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This activity has been designed to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.
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All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/78605; and 4) view/print certificate.
Release date: June 10, 2016; Expiration date: June 10, 2017
Learning Objectives
Upon completion of this activity, participants will be able to:
Explain the role of TGP to assess the growth and spread of a tumor
Discuss the importance of genetic counseling when using TGP for patients with cancer
Genetic testing to inform disease prognostication, therapy targeting, and hereditary cancer risk assessment is increasingly critical to oncology care. The emergence of next-generation sequencing (NGS)–based multigene somatic or tumor tests in the outpatient clinic portends an urgent need for oncologists to evaluate how new genetic/genomic tests are integrated into the care of patients with cancer. Traditional germline genetic tests sequence a patient's DNA in an effort to identify gene mutations that increase a patient's risk for disease and that may be shared by family members. Tumor genomic profiling (TGP) sequences the genes of the tumor itself (somatic genes) in an effort to identify mutations and/or pathways that may be targeted for cancer treatment. In light of the growing number of genetic tests performed in the routine practice of oncology and the mounting time limitations of the outpatient clinic, new models are needed to appropriately and yet efficiently prepare patients undergoing a genetic test for all the results they may receive, whether testing is performed to evaluate prognosis, to target a precision therapy, or to evaluate hereditary risk of cancer. Indeed, it is likely that in the coming years, medical oncologists will, when choosing treatments, concurrently evaluate both a tumor's somatic profile and the germline genomic background within which a tumor has developed, because both may have an important role in guiding therapy choices. Many examples of the predictive power of tumor genomic testing for targeted therapy exist (eg, BRAF V600E testing for melanoma), whereas, for example, the relevance of germline BRCA1/2 status to the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitor therapy in patients with ovarian cancer is an early example of the importance of integrated somatic and germline genomics.1,2
The objectives of this article are to increase awareness among oncologists and cancer care providers that the discovery of hereditary cancer risk as a secondary finding of TGP (ie, a finding indirectly related to the purpose of TGP) is relevant to patient care, to highlight current and recently published3 (ASCO 2015) standards for informed consent for hereditary cancer risk assessment, and, finally, to propose benchmarks for genetic counseling and informed consent that will meet the integrated (ie, somatic plus germline) genomics responsibilities and needs of the medical oncologist performing TGP. To begin to frame this review, a list of genes currently tested on many TGP panels that have secondary hereditary cancer risk relevance is provided in Appendix 1. Most information related to germline mutations presented herein is adapted from GeneReviews4 and supplemented where indicated, whereas somatic mutation frequencies are drawn from data published using the COSMIC database5,6 and estimates are extracted from The Cancer Genome Atlas (TCGA). Our goal is to promote discussion regarding the evolving management of patients who undergo TGP, and the central role of the medical oncologist in navigating patient preferences and decisions related to somatic gene testing and germline genetic information discovery.
