ASCO previously identified genetic discrimination by employers and health insurance companies as a significant barrier to uptake of genetic and genomic testing services and called for federal antidiscrimination protections. In 2008, the signing into law of the Genetic Information Nondiscrimination Act62 established significant protections against genetic discrimination by employers and health insurers.63 The Genetic Information Nondiscrimination Act prohibits health insurance carriers from denying coverage because an individual took or refused to take a genetic test, or from denying coverage based on test results, and prohibits employers from using this information as the basis for employment decisions. It is hoped that these protections will ensure that individuals who stand to benefit from genetic tests are not deterred by fears of discrimination based on test results, particularly as genetic testing becomes an increasingly standard part of medical practice. However, it is important for patients to be aware that, at this time, there are no special protections against the use of genetic information to inform the provision of life insurance, disability insurance, or long-term care insurance.64
Results from genetic and genomic testing facilitated by health care providers can only be disclosed by health care providers and laboratories in limited circumstances permitted by state and federal privacy laws and regulations, including the Health Insurance Portability and Accountability Act.65 However, companies that provide genetic tests directly to consumers may not be obligated to comply with these rules and could use or disclose consumers' genetic information in ways that would not be permitted within the traditional health care system.66 Individuals considering DTC testing should become familiar with the terms of company policies related to privacy and data security, including how genetic information can be shared with outside parties or become part of their medical records. In addition, these individuals should be mindful of potentially misleading claims about the privacy of DTC tests, including that DTC tests have more privacy protections than professionally mediated tests because results do not necessarily become part of a patient's medical record.34 Misleading claims should be investigated by the Federal Trade Commission (FTC), which has the authority to regulate claims about the risks and benefits of genetic tests, including privacy risks.34,35,66–68
ASCO recommends that individuals considering genetic testing become familiar with company policies related to privacy and data security. Laboratories providing testing should develop written privacy policies that are easily accessible to individuals considering testing. Any claims about the privacy of DTC testing should be truthful and nonmisleading.
In its 2003 statement update, ASCO observed that federal regulation of genetic tests was insufficient and recommended additional oversight of laboratories that provide testing for genetic cancer risks. To date, little progress has been made toward increasing oversight of genetic and genomic tests. Given the potential impact of genetic tests for cancer risk on patients, consumers, and families, the federal regulatory framework must be strengthened to ensure that tests results form a reliable foundation for medical decision making.
Most genetic tests and genomic risk profiles are made by individual testing laboratories for in-house use (home brews) and are primarily regulated under the Clinical Laboratory Improvement Amendments (CLIA).69 Under CLIA, laboratories that provide testing services are required to meet standards for quality, accuracy, and reliability. Beyond these general requirements, the Center for Medicare and Medicaid Services (CMS) can set additional standards for analytic validity and require proficiency testing to establish the accuracy of tests across laboratories. CMS has not established additional requirements for genetic and genomic testing, despite calls from ASCO and other groups.34,70–72 ASCO continues to support its previous recommendation that all genetic testing laboratories participate in some form of proficiency testing.2 As noted in ASCO's 2003 statement update, laboratories should, at a minimum, meet the highest available standards for laboratory genetics services established by the certifying or regulating bodies in their home countries. In the United States, this includes successful participation in the College of American Pathologists inspection and American College of Medical Genetics/College of American Pathologists survey program, and state licensing and credentialing of laboratory directors and staff.
The US Food and Drug Administration (FDA) can also regulate genetic and genomic tests but has generally chosen not to exercise its authority.34 However, recent activities may signal a change in course. In 2007, the FDA released draft guidance that asserted FDA authority over a subset of laboratory tests.73 More recently, FDA used its authority to remove a cancer diagnostic test from the market based on concerns about its clinical validity.74 ASCO supports FDA oversight of the safety and effectiveness of genetic and genomic tests. Regulatory standards should be clear and efficient and should not unreasonably hinder scientific development or the delivery of quality oncology and preventive care.75 Efforts should be made to clarify the roles of the FDA and CMS and avoid duplicative oversight efforts. In addition, FDA and other stakeholders within the Department of Health and Human Services (DHHS) should work with FTC to ensure adequate oversight of advertising claims made by genetic test manufacturers.
