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DNA sequencing advances through next-generation sequencing (NGS) and several practice changing events, have led to shifting paradigms for inherited cancer predisposition testing. These changes necessitated a means by which to maximize health benefits without unnecessarily inflating healthcare costs and exacerbating health disparities.
NGS-based tests encompass multi-gene panel tests, whole exome sequencing, and whole genome sequencing, all of which test for multiple genes simultaneously, compared to prior sequencing practices through which testing was performed sequentially for one or two genes. Taking an ecological approach, this article synthesizes the current literature to consider the broad impact of these advances from the individual patient-, interpersonal-, organizational-, community- and policy-levels. Furthermore, the authors describe how multi-level factors that impact genetic testing and follow-up care reveal great potential to widen existing health disparities if these issues are not addressed.
As we consider ways to maximize patient benefit from testing in a cost effective manner, it is important to consider perspectives from multiple levels. This information is needed to guide the development of interventions such that the promise of genomic testing may be realized by all populations, regardless of race, ethnicity and ability to pay.
Implementing genetic testing for hereditary cancer predisposition into clinical care holds great promise for reducing cancer associated morbidity and mortality. Approximately 5–15% of cancers have an inherited basis, including those of the breast, ovary and colorectum. Given that breast and colorectal cancers are among the most commonly diagnosed cancers in the U.S., genetic testing provides a great opportunity to prevent cancers or detect them early when they may be easier or less costly to treat.
For individuals, families and society to reap the benefits from genomic technologies, they must be aware of and have access to the genetic testing as well as subsequent preventive care. Poor implementation of genomic technologies can lead to increased health expenditures, without accompanying improvements in health outcomes. Poor implementation can even cause harm or increase existing health inequities. On the other hand, successful implementation of genomic technologies requires careful consideration of a variety of interrelated factors that impact advances in genomic technologies as well as access to both testing and preventive services.
Acknowledging evidence that multiple interacting factors impact health, the Social Ecological Model (SEM)1–3 organizes factors into multiple different levels as illustrated in Figure 1. Briefly, the individual level includes knowledge, attitudes, beliefs, preferences, values, sociodemographics, as well as genotype and phenotype of individual patients. Interpersonal-level factors include the healthcare provider, patient-provider interactions, and family networks/communication. Organizational level factors include health insurance plans, institutions (such as hospitals) and the processes employed by institutions to deliver and implement genomic technologies into health care. The community and policy levels include research institutions, support organizations, media, guidelines from national professional associations, laws, and regulations. In this article we incorporate an ecological approach, clinical experiences, and prior research to describe the evolution and impact of genetic/genomic testing along with many of the factors that should be considered for the widespread and successful implementation of genetic testing to identify and manage hereditary cancer predisposition.
With the completion of the Human Genome Project (HGP) in 2003 after 10 years and at an estimated cost of 2.7 billion dollars,4, 5 it was widely recognized that translation of the genome to routine clinical care would require more information. When the HGP began, DNA sequencing was performed through a chain-termination method (called “Sanger sequencing”) to accurately obtain long sequence reads (about 200 nucleotides),6 but limitations included high cost, restrictions in scale, and long turnaround time. During the HGP an approach called “shotgun sequencing” was developed to overcome some of the limitations to Sanger sequencing, including reductions in time and cost. Since then, there have been additional advances in DNA sequencing through the development of next-generation sequencing (NGS) technologies with costs of clinical whole genome sequencing (WGS) recently dropping to less than $1,000.7
NGS-based tests have led to paradigm shifts in genetic testing, enabling us to test for multiple conditions simultaneously (called ‘multi-gene panel testing’) compared to the prior phenotype-directed approaches with sequential testing of one condition at a time through use of Sanger sequencing. At the same time that NGS-based technology has become increasingly used in clinical practice to evaluate patients for inherited cancer predisposition, several additional practice-changing events have occurred including: 1) implementation of the Affordable Care Act, 2) fall of the BRCA patent, and 3) celebrity disclosures.8 Additionally, compared to >$4000 for testing for only BRCA1 and BRCA2 prior to the fall of the patent9, NGS has led to costs as low as $250 for multiple inherited cancer genes including BRCA.10 In addition to the use of NGS-based sequencing for germline testing, it has also been used to sequence tumors to identify therapeutic targets which also has the potential to identify pathogenic variants if confirmed in the germline which would lead to inherited predisposition.11 In fact, sequencing of over 1500 tumor samples identified germline pathogenic variants in known Mendelian disease-associated genes in over 15% of patients, the majority of which were in cancer susceptibility genes.12 Consequently, care delivery issues surrounding potential germline significance of tumor sequencing results is highly important and complex issue as recently reviewed by Jain et al11 and is not a focus of the current article.
