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1 Introduction

With the completion of the Human Genome Project in 2003, it was widely acknowledged that more information was needed before the genome could be translated into everyday clinical practice. During this time, DNA sequencing was performed using chain-termination method, now referred to as Sanger sequencing [1]. For over 30 years, Sanger sequencing has been the “gold standard” to accurately obtain long sequence reads (about 200 nucleotides). However, drawbacks to Sanger sequencing included restrictions in scale, turnaround time, and cost of genetic testing.

Next-Generation Sequencing (NGS) or massively parallel sequencing technology was first described in 2000 [2]. NGS results from running multiple reactions simultaneously to generate large quantities for sequence data in parallel [3–6]. Along with this technology, sequencers were developed that could run these reactions on a larger scale. It was not until 2008 that this technology was documented as having successfully sequenced a complete human genome [7]. Since then, this technology has revolutionized clinical genetics as costs of sequencing have plummeted. Since the introduction of NGS in 2008, the National Human Genome Research Institute’s (NHGRI) analysis shows the cost of sequencing one whole human genome was reduced from almost $10,000,000 to less than $10,000 [8]. Costs are expected to drop below $1,000 and take just days to complete; recognizing this does not take into account the time and cost for data interpretation of the results to the patient.

There are a plethora of NGS gene panels available for phenotypically targeting testing (e.g., deafness, cardiomyopathies, cancer) covering a handful to >100 genes and ranging in price from $1,500 to $10,000 ([9]; www.ncbi.nlm.nih.gov/gtr/; www.genetests.org). In addition, several laboratories offer clinical WGS/WES ranging from $4,500 to $10,000 [10]. Compared to the average timeframe and cost of $1,000–2,000 for single gene Sanger sequencing, NGS has shifted the genetic testing paradigm (Fig. 1). It is predicted “to become a central piece of routine healthcare management which can be practiced regularly by physicians from their offices” [11].

Fig. 1
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The evolving paradigm of genetic testing for inherited cancer

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It is not clear how the genetic information provided by NGS should be integrated into current clinical practice. However, new models for providing genetic counseling and informed consent will clearly need to be developed and evaluated. The purpose of this chapter is to highlight issues to consider when utilizing NGS in a clinical cancer setting and to propose approaches to counseling patients about NGS genetic testing.

2 Factors to Consider with Next-Generation Sequencing Testing

Clinical applications of NGS include multigene panels, whole-genome sequencing (WGS), and whole-exome sequencing (WES). All NGS technology utilizes the human genome reference sequence as a comparison in order to identify DNA variation in a sample. It is important to keep in mind that the reference genome is incomplete and inaccurate for some regions. The accuracy of NGS is usually measured by sequencing depth; this refers to the average number of times that a specific base/nucleotide is sequenced. The greater the number of times the genome is sequenced, the greater the sequencing depth and the more accurate the individual base calls. WGS using NGS can routinely call base changes with greater than 99.9 % sensitivity and specificity at a depth of 30-fold and greater than 95 % of genome is covered at an average sequencing depth of 30-fold [12].

Currently, NGS may not consistently identify variations larger than a few base pairs in size like insertions and deletions, trinucleotide repeats, and copy number variations (CNVs) across all testing platforms. As a result, most labs supplement NGS test with other techniques, like Multiplex Ligation-dependent Probe Amplification (MLPA) or array-based tests to provide evaluation of larger, structural genomic changes. Perhaps over time as the NGS technology and bioinformatics advances, these limitations will be minimized and potentially overcome.

NGS analyzes a large number of genes, thus a large number of amino acid sequence changes (“missense” variants) called variants of uncertain significance (VUS) may be identified. For many of these genes, there are no means by which to determine whether a particular amino acid change impairs the function of the resulting protein. Although there are a number of computational tools to predict pathogenicity, the clinical validity remains uncertain without a direct functional assay and familial segregation data [13–15]. The likelihood of detecting a VUS is directly related to the number of genes tested, thus multigene testing results in a higher VUS rate given that multiple genes are tested for simultaneously. WGS can generate 3–4 million variants that differ from the human reference sequence, while WES generates 15,000–20,000 variants within the coding region [16]. Multigene panels have reported to average around 2.1 VUS per sample [17]. Given the increased likelihood for variants, the clinical challenge of accurately and efficiently interpreting the significance of the VUSs should be taken into consideration when using NGS.