In the absence of increased federal oversight, variations in state regulation of genetic and genomic tests have become more apparent. Although most states require laboratories to comply with basic CLIA standards, some impose additional requirements for laboratory certification and licensure that exceed these standards (eg, New York, Washington).76 Also, according to research originally conducted by the Genetics and Public Policy Institute in 2007 and reviewed by ASCO staff in 2009, although most states permit some form of DTC testing, some prohibit it (eg, Alabama, Connecticut, Michigan) or only allow it subject to strict laboratory licensure requirements and marketing restrictions (eg, New York, California).77 These variations create inconsistent protections for patients and consumers and inconsistent compliance obligations for laboratories and testing companies. The impact of these inconsistencies was evident in the past year, as health officials in New York and California threatened to take enforcement actions against DTC genetic testing companies that failed to meet state-specific laboratory and other requirements.78,79
ASCO's call for increased federal oversight of genetic testing echoes the recommendations set out in the Secretary's Advisory Committee on Genetics, Health, and Society's (SACGHS) 2008 report, “U.S. System of Oversight of Genetic Testing: A Response to the Charge of the Secretary of Health and Human Services (“2008 Oversight Report”).”80 In its 2008 Oversight Report, SACGHS called for DHHS to establish a mandatory registry for genetic and other laboratory-developed tests that would include information about the analytic validity, clinical validity, and clinical utility of genetic tests, and be publicly available online. ASCO supports this recommendation and joins several other groups in advocating for the creation of a registry that includes DTC tests.81,82As a centralized information resource, a registry could help to inform the decisions of health care professionals, patients, and others about the quality, accuracy, and reliability of genetic tests and testing laboratories. In addition, a registry could facilitate increased federal oversight of genetic testing.
Although DHHS has not yet created a registry, ASCO is hopeful that a renewed call for action by SACGHS will encourage DHHS to carry out this and other recommendations initially proposed in the 2008 Oversight Report. A SACGHS paper on DTC genetic testing, expected in 2010, will suggest that DHHS take specific action steps based on 10 recommendations from the Oversight Report, to address issues raised by DTC tests. In addition to calling for a genetic test registry that includes DTC tests, it is anticipated that the upcoming SACGHS paper will recommend convening an DHHS-FTC task force to develop specific guidelines for advertising, promotion, and claims about DTC tests; identifying gaps in state and federal privacy protections for consumers of DTC tests; and developing an educational initiative specific to DTC tests. ASCO endorses these initiatives as well as the call for greater stakeholder input in rulemaking.83
ASCO recommends increased oversight by FDA and CMS that sets standards for the accuracy, validity, and quality of genetic tests and testing laboratories. Regulatory standards should be applied in a manner that is clear and efficient and does not unreasonably hinder scientific development or the delivery of quality oncology and preventive care. To facilitate increased oversight, ASCO supports the creation of a mandatory, publicly available registry that requires the manufacturers of genetic tests, including DTC tests, to disclose information about their tests' analytic validity, clinical validity, and clinical utility.
The recent emergence of genetic tests that have uncertain clinical utility and the availability of DTC testing require oncologists, other health care providers, patients, and consumers to think in new ways about topics ranging from informed consent to privacy, education, and counseling. ASCO believes that the basic principles established in its prior statements on cancer genetic testing are appropriate, in updated form, to guide the responsible integration of these new genetic and genomic technologies into clinical practice. ASCO remains committed to providing educational opportunities that delineate both the promise and limitations of genetic and genomic testing in the context of clinical oncology and preventive medicine. To keep up with the rapid pace of scientific advancement and changes in the regulatory and policy environment, ASCO will continue to review and update these recommendations periodically.
