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Strategies for clinical implementation of screening for hereditary cancer syndromes
Seminars in Oncology ] (2016) ]]]–]]]
Contents lists available at ScienceDirect
Seminars in Oncology journal homepage: www.elsevier.com/locate/ysonc
Strategies for clinical implementation of screening for hereditary cancer syndromes Brandie Healda,n, Jessica Marquarda, Pauline Funchaina,b a b
Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
a r t i c l e in fo
Keywords: Genetic counseling Germline genetic testing Hereditary cancer syndromes
a b s t r a c t Hereditary cancer syndromes generally account for 5%–10% of malignancies. While these syndromes are rare, affected patients carry significantly elevated risks of developing cancer, as do their at-risk relatives. Identification of these patients is critical to ensure timely and appropriate genetic testing relevant to cancer patients and their relatives. Several guidelines and tools are available to assist clinicians. Patients suspected to have hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling by a qualified genetics professional. Germline testing ranges from testing for a known specific familial mutation to testing of a broad differential diagnosis using a pan-cancer multi-gene panel. Taking a family history, referring specific types of tumors with higher likelihood of heredity, implementing universal screening protocols such as microsatellite instability/immunohistochemistry (MSI/IHC) for specific tumors, and referring patients with somatic tumor testing that have potentially germline consequences are all important components to the identification of hereditary cancer syndromes in the oncology clinic. & 2016 Elsevier Inc. All rights reserved.
Hereditary cancer syndromes account for 5%–10% of all malignancies. These syndromes are associated with significantly elevated risks of developing cancer and members of the patient’s family may also be at risk to inherit the condition. Identification of these patients is critical to ensure timely and appropriate genetic testing, and potentially life-saving initiation of surveillance for secondary cancers in the individual tested, as well as in affected family members. Certain cancers by virtue of their tumor types alone should prompt further hereditary evaluation; however, for most patients this identification process will involve an in-depth exploration of the patient’s personal and family cancer history. Guidelines for obtaining a family history and risk stratification tools have been developed. Patients suspected of hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling. This article outlines the critical elements for hereditary cancer risk assessment, genetic testing, and genetic counseling.
1. Collection of family health history Gathering family history is the first step in assessing an individual’s risk for a hereditary cancer syndrome. Discussion Acknowledgment of grant or other financial support: none. n Corresponding author. Cleveland Clinic, 9500 Euclid Ave NE50, Cleveland, OH 44195. Tel.: 216-444-8114; fax: 216-445-6935. E-mail address: [email protected] (B. Heald). http://dx.doi.org/10.1053/j.seminoncol.2016.08.008 0093-7754/& 2016 Elsevier Inc. All rights reserved.
and documentation of a patient’s family history of cancer should be performed at the initial visit and updated throughout the course of treatment. Ideally, a three-generation pedigree is used for an accurate genetic risk assessment. However, obtaining a full pedigree for each patient may be impractical in a busy clinical setting. The American Society of Clinical Oncology (ASCO) has put forth recommendations for the collection and use of family history for oncology patients [1]. The recommended elements for a minimum cancer family history are listed in Table 1 [1]. Patients should be asked about the type and age of onset of cancers in firstand second-degree relatives on both maternal and paternal sides of the family. Pertinent information regarding cancer in thirddegree relatives, such as first-cousins, can also be gathered since this information is relevant in determining whether a patient meets National Comprehensive Cancer Network (NCCN) Criteria for Further Genetic Risk Assessment [2,3]. Ethnicity should be ascertained as certain populations have a higher incidence of hereditary cancer syndromes, eg, hereditary breast and ovarian cancer syndrome in Ashkenazi Jews. Asking whether family members have had genetic testing is also important as all patients with a family history of a known deleterious mutation in a cancer predisposition gene should be referred for genetic counseling [1–3]. Once the family history is collected and reviewed, the next step is interpreting the family history to determine if a referral for genetic counseling is indicated. In general, red flags for hereditary cancer syndromes include early onset (ie, under age 50) cancer,
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Table 1 Family history information that should be obtained for a hereditary cancer risk assessment. First-degree relatives: siblings, parents, children Second-degree relatives: grandparents, aunts, uncles, grandchildren, nieces, nephews, half-siblings Both maternal and paternal sides Ethnicity (eg, Ashkenazi Jewish ancestry) For each cancer diagnosis: age at diagnosis, type of primary cancer Results of any cancer predisposition testing in any relative
several relatives on the same side of the family affected with the same or related cancers (ie, breast and ovarian cancer; colon and endometrial cancer), and multiple primary cancers in the same individual. Detailed criteria for further genetic risk assessment for breast/ovarian cancer, as well as colorectal cancer are outlined in the NCCN Genetic/Familial High-Risk Assessment Guidelines [2,3]. Potential barriers for meaningful utilization of family history include limitations of both patients and providers. Many patients are not aware of their family history, or may have inaccurate information on the types of cancers or ages of diagnosis in the family. A population-based survey of cancer family history by Mai et al revealed that lung, prostate, colon, and breast cancers were accurately reported for first- and second-degree relatives 40%–60% of the time [4]. For providers, barriers include lack of adequate time for family history collection as well as lack of ability to perform an accurate initial risk assessment or provide recommendations for next steps according to family history. A vignette-based study surveying physicians’ recommendations for genetic counseling demonstrated that many providers under- and over-refer patients that should and should not prompt a genetics referral, respectively [5]. A strategy to overcome family history barriers is the use of structured family history collection tools and risk assessment algorithms. Paper-based patient questionnaires may increase recognition of patients that would benefit from genetic counseling [6]. Several electronic resources are available to both patients and providers to collect family history. Some of these tools also incorporate risk assessment models which may assist in identifying high-risk patients. A list of currently available programs can be found in Table 2. 2. Tumors warranting a genetic evaluation, regardless of family history While genetic risk assessment is largely based on an individual’s family history of cancer, in some cases, a genetic counseling referral is indicated based on personal history alone. Patients with