Given the low cost and high availability, it is predicted that healthcare providers will soon routinely use genetic testing in the management of their patients.13 In fact, availability of large-scale genomic testing approaches, including whole genome sequencing (WGS) and whole exome sequencing (WES) led the American College of Medical Genetics (ACMG) to develop a policy statement to identify genes for which to report constitutional (inherited) mutations, regardless of the original indication for testing (called “secondary” or “incidental” findings).14 These 56 disease-associated genes (“ACMG-56”) include mostly inherited cancer and cardiac-related genes that were selected because actions can be taken by these individuals to reduce morbidity or mortality associated with these genetic risks. Per this policy, disclosure of pathogenic variants in these genes should not be limited by the age of the person being sequenced, which is an important consideration given that ACMG practice guidelines for genetic testing in minors recommends testing only if it impacts their medical management.15 Taken together, this policy represents an important beginning which is expected to evolve as evidence-based management options are determined for more genetic conditions and data is collected on optimal gene-based care delivery models.
NGS-based multi-gene panel testing has led to a paradigm shift where multiple genes are simultaneously tested, including some genes which may not be clinically indicated per current guidelines, based on the patient’s personal and family history. These developments have resulted in significant changes to the delivery of genetic risk assessment services. Traditionally, a patient’s risk was evaluated based on personal and family history of cancer, ages of diagnosis, and other phenotypic features. Genetic counselors and other healthcare professionals then generated a differential diagnosis to determine a stepwise approach to testing for genes for which there was a clinical indication, and focused their discussions based on cancer risks and management options for mutations in those specific genes. However, use of multi-gene panel tests eliminate the need to generate an extensive differential diagnosis. Thus, in contrast to using a stepwise genetic testing approach, the clinical practice paradigm has been shifting to a model where a patient is broadly consented about multiple hereditary cancer syndromes and the possibility of secondary findings and then tested.
Even though the need to generate an extensive differential diagnosis is no longer essential, it is important to recognize that a baseline proficiency in genetics remains crucial in choosing the appropriate test for the patient, interpretation of results, placing all results in proper clinical context (including unexpected positive results, variants of uncertain significance (VUS), and negative results), and making appropriate management recommendations. As such, the complexity of care based on genetic testing results is expected to become exponentially more complex.16, 17 With more genes tested simultaneously, the detection of more mutations (including secondary findings) and VUS results have increased.18 Furthermore, genes confer different levels of cancer risk, with varied levels of evidence to confirm cancer associations and risk stratification.9, 19, 20 Consequently, as our ability to test for more genes at a lower cost has been realized, these technical capabilities have surpassed our medical knowledge leaving several uncertainties and unanswered questions about some of the genes that are included in various multi-gene panel tests.
As outlined in Table 1, multi-gene panel tests for inherited cancer may include genes of high, moderate or unknown cancer risks.21 Mutations in high penetrance genes would typically be “actionable” as they generally lead to changes in guideline-based medical management, whereas mutations identified in moderate penetrance genes or those with unknown cancer risks may or may not warrant a change in care beyond that recommended based on the personal and family history of cancers. Cancer-related multi-gene panel tests generally fall into the three following categories: (1) inclusion of only high penetrance genes for specific cancer(s), (2) inclusion of high, moderate, and unknown penetrance genes for specific cancer(s), and (3) “comprehensive” cancer panels with inclusion of genes (often of variable penetrance) associated with multiple cancers or hereditary cancer syndromes.9 Additionally, several laboratories also offer the option of custom panels, where it is possible to choose the specific genes for which the patient is tested. Given that many labs offer multi-gene panel tests for inherited cancer predisposition in the U.S., it is not surprising that there exists substantial variation in the types of tests offered, platform used for testing, number of genes included on the tests, and methods used for interpretation of results.9
Prior studies indicate that multi-gene panel tests identify mutations in inherited cancer genes that are both expected and unexpected based on personal and family history.9 Specifically, there have been multiple studies to demonstrate scenarios in which the genotype (mutation result) does not match the phenotype (personal and family cancer history), suggesting that current understanding of genotype/phenotype associations based on targeted testing among only those meeting high risk criteria for a particular syndrome is incomplete.22–24 Consequently, the detection of these unexpected findings pose challenges to individuals, their family members, and healthcare providers. Finally, the higher rates of variants of uncertain significance (VUS) results as more genes are tested may pose clinical challenges. The concern is that patients and/or providers may incorrectly assume a VUS is responsible for disease risk and this misconception could lead to inappropriate medical management. These and other potential concerns and benefits of implementing multi-gene panel tests are summarized in Table 2.
This paradigm shift in genetic testing practices necessitates changes in the approach to genetic counseling of patients, recognizing that the optimal approach is currently unknown.25 One approach adopted by many hereditary cancer clinics including our own incorporate a pre-test genetic counseling session during which the following is discussed: (1) a brief overview of multiple syndromes in general terms with discussion of specific conditions for which the patient may be at high risk based on personal and/or family history, (2) discussion of high penetrance (“actionable”) versus moderate penetrance (“not likely actionable”) genes, and (3) expectation of higher rates of VUS.18 A detailed discussion of specific conditions is deferred to the post-test session, during the disclosure of genetic test results.