Integrated Genomics: The Overlap of TGP and Hereditary Cancer Risk Assessment
Precision Medicine and the Emergence of TGP in the Oncology Clinic
Drastic improvements in the speed of DNA sequencing coupled with falling costs, have led to increased accessibility to and use of NGS-based DNA sequencing technologies, such as TGP, in the care of patients with cancer.7 TGP identifies a variety of genomic alterations in tumors in an effort to identify targetable molecular pathways for treatment. Examples of TGP developed by academic institutions include Fox Chase Cancer Center's Targeted Cancer Panel and Dana-Farber Cancer Center's OncoMap, whereas examples of commercial TGP include FoundationOne (Foundation Medicine) and Molecular Intelligence (Caris). Among the advantages of newer TGP platforms is that archival paraffin-embedded tissue may be used as the source of DNA for testing, meaning additional biopsies or blood specimens are usually unnecessary. Along with a list of actionable mutations, many commercial TGPs also provide therapeutic suggestions and detailed clinical rationale, including both FDA-approved agents and experimental agents accessible via clinical trials. Additional resources, such as cBioPortal, offer comprehensive somatic mutation databases that can also be used by clinicians ordering TGP. With a growing number of laboratories offering TGP, and the increasing clinical relevance of molecular pathway targeting across disease sites, TGP integration into oncology practice will continue to grow. Early data suggest precision medicine treatment guided by TGP can improve outcomes without compromising safety8,9; indeed, genomically targeted therapy has been shown to be an independent predictor of higher response rates (31% vs 10.5%; P<.001) and prolonged progression-free survival (5.9 vs 2.7 months; P<.001).8 As the use of TGP increases, in addition to increasing collaboration among genetics specialists and oncologists within tertiary centers, remote genomic consultation for community practices may also be feasible and may help community oncologists better interpret the findings of TGP and guide their patients toward appropriate therapies and clinical trials, with a goal of improving outcomes.10
Somatic (Tumor) Mutations and Variants: A Reflection of the Patient's Germline
Identifying somatic (tumor) pathogenic variants for therapy targeting is the goal of TGP. What may be underappreciated, however, is that a substantial number of genes sequenced by TGP are also relevant to hereditary cancer risk, and that the pathogenic variants and variants of uncertain significance (VUS) identified in a patient's tumor may also be present in their germline. Indeed, the tumor genome is, in a sense, derived from the germline genome. In contradistinction, many tumors may also harbor somatic mutations in genes known to be associated with hereditary cancers that contribute to the molecular pathogenesis of the tumor (eg, tumor driver or passenger mutations) but that are less likely to be present in the germline of the patient and are likely unrelated to a hereditary cancer risk. Because most hereditary cancer risk gene mutations are inherited in an autosomal dominant fashion, it is important to remember that only one mutated allele is needed to predispose a carrier to increased cancer risk. Table 1 provides a gene-by-gene comparison of the cancer risks associated with carrying a germline mutation, estimates of the prevalence of mutations in these genes in patients with select cancer types (germline mutation prevalence), estimates of prevalence of mutations in these genes in the general population, and the prevalence of somatic (tumor) mutations in these genes in select tumor types.
Somatic Mutations in Genes Relevant to Hereditary Cancer Risk: Important Considerations
When a mutation in a gene relevant to hereditary cancer risk is detected by TGP, a cancer care provider should consider the following items before further investigating whether the somatic mutation may also be present in the patient's germline.
Was the Patient Made Aware That Their TGP Might Identify a Potential Hereditary Cancer Risk and, if so, Does the Patient Want to Investigate It?: If a patient was not informed that hereditary risk information might be identified by TGP before testing was conducted, it is important to carefully assess their wishes while providing balanced information on the pros and cons of examining hereditary risks further. Ideally, this discussion should occur before ordering TGP (Figure 1). A result from TGP (mutations and/or VUS) that suggests a possible increased hereditary cancer risk may be thought of as a secondary finding, here defined as information that is potentially relevant to the patient that is discovered indirectly through testing the tumor genome. We and others (including the contributors to the recent ASCO policy statement update3)support that patients have the right to opt out of receiving secondary genetic information, but in the context of hereditary cancer risk it is difficult for the cancer care provider not to weigh the potentially grave medical implications (cancer risks) and legal implications (duty to inform) of this decision for the patient and family members.3,11 Moreover, providers should equally appreciate that the decisions surrounding the investigation of hereditary cancer risks are often difficult ones for patients and family members, and may lead to increased distress related to family members' welfare and fears of insurance discrimination and social stigmatization.12
Can the Laboratory Performing the Test Tell the Provider Whether a Detected Somatic Mutation or Variant is Also Present in the Germline?: Laboratories that perform TGP and whose testing procedures include a normal blood sample may be willing to disclose germline findings to providers. Laboratories sequencing a tumor sample only may also be able to predict whether a variant is present in the germline.13 Although it offers guidance, this information
Pros and cons of 3 time points to discuss TGP hereditary risks.
aAlthough the discussion of hereditary cancer risks at the time TGP is ordered is considered optimal, we appreciate that this approach may not be possible for all patients or in all clinical settings.