certain malignancies or benign tumor types such as epithelial ovarian cancer, triple-negative breast cancer, male breast cancer, diffuse gastric cancer, adrenocortical carcinoma, cerebellar hemangioblastoma, medullary thyroid cancer, paraganglioma, or pheochromocytoma should be offered genetic counseling due to the high incidence of hereditary mutations even in the absence of a contributing family history. Table 3 summarizes tumors that warrant genetic counseling, as well as the incidence of the related syndrome(s) in simplex cases. 3. Risk assessment models Several risk assessment models have been developed to predict the likelihood of a patient or family harboring a germline mutation for the more common hereditary cancer syndromes. These tools are available online and are intended to be completed by a healthcare provider. As highlighted in Table 4, there are multiple tools for hereditary breast and ovarian cancer syndrome and Lynch syndrome risk assessment, but tools also exist for hereditary pancreatic cancer, hereditary melanoma, and the PTEN-hamartoma tumor syndrome. Risk prediction tools for hereditary breast and ovarian cancer syndrome are based on the patient’s ethnic background and personal and family history of female breast and ovarian cancer, although some models also account for male breast cancer, prostate cancer, and pancreatic cancer. BOADICEA and the TyrerCuzik model not only offer risk prediction for BRCA1 and BRCA2, but also calculate the lifetime risk of developing breast and ovarian cancer and breast cancer, respectively. In the early days of commercial BRCA1 and BRCA2 testing, patients with 410% pretest probability by a risk prediction model were recommended to undergo BRCA1 and BRCA2 genetic testing [7]. However, in modern practice, personal and family history testing guidelines, such as those offered by NCCN, have largely replaced this approach. Regardless, these tools still have utility in identifying patients appropriate for genetic counseling and/or as a genetic counseling to help patients understand the likelihood of harboring a BRCA1 or BRCA2 mutation [8]. Three models have been developed for Lynch syndrome: MMRpro, PREMM1,2,6, and MMRpredict. PREMM1,2,6 has the best sensitivity (90%) among the three models but the lowest specificity (67%), while MMRpredict is the most specific (90%) with a sensitivity of 69% [9]. MMRpro offers the advantage that it will predict the likelihood of identifying a germline MLH1, MSH2, or MSH6 mutation as well as estimate the cancer risk for unaffected relatives. MMRpro and PREMM1,2,6 have the greatest discriminatory power to identify patients with colorectal cancer from both average risk and clinic populations for tumor or germline-based
Table 2 Electronic family history collection tools. Tool Name
Description
Breast Cancer Genetics Referral Screening Free web-based questionnaire available to patients and providers to assess for HBOC Tool [37] Cancer Gene Connect [38] Trademarked software utilizing patient entered data to assess for hereditary cancer syndromes; clinical documentation and follow-up features Colon Cancer Risk Assessment Cleveland Clinic’s free web-based patient questionnaire to assess colon cancer risk Family HealthLink [39] Ohio State University’s free web-based patient questionnaire assessing cancer and cardiovascular risk Health Heritage [40] North Shore University’s free web-based patient questionnaire assessing cancer and cardiovascular risk Hughes RiskApps [41] Trademarked software to identify patients at risk for HBOC My Family Health Portrait [42] Surgeon General’s free web-based patient entered family health history collection tool MeTree [43] Genomedical Connection patient entered tool to collect family health history and performs clinical decision support HBOC ¼ hereditary breast ovarian cancer syndrome. Adapted from National Society of Genetic Counselors Health Information Technology Special Interest Group [44].
Risk assessment Yes Yes Yes Yes Yes Yes No Yes
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Table 3 Tumor types that warrant genetics referral regardless of family history. Tumor type
Referral criteria
Associated syndrome(s)
Associated gene(s)
% with hereditary syndrome*
Invasive ovarian, fallopian tube, primary peritoneal cancer
All high grade epithelial
Hereditary breast ovarian cancer
BRCA1, BRCA2
13%–18% [45,46]
All diagnosed Z 60 years All All diagnosed Z40 years
MLH1, MSH2, EPCAM, MSH6, PMS2 BRIP1, PALB2, RAD51C, RAD51D, TP53 BRCA1, BRCA2 BRCA1, BRCA2 CDH1
o1% [47] Up to 6% [46,48,49]
Triple-negative breast cancer Male breast cancer Diffuse gastric cancer
Lynch syndrome Other rare and newly described syndromes Hereditary breast ovarian cancer Hereditary breast ovarian cancer Hereditary diffuse gastric cancer
Adrenocortical carcinoma
All
Li-Fraumeni syndrome
TP53
Cerebellar hemangioblastoma Medullary thyroid cancer Pheochromocytoma & paraganglioma
All
Lynch syndrome Von Hippel Lindau
MLH1, MSH2, EPCAM, MSH6, PMS2 VHL
Multiple endocrine neoplasia type 2 Hereditary paraganglioma and pheochromocytoma syndrome Multiple endocrine neoplasia type 2 Neurofibromatosis type 1 Von Hippel Lindau Other rare syndromes
RET SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX RET NF1 VHL FH, HIF2A, KIF1Bβ, MEN1, MDH2, PHD1, PHD2
All All
5%–18% [50–53] 13% [54] 14%–19% of those fulfilling HDGC criteria [55,56] 42% of pediatric cases [57]; 4%–6% of adults [58,59] o3% [60] 14% [61] 7% [62] 10% [63] 3% [63] 1% [63] 3% [63] Unknown
HDGC ¼ hereditary diffuse gastric cancer n
Incidence with no contributing personal or family history; incidence is higher for individuals with syndromic features or a suggestive family history.