It is challenging for genetic counselors and other members of the healthcare team to consistently advise patients on appropriate medical management following the detection of a VUS and this may add to patient distress [18]. VUS results add an additional layer of complexity to the conduct of cancer genetic risk assessment, as the result should be interpreted in the context of the family history and additional information available on the VUS.

Furthermore, the reporting of VUS results is not standardized between different genetic testing laboratories, thus familiarity and understanding of one laboratories classification does not translate into the same interpretation at another laboratory, which may greatly impact clinical utility. Laboratories should classify variants according to the American College of Medical Genetics (ACMG) guidelines and document supporting evidence regarding each variant’s known or possible role in disease [19]. Clinicians must have an understanding of methodology behind VUS classification, where to obtain more information about a VUS, and how to utilize the information to better guide the management of their patients.

3 Cancer Multigene Panel Testing

Next-generation sequencing can address the growing number of cancer susceptibility genes with overlapping phenotypes with potential time and cost savings with gene panel testing. Gene panels may improve the detection rate of hereditary cancer syndromes. They may also expand the range of phenotypes associated with mutations in various genes and contribute to the understanding of the natural history of hereditary cancer syndromes. The traditional approach to genetic testing has involved analyzing a single gene or a few genes related to a single syndrome based on the pattern of cancers observed in a family. However, this method may have led to underrecognition of patients with mutations given 30 and 50 % of individuals with a mutation do not have a family history significant enough to warrant genetic testing [20]. Gene panels allow for concurrent analysis of genes in which mutations confer variable levels of cancer risk and variable tumor spectrums, thus attending to syndromes with overlapping phenotypes and also addressing the limits of an uninformative family history.

Cancer panels can include genes of high, moderate, or unknown cancer risks as summarized in Table 1 [21]. High-penetrance genes are those genes that, when mutated, confer high cancer risks, with published managements guidelines for those with mutations. Moderate penetrance genes are genes that when mutated, confer moderate cancer risk, with no management guidelines for those with mutations. The last category for cancer genes included on panels is unknown penetrance; genes that when mutated are known to be prevalent within a certain cancer patient population; however, the degree of cancer risk and tumor spectrum are not well understood, and they have no management guidelines for those with mutations.

Table 1 Three categories of genes found on next-generation sequencing cancer panels
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As of August 2014, there are nine laboratories offering NGS cancer susceptibility gene panels. Each laboratory has a different approach as to the number of panels it offers and/or genes included on each panel. The panels offered fall into three categories: (1) cancer-specific high-penetrance gene panel; (2) cancer-specific gene panel with high, moderate, and unknown penetrance genes; and (3) “comprehensive” cancer panels that include genes associated with multiple cancers or hereditary cancer syndromes [22]. This personalized approach using gene panels can provide a more objective risk and can parse out who is at risk for highly penetrant cancer syndrome, who is at moderate risk due to lower penetrance genes or multifactorial inheritance, and who is at average population risk [23, 24].

When addressing cancer genetic panel testing, the first challenge comes with defining the appropriate patients for this testing. There are no clear guidelines on when to order NGS cancer panels. The National Comprehensive Cancer Network (NCCN) addressed the use of gene panels in their 2014 Guidelines for Risk Assessment [25]. The authors of the NCCN guidelines indicated that cancer gene panels could be considered after highly penetrant syndromes have been ruled out and there is still reason to believe the family history is suggestive of a hereditary cancer syndrome. Genetic counselors and health professionals can use these early guidelines to determine when to consider counseling for NGS cancer panels. The American College of Medical Genetics (ACMG) has developed a position statement for whole-exome and whole-genome sequencing (“Points to consider in the clinical application of genomic sequencing,” 2012) that can be adapted to apply to NGS cancer panels and be used by genetic counselors to guide their cancer risk assessments (Table 2). Most pediatric genetic panel testing is guided by this ACMG statement. The American Society of Clinical Oncology (ASCO) recently updated their recommendations on genetic testing for cancer susceptibility in response to the advancements in genetic testing technology. Initially ASCO recommended that clinical genetic testing only be offered to those with a personal or family history suggestive of an inherited cancer syndrome. ASCO has since updated this recommendation indicating that individuals without a family history may be appropriate candidates for cancer susceptibility testing if analytic and clinical utility has been established, meaning the results can be adequately interpreted, and can impact medical decision making and clinical outcomes [26]. Given this recommendation, gene panel testing could be offered to a wider patient population who do not meet the standard testing criteria [27]. It should be noted that of the few published studies looking at gene panel testing in a clinical setting, they all report most of the patients testing positive for a genetic mutation either had cancer or had a significant family history [17, 28–30]. Gene panels should be considered as a testing strategy when there is a particularly complicated personal or family history, a suspicion of multiple cancer syndromes, or other clinical scenarios described in Table 3 [22].