Adopted on October 19, 2009, by the American Society of Clinical Oncology.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Mark E. Robson, AstraZeneca, Kudos Pharmaceuticals Expert Testimony: None Other Remuneration: None
Conception and design: Mark E. Robson, Courtney D. Storm, Jeffrey Weitzel, Dana S. Wollins, Kenneth Offit
Administrative support: Courtney D. Storm
Collection and assembly of data: Mark E. Robson, Courtney D. Storm, Jeffrey Weitzel, Dana S. Wollins, Kenneth Offit
Data analysis and interpretation: Mark E. Robson, Courtney D. Storm, Jeffrey Weitzel, Dana S. Wollins, Kenneth Offit
Manuscript writing: Mark E. Robson, Courtney D. Storm, Jeffrey Weitzel, Dana S. Wollins, Kenneth Offit
Final approval of manuscript: Mark E. Robson, Courtney D. Storm, Jeffrey Weitzel, Dana S. Wollins, Kenneth Offit
|1.||Statement of the American Society of Clinical Oncology: Genetic testing for cancer susceptibility J Clin Oncol 14: 1730– 1736,1996 American Society of Clinical Oncology Medline, Google Scholar|
|2.||American Society of Clinical Oncology Policy Statement update: Genetic testing for cancer susceptibility J Clin Oncol 21: 2397– 2406,2003 American Society of Clinical Oncology Link, Google Scholar|
|3.||J Garber, K Offit: Hereditary cancer predisposition syndromes J Clin Oncol 23: 276– 292,2005 Link, Google Scholar|
|4.||NM Lindor, ML McMaster, CJ Lindor , etal: Concise handbook of familial cancer susceptibility syndromes: second edition J Natl Cancer Inst Monogr 38: 1– 93,2008 Medline, Google Scholar|
|5.||W Olaya, P Esquivel, JH Wong , etal: Disparities in BRCA testing: When insurance coverage is not a barrier Am J Surg 198: 562– 565,2009 Crossref, Medline, Google Scholar|
|6.||M Daly, J Axilbund, E Bryant , etal: Genetic/familial high-risk assessment: Breast and ovarian J Natl Compr Canc Netw 4: 156– 176,2006 Crossref, Medline, Google Scholar|
|7.||RS Tuma: Genome-wide association studies provoke debate and a new look at strategy J Natl Cancer Inst 101: 1041– 1043,2009 Crossref, Medline, Google Scholar|
|8.||Questions About the BRCA1 and BRCA2 Gene Study and Breast Cancer National Human Genome Research Institute http://www.genome.gov/10000940 Google Scholar|
|9.||JT Bacani, M Soares, R Zwingerman , etal: CDH1/E-cadherin germline mutations in early-onset gastric cancer J Med Genet 43: 867– 872,2006 Crossref, Medline, Google Scholar|
|10.||AR Brooks-Wilson, P Kaurah, G Suriano , etal: Germline E-cadherin mutations in hereditary diffuse gastric cancer: Assessment of 42 new families and review of genetic screening criteria J Med Genet 41: 508– 517,2004 Crossref, Medline, Google Scholar|
|11.||YH Choi, M Cotterchio, G McKeown-Eyssen , etal: Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario Hered Cancer Clin Pract 7: 14,2009 Crossref, Medline, Google Scholar|
|12.||JM Ford: Inherited susceptibility to gastric cancer: Advances in genetics and guidelines for clinical management ASCO Educational Sessions 116– 125,2002 Google Scholar|
|13.||P Kaurah, A MacMillan, N Boyd , etal: Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer JAMA 297: 2360– 2372,2007 Crossref, Medline, Google Scholar|
|14.||HT Lynch, W Grady, G Suriano , etal: Gastric cancer: New genetic developments J Surg Oncol 90: 114– 133,2005 discussion 133 Crossref, Medline, Google Scholar|
|15.||K Offit, JE Garber: Time to check CHEK2 in families with breast cancer? J Clin Oncol 26: 519– 520,2008 Link, Google Scholar|
|16.||C Oliveira, J Senz, P Kaurah , etal: Germline CDH1 deletions in hereditary diffuse gastric cancer families Hum Mol Genet 18: 1545– 1555,2009 Crossref, Medline, Google Scholar|
|17.||PD Pharoah, P Guilford, C Caldas , etal: Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families Gastroenterology 121: 1348– 1353,2001 Crossref, Medline, Google Scholar|
|18.||F Quehenberger, HF Vasen, HC van Houwelingen: Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: Correction for ascertainment J Med Genet 42: 491– 496,2005 Crossref, Medline, Google Scholar|