Lynch syndrome testing [10]. NCCN and US Multi-Society Task Force on Colorectal Cancer recommend a genetic risk assessment for anyone with Z 5% risk on these models [3,9]. 4. Universal screening for Lynch syndrome Patients whose tumors are found to have phenotypes of defective DNA mismatch repair (MMR) through abnormal expression of MMR proteins by immunohistochemistry (IHC) or microsatellite instability (MSI), not explained by somatic BRAF V600E mutation and/or MLH1 promoter hypermethylation should then be sent for genetic counseling and testing for germline mutations in DNA MMR genes. The Amsterdam Criteria and Bethesda Guidelines (see Lynch syndrome chapter) are clinical tools to help find families and colorectal cancers, respectively, which are more likely to be related to Lynch syndrome. However, in addition to being cumbersome to recall, the criteria have reduced sensitivity and specificity for Lynch syndrome compared to tumor screening strategies [9]. In 2009 the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) recommended that all newly diagnosed colorectal cancers undergo screening for Lynch syndrome based on the
premise that making a diagnosis of Lynch syndrome in a colorectal cancer patient would result in improved health outcomes in atrisk relatives [11]. This EGAPP recommendation has been included as one of the Healthy People 2020 Genomics Initiatives [12]. Universal screening for Lynch syndrome among endometrial cancers has been adapted by many large medical centers and is endorsed by the Society of Gynecologic Oncology [13]. Challenges with implementation of universal screening and patient follow through with genetic counseling and genetic testing has been identified [14–17]. However, centers with high level of genetic counselor participation in the universal screening program have been shown to have greater patient follow through [14]. 5. Genetic testing and genetic counseling Genetic testing should be offered to patients who meet professional society or expert opinion guidelines. Upon identification of kindred suspicious of having a hereditary cancer syndrome, the approach to genetic testing should be individualized to the family. In current clinical practice, there are three types of germline testing to consider: single-site mutation analysis, single gene/ syndrome testing, and next generation sequencing gene panels.
Table 4 Online risk assessment models for hereditary cancer syndromes. Syndrome
Model name
URL
Hereditary breast ovarian cancer syndrome
BRCAPRO IBIS Breast Cancer Risk Evaluation Tool (Tyrer-Cuzik Model Penn II Model BOADICEA MMRpro PREMM1,2,6 MMRpredict PancPRO MelaPRO Cleveland Clinic PTEN Calculator
http://www4.utsouthwestern.edu/breasthealth/cagene/ http://www.ems-trials.org/riskevaluator/ http://apps.afcri.upenn.edu/itacc/penn2/index.asp http://ccge.medschl.cam.ac.uk/boadicea/ http://www4.utsouthwestern.edu/breasthealth/cagene/ http://premm.dfci.harvard.edu/ http://hnpccpredict.hgu.mrc.ac.uk/ http://www4.utsouthwestern.edu/breasthealth/cagene/ http://www4.utsouthwestern.edu/breasthealth/cagene/ http://www.lerner.ccf.org/gmi/ccscore/
Lynch syndrome
Hereditary pancreatic cancer Hereditary melanoma PTEN hamartoma tumor syndrome
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For patients with a known mutation in the family it is most appropriate to offer testing for the mutation known to occur in the family. This testing is relatively inexpensive and results are often available in less than two weeks. Results yield a positive or negative finding with no concern for a variant of uncertain significance, which is a genetic change unknown if it affects gene function or it if is benign genetic variation. For autosomal dominantly inherited syndromes, if the mutation is confirmed, the patient is at risk for the condition and there is potential for him/ her to pass the mutation on to his or her children. If the mutation is not found, this patient would be considered at general population risk to develop the syndrome-associated cancers and could not pass the mutation on to his or her children. This would be considered a “true negative” test result. If there is no known mutation in the family, genetic testing should ideally be initiated on a member of the family who has had cancer. In the event the affected relative is unable or unwilling to pursue testing then the cancer unaffected patient must be informed of the limitations of genetic testing. Specifically, if the genetic test fails to identify a mutation, this should not offer complete reassurance, since it is not known whether no mutation is present in the family or if the family has a mutation but the patient who was tested did not inherit it. Further, it is possible that there is a mutation present in the assayed gene(s) that cannot be detected with current technology or if a mutation is present in a different gene that was not tested. Therefore, given the inherent uncertainty in these “indeterminate negative” genetic tests it is important to counsel the patient regarding his or her empiric cancer risk based on personal and family history [18]. Once detailed risk assessment confirms suspicion for one or more hereditary cancer syndromes, germline genetic testing is ordered. Traditionally, clinical sequencing has been performed primarily with Sanger sequencing, targeted to high-risk/-penetrance genes most likely to be associated with the clinical phenotype. Recommendations for single-gene/syndrome genetic testing exist from a number of medical professional societies [2,3,9,19–21]; however, if multiple hereditary cancer syndromes are suspected in a family, Sanger sequencing may not be cost-effective. Decreasing cost and increasing access to next-generation sequencing has led to multiple gene panels tailored for hereditary cancer syndromes. Panels range from cancer-specific panels to broad pan-cancer gene panels. Panels offer the advantage of exploring multiple genes, including moderate-risk and/or newer genes, on one platform at a lower cost per gene compared to Sanger sequencing. Panel testing has been shown to increase