Multi-gene panel testing has several potential benefits as well as challenges for patients as outlined in Table 2. Benefits include the potential to improve the detection rate of hereditary cancer syndromes, expand the range of clinical phenotypes associated with mutations in various genes and contribute to better understanding of the natural history of many of these conditions. However, there are also many uncertainties that must be conveyed to patients with regard to VUS results and mutations in genes where cancer risks are not well defined. Furthermore, it may prove challenging for patients who receive unanticipated results.
As multi-gene and whole exome/genome testing becomes more widely available, disparities that exist in the receipt of genetic testing for hereditary cancer26–31 are likely to remain an ongoing challenge. Currently, national practice guidelines indicate that all women diagnosed with breast cancer at or below age 50 should be offered Cancer Genetic Risk Assessment (CGRA) services which include genetic counseling and consideration of genetic testing,19 Among limited studies in Hispanics and/or Blacks,32–38 lack of awareness, cost concerns, competing life concerns and lower self-efficacy are key barriers to access. Awareness of genetic testing for hereditary cancer among Blacks (34.5%) and Hispanics (23.7%) is lower compared to NHW (54.4%)39 yet when aware, interest in genetic services is high.40 In fact, there was 100% acceptance of CGRA services among high risk patients recruited through a safety-net clinic of primarily underserved Hispanic women, and 96% of those offered genetic testing agreed.38 Taken together, findings from us and others,38, 40–47 suggest that many minority patients are interested in pursuing CGRA services when given the opportunity and barriers are removed.
When considering follow-up care among individuals with hereditary predisposition to cancer from diverse populations, there remains little published data to evaluate disparities. The only published study of follow-up care among minority BRCA mutation carriers from a large African American kindred indicated that surveillance was preferred over risk-reducing surgery.48 Thus, more research is needed to ensure that once individuals are identified with high-risk cancer gene mutations they are able to access appropriate cancer surveillance and risk reducing options. Ultimately, the underuse of CGRA services among minority and socioeconomically underserved groups who also carry a disproportionate burden of early onset breast cancer49 underscores the vital need to understand and address existing patient, interpersonal, institutional, and policy-level barriers through development and testing of interventions.
When considering the increasing availability and use of multi-gene panel tests, it is important to recognize that providers’ genomic self-efficacy and intention to order genetic testing may be impacted by the receipt of more complex test results and higher VUS rates that occur with multi-panel testing. Thus, provider-level factors are critical when considering the adoption rates of multi-gene panel tests and acting on positive results. Previously published data from us and others39, 50–53 suggest limited knowledge about cancer genetics among healthcare providers. In fact, providers indicate significantly less confidence about interpreting and counseling based on results of multi-gene panel tests, compared to single gene tests.53 Furthermore, we and others26, 39, 40, 54–57 have demonstrated low genomic self-efficacy among providers, who indicate significantly less confidence about interpreting and counseling based on results of multi-gene panel tests, compared to single gene tests.53 These findings highlight the importance of fostering provider-level involvement in the development of clinical decision support interventions to ensure that providers have accurate knowledge, self-efficacy, clinical skills, and resources needed to provide appropriate care based on family history and test results and that the interventions are acceptable, feasible and sustainable in different clinical contexts. Common provider-level barriers to guideline-concordant genomic care include: low levels of perceived clinical value of testing; gaps in genomic knowledge and skills (i.e., low genomic self-efficacy); and other competing clinical and educational priorities.58, 59 Despite this lack of knowledge and time constraints, healthcare providers generally welcome ongoing educational opportunities related to genomics.52, 60, 61
Multi-gene panel tests have posed a number of challenges to healthcare providers, including higher rates of VUS results as more genes are tested, uncertainty in risks associated with some genes, and unexpected findings that do not match the patterns of cancers present in the family. For example, increasing use of multi-gene panel tests with testing for TP53 amongst families without classic features of Li-Fraumeni Syndrome has led to detection of unexpected mutations, which is anticipated to result in expansion of the clinical phenotype.62 Consequently, clinicians and researchers are pursuing efforts to better understand how cancer presents among individuals who are unexpectedly found to have a TP53 mutation. More information about cancer risks in these individuals is needed to further tailor medical care for these families. Another challenge occurs when mutations are identified in genes in which cancer associations remain unproven or in genes of moderate penetrance. In these cases, appropriate medical management should generally be based primarily on personal and family cancer history rather than genetic test results, yet there is room for results misinterpretation and over- or under management in cases where providers misunderstand results;19 and providers may advise patients to undergo screening and/or surgery which may not be warranted. Consequently, it remains important to widely develop and foster programs to educate healthcare providers in the field of clinical cancer genetics, and promote both academic-community partnerships and multi-disciplinary care through which access to healthcare providers with expertise in genetics may be enhanced.