Abbreviation: TGP, tumor genomic profiling.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 14, 6; 10.6004/jnccn.2016.0080
If a Mutation or Variant Identified by TGP is Predicted to be Present in the Germline, is it Likely This Germline Mutation or Variant is Associated With Increased Hereditary Cancer Risk?: Causality (germline variant→hereditary cancer risk) is challenging to establish, and providers should not assume that all germline mutations or variants in a hereditary cancer risk gene lead to increased cancer risk. Many tumors have a high rate of somatic variants and mutations in genes that, when found in the germline, are not related to increased risk of these same tumors. For example, somatic APC mutations are found in a substantial minority of endometrial cancers, but germline APC mutations do not increase the risk of endometrial cancer. In some cases, a suspicious family history may also lend evidence to a germline/hereditary risk (eg, a strong family history of diffuse gastric cancer and lobular breast cancer in a patient with a CDH1 mutation by TGP).
Common and Rare Germline Variants: Parsing the Pathogenic From the Benign
Most germline variants identified through TGP in hereditary cancer risk genes are likely to be rare and benign polymorphisms. If patients are interested, suspected pathogenic variants should be investigated through dedicated germline testing. Commercial laboratories now offer multigene panels that are useful if multiple possible germline variants are under evaluation. However, providers should be aware that it is standard of care for patients to receive pretest and posttest genetic counseling accompanying germline testing.3,14–16 Independent telephone counseling services (eg, InformedDNA) are available for pretest and posttest counseling if onsite counselors are not available. Those cancer care providers wishing to investigate the potential clinical significance of a suspected germline mutation/variant may also refer to an online gene-specific mutation database. Although online variant databases may be used to supplement decision-making, these resources should not replace clinical diagnostic testing. Examples of such resources include the NCI's ClinVar and BIC databases, the Leiden Online Variant Database (LOVD), the ARUP Laboratory database for BRCA1/2, and the InSiGHT database for the APC and the mismatch repair genes of Lynch syndrome. So called in silico modeling programs (eg, Polyphen, SIFT, EvoD) can also provide indirect evidence about the potential pathogenicity of a particular germline variant. However, providers should be aware that in silico models frequently offer discordant results and may overcall variant pathogenicity.
Prevalence of Pathogenic Germline Mutations in Patients Predicted by TGP
Several recently reported studies have examined the prevalence of pathogenic germline mutations among patients undergoing TGP. Catenacci et al17 reviewed 111 patients who underwent TGP and found that 21 had likely deleterious variants in a hereditary cancer gene. Although only 7 of 21 underwent commercial germline testing, 3 were found to carry BRCA1/2 mutations. A collaborative study between our group and Foundation Medicine presented in abstract at the 2015 ASCO Annual Meeting identified likely pathogenic mutations in 3.1% to 7% of a sample of 15,060 tumors undergoing FoundationOne testing, including mutations in BRCA1, BRCA2, MLH1, MUTYH, PMS2, RET, and TP53. Most germline variants identified in the 20 cancer risk genes studied had not been previously reported.13 An abstract by Everett et al18 at the Collaborative Group of the Americas annual meeting identified 5 pathogenic germline variants in 2,016 patients/tumors sequenced [MLH1(x2), MSH2(x2), APC] and 4 monoallelic MUTYH carriers and 4 carriers of the moderate penetrance APC I1307K variant. Finally, a recent publication from Memorial Sloan Kettering Cancer Center revealed potential pathogenic germline variants in 246 (15.7%) of 1,566 patients who underwent TGP.19 It is important to note that the actual prevalence of pathogenic germline mutations uncovered with TGP will vary by tumor type, with the highest rates seen in bladder, squamous cell lung, and kidney tumors in our analysis.12
Genetic Counseling for Genetic Tests of Somatic and Germline Genes: Expectations for TGP
Informed Consent and Counseling for Genetic Tests to Evaluate Hereditary Cancer Risk
Before conducting diagnostic testing to evaluate hereditary/germline cancer risk, genetic counseling and formal informed consent are standard of care.3,14–16 The informed consent process comprises 4 elements: patient competence, appropriate and accurate information, assessment of patient understanding, and patient voluntariness to assent to testing.20,21 In obtaining informed consent before a genetic test, the goal of the counselor is to reinforce understanding of possible test results; test limitations, especially “negative” results for which no mutations to explain a strong family history are found; and implications of possible test results for the patient. ASCO has endorsed informed consent for germline/hereditary cancer risk testing since 1996.3,14–16