the mutation detection rate and may be beneficial to patients with a broad differential diagnosis, atypical cancer phenotype, or missing family history information [22–27]. However, these multigene tests have significantly higher rates of finding variants of uncertain significance. Panel testing might also identify mutations in genes of unclear clinical utility or inconsistent with the cancers reported in the family history. Testing also becomes more complicated as some of the genes included on the panels predispose to cancer risk in the heterozygous state but may be linked to autosomal recessive conditions, of varying cancer risks, which could have further implications for other members of the family. Given the potential uncertainty and complexity of panel-based results, it is strongly recommended that these tests are ordered by genetic counselors or healthcare providers knowledgeable in hereditary cancer genetics [28,29]. Genetic testing should always be conducted in the setting of pre- and post-test genetic counseling. Ideally, these services are provided by a healthcare provider who has experience in cancer genetics [29,30]. This might include genetic counselors, medical geneticists, nurses credentialed through the Genetics Nursing Credentialing Commission, oncology nurses with specialized
training in cancer genetics/hereditary cancer syndromes, or board-certified physicians with experience in cancer risk assessment and genetics [30]. If referral to these services is available, managing physicians should stress to patients the importance of using these services. If genetics specialists are unavailable for onsite referral there are telegenetics resources available through companies. Obtaining informed consent is a critical component to pre-test genetic counseling, including discussion about the gene-specific cancer risks; medical management options; potential genetic testing outcomes; risks to family members and importance of sharing results with relatives; costs; psychological risks and benefits; insurance and employment discrimination risks and protections; confidentiality issues; potential use of DNA for future research; and plans for results disclosure [29]. The most recent ASCO guidelines address special considerations for informed consent when ordering multigene panel genetic tests, highlighting the importance discussing the higher likelihood of identifying variants of uncertain significance, potential reproductive implications for genes linked to autosomal recessive genetic disorders, and implications of identifying mutations in moderate-penetrance genes, high-risk genes that are inconsistent with the family history, or less well-characterized genes [29].
6. Future directions: Tumor (somatic) mutations with germline implications Over the last decade, The Cancer Genome Atlas (TCGA) project, characterizing the somatic genomes of more than 25 different cancer types, has launched somatic tumor profiling and the beginnings of personalized cancer medicine. Tumor genomic profiling has been used to ascertain somatic alterations for which effective targeted agents are available, such as crizotinib for tumors harboring an ALK-fusion, and to qualify patients for clinical trials with novel targeted therapies. Historically, tumor genomic profiling has not included analysis of matched normal tissue, and thus cannot assess whether alterations identified in the tumor are somatic only, as opposed to both somatic and germline. However, recent data suggest that up to 10% of tumors tested with somatic genomic profiling have at least one somatic alteration that is also found in germline DNA and clinically relevant as a potentially heritable mutation with consequences for the patient as well as family members [31–34]. While there are no clear guidelines as to which somatic alterations found on tumor genomic profiling should prompt referral for germline genetic evaluation the finding of somatic mutations in genes known to be associated with hereditary cancer syndromes, such as BRCA1/2 or the MMR genes associated with Lynch syndrome, should be carefully considered, particularly if the somatic gene finding and the cancer type make clinical sense (eg, a CDH1 mutation in a diffuse gastric cancer.) While paired sequencing of tumor and normal DNA can facilitate somatic variant calling, the frequent identification of germline mutations has made genetics expertise a valuable component of many academic molecular tumor boards [35,36]. As tumor genomic profiling becomes more common, both oncology practitioners and patients will need to familiarize themselves with the implications of unanticipated germline findings. ASCO’s recent policy statement on genetic and genomic testing recommends that oncology providers include the possibility of germline findings in the informed consent process for patients undergoing somatic tumor testing [29]. Patients need to be made aware of the benefits and risks to themselves as well as their relatives should somatic testing reveal an incidental germline finding and patients should be given the option to receive, or
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decline receipt, of this information if they so choose. Additionally, pre- and post-test counseling for these types of germline findings are encouraged. Clinical screening for hereditary cancer syndromes has rapidly evolved over the last decade, and has become more complex in terms of diagnostic algorithms and testing options. Eliciting a comprehensive family history, having an understanding of the subsets of cancer patients at higher risk for hereditary cancer syndromes, using available risk assessment tools, implementing universal screening for specific tumor types, using the expertise of genetics providers, and understanding germline implications of somatic testing are all best practices to effectively screen and identify patients with hereditary cancer syndromes in an oncology practice.
Financial disclosure/conflict of interest B. Heald is on the Speaker’s Bureau for Myriad Genetics Laboratory and the Advisory Board for Invitae.