|19.||FM Richards, SA McKee, MH Rajpar , etal: Germline E-cadherin gene (CDH1) mutations predispose to familial gastric cancer and colorectal cancer Hum Mol Genet 8: 607– 610,1999 Crossref, Medline, Google Scholar|
|20.||GH Sakorafas, H Friess, G Peros: The genetic basis of hereditary medullary thyroid cancer: Clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy Endocr Relat Cancer 15: 871– 884,2008 Crossref, Medline, Google Scholar|
|21.||JP Struewing, P Hartge, S Wacholder , etal: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews N Engl J Med 336: 1401– 1408,1997 Crossref, Medline, Google Scholar|
|22.||HF Vasen, A Stormorken, FH Menko , etal: MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: A study of hereditary nonpolyposis colorectal cancer families J Clin Oncol 19: 4074– 4080,2001 Link, Google Scholar|
|23.||S Waguespack, S Wells, J Ross , etal: Thyroid cancer SEER AYA Monogr 143– 154,2006 Google Scholar|
|24.||F Weber, C Eng: Editorial: Germline variants within RET: Clinical utility or scientific playtoy? J Clin Endocrinol Metab 90: 6334– 6336,2005 Crossref, Medline, Google Scholar|
|25.||ME Robson, K Offit: Management of an inherited predisposition to breast cancer N Engl J Med 357: 154– 162,2007 Crossref, Medline, Google Scholar|
|26.||M Foster, J Mulvihill, R Sharp: Evaluating the utility of personal genomic information Genet Med 11: 570– 574,2009 Crossref, Medline, Google Scholar|
|27.||S Chao, J Roberts, T Marteau , etal: Health behavior changes after genetic risk assessment for Alzheimer disease: The REVEAL Study Alzheimer Dis Assoc Disord 22: 94– 97,2008 Crossref, Medline, Google Scholar|
|28.||K Offit, E Groeger, S Turner , etal: The “duty to warn” a patient's family members about hereditary disease risks JAMA 292: 1469– 1473,2004 Crossref, Medline, Google Scholar|
|29.||C Storm, A Agarwal, K Offit: Ethical and legal implications of cancer genetic testing: Do physicians have a duty to warn patients' relatives about possible genetic risks? J Oncol Pract 4: 229– 230,2008 Link, Google Scholar|
|30.||Direct-to-consumer testing companies Genetics and Public Policy Center http://www.dnapolicy.org/resources/DTCcompanieslist.pdf Google Scholar|
|31.||E Matloff, A Caplan: Direct to confusion: Lessons learned from marketing BRCA testing Am J Bioeth 8: 5– 8,2008 Crossref, Medline, Google Scholar|
|32.||Directives of the AMA House of Delegates. D-480.997. Direct-to-consumer genetic testing American Medical Association http://www.ama-assn.org/ad-com/polfind/Directives.pdf Google Scholar|
|33.||ACMG Statement on Direct-to-Consumer Testing American College of Medical Genetics http://www.acmg.net/StaticContent/StaticPages/DTC_Statement.pdf Google Scholar|
|34.||ASHG Statement on Direct-to-Consumer Testing in the United States Am J Hum Genet 81: 635– 637,2007 American Society of Human Genetics Crossref, Google Scholar|
|35.||ACOG Committee Opinion No. 409: Direct to consumer marketing of genetic testing Obstet Gynecol 111: 1493– 1494,2008 American College of Obstetrics and Gynecology Crossref, Medline, Google Scholar|
|36.||A McGuire, CM Diaz, SG Hilsenbeck: Social networkers' attitudes toward direct-to-consumer personal genome testing Am J Bioeth 9: 3– 10,2009 Crossref, Medline, Google Scholar|
|37.||A Salkin: When in doubt, spit it out New York Times 2008 ST1:9 14 Google Scholar|
|38.||MJ Khoury, C McBride, SD Schully , etal: The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health-Centers for Disease Control and Prevention Multidisciplinary Workshop Genet Med 11: 559– 567,2009 Crossref, Medline, Google Scholar|
|39.||N Fleming: Rival Genetic Tests Leave Buyers Confused http://www.timesonline.co.uk/tol/news/uk/science/article4692891.ece Google Scholar|
|40.||K Davies: Keeping score of your sequence http://www.bio-itworld.com/BioIT_Article.aspx?id=84352 Google Scholar|
|41.||PC Ng, SS Murray, S Levy , etal: An agenda for personalized medicine Nature 461: 724– 726,2009 Crossref, Medline, Google Scholar|
|42.||AL McGuire, W Burke: An unwelcome side effect of direct-to-consumer personal genome testing: Raiding the medical commons JAMA 300: 2669– 2671,2008 Crossref, Medline, Google Scholar|