2015 ASCO Guidelines Update: An update to the ASCO policy statement on genetic and genomic testing was recently published.3 This expert group acknowledges the growing complexity of genetic testing and the need to inform patients about hereditary risk information that may be discovered by TGP. Although these guidelines support many of the points raised herein, the optimal approach to inform patients of hereditary implications of TGP remains poorly defined, and further research is encouraged.
The Evolving Role of Genetic Counseling for TGP: The Example of Whole-Exome Sequencing and Whole-Genome Sequencing
The role of genetic counseling relative to TGP remains poorly defined in the genetic counseling and oncology communities. Early research from our group conducted as TGP was becoming available in the clinic found that neither oncologists nor genetic counselors perceived, at that time, a role for counseling accompanying TGP. Further, most genetic counselors reported feeling poorly prepared to provide counseling in the context of TGP.22 However, as the use of large TGP panels containing hundreds of genes (many with relevance to hereditary cancer risk) has continued to increase, it is becoming increasingly important to readdress the question of formal counseling and how it might be delivered in the setting of TGP. With limited onsite genetic counseling resources in the community, counselors may not be available for patients before a TGP is ordered in an oncology practice. New formats for delivery of counseling services using video, Web-based, and telephone options are being evaluated an effort to reduce barriers to access as genomic testing demands increase.23,24 Nonetheless, increasingly complex testing technologies and innovative counseling models also present challenges related to patient uptake and understanding of genetic information due to varying levels of technological savvy, health and genomic health literacy and numeracy skill, and information expectations.25,26
Indeed, whole-exome sequencing (WES), whole-genome sequencing (WGS), and large multigene panel tests are together spurring the evolution of genetic counseling that is necessary to meet the increasing demands of these powerful technologies.25,27,28 Specifically, patients undergoing WES/WGS are at risk of discovering a variety of incidental findings (herein defined as information that is unrelated to the primary purpose for testing), including carrier status for a variety of hereditary syndromes, which could affect reproductive decision-making, disease predisposition (including cancer), ancestry, and the diagnosis of unsuspected disorders. In their 2013 policy statement, the American College of Medical Genetics and Genomics (ACMG) specifically outlined several points that are critical to include during informed consent for WES/WGS where incidental findings are the concern.27 In particular, it is recommended that a thorough discussion of potential incidental findings is included in the counseling session for WES/WGS, emphasizing the chance that these findings could have major clinical significance. Per ACMG, patients should also be given the opportunity to opt out of receiving incidental results, and, in doing so, uphold their autonomy to choose whether to receive incidental genomic information despite their provider's duty to warn of a serious genetic risk. The parallels of incidental findings from WES/WGS and secondary findings from TGP are apparent, and further research into the management of TGP secondary findings is specifically called for in the most recent genetic testing policy statement from ASCO.3
In response to the mounting demands of WES/WGS, and multigene panel counseling, genetic counselors have reported remodeling sessions to de-emphasize test technology and instead to focus time on addressing misconceptions about the test or possible results.14,29 Many counselors now highlight the high potential to discover one, if not several, VUS that will not immediately impact management and the potential for findings that could impact health management in an unanticipated way, such as a young woman with early-onset colorectal cancer found to have a BRCA2 mutation on a multigene hereditary cancer panel. Counseling adaptations that are occurring due to the demands of WES/WGS and other tests have direct relevance to TGP and the secondary discovery of hereditary risk information. Cancer patients eligible for TGP may have limited pretest awareness or understanding of hereditary cancer risk or how genes are related to this, or may also not understand how a tumor test differs from a germline test.30,31 They are also unlikely to be aware of the potential impact TGP may have on family members, or how a potential risk would be verified and the possible related costs. Most importantly, patients for whom a TGP is to be ordered may not appreciate the need to state their preferences regarding discovery of information related to hereditary cancer risk, nor the potential to opt out of pursuing/receiving such information if they choose.