Table 2 ACMG indications for diagnostic testing using next-generation sequencing
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Table 3 Possible clinical scenarios to consider offering gene panel and/or WES/WGS genetic testing
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Cancer panel testing may identify mutations in hereditary cancer genes that are both expected and unexpected by the personal and family history [22]. Research studies using panel testing have found mutations in genes that do not clearly match the family pedigree; this suggests that the current understanding of the cancer genotype–phenotype may still be incomplete since the classic style of genetic testing selected only those meeting high-risk criteria for a particular syndrome [31–33].

Thus, the interpretation of these incidental findings in family cancer risk assessment and management is evolving. While some gene alterations may have a substantial impact on cancer risk recommendations, other mutations may be more difficult to interpret clinically because of a lack of correlation with family history (e.g., a BRCA1 mutation in a family with hereditary colon cancer) or a lack of evidence-based recommendations for management (e.g., RAD50 mutation). Medical management guidelines do not exist for many of the genes tested and the appropriate clinical response remains unclear. In some cases, appropriate medical management will be based on a patient’s personal and family history more so than genetic test results. Another option is to extrapolate risk reduction strategies from more extensively studied genes (e.g., BRCA1/2) that impart cancer risk [34]. Data regarding cancer risks may not be available for all genes being tested, and risk estimates may be especially difficult for patients who carry variants and/or mutations in multiple genes. A prime example is the PALB2 gene; it has been understood that PALB2 is associated with a moderate risk for breast cancer but the exact breast cancer risk has been not well understood. A recent study examining the breast cancer risk in families with a PALB2 mutation found a breast cancer risk eight to nine times greater among women younger than 40 with a PALB2 mutation compared to the general population [35].

A final factor to consider when utilizing cancer gene panels is the higher rates of VUS. VUS can be challenging clinically for several reasons, including that many patients and providers make the mistake of assuming that a VUS is responsible for disease risk in a family leading to misguided risk-reducing medical management. As discussed earlier, while it does take a great deal of time and resources, many VUS are reclassified as benign.

However, genetic panel test results may still be beneficial for excluding a diagnosis (in the case of a negative result) or allowing targeted testing for family members (in the case of a positive result). It may be difficult to get the cost of family members testing covered for mutations in moderate-penetrant or unknown-penetrant genes. It is possible that more information will be discovered about the phenotype and cancer risks related to each syndrome as more patients are tested and a larger pool of patients with hereditary cancer syndromes are identified. In much the same way that testing criteria and medical management guidelines have evolved for families at high risk for hereditary breast and ovarian cancer syndrome, it is plausible that management guidelines for cancer syndromes with incomplete penetrance will be developed in the future.

4 Exome and Genome Testing in a Cancer Setting

Further adding complexity to the genetic testing landscape is the concept of exome (i.e., the protein coding regions of the gene) and whole-genome testing. In the future, it is anticipated that multigene tests may be replaced by whole-exome or whole-genome sequencing, as sequencing costs continue to decrease.