Interactions between patients and their healthcare providers play an important role in the utilization, access, and uptake of genetic testing. In fact, provider recommendation was the most important factor associated with genetic testing among a large sample of breast cancer survivors, with providers significantly less likely to discuss genetic testing with minority patients.55 Moreover, a study of 3016 breast cancer survivors demonstrated lower patient-reported rates of physician recommendation for hereditary cancer testing among Black women, even after adjusting for mutation risk.56 Furthermore, Black women with ovarian cancer had a 75% lower odds of provider discussion of genetic counseling than NHW women.63 In contrast to the high hereditary cancer testing rates at academic centers,64, 65 much lower rates are reported through administrative data of commercially insured patients,31 suggesting that provider or system-level barriers contribute to low utilization rates among underserved populations including minorities and rural dwellers. Provider-level factors are salient, given that care for Blacks is concentrated among a relatively small number of providers who may face special challenges in providing high-quality care for their patients,66–69 and are less likely to order genetic testing for breast cancer.70 Consequently, it remains important to better understand patient-provider interactions across all populations and develop interventions to address barriers.
There currently remains a tremendous need to evaluate and refine new genetic counseling strategies to deliver genetic testing services and manage population needs, particularly as use of genomic testing technologies continues to increase. When considering evolving approaches to genetic counseling, it is beneficial to put approaches in the context of both existing behavioral theories and desired outcomes, particularly when disclosing genetic test results and communicating recommended risk management. The maximal value of hereditary cancer genetic testing will be realized only when risk notification translates into relevant actions taken by providers and patients who accurately interpret genetic risks, and understand evidence-informed guidelines or options to reduce risks.
Genetic counseling and testing provides an opportunity to motivate patients to adopt and sustain the behavioral changes necessary to reduce their cancer risks and improve health outcomes. The heightened personalization of genetic information has been posited to amplify motivation to engage in strategies to reduce their risk.71 Moreover, there have been high expectations that personalization of risk assessment afforded by genomics would hold great promise as a tool to motivate individuals to adopt risk reducing behaviors more effectively than communicating disease risks using other types of risk information.72–74 Risk communication and health behavior change theories support these expectations suggesting that a positive genetic test result would increase the salience of risk, and in turn, intensify personal and familial risk perceptions thereby enhancing motivation.75 However, available evidence suggests that simply communicating genetic test results and medical recommendations has modest to no effect on health behaviors.76 This underscores the need for genetic service providers to adopt “next generation genomic counseling” approaches for motivating guideline-based care77 to optimize outcomes among individuals and their families who are at risk for inherited cancer predisposition.
“Next generation counseling” supplements notification of genetic test results with theory-based behavioral interventions and motivational strategies tailored to the individual. Given the complexity of the relationships between genetic risk communication, informed decision making, and health behavior, it is often necessary to judiciously combine constructs from several theories or models that have been effectively used in prior research and apply them in “next generation counseling”.78, 79 Risk communication and behavior change are complex processes that often require multi-faceted interventions. The Extended Parallel Process Model (EPPM),80–85 Health Action Planning Approach (HAPA)82 and the Ottawa Decision Support Framework (ODSF)80 may be useful in the context of inherited cancer risk communication. The EPPM is based on elements of Protection Motivation Theory,81 Theory of Planned Behavior86 and the Health Belief Model.86, 87 Further, EPPM considers the role of emotions, cognitions and interpersonal influences on risk communication and behavior change. Briefly, EPPM focuses on channeling fear in a positive protective direction aimed at controlling the danger (e.g., getting a risk-reducing salpingo-oophorectomy) rather than controlling the fear (e.g., derogating the message and not taking action). Fear is aroused when individuals feel threatened (threat or risk appraisal process); they believe they and/or their family members are at risk for inherited cancer (perceived risk) and consider it a life-threatening disease (perceived severity). Individuals are more likely to engage in a danger control process (i.e., protection motivation) through uptake of risk reduction strategies if they believe that the desired course of action is effective in reducing their risks (response efficacy) and they have high levels of confidence in their ability to take such action (self-efficacy). Strategies for bolstering self-efficacy help patients emphasize facilitators and overcome barriers.88, 89
While the EPPM focuses on strategies to promote motivation and increase intentions to engage in health behavior, HAPA recognizes that a substantial number of individuals are already motivated to engage in health behavior and form goal intentions, but fail to carry out those intentions.90–92 According to HAPA, successful behavior change involves both a pre-intentional motivational phase in which intention is formed and a post-intentional volitional phase in which intention is translated into action. To this end, the HAPA attempts to bridge the “motivation/intention–behavior gap” with a personalized and engaging action and coping planning component in the form of an implementation intention. Implementation intention suggests that patients are more likely to carry out an intended action if they identify when, where and how they will do so.93 Thus, behavior change is more likely to occur if providers collaborate with patients to help them create action plans.