|43.||Resource document for curriculum development in cancer genetics education J Clin Oncol 15: 2157– 2169,1997 American Society of Clinical Oncology Link, Google Scholar|
|44.||RT Zon, E Goss, VG Vogel , etal: American Society of Clinical Oncology Policy Statement: The role of the oncologist in cancer prevention and risk assessment J Clin Oncol 27: 986– 993,2009 Link, Google Scholar|
|45.||Working Group: Evidence Reports Evaluations of Genomic Applications in Practice and Prevention (EGAPP) http://www.egappreviews.org/workingrp/reports.htm Google Scholar|
|46.||C Erikson, E Salsberg, G Forte , etal: Future supply and demand for oncologists: Challenges to assuring access to oncology services J Oncol Pract 3: 79– 86,2007 Link, Google Scholar|
|47.||K Offit: Genomic profiles for disease risk: Predictive or premature? JAMA 299: 1353– 1355,2008 Crossref, Medline, Google Scholar|
|48.||A Jannssens, M Gwinn, L Bradley , etal: A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions Am J Hum Genet 82: 593– 599,2008 Crossref, Medline, Google Scholar|
|49.||MJ Khoury: The case for a global human genome epidemiology initiative Nat Genet 36: 1027– 1028,2004 Crossref, Medline, Google Scholar|
|50.||C McBride, S Alford, R Reid , etal: Putting science over supposition in the arena of personalized genomics Nat Genet 40: 939– 942,2008 Crossref, Medline, Google Scholar|
|51.||MJ Khoury, C McBride, S Schully , etal: The Scientific Foundation for Personal Genomics: Recommendations from a National Institutes of Health–Centers for Disease Control and Prevention Multidisciplinary Workshop Genet Med 11: 559– 567,2009 Crossref, Medline, Google Scholar|
|52.||M Khoury: Commentary: The case for a global human genome epidemiology initiative Nat Genet 36: 1027– 1028,2004 Crossref, Medline, Google Scholar|
|53.||Translation Research Funding Opportunity Announcement Centers for Disease Control and Prevention http://www.cdc.gov/genomics/about/funding/fund2007_11_29.htm Google Scholar|
|54.||Request for applications: Translation of common disease genetics into clinical applications National Institutes of Health http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-08-004.html Google Scholar|
|55.||Program announcements on development, application, and evaluation of prediction models for cancer risk and prognosis National Cancer Institute http://grants.nih.gov/grants/guide/pa-files/PA-07-021.html Google Scholar|
|56.||Translation programs in education, surveillance, and policy Centers for Disease Control and Prevention: Genomic Applications in Practice and Prevention (GAPP) http://www.cdc.gov/od/pgo/funding/GD08-801.htm Google Scholar|
|57.||RA Novick: One step at a time: Ethical barriers to home genetic testing and why the U.S. health care system is not ready New York Univ J Legislation Public Policy 11: 621– 649,2008 Google Scholar|
|58.||ML Maitland, A DiRienzo, MJ Ratain: Interpreting disparate responses to cancer therapy: The role of human population genetics J Clin Oncol 24: 2151– 2157,2006 Link, Google Scholar|
|59.||MJ Hall, OI Olopade: Disparities in genetic testing: Thinking outside the BRCA Box J Clin Oncol 24: 2197– 2203,2006 Link, Google Scholar|
|60.||CN Ricker, S Hiyama, S Fuentes , etal: Beliefs and interest in cancer risk in an underserved Latino cohort Prev Med 44: 241– 245,2007 Crossref, Medline, Google Scholar|
|61.||R Lubitz, M Komaromy, B Crawford , etal: Development and pilot evaluation of novel genetic educational materials designed for an underserved patient population Genet Test 11: 276– 290,2007 Crossref, Medline, Google Scholar|
|62.||Genetic Information Non-Discrimination Act of 2008 (GINA), Public Law No. 110-233 Google Scholar|
|63.||Statement of Senator Olympia Snowe introducing the Genetic Information Nondiscrimination Act, January 22, 2007 http://frwebgate.access.gpo.gov/cgi-bin/getpage.cgi?dbname=2007_record&page=S846&position=all Google Scholar|