In anticipation of these tremendous technologic advances, the American College of Medical Genetics (ACMG) recently issued guidelines pertaining to a minimal list of actionable genes (i.e., 56 genes related to roughly 25 genetic conditions) for which testing should be reported when performing exome or genome sequencing [36]. These constitute conditions that may be unrelated to the indication for ordering the sequencing, but of medical value for patient care (thus referred to as “incidental findings”). These conditions, determined by the ACMG to be well recognized and known to have a strong link of causation, were included on this list if preventative measures and treatments exist. Groups of conditions included on this list encompass cancer predisposing conditions, later-onset cardiac-related syndromes, and connective tissue syndromes.

The initial guidelines were revised in 2014 to recommend an opt out clause for incidental findings [37]. Furthermore, the ACMG guidelines recommended that seeking and reporting incidental findings not be limited by the age of the person being sequenced. It is important to consider the ACMG incidental findings guidelines in the context of ACMG guidelines pertaining to testing in children which indicate that predictive genetic testing of minors be considered only if effective medical interventions are available to treat, prevent, or retard the course of disease [38]. These guidelines are not contradictory, because incidental findings, by definition, are outside of the indication for which testing was done in contrast to specifically testing a child for an adult-onset condition.

In addition to the debate surrounding return of incidental findings from germline exome and whole-genome testing, there remain questions surrounding return of results in the setting of tumor-focused testing. Interestingly, the ACMG guidelines stated that “incidental variants should be reported for the normal sample of a tumor-normal sequenced dyad.” It is important to note that this guideline could have significant implications for the field of oncology [39]. Given that the vast majority of clinical sequencing tests ordered in the oncology setting are tumor exome or genome sequencing to identify somatic mutations to guide treatment decisions, germline results are not directly related to testing indication. Consequently, these guidelines have profound implications pertaining to initial and follow-up discussions between patients and their oncologists. Specifically, a clear discussion between the oncologist and patient about the potential to include germline analysis as part of the tumor test would be required, which would include covering germline-related issues such as risks and benefits of testing, risks to family member, as well as factors related to privacy and insurability. In fact, a recent study reported on the implementation of a whole-genome sequencing protocol of tumors and paired germline DNA, which included options for receiving incidental germline findings [40]. In this study, genetic counselors documented patient family histories, secured informed consent, and actively participated in the multidisciplinary tumor board to provide clinical context of germline results and recommendations for results disclosure. This study serves to highlight the future opportunities for genetic professional involvement in these types of efforts as use of whole-genome sequencing in oncology treatment broadens.

5 Impact on Paradigm Shift from Syndrome-Based to Multigene Testing

With the availability of new testing options, there will also be changes in the delivery of genetic risk assessment services. Traditionally, cancer genetic counseling has evaluated a patient’s risk based on personal and family history of cancer, age of diagnosis, and other phenotypic features. Both the ACMG and NCCN recommend that genetic counseling should be performed by a cancer genetic professional [19, 25]. Genetic counselors and professionals have used their expert knowledge to choose which genes to test and then counseled the patient about the cancer risks and management options for mutations in those specific genes. Genes that are unlikely to be mutated are not analyzed in this model. However, plummeting costs of testing are resulting in many genes being tested simultaneously (either through panels of genes focused on a particular cancer type or WGS/WES sequencing).

As a result, the need to generate an extensive differential diagnosis and eliminate possible diagnoses using a stepwise genetic testing approach is lessening and clinical practice paradigms appear to be shifting toward a model where a patient is “tested first” (without the need to generate an extensive differential diagnosis based on clinical information) following broad consent. Once results are available, additional information is collected to put the diagnosis into proper clinical context. Many patients may not be adequately prepared for the possible outcomes and/or their perceived understanding or expectations may not align with the actual results [27]. This may result in a great need and time for posttest genetic counseling than pretest counseling [41].

It is worth considering that although broad testing without the need to generate a differential diagnosis may make it easier to order comprehensive testing, it will still require proficiency in genetics due to required familiarity with the various gene panel and WGS/WES options, choosing the one best suited for each patient, result interpretation, putting the result in proper clinical context, and making appropriate management recommendations. As such, it is anticipated that provision of care based on genetic testing results will become exponentially more complex resulting in an increased need for the involvement of genetic counselors and professionals in patient care, an issue already recognized as part of several best practices guidelines from numerous professional guidelines [25, 26, 42–45].