Recommended actions for individuals with hereditary cancer risks are sometimes influenced by individual-level patient considerations such as timing (i.e., at what age family planning is complete and a woman is ready to consider risk-reducing salpingo-ophorectomy) or preferences between two options (i.e., breast cancer surveillance or risk reducing mastectomy), Consistent with ODSF’s conceptualization of decision support interventions, a central goal of cancer risk communication and behavior change counseling is to facilitate informed decision-making about risk reduction strategies, and prevent adverse psychosocial sequelae. Low levels of knowledge, and high decisional conflict can be impediments to informed decision making, thus these outcomes should also be considered.94
Delivery style is important when implementing risk communication, behavior change and fear management interventions. There is strong evidence documenting the effectiveness of motivational interviewing (MI) in changing a broad array of health behaviors including cancer prevention behaviors. MI is a patient-centered counseling strategy based on autonomy and respect to help patients overcome their ambivalence, and strengthen motivation and commitment to taking action.95–99 MI enables genetic counselors to respond appropriately to patients’ cognitive and affective responses to fear-arousing risk information such as discussing personal and familial risks of inherited cancer predisposition. There is evidence that MI reduces defensive responses (message rejection, paralyzing fear) after receiving fear-arousing cancer information and effectively motivates people to engage in preventive behavior.96, 100–104 MI is also culturally responsive because providers can incorporate the cultural and social context into the interaction; thus it is particularly well suited for minority and other underserved populations.105, 106 MI also draws on the patient’s interpersonal resources to galvanize family support and communication about genetic risk and medical recommendations with their primary health care provider.
In addition to motivating use of guideline-based risk reduction strategies, next-generation genomic counseling can be used to promote family communication of genetic test results. Improving family communication and motivating relatives of mutation carriers to access clinical cancer genetic services is a priority for maximizing health outcomes and broad translation of genetics into preventive care delivery that can have a broad impact on population health.
Once an individual is identified to have a mutation in an inherited cancer predisposition gene, this information is very important to share with their at-risk (and often unaffected) family members so they too can be proactive with cancer risk management and prevention options if they are identified to also have the familial mutation. This is because most inherited cancer predisposing conditions are inherited in an autosomal dominant fashion, thus the risks of carrying a mutation among first- and second-degree relatives of a known mutation carrier are 50% and 25%, respectively. It is usually up to the first individual within the family identified with a mutation to share their positive genetic test result with their relatives. Studies to evaluate family sharing of genetic test results have primarily been on non-Hispanic white (NHW) populations at academic cancer centers where low rates of testing have been reported,107–109 with even lower rates among Blacks based on very limited studies.110–112
Multiple factors may influence communication of genetic risk information to family members, including lack of recognition that certain family members are ‘at risk’.113 Other factors include perceived responsibility to tell, relationship type, physical or emotional closeness, perceptions of whether relatives want to know, anticipation of relative’s reactions, personal emotions, and perceptions that discussing cancer is not accepted within the family.113–115
Hereditary cancer testing rates among at-risk family members are generally low (ranging between 15–51%).107–109,107–109 Although studies have generally included limited racial/ethnic diversity among participants, one study reported that Black women (n=7) were significantly less likely to share test results.111 A Bahamian study of BRCA carriers reported that <20% of at risk relatives came for free testing.112 Additional research on family member testing among racial and ethnic minorities is necessary to identify the most promising ways to improve family risk communication and genetic testing uptake.
Several organizational-level factors threaten to further widen genomic disparities among underserved populations through their effects on healthcare access, health insurance coverage, and out-of-pocket costs.116 Major barriers to receiving and benefiting from hereditary cancer testing reported through an interview study of clinicians, insurance executives and patients included key organizational-level factors such as poor coordination of the timing of tests relative to treatment decisions and reimbursement-related disincentives, including high out-of-pocket costs.117 Furthermore, availability and quality of genetic services varies according across medical institutions as described in more detail below.
Although sometimes overlooked, differences in hospital procedures and hiring practices may impact genetic testing access and uptake. Clinical genetic service delivery varies by institution and by the types of providers who deliver these specialized services at various community hospitals or academic institutions.50, 51, 70, 118 Based on cross-sectional data, genetic service providers are more likely than other types of healthcare practitioners to provide patients with written summary information they can share with their family members; and observational studies suggest that family sharing letters increase family communication of test results and/or relatives’ use of genetic services.119, 120 Furthermore, one study of BRCA carriers reported lower testing rates among relatives treated at public hospitals compared to large cancer centers.110 Finally, not all institutions or geographic areas even have genetic professionals or offer genetic services as evidenced by a 2012 national survey of primary care physicians where over 53% indicated they did not have access to genetics experts.121
Evidence that institutional factors are influencing disparities in genetic testing is demonstrated through data published on the identification of individuals with hereditary colorectal cancer. Academic institutions and large cancer centers are more likely to have adopted an evidence-based method to systematically screen colorectal and/or endometrial tumors to identify individuals at high risk for Lynch syndrome,122, 123 the most common cause of hereditary colorectal and endometrial cancers. Additionally, there is great variability in procedures used to follow-up with patients after they are identified to be at high risk.124 Furthermore, these procedural differences may impact the number of individuals who undergo confirmatory genetic testing for Lynch syndrome and are informed of steps that are proven to reduce morbidity and mortality related to Lynch syndrome.124, 125 Moreover, several institutions do not even track patient outcomes and had no routinized method of ensuring that patients were aware of their risks for hereditary cancer. Consequently, it remains important to develop automated measures, potentially through IT solutions, by which to improve identification and referral of high-risk populations who may then access genetic counseling and testing services.