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[56] Hansford S, Kaurah P, Li-Chang H, et al. Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond. JAMA Oncol 2015;1:23–32. [57] Wasserman JD, Novokmet A, Eichler-Jonsson C, et al. Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a Children's Oncology Group study. J Clin Oncol 2015;33:602–9. [58] Herrmann LJ, Heinze B, Fassnacht M, et al. TP53 germline mutations in adult patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2012;97: E476–85. [59] Raymond VM, Else T, Everett JN, Long JM, Gruber SB, Hammer GD. Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2013;98:E119–25. [60] Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a lynch syndrome-associated cancer. J Clin Oncol 2013;31:3012–8. [61] Catapano D, Muscarella LA, Guarnieri V, Zelante L, D'Angelo VA, D'Agruma L. Hemangioblastomas of central nervous system: molecular genetic analysis and clinical management. Neurosurgery 2005;56:1215–21 discussion 21. [62] Romei C, Tacito A, Molinaro E, et al. Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer? Clin Endocrinol 2015;82:892–9. [63] Brito JP, Asi N, Bancos I, et al. Testing for germline mutations in sporadic pheochromocytoma/paraganglioma: a systematic review. Clin Endocrinol 2015;82:338–45.
Contents lists available at ScienceDirect
Seminars in Oncology journal homepage: www.elsevier.com/locate/ysonc
Strategies for clinical implementation of screening for hereditary cancer syndromes Brandie Healda,n, Jessica Marquarda, Pauline Funchaina,b a b
Center for Personalized Genetic Healthcare, Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
a r t i c l e in fo
Keywords: Genetic counseling Germline genetic testing Hereditary cancer syndromes
a b s t r a c t Hereditary cancer syndromes generally account for 5%–10% of malignancies. While these syndromes are rare, affected patients carry significantly elevated risks of developing cancer, as do their at-risk relatives. Identification of these patients is critical to ensure timely and appropriate genetic testing relevant to cancer patients and their relatives. Several guidelines and tools are available to assist clinicians. Patients suspected to have hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling by a qualified genetics professional. Germline testing ranges from testing for a known specific familial mutation to testing of a broad differential diagnosis using a pan-cancer multi-gene panel. Taking a family history, referring specific types of tumors with higher likelihood of heredity, implementing universal screening protocols such as microsatellite instability/immunohistochemistry (MSI/IHC) for specific tumors, and referring patients with somatic tumor testing that have potentially germline consequences are all important components to the identification of hereditary cancer syndromes in the oncology clinic. & 2016 Elsevier Inc. All rights reserved.
Hereditary cancer syndromes account for 5%–10% of all malignancies. These syndromes are associated with significantly elevated risks of developing cancer and members of the patient’s family may also be at risk to inherit the condition. Identification of these patients is critical to ensure timely and appropriate genetic testing, and potentially life-saving initiation of surveillance for secondary cancers in the individual tested, as well as in affected family members. Certain cancers by virtue of their tumor types alone should prompt further hereditary evaluation; however, for most patients this identification process will involve an in-depth exploration of the patient’s personal and family cancer history. Guidelines for obtaining a family history and risk stratification tools have been developed. Patients suspected of hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling. This article outlines the critical elements for hereditary cancer risk assessment, genetic testing, and genetic counseling.
1. Collection of family health history Gathering family history is the first step in assessing an individual’s risk for a hereditary cancer syndrome. Discussion Acknowledgment of grant or other financial support: none. n Corresponding author. Cleveland Clinic, 9500 Euclid Ave NE50, Cleveland, OH 44195. Tel.: 216-444-8114; fax: 216-445-6935. E-mail address: [email protected] (B. Heald). http://dx.doi.org/10.1053/j.seminoncol.2016.08.008 0093-7754/& 2016 Elsevier Inc. All rights reserved.
and documentation of a patient’s family history of cancer should be performed at the initial visit and updated throughout the course of treatment. Ideally, a three-generation pedigree is used for an accurate genetic risk assessment. However, obtaining a full pedigree for each patient may be impractical in a busy clinical setting. The American Society of Clinical Oncology (ASCO) has put forth recommendations for the collection and use of family history for oncology patients [1]. The recommended elements for a minimum cancer family history are listed in Table 1 [1]. Patients should be asked about the type and age of onset of cancers in firstand second-degree relatives on both maternal and paternal sides of the family. Pertinent information regarding cancer in thirddegree relatives, such as first-cousins, can also be gathered since this information is relevant in determining whether a patient meets National Comprehensive Cancer Network (NCCN) Criteria for Further Genetic Risk Assessment [2,3]. Ethnicity should be ascertained as certain populations have a higher incidence of hereditary cancer syndromes, eg, hereditary breast and ovarian cancer syndrome in Ashkenazi Jews. Asking whether family members have had genetic testing is also important as all patients with a family history of a known deleterious mutation in a cancer predisposition gene should be referred for genetic counseling [1–3]. Once the family history is collected and reviewed, the next step is interpreting the family history to determine if a referral for genetic counseling is indicated. In general, red flags for hereditary cancer syndromes include early onset (ie, under age 50) cancer,