Reviewing TGP With the Patient: Defining Needs and Goals
TGP use is highly likely to increase in the coming years as more actionable treatment targets are identified, costs of testing fall, and clinical trial data accumulate demonstrating the successes of targeted therapy. Despite evolving practices for counseling and informed consent before germline testing, relatively little attention has been given to developing clinical standards and discussion points to inform patients of the potential hereditary implications of TGP. This current gap must be immediately addressed if TGP practices are to meet proposed standards for genetic testing supported by ASCO and other groups. To this end, we propose that at the time a TGP is ordered on a patient, providers should:
Have a working knowledge of the genes on the TGP that are relevant to hereditary cancer risk (Table 1).
Discuss the possibility of discovery of somatic genetic findings suggestive of a potential hereditary risk of cancer.
Review procedures to evaluate germline cancer risk (eg, counseling, additional testing, costs) if a somatic mutation suspicious for a germline mutation is discovered.
Emphasize the importance of discovery of a germline genetic mutation for family members and document the patient's wishes for discussion of hereditary cancer risks with family members.
If requested, offer the patient consultation with a genetic counselor either before or after (or both) TGP is completed, or if there is uncertainty about the relevance of a somatic finding to germline risk.
After an adequate understanding of possible germline implications is achieved by the patient, allow the patient (if they choose) to opt out of further discussions of germline genetic risks, and this decision should be documented.
Not make assumptions about the risks associated with variants and mutations in hereditary risk genes discovered by TGP; diagnostic germline testing should be considered the gold standard to determine pathogenicity of a genetic finding discovered through TGP. Genetic testing for hereditary cancer risk should be accompanied by professional genetic counseling.
Conclusions
The risks and implications of TGP should be discussed with patients at the time TGP is ordered. Although formal genetic counseling accompanying TGP is not currently standard of care, there remains a responsibility on the part of the provider to verify patient understanding of TGP and its hereditary implications, and to determine and document patient preferences for receipt of such information if it is discovered. When hereditary cancer risk is suggested by TGP, diagnostic germline testing in a CLIA-approved laboratory accompanied by professional genetic counseling should be pursued.
Appendix 1
Hereditary Cancer Risk Genes Frequently Sequenced on Tumor Genomic Profilesa
Ms. Forman has disclosed that she is a scientific advisor for Invitae Corporation and has received consulting fees from Myriad Genetics, Inc. Dr. Hall has disclosed that he receives research support from Myriad Genetics, Inc., Invitae Corporation, and Foundation Medicine, Inc. The remaining authors have have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
CE AUTHORS
Deborah J. Moonan, RN, BSN, Director, Continuing Education, has disclosed that she has no relevant financial relationships.
Ann Gianola, MA, Senior Manager, Continuing Education Accreditation & Program Operations, has disclosed that she has no relevant financial relationships.
Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships.
Rashmi Kumar, PhD, Senior Manager, Clinical Content, has disclosed that she has no relevant financial relationships.
Susan D. Darlow, PhD, Oncology Scientist/Medical Writer, has disclosed that she has no relevant financial relationships.
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