Abstract
Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.
NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.
Accreditation Statements
In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-19-011-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/86075; and (3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.
Release date: September 10, 2019; Expiration date: September 10, 2020
Learning Objectives:
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal
Disclosure of Relevant Financial Relationships
The NCCN staff listed below discloses no relevant financial relationships:
Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.
Individuals Who Provided Content Development and/or Authorship Assistance:
Samir Gupta, MD, Panel Vice Chair, has disclosed that he has no relevant financial relationships.
Dawn Provenzale, MD, MS, Panel Chair, has disclosed that she has no relevant financial relationships.
Xavier Llor, MD, PhD, Panel Member, has disclosed that he is a scientific advisor for Exact Sciences.
Amy L. Halverson, MD, Panel Member, has disclosed that she has no relevant financial relationships.
William Grady, MD, Panel Member, had disclosed that he receives grant/research support from Janssen Pharmaceuticals and Tempus; receives consulting fees/honoraria from Boehringer-Ingelheim; and is a scientific advisor for Guardant Health, Freenome, and SEngine.
Daniel C. Chung, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Sigurdis Haraldsdottir, MD, PhD, Panel Member, has disclosed that she has no relevant financial relationships.
Arnold J. Markowitz, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Thomas P. Slavin Jr, MD, Panel Member, has disclosed that he has no relevant financial relationships.
Heather Hampel, MS, CGC, Panel Member, has disclosed that she is a scientific advisor for and receives consulting fees/honoraria from InVitae Genetics.
Reid M. Ness, MD, MPH, Panel Member, has disclosed that he has no relevant financial relationships.
Jennifer M. Weiss, MD, MS, Panel Member, has disclosed that he has no relevant financial relationships.
Mary A. Dwyer, MS, Senior Manager, Guidelines, NCCN, has disclosed that she has no relevant financial relationships.
Ndiya Ogba, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that she has no relevant financial relationships.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/disclosures/guidelinepanellisting.aspx.
This activity is supported by educational grants from AstraZeneca, Celgene Corporation, Clovis Oncology, Eisai, Genentech, Genomic Health, Inc., Novartis, Taiho Oncology, Inc., and TESARO. This activity is supported by an independent educational grant from AbbVie. This activity is supported by educational funding provided by Amgen. This activity is supported by an unrestricted educational grant from Gilead Sciences, Medical Affairs.
Overview
Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States; in 2019, an estimated 101,420 new cases of colon cancer and 44,180 new cases of rectal cancer will be diagnosed.1 Approximately 20% to 30% of CRCs are potentially linked to genetic factors, and hereditary CRC syndromes constitute 3% to 5% of all CRCs.2–5 Hereditary CRC syndromes are associated with early onset of CRC and some with risk for extracolonic cancers.6,7 Genetic susceptibility to CRC includes well-defined inherited syndromes, such as Lynch syndrome, familial adenomatous polyposis (