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Table 1 Family history information that should be obtained for a hereditary cancer risk assessment. First-degree relatives: siblings, parents, children Second-degree relatives: grandparents, aunts, uncles, grandchildren, nieces, nephews, half-siblings Both maternal and paternal sides Ethnicity (eg, Ashkenazi Jewish ancestry) For each cancer diagnosis: age at diagnosis, type of primary cancer Results of any cancer predisposition testing in any relative
several relatives on the same side of the family affected with the same or related cancers (ie, breast and ovarian cancer; colon and endometrial cancer), and multiple primary cancers in the same individual. Detailed criteria for further genetic risk assessment for breast/ovarian cancer, as well as colorectal cancer are outlined in the NCCN Genetic/Familial High-Risk Assessment Guidelines [2,3]. Potential barriers for meaningful utilization of family history include limitations of both patients and providers. Many patients are not aware of their family history, or may have inaccurate information on the types of cancers or ages of diagnosis in the family. A population-based survey of cancer family history by Mai et al revealed that lung, prostate, colon, and breast cancers were accurately reported for first- and second-degree relatives 40%–60% of the time [4]. For providers, barriers include lack of adequate time for family history collection as well as lack of ability to perform an accurate initial risk assessment or provide recommendations for next steps according to family history. A vignette-based study surveying physicians’ recommendations for genetic counseling demonstrated that many providers under- and over-refer patients that should and should not prompt a genetics referral, respectively [5]. A strategy to overcome family history barriers is the use of structured family history collection tools and risk assessment algorithms. Paper-based patient questionnaires may increase recognition of patients that would benefit from genetic counseling [6]. Several electronic resources are available to both patients and providers to collect family history. Some of these tools also incorporate risk assessment models which may assist in identifying high-risk patients. A list of currently available programs can be found in Table 2. 2. Tumors warranting a genetic evaluation, regardless of family history While genetic risk assessment is largely based on an individual’s family history of cancer, in some cases, a genetic counseling referral is indicated based on personal history alone. Patients with
certain malignancies or benign tumor types such as epithelial ovarian cancer, triple-negative breast cancer, male breast cancer, diffuse gastric cancer, adrenocortical carcinoma, cerebellar hemangioblastoma, medullary thyroid cancer, paraganglioma, or pheochromocytoma should be offered genetic counseling due to the high incidence of hereditary mutations even in the absence of a contributing family history. Table 3 summarizes tumors that warrant genetic counseling, as well as the incidence of the related syndrome(s) in simplex cases. 3. Risk assessment models Several risk assessment models have been developed to predict the likelihood of a patient or family harboring a germline mutation for the more common hereditary cancer syndromes. These tools are available online and are intended to be completed by a healthcare provider. As highlighted in Table 4, there are multiple tools for hereditary breast and ovarian cancer syndrome and Lynch syndrome risk assessment, but tools also exist for hereditary pancreatic cancer, hereditary melanoma, and the PTEN-hamartoma tumor syndrome. Risk prediction tools for hereditary breast and ovarian cancer syndrome are based on the patient’s ethnic background and personal and family history of female breast and ovarian cancer, although some models also account for male breast cancer, prostate cancer, and pancreatic cancer. BOADICEA and the TyrerCuzik model not only offer risk prediction for BRCA1 and BRCA2, but also calculate the lifetime risk of developing breast and ovarian cancer and breast cancer, respectively. In the early days of commercial BRCA1 and BRCA2 testing, patients with 410% pretest probability by a risk prediction model were recommended to undergo BRCA1 and BRCA2 genetic testing [7]. However, in modern practice, personal and family history testing guidelines, such as those offered by NCCN, have largely replaced this approach. Regardless, these tools still have utility in identifying patients appropriate for genetic counseling and/or as a genetic counseling to help patients understand the likelihood of harboring a BRCA1 or BRCA2 mutation [8]. Three models have been developed for Lynch syndrome: MMRpro, PREMM1,2,6, and MMRpredict. PREMM1,2,6 has the best sensitivity (90%) among the three models but the lowest specificity (67%), while MMRpredict is the most specific (90%) with a sensitivity of 69% [9]. MMRpro offers the advantage that it will predict the likelihood of identifying a germline MLH1, MSH2, or MSH6 mutation as well as estimate the cancer risk for unaffected relatives. MMRpro and PREMM1,2,6 have the greatest discriminatory power to identify patients with colorectal cancer from both average risk and clinic populations for tumor or germline-based
Table 2 Electronic family history collection tools. Tool Name
Description
Breast Cancer Genetics Referral Screening Free web-based questionnaire available to patients and providers to assess for HBOC Tool [37] Cancer Gene Connect [38] Trademarked software utilizing patient entered data to assess for hereditary cancer syndromes; clinical documentation and follow-up features Colon Cancer Risk Assessment Cleveland Clinic’s free web-based patient questionnaire to assess colon cancer risk Family HealthLink [39] Ohio State University’s free web-based patient questionnaire assessing cancer and cardiovascular risk Health Heritage [40] North Shore University’s free web-based patient questionnaire assessing cancer and cardiovascular risk Hughes RiskApps [41] Trademarked software to identify patients at risk for HBOC My Family Health Portrait [42] Surgeon General’s free web-based patient entered family health history collection tool MeTree [43] Genomedical Connection patient entered tool to collect family health history and performs clinical decision support HBOC ¼ hereditary breast ovarian cancer syndrome. Adapted from National Society of Genetic Counselors Health Information Technology Special Interest Group [44].