Insurance coverage for genetic testing varies greatly based on the type of testing (single-gene versus multi-gene), type of insurance, as well whether testing is ordered for diagnostic, preventive or informational purposes.126 Despite the increasing use of multi-gene panel tests, many payers consider these tests investigational or experimental. Although most payers have coverage policies in place for BRCA testing, private insurers do not formally cover multi-gene panel tests despite their increasing availability.
Although Medicare has had limited coverage for preventive services, as the largest healthcare reimbursement system in the US its reimbursement policies are often closely followed by private insurers. Per Medicare guidelines, covered services encompass those that are ‘reasonable and necessary for the diagnosis or treatment of illness or injury’ and services exclude tests for screening ‘that are performed in the absence of signs, symptoms, complaints, or personal history of disease or injury.’ In contrast, Medicaid does not universally exclude genetic testing coverage among asymptomatic individuals, however state level management has led to variation in coverage across the country.
When considering private health insurance plans, criteria for coverage generally include that testing have direct influence on disease treatment management, diagnostic utility, or preventive measures for those at high-risk.127 Policy exclusions often encompass testing for informational purposes, population screening in the absence of family history, and for minors tested for adult onset conditions. Despite these challenges, private insurance companies generally have broader reimbursement guidelines for genetic testing and services compared to public insurers.
Even if initial testing costs are covered, recommended interventions may not be accessible for some patients. Coverage for costly preventive services such as prophylactic surgeries are also not incentivized as the average individual in the US stays with their insurance company for less than 6 years.127 Furthermore, without guaranteed future cost savings, there is potential to deter payers from covering the upfront costs of prevention. Consequently, it remains important to evaluate cost-effectiveness of gene-based care, in order to maximize health benefits while minimizing non-guideline concordant care. Policies may also be needed to ensure appropriate services are covered by health plans.
Several community- and policy-level factors have the potential to help alleviate genomic disparities among underserved groups through ensuring healthcare access, broadening health insurance coverage, and increasing levels of community engagement. Even as costs and availability of genetic testing decrease, other community- and policy-level factors will continue to influence whether the potential health benefits of genomic technology are fully, and equitably realized. Consequently, policy issues must be considered to minimize potential harms from implementing genomics into medicine.
The fall of the BRCA patent in conjunction with innovations in NGS technology have increased the availability of genetic testing at significantly decreased costs. However, this shift from single gene testing to multi-gene panel testing for inherited cancer predisposition has led to vague regulatory standards, with payers yet to adopt clear coding and reimbursement guidelines for panel-based testing.128 Cited justification for lack of coverage for panels include limited data pertaining to clinical validity and clinical utility.19 Thus it remains imperative for research institutions to conduct comparative effectiveness and cost effectiveness studies to evaluate genetic testing approaches to define appropriate use of panels, in order to inform policy-level decisions related to new genomic advances.
WES and WGS will soon be cheaper than conducting a series of single gene tests and just as inexpensive as multi-gene panel testing. However, interpretation of the data is still in its infancy and there are several issues that should be addressed related to results interpretation and disclosure. Recognizing the increasing availability of WGS and WES, the ACMG set forth guidelines stating that whenever this testing is performed, laboratories offer to report results of 56 genes in 24 conditions regardless of the clinical indication for the testing. These conditions met the panel’s criteria for clinical validity as they could provide medical benefit to the patient if the information was learned before the onset of symptoms. These findings are considered ‘incidental’ or ‘secondary’ if they are ‘not apparently relevant to the diagnostic indication for which the sequencing test was ordered.’14 Although these recommendations were considered ‘opportunistic screening’ to promote access to additional actionable genetic information, there was no consideration of insurance reimbursement for both the test and subsequent follow-up care for those identified to have mutations, which leaves patients with the potential for greater harm129 and widening of health disparities.
The US health system is already fraught with widespread disparities, with genetic testing being no exception.130 Even as genetic testing becomes more widely available, accessible, and affordable, this is not enough to reduce health disparities. Learning about a genetic mutation and being unable to access preventive services may cause anxiety and other negative consequences and could further exacerbate cancer disparities. Racial minorities and those with lower socioeconomic status are more likely to be diagnosed with and die from cancer.131 After a positive genetic test, the inability to pay for preventive services in order to reduce cancer-related morbidity and mortality will only exacerbate disparities. Consequently, when making recommendations for coverage or access to predictive genetic testing, it is imperative for policy makers, insurance companies, professional organizations and advisory committees, and advocacy groups consider access to and reimbursement for preventive services.127 It follows that initial cost/benefit considerations pertaining to genetic testing must factor into follow-up interventions in order to attain health benefits of testing.