6 Importance of Informed Consent

When genetic counseling for highly penetrant cancer syndromes was first performed, there were concerns about the lack of knowledge of the cancer risks associated with each syndrome, what early detection and/or risk-reducing options would be available for patients with mutations, and whether patients would experience significant anxiety upon learning they carried a mutation. As an increasing number of individuals with hereditary cancer syndromes were identified, the knowledge of highly penetrant cancer syndromes increased, improving the ability to create effective clinical guidelines for management.

Studies have shown that individuals receiving mutation-positive results describe an increase in anxiety, but that anxiety often returns to baseline with the passage of time [46, 47]. Organizations like the NCCN, American Society of Clinical Oncology, and the U.S. Preventive Services Task Force have acknowledged the research that shows the benefits of genetic counseling and testing for hereditary cancer syndromes; they have written guidelines and recommendations for cancer predisposition testing, all of which include pretest counseling as part of the informed consent process [25, 26, 48].

While existing genetic counseling models encourage in-depth discussion of the syndrome to be tested, these models do not address testing multiple syndromes, simultaneously [49]. Communicating the risks for NGS testing that is usually conveyed with single gene testing would likely lead to information overload, in which there is too much information to absorb in a short time, potentially impeding patient understanding and decision-making ability [22, 41, 49].

The pretest genetic counseling model will need to involve a discussion of the range of information that could be learned from NGS genetic testing including risks, benefits, and limitations of testing and implications for both the patient and family members, such as the increased risk of discovering unanticipated results and VUSs [21, 49]. Along with the progress of genetic testing technology, genetic counseling will also have to shift and adapt to ensure patients are educated about the unique benefits and risks of NGS genetic panel testing in order to facilitate informed consent.

7 Suggested Genetic Counseling Approaches to Next-Generation Sequencing Tests

The paradigm shift in genetic testing practices will lead to changes in the approach to genetic counseling of patients, recognizing that the optimal approach is currently unknown [49]. Many of the genes on cancer panels and WGS/WES testing confer a risk for multiple different cancers. Most patients seeking genetic testing primarily based on risk for more common heritable adult malignancies (breast, colon), uncovering additional cancer risks may be unanticipated outcome of the testing and should be discussed pretest [27].

Patients should be informed of the option of single-gene, syndrome-specific testing, or WGS/WES and which may more quickly identify actionable mutations, especially when pending a treatment decision [22]. For people of childbearing age, genes that have distinct monoallelic and biallellic expression should be covered in regards to risk of having a child with a more severe autosomal recessive cancer syndrome [50].

While adapting the amount of information shared with the patient, it is important to maintain patient autonomy and the ability to make an informed decision. A suggestion to help present this information in a timely and effective manner is to group the genes into the aforementioned three categories (Table 1) [21]. This technique could help patients understand that mutations in different genes are associated with different levels of risks for cancer and not all results have clear management guidelines.

It may also be helpful to group the cancers associated with each panel test. The genetic professional could then broadly describe how the increased cancer risk for each organ may/could be managed. For example, some genes on the breast panels would put a patient at risk for breast and pancreatic cancer; the genetic counselor would explain increased breast cancer surveillance options and then explain the limited screening options for pancreatic cancer. Patients should know a deleterious mutation could mean a risk for multiple sites of cancer and understand the degree to which surveillance and management strategies exist and are efficacious for each site of cancer.

One approach adopted by the Genetic Risk Assessment Service at the Moffitt Cancer Center includes a pretest 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 risk based on personal and/or family history, (2) discussion of high penetrance (“actionable”) versus moderate penetrance (“not likely actionable”) genes, and (3) communication of higher rates of variants of uncertain significance (VUS) [51]. A detailed discussion of specific conditions is deferred to the posttest session, during the disclosure of genetic test results.

Another suggested genetic counseling approach utilized at Dana-Farber Cancer Institute’s Center for Cancer Genetics and Prevention is to present information in a framework linking function and phenotype in the pretest session. They encourage particular attention on the education of moderate-penetrance genes, the risk for variants of uncertain significance, and emphasis on genes most likely to be mutated given the family history reported [41]. They also recommend focusing on high penetrance genes associated with a severe phenotype where they defined risk-reducing strategies in order to reduce possible distress in the event an unexpected mutation is found [41] For example, if a patient were to test positive for a CDH1 mutation and the family history is negative for breast and/or gastric cancer, it could be called into question the appropriateness of a gastrectomy [22]. Posttest counseling is recommended for all patients found to carry a mutation, a VUS, or for those who test negative and have a striking cancer family history in order to ensure proper interpretation of results [41].