Risk assessment Yes Yes Yes Yes Yes Yes No Yes
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Table 3 Tumor types that warrant genetics referral regardless of family history. Tumor type
Referral criteria
Associated syndrome(s)
Associated gene(s)
% with hereditary syndrome*
Invasive ovarian, fallopian tube, primary peritoneal cancer
All high grade epithelial
Hereditary breast ovarian cancer
BRCA1, BRCA2
13%–18% [45,46]
All diagnosed Z 60 years All All diagnosed Z40 years
MLH1, MSH2, EPCAM, MSH6, PMS2 BRIP1, PALB2, RAD51C, RAD51D, TP53 BRCA1, BRCA2 BRCA1, BRCA2 CDH1
o1% [47] Up to 6% [46,48,49]
Triple-negative breast cancer Male breast cancer Diffuse gastric cancer
Lynch syndrome Other rare and newly described syndromes Hereditary breast ovarian cancer Hereditary breast ovarian cancer Hereditary diffuse gastric cancer
Adrenocortical carcinoma
All
Li-Fraumeni syndrome
TP53
Cerebellar hemangioblastoma Medullary thyroid cancer Pheochromocytoma & paraganglioma
All
Lynch syndrome Von Hippel Lindau
MLH1, MSH2, EPCAM, MSH6, PMS2 VHL
Multiple endocrine neoplasia type 2 Hereditary paraganglioma and pheochromocytoma syndrome Multiple endocrine neoplasia type 2 Neurofibromatosis type 1 Von Hippel Lindau Other rare syndromes
RET SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX RET NF1 VHL FH, HIF2A, KIF1Bβ, MEN1, MDH2, PHD1, PHD2
All All
5%–18% [50–53] 13% [54] 14%–19% of those fulfilling HDGC criteria [55,56] 42% of pediatric cases [57]; 4%–6% of adults [58,59] o3% [60] 14% [61] 7% [62] 10% [63] 3% [63] 1% [63] 3% [63] Unknown
HDGC ¼ hereditary diffuse gastric cancer n
Incidence with no contributing personal or family history; incidence is higher for individuals with syndromic features or a suggestive family history.
Lynch syndrome testing [10]. NCCN and US Multi-Society Task Force on Colorectal Cancer recommend a genetic risk assessment for anyone with Z 5% risk on these models [3,9]. 4. Universal screening for Lynch syndrome Patients whose tumors are found to have phenotypes of defective DNA mismatch repair (MMR) through abnormal expression of MMR proteins by immunohistochemistry (IHC) or microsatellite instability (MSI), not explained by somatic BRAF V600E mutation and/or MLH1 promoter hypermethylation should then be sent for genetic counseling and testing for germline mutations in DNA MMR genes. The Amsterdam Criteria and Bethesda Guidelines (see Lynch syndrome chapter) are clinical tools to help find families and colorectal cancers, respectively, which are more likely to be related to Lynch syndrome. However, in addition to being cumbersome to recall, the criteria have reduced sensitivity and specificity for Lynch syndrome compared to tumor screening strategies [9]. In 2009 the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) recommended that all newly diagnosed colorectal cancers undergo screening for Lynch syndrome based on the
premise that making a diagnosis of Lynch syndrome in a colorectal cancer patient would result in improved health outcomes in atrisk relatives [11]. This EGAPP recommendation has been included as one of the Healthy People 2020 Genomics Initiatives [12]. Universal screening for Lynch syndrome among endometrial cancers has been adapted by many large medical centers and is endorsed by the Society of Gynecologic Oncology [13]. Challenges with implementation of universal screening and patient follow through with genetic counseling and genetic testing has been identified [14–17]. However, centers with high level of genetic counselor participation in the universal screening program have been shown to have greater patient follow through [14]. 5. Genetic testing and genetic counseling Genetic testing should be offered to patients who meet professional society or expert opinion guidelines. Upon identification of kindred suspicious of having a hereditary cancer syndrome, the approach to genetic testing should be individualized to the family. In current clinical practice, there are three types of germline testing to consider: single-site mutation analysis, single gene/ syndrome testing, and next generation sequencing gene panels.
Table 4 Online risk assessment models for hereditary cancer syndromes. Syndrome
Model name
URL
Hereditary breast ovarian cancer syndrome
BRCAPRO IBIS Breast Cancer Risk Evaluation Tool (Tyrer-Cuzik Model Penn II Model BOADICEA MMRpro PREMM1,2,6 MMRpredict PancPRO MelaPRO Cleveland Clinic PTEN Calculator
http://www4.utsouthwestern.edu/breasthealth/cagene/ http://www.ems-trials.org/riskevaluator/ http://apps.afcri.upenn.edu/itacc/penn2/index.asp http://ccge.medschl.cam.ac.uk/boadicea/ http://www4.utsouthwestern.edu/breasthealth/cagene/ http://premm.dfci.harvard.edu/ http://hnpccpredict.hgu.mrc.ac.uk/ http://www4.utsouthwestern.edu/breasthealth/cagene/ http://www4.utsouthwestern.edu/breasthealth/cagene/ http://www.lerner.ccf.org/gmi/ccscore/
Lynch syndrome
Hereditary pancreatic cancer Hereditary melanoma PTEN hamartoma tumor syndrome
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For patients with a known mutation in the family it is most appropriate to offer testing for the mutation known to occur in the family. This testing is relatively inexpensive and results are often available in less than two weeks. Results yield a positive or negative finding with no concern for a variant of uncertain significance, which is a genetic change unknown if it affects gene function or it if is benign genetic variation. For autosomal dominantly inherited syndromes, if the mutation is confirmed, the patient is at risk for the condition and there is potential for him/ her to pass the mutation on to his or her children. If the mutation is not found, this patient would be considered at general population risk to develop the syndrome-associated cancers and could not pass the mutation on to his or her children. This would be considered a “true negative” test result. If there is no known mutation in the family, genetic testing should ideally be initiated on a member of the family who has had cancer. In the event the affected relative is unable or unwilling to pursue testing then the cancer unaffected patient must be informed of the limitations of genetic testing. Specifically, if the genetic test fails to identify a mutation, this should not offer complete reassurance, since it is not known whether no mutation is present in the family or if the family has a mutation but the patient who was tested did not inherit it. Further, it is possible that there is a mutation present in the assayed gene(s) that cannot be detected with current technology or if a mutation is present in a different gene that was not tested. Therefore, given the inherent uncertainty in these “indeterminate negative” genetic tests it is important to counsel the patient regarding his or her empiric cancer risk based on personal and family history [18]. Once detailed risk assessment confirms suspicion for one or more hereditary cancer syndromes, germline genetic testing is ordered. Traditionally, clinical