Traditional payer coverage and reimbursement policies in the U.S. generally favor payment for diagnosis and treatment more often than prevention.127 These policies make it necessary to pursue specific ad hoc coverage through an onerous process by which congress adds exceptions to ensure specific preventive services are covered (e.g., mammograms, colonoscopies, etc).132 With the passing of the Affordable Care Act in 2010, coverage for preventive services were substantially changed in the US. The two broad changes to reimbursement for genetic testing include: 1) private insurers must cover any preventive services recommended by the US Preventive Services Task Force (USPSTF), free of cost; and 2) all insurers must cover ten essential health benefits related to preventive and wellness services. Although these changes were made to improve access to and coverage of preventive services, gaps remain in coverage for genetic testing in those at risk for hereditary cancer predisposition. These include: 1) gender-specific recommendations, where men are explicitly excluded from the guidelines for BRCA testing thus there is no mandate for insurers to cover such testing in men; 2) the guidelines do not apply to individuals with a prior cancer diagnosis, as the scope of the evidence synthesis only includes asymptomatic individuals with no personal history of cancer; and 3) the guidelines do not address genetic testing for other hereditary cancer syndromes. Furthermore, the scope of the USPSTF recommendations made were solely focused on genetic counseling and testing, thus care following genetic counseling and testing were not part of these recommendations. When the preventive services provisions of the ACA went into effect, ambiguity arose regarding what insurance companies were required to cover, highlighting the opposing views between payers trying to minimize costs versus advocacy groups striving for broader interpretation.
From both societal and patient-centered perspectives, the underuse and overuse of genomic testing and subsequent medical care should be avoided. In contrast, appropriate use of genomic testing and technological advances should be promoted as it can lead to high value in health care (i.e., beneficial health outcomes relative to costs).133 Thus the costs and availability of genetic testing are not the only, and perhaps not even the most important consideration in discussions of genetic testing implementation. As genetic testing strategies evolve with the ability to test for many genes at relatively low or perhaps even no additional cost, secondary findings will be identified in genes unrelated to the presenting clinical phenotype. Although these findings may sometimes result in health value, early research has led to the growing recognition that return of secondary findings does not necessarily lead to clinical health benefits and there is a need for more research in this area.134, 135 Existing efforts suggest that participants’ and families’ responses to genomic information can positively and negatively impact downstream utilization of health services.136, 137 This raises concerns that broader use of genomic tests may lead to wasted or inappropriate use of medical resources resulting in less cost-effective care or harm to patients. Ultimately, there remains a need to better understand the impact of integrating genomic sequencing into clinical care, to guide professional organizations and policymakers to develop approaches and policies to better ensure that the benefits of testing are maximized and provide value relative to direct and downstreamcosts.134, 135, 138
Benefits from genetic testing do not arise from testing itself, but rather from appropriately acting on the information from testing; yet this is often dependent on their subsequent access to preventive care. In this regard, the policy recommendations made by both the American College of Medical Genetics (related to the reporting of secondary findings) and the Affordable Care Act (e.g. through mandating BRCA testing coverage in certain cases and relevant preventive services such as prophylactic surgery and enhanced surveillance) do not equate to insurance coverage for preventive interventions or automatically translate into improved health outcomes.127 Variations in preventive services coverage threaten to exacerbate health disparities if only privileged segments of society can access these services and/or if these services do not extend to other hereditary cancer syndromes (such as Lynch syndrome) for which surveillance and treatments are also known to be effective at reducing cancer-related morbidity and mortality.
Finally, market and policy shifts have led to a rapidly growing demand for CGRA services, as results of genetic testing are increasingly incorporated into cancer care. With the evolution of genetic testing practices, deviation from the traditional in person genetic counseling sessions have resulted in alternate service delivery models including phone genetic counseling, which has great potential to improve accessibility to these specialized services.139 In fact, telephone genetic counseling has been successfully used to increase reach and access to CGRA among a geographically diverse sample of high-risk women, without long-term adverse psychosocial consequences.43, 140, 141 Furthermore, results from prior studies have demonstrated that telephone genetic counseling may lead to cost savings compared to in person sessions.141, 142 In parallel, academic medical centers and commercial companies have increasingly started to offer telephone genetic testing options to increase the reach of CGRA services while improving accessibility.