As noted earlier, it is important that patients understand the chance of a VUS result and the limitations of such results. Genetic counselors should consider sharing the VUS rate reported by the elected laboratory when considering NGS panels or WGS/WES testing. Patients should understand that VUSs will not be treated as deleterious nor causative of a cancer predisposition. Part of the posttest counseling session should cover expectation and plans for recontact should be discussed and patient should be encouraged to periodically check in and update contact information [22]. This is particularly important to VUS reclassification as many labs review their VUS data on a regular basis and will release updated results.

There currently remains a tremendous need to develop and refine new genetic counseling strategies to deliver genetic testing services to manage population needs particularly as use of genomic testing technologies continues to increase.

8 Documenting Genetic Testing

There are multiple NGS cancer panels with varying sets of genes, and more genes may be added to these panels as our knowledge about cancer susceptibility improves. While many genetic professionals document the type of genetic testing ordered, it will become more important to document which genes were tested for each patient and which lab was used [21]. It will also be helpful to document the testing platform, depth of coverage, and presence of a deletion/duplication assay. As part of posttest genetic counseling, genetic counselors should continue to inform patients that updated testing may be available for them in the future. The protocol for patients to be notified of such updates (e.g., who has the responsibility to follow up to discuss advances in testing options) should be clear.

9 Laboratory Considerations

Organizations that have authority to regulate genetic testing include the U.S. Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services through the Clinical Laboratory Improvement Amendments (CLIA) [52, 53]. A genetic test may be developed as a “test kit” or a “home brew.” Test kits are prepackaged with reagents and instructions and sold to laboratories, whereas home brews are assembled in house by the laboratory. Test kits are regulated by the FDA as medical devices, thus manufacturers must submit data on analytic and clinical validity and utility to the FDA for approval prior to marketing. Consequently, it is no surprise that the FDA has only approved four test kits to detect mutations in human DNA, of the hundreds of diseases for which genetic tests are currently available clinically [52]. In contrast, home brews are under CLIA oversight, which requires laboratories to perform proficiency testing themselves to demonstrate their ability to accurately perform the test and interpret the results but they do not need to demonstrate clinical validity or utility. Thus, under CLIA, the decision to offer a new genetic test is within the sole discretion of each clinical laboratory director. As a result, most genetic testing is currently overseen by CLIA rather than the FDA, which illustrates that manufacturers prefer the less regulated status and that the regulatory regime allows them to avoid stringent FDA oversight. Ultimately, there are clear opportunities to develop a regulatory system to ensure that patients and providers receive greater assurance that genetic tests are accurate and reliable and provide information that they are relevant to healthcare decision making. At the present time, mutation detection strategies and detection rates for a given gene may vary by testing laboratory due to the techniques used, the patient’s mutation may be detected by one laboratory but not another. Consequently, practitioners who provide genetic testing services require familiarity with laboratory testing approaches, as patients rely on them to research and select the laboratory best suited for their genetic needs.

Unlike many tests used in medicine, for many years there has been lack of FDA oversight for genetic testing, thus test validity and clinical utility may differ substantially between labs. Therefore, there has been heightened importance to understand variations in laboratory practices and the meaning of terms, such as analytical sensitivity, reported range, coverage, and variant filtering, when determining whether to perform a disease-targeted gene panel, exome, or genome analysis and which laboratory to utilize. Not only is the quality of the result received be impacted by these factors, but also on the ability to interpret the result itself. This is particularly true for conditions, such as those associated with moderate penetrance genes, where national best practices guidelines do not currently exist due to paucity of data.