sequencing has been performed primarily with Sanger sequencing, targeted to high-risk/-penetrance genes most likely to be associated with the clinical phenotype. Recommendations for single-gene/syndrome genetic testing exist from a number of medical professional societies [2,3,9,19–21]; however, if multiple hereditary cancer syndromes are suspected in a family, Sanger sequencing may not be cost-effective. Decreasing cost and increasing access to next-generation sequencing has led to multiple gene panels tailored for hereditary cancer syndromes. Panels range from cancer-specific panels to broad pan-cancer gene panels. Panels offer the advantage of exploring multiple genes, including moderate-risk and/or newer genes, on one platform at a lower cost per gene compared to Sanger sequencing. Panel testing has been shown to increase the mutation detection rate and may be beneficial to patients with a broad differential diagnosis, atypical cancer phenotype, or missing family history information [22–27]. However, these multigene tests have significantly higher rates of finding variants of uncertain significance. Panel testing might also identify mutations in genes of unclear clinical utility or inconsistent with the cancers reported in the family history. Testing also becomes more complicated as some of the genes included on the panels predispose to cancer risk in the heterozygous state but may be linked to autosomal recessive conditions, of varying cancer risks, which could have further implications for other members of the family. Given the potential uncertainty and complexity of panel-based results, it is strongly recommended that these tests are ordered by genetic counselors or healthcare providers knowledgeable in hereditary cancer genetics [28,29]. Genetic testing should always be conducted in the setting of pre- and post-test genetic counseling. Ideally, these services are provided by a healthcare provider who has experience in cancer genetics [29,30]. This might include genetic counselors, medical geneticists, nurses credentialed through the Genetics Nursing Credentialing Commission, oncology nurses with specialized
training in cancer genetics/hereditary cancer syndromes, or board-certified physicians with experience in cancer risk assessment and genetics [30]. If referral to these services is available, managing physicians should stress to patients the importance of using these services. If genetics specialists are unavailable for onsite referral there are telegenetics resources available through companies. Obtaining informed consent is a critical component to pre-test genetic counseling, including discussion about the gene-specific cancer risks; medical management options; potential genetic testing outcomes; risks to family members and importance of sharing results with relatives; costs; psychological risks and benefits; insurance and employment discrimination risks and protections; confidentiality issues; potential use of DNA for future research; and plans for results disclosure [29]. The most recent ASCO guidelines address special considerations for informed consent when ordering multigene panel genetic tests, highlighting the importance discussing the higher likelihood of identifying variants of uncertain significance, potential reproductive implications for genes linked to autosomal recessive genetic disorders, and implications of identifying mutations in moderate-penetrance genes, high-risk genes that are inconsistent with the family history, or less well-characterized genes [29].
6. Future directions: Tumor (somatic) mutations with germline implications Over the last decade, The Cancer Genome Atlas (TCGA) project, characterizing the somatic genomes of more than 25 different cancer types, has launched somatic tumor profiling and the beginnings of personalized cancer medicine. Tumor genomic profiling has been used to ascertain somatic alterations for which effective targeted agents are available, such as crizotinib for tumors harboring an ALK-fusion, and to qualify patients for clinical trials with novel targeted therapies. Historically, tumor genomic profiling has not included analysis of matched normal tissue, and thus cannot assess whether alterations identified in the tumor are somatic only, as opposed to both somatic and germline. However, recent data suggest that up to 10% of tumors tested with somatic genomic profiling have at least one somatic alteration that is also found in germline DNA and clinically relevant as a potentially heritable mutation with consequences for the patient as well as family members [31–34]. While there are no clear guidelines as to which somatic alterations found on tumor genomic profiling should prompt referral for germline genetic evaluation the finding of somatic mutations in genes known to be associated with hereditary cancer syndromes, such as BRCA1/2 or the MMR genes associated with Lynch syndrome, should be carefully considered, particularly if the somatic gene finding and the cancer type make clinical sense (eg, a CDH1 mutation in a diffuse gastric cancer.) While paired sequencing of tumor and normal DNA can facilitate somatic variant calling, the frequent identification of germline mutations has made genetics expertise a valuable component of many academic molecular tumor boards [35,36]. As tumor genomic profiling becomes more common, both oncology practitioners and patients will need to familiarize themselves with the implications of unanticipated germline findings. ASCO’s recent policy statement on genetic and genomic testing recommends that oncology providers include the possibility of germline findings in the informed consent process for patients undergoing somatic tumor testing [29]. Patients need to be made aware of the benefits and risks to themselves as well as their relatives should somatic testing reveal an incidental germline finding and patients should be given the option to receive, or
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decline receipt, of this information if they so choose. Additionally, pre- and post-test counseling for these types of germline findings are encouraged. Clinical screening for hereditary cancer syndromes has rapidly evolved over the last decade, and has become more complex in terms of diagnostic algorithms and testing options. Eliciting a comprehensive family history, having an understanding of the subsets of cancer patients at higher risk for hereditary cancer syndromes, using available risk assessment tools, implementing universal screening for specific tumor types, using the expertise of genetics providers, and understanding germline implications of somatic testing are all best practices to effectively screen and identify patients with hereditary cancer syndromes in an oncology practice.
Financial disclosure/conflict of interest B. Heald is on the Speaker’s Bureau for Myriad Genetics Laboratory and the Advisory Board for Invitae.
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