Genetics is qualitatively different from other topics in medicine as it underlies all of pathophysiology, thus is the fundamental science of health and disease.143 Emerging advances in genetics and genomics are increasingly influencing the healthcare environment with unprecedented opportunities for widespread implementation of genomic sequencing given the technological advances and plummeting costs. Successful and equitable implementation requires consideration of testing from multiple levels, including the individual-, interpersonal-, organizational-, community- and policy-levels as we have illustrated. Furthermore, we highlighted the importance of simultaneously considering and addressing the longstanding disparities in receipt of genetic testing across populations as new genomic services are implemented in order to prevent existing disparities from increasing. Ultimately, there exists tremendous potential for genomic testing to prevent disease and positively impact health. However for the full promise of genomics to be realized, it is imperative to consider access to both testing services, implementation issues (including new care delivery models) and follow-up care across the population at large.
Advances in DNA sequencing technologies, in conjunction with policy changes, have led to a paradigm shift in germline genetic testing for inherited diseases. The practice paradigm of sequential testing when Sanger sequencing was used and the BRCA genes were patented is being replaced by the increasing use of multi-gene tests with an ever expanding option of genes for which to test at minimal or no additional cost. These changes have led to testing capabilities that have surpassed our knowledge about evidence-based management for individuals with mutations in: 1) genes in which limited data is available, and 2) previously characterized genes in lower risk individuals who unexpectedly are identified with a condition that does not match the indication for testing.
As we consider means by which to maximize patient benefit from testing in a cost effective manner, it is important to consider perspectives from multiple levels, including patient, provider and societal, as well as policy level factors. It has been widely recognized that that healthcare provider proficiency in genetics is limited with substantial need for education and decision support. The rapid advances in genomic testing, with point-of-care significance to cancer patients identified with inherited cancer predisposition has led to increasing demand for services with a limited workforce with specific content expertise in this area. Thus establishing and fostering an interface between genetics experts and other healthcare providers has become increasingly important so that more complex cases can be triaged to the experts and decision support is available for cases that may be more straightforward.
Advances in genomic testing for inherited cancer have led to policy-level changes to expand coverage for BRCA testing through the ACA based on the USPSTF recommendations, yet there are clearly areas that remain unaddressed, including those with mutations in other inherited cancer genes, those affected with cancer, as well as the provision of follow-up care coverage following testing. The latter issue is particularly important given that the benefits of testing do not result from testing itself but rather acting on the results following the detection of a mutation in an inherited cancer gene. Simultaneously, it is important to recognize that benefits from a societal perspective often differ from a payer perspective (where benefit is primarily measured at the patient medical health level, often without consideration of psychological or family benefits of testing). Thus there remains a great need to develop policies such that the greatest number of individuals may benefit from these tremendous advances in a cost effective manner. Specific areas that still require addressing are policies to enhance awareness, access and follow-up care across the entire population of high-risk individuals. Furthermore, patient utility from testing extends beyond personal health utility to improve their own outcomes to potential for testing to have psychological and other patient benefits including those to family members. Thus given the differences in payer and societal perspectives when considering utility of genetic testing, it remains critical to generate population-level data regarding genomic testing implementation to inform development of evidence-based guidelines which equitably improve outcomes across all populations yet do not result in substantial wasted healthcare spending.
Finally, as genomic testing is implemented into routine healthcare, it is important to ensure that existing health disparities in gene-based care are not further widened. This may only be accomplished through focused efforts to better understand and develop interventions such that the promise of genomic testing may be realized by all populations, regardless of race, ethnicity and ability to pay.
We expect that over the next few years as data is collected, compiled and analyzed, there will be additional information upon which evidence-based practice guidelines will be developed for genes that are currently less well understood. Furthermore, we expect expansion of the clinical phenotype as mutations in genes are detected in individuals without a characteristic personal and/or family history suggestive for that condition. This may also impact the evidence-informed guidelines for disease screening and prevention options.
Furthermore, we expect increasing use of WES and WGS as costs continue to drop and it comes to a point where these tests are less costly from a technological standpoint than multi-gene panel tests. Thus testing may no longer be focused on disease-focused phenotypes or even specialty-focused testing (e.g., cancer, cardiac, etc) and increasingly lead to potential to identify secondary findings. These changes will broaden the responsibility of providers who order the test to secure consent prior to testing and determine scope of analysis for each patient based on their preferences. It will also heighten the need to collaboration between primary care providers, healthcare providers across various specialties and genetics experts, given that interpretation of results may become increasingly complex and outside the scope of the testing providers expertise. Educational efforts and decision support tools will become critically important in order to enhance proficiency in genetics across all healthcare providers and empower both patients and providers with information upon which to base their gene-based healthcare decisions.
Finally, unless there are concerted efforts to implement genomics across underserved populations, disparities in gene-based care among racial and ethnic minorities, as well as rural dwellers, are expected to widen. This will require a focused understanding such that these disparities may be addressed at multiple levels such that the great promise of genetics to benefit health may be realized.
This paper was supported in part by a grant from the National Cancer Institute at the National Institutes of Health (1R01CA129142) and the University of New Mexico Comprehensive Cancer Center Support Grant: Development Funds (P30CA118100).
Declaration of Interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
* Of interest
** Of considerable interest