Recent developments suggest that the FDA is planning to increase its oversight of genetic testing. In November 2013, the FDA demanded that 23andMe immediately stop selling and marketing its DNA testing service until it receives clearance from the agency. This was a direct to consumer test sold through the company’s website through which saliva samples are analyzed to give clients information on risks of developing certain diseases. Subsequently, the FDA outlined plans to regulate thousands of diagnostic tests, including genetic tests. This new policy is likely to have a big impact on the increasingly common practice of using genetics to decide how to treat cancer patients [54].

In addition to the increased regulation anticipated for genetic testing through FDA oversight, there remain several factors to consider when choosing a laboratory for genetic testing. Furthermore, although these tests did not initially include the BRCA genes given that a single U.S. lab held and enforced their gene patent, precluding other labs from offering clinical testing. This all changed in June 2013 following the Supreme Court decision that genes cannot be patented, which has resulted in an increasing number of labs offering BRCA testing. Consequently, the cost of the BRCA test has substantially decreased. For example, prior to the loss of the patent, the list price of complete BRCA testing was over $4,000; in contrast, since the fall of the patent, the cost has plummeted to as low as $1,500 through a lab that offers testing for 211 genes including BRCA. As a result, navigating through the various testing options has become increasingly complicated for healthcare providers as they must now evaluate various factors when choosing the appropriate lab such as: (1) completeness of the testing; (2) quality of interpretation of complicated results such as variants of uncertain significance (VUS) and openness in sharing how this is done with clinicians; (3) genes included on multigene tests which fit the patient’s needs best; (4) practices regarding sharing of deidentified data in public databases to enhance interpretation of genetic data worldwide rather than maintaining it internally to protect commercial interests; and (5) testing laboratory billing practices whereby health insurers are billed a much higher amount than the published list price of the test (Table 4).

Table 4 Factors to consider when choosing a laboratory for next-generation sequencing
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10 Evolving Role of Genetics Professionals

As widely acknowledged, healthcare provider knowledge and training are insufficient to make optimal use of genetic testing services despite the general agreement that genetics competency is of high clinical relevance [55, 56]. In fact, a recent Florida-wide survey of healthcare providers who order BRCA testing indicated both the need for and an interest in ongoing educational opportunities and resources among community providers who order genetic testing [57].

Within the United States, despite efforts to expand community-based best practices for provision of genetic counseling and testing services, market forces are compelling an increasing number of clinicians with limited training or experience in genetic risk assessment to order and interpret genetic tests [43, 58–61]. One of the most commonly cited reasons for encouraging genetic testing without the involvement of a genetics health professional is the perceived “severe shortage” of these professionals [62]. However, while historically this perception may have been accurate, the recent survey conducted by the National Society of Genetic Counselors demonstrated that access to certified genetic counselors (CGC) is excellent and in line with physicians [63]. Moreover, in-person consultations are now supplemented with telegenetic services, particularly for patients in rural and underserved areas [64]. Furthermore, there has been tremendous growth with a 75 % increase since 2006 and 4,000 CGCs currently, with an expected annual growth rate of approximately 10 % [65].

11 Genetic Professional Issues

While the number of CGCs continues to increase, there remains a gap in reimbursement for services rendered these masters-trained healthcare providers can often not bill insurers independently for services rendered. As the reimbursement scheme in the US is primarily focused on a fee for service model, most Cancer Genetic Risk Assessment Services cost more to administer than the direct revenue they generate [66]. This recognition of the lack of reimbursement for genetic services delivered by CGCs coupled with data to suggest that provision of genetic counseling through a trained genetics professional can lead to increased cost effectiveness and enhance quality of care [67–72] is beginning to influence policy shifts at the state and payer level [50, 73].

12 Importance of Collaborative Research

Ultimately, given the limited proficiency in genetics among the U.S. healthcare workforce, there remain tremendous opportunities for genetics professionals to serve as a hub of information. This is particularly important with the tremendous advances in genetic testing technology through which multigene testing has become a feasible and widespread option [17, 29, 74]. Innovative approaches to delivering genetics services to an increasing number of patients in community settings have been demonstrated through establishing academic–community partnerships that focus on collaboration between genetics and nongenetics providers to offer genetic testing for hereditary cancers [58, 75, 76]. These collaborative partnerships leverage the expertise of genetics professionals for challenging cases that enable patients to remain in their community and to allow for better access to resources for long-term follow-up care.