|64.||Genetic Information Nondiscrimination Act (GINA) 2008 National Human Genome Research Institute http://www.genome.gov/24519851 Google Scholar|
|65.||Health Insurance Portability and Accountability Act of 1996 (HIPAA), Public Law Number 104-191, and the HIPAA Privacy Rule, 45 C.F.R. Parts 160 and 164 Google Scholar|
|66.||JA Gniady: Regulating direct-to-consumer genetic testing: Protecting the consumer without quashing a medical revolution Fordham Law Rev 76: 2429– 2475,2008 Medline, Google Scholar|
|67.||U.S. system of oversight of genetic testing: A response to the charge of the Secretary of Health and Human Services, April 2008 Secretary's Advisory Committee on Genetics, Health, and Society http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_oversight_report.pdf Google Scholar|
|68.||At-home genetic tests: A healthy dose of skepticism may be the best prescription Federal Trade Commission http://www.ftc.gov/bcp/edu/pubs/consumer/health/hea02.shtm Google Scholar|
|69.||Clinical Laboratory Improvement Amendments of 1988 (CLIA), Public Law Number 100-578 Google Scholar|
|70.||Comments on draft report of the Secretary's Advisory Committee on Genetics, Health and Society on the Oversight of Genetic Testing 2007 American Society of Clinical Oncology 12 21 Google Scholar|
|71.||Letter to the Centers for Medicare and Medicaid Services (CMS) requesting a genetics specialty under the Clinical Laboratory Improvement Amendments (CLIA), June 6, 2006 Genetic Alliance http://www.geneticalliance.org/ws_display.asp?filter=policy.clia.letter Google Scholar|
|72.||Creating a genetic testing specialty under CLIA: What are we waiting for? Genetics and Public Policy Center http://www.dnapolicy.org/pub.reports.php?action=detail&report_id=25 Google Scholar|
|73.||Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays U.S. Food and Drug Administration http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071455.pdf Google Scholar|
|74.||A Pollack: Cancer test for women raises hope, and concern The New York Times 2008 F1:8 26 Google Scholar|
|75.||Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays U.S. Food and Drug Administration http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071455.pdf Google Scholar|
|76.||Clinical Laboratory Improvement Amendments: How to Obtain a CLIA Certificate Center for Medicare & Medicaid Services http://www.cms.hhs.gov/CLIA/downloads/HowObtainCLIACertificate.pdf Google Scholar|
|77.||Survey of Direct-to-Consumer Testing Statutes and Regulations, June 2007 Genetics and Public Policy Center http://www.dnapolicy.org/resources/DTCStateLawChart.pdf Google Scholar|
|78.||R Turna: Will Other States follow NY, Calif. In Taking on DTC Genetic Testing Firms? http://www.genomeweb.com/dxpgx/will-other-states-follow-ny-calif-taking-dtc-genetic-testing-firms-0 Google Scholar|
|79.||J Brody: Buyer beware of home DNA tests The New York Times 2009 D6:9 1 Google Scholar|
|80.||U.S. system of oversight of genetic testing: A response to the charge of the Secretary of Health and Human Services, April 2008 Secretary's Advisory Committee on Genetics, Health, and Society http://oba.od.nih.gov/oba/SACGHS/reports/SACGHS_oversight_report.pdf Google Scholar|
|81.||G Javitt, S Katsanis, J Scott , etal: Developing the blueprint for a genetic testing registry Public Health Genomics 13: 95– 105,2010 Crossref, Medline, Google Scholar|
|82.||K Zonno, S Terry: A call for action from Genetic Alliance: Registry of genetic tests—A critical stepping stone to improving the genetic testing system Genet Test Mol Biomarkers 13: 153– 154,2009 Crossref, Medline, Google Scholar|
|83.||S Au: Direct-to-Consumer Genetic Testing: Discussion of Final Draft Paper Presented at the Twentieth Meeting of the Secretary's Advisory Committee on Genetics, Health, and Society October 9, 2009 Washington, DC http://oba.od.nih.gov/oba/SACGHS/meetings/October2009/Au_DTC_10-7-09.pdf Google Scholar|
ASCO and the authors appreciate the contributions of Jenna M. Kohnke, Jonathan Larsen, Peter Thom, and the members of ASCO's Ethics and Cancer Prevention Committees.