Another example of this type of partnership is the Florida-based project (called the Inherited Cancer Research (ICARE) Initiative) for which external peer-reviewed funding was secured in 2010 to develop an infrastructure to support research, education, and outreach initiatives focused on genetic counseling and testing for inherited cancer predisposition. Recognizing the limited number of genetics professionals across Florida [50], a statewide network of over 100 healthcare providers who offer genetic services was developed. These individuals are offered education and outreach about inherited cancer predisposition with the overarching goal of enhancing the provision of genetic services across the state and beyond. In addition to educational and outreach efforts, ICARE Partners refer high-risk patients to the research registry to provide the research link, which has in turn contributed to the tremendous growth of the registry since initiation of the grant in summer 2010 with almost 1,400 high-risk individuals recruited to date, including almost 900 BRCA carriers.

Specific educational resources available to ICARE Partners include access to:

  1. 1.

    Bimonthly Case Conferences: 1 h web-based teleconferences during which brief educational updates are provided during the first 15 min, after which 3–4 clinical cases are presented, including reason for referral, review of the pedigree including differential diagnosis, risk assessment, testing options, and management plan. Each case includes discussion items and a take-home message.

  2. 2.

    Inherited Cancer Registry newsletter: a biannual four page newsletter which briefly outlines recent clinical and research updates pertaining to risk assessment, testing options, and management of those with inherited cancer predisposition. Also included within the newsletter is a section on statewide clinical trials for those with inherited cancer, as personalized treatments based on germline mutations are often only available at a small number of study sites. The newsletter is a means by which updated information is disseminated to healthcare providers and patients who participate in the research registry (newsletters are available at the ICARE website, which can be accessed through the following link: http://inheritedcancer.net).

  3. 3.

    Access to ICARE-based experts for inquiries: A dedicated telephone line and e-mail address have been established to provide centralized access to healthcare providers requesting information about Florida genetic services. This infrastructure has facilitated access for providers across the state to seek input from genetic professionals, when faced with complicated patients. This service is provided through a board-certified GC who is specifically available to give a description of resources available through Florida genetic services’ efforts and give general guidance pertaining to inherited cancer predisposition to ICARE partners.

Another issue which has become increasingly important is the interpretation of genetic tests. As more data become available, the ability to interpret test results also increases, highlighting the importance for: (1) encouraging patient participation in research registries, (2) development of international consortia to increase sample sizes through pooling data [15, 77–79], and (3) the importance of submission of data to public databases [77, 80].

13 Conclusion

While NGS-based technology is available and use of this technology is increasing, the understanding of how best to counsel patients for whom we recommend this testing is still evolving. It is essential that future research focuses on the outcomes of using this technology, with hope to limit the potential for harm and to maximize the benefit to the patient [48]. This was the approach used to develop counseling models for highly penetrant cancer syndromes such as hereditary breast and ovarian cancer syndrome and Lynch syndrome.

As clinicians are faced with the decision of a single gene/syndrome test (e.g., BRCA1/BRCA2 test) versus a cancer panel test (e.g., breast and/or ovarian cancer panel), or WGS/WES genetic testing there are multiple factors that need to be considered. For example, NGS genetic tests may lead to an improved detection rate for the causative gene mutation; however, depending on the finding, there may not be sufficient data in the medical literature to guide the clinician on how to medically manage that patient. Collaborative epidemiologic work will also be necessary to gather information about genes included in the NGS panels; this will help provide more substantial information about each gene’s associated tumor spectrums and cancer risks, which will lead to the development of appropriate clinical management [81].

In addition, the improved detection rate of a cancer panel or cancer WGS/WES testing should be weighed against a higher risk to find a variant of unknown significance (VUS). Lastly, each laboratories approach to a panel and WGS/WES testing may differ, and therefore the ordering clinician will have several factors to consider when choosing between tests/laboratories (Table 1). There is not enough published literature to establish guidelines regarding which patients are best suited for a single gene/syndrome test versus a cancer panel test versus WGS/WES testing. Until such guidelines are established, all the factors should be considered when presenting a patient with genetic testing options and choosing which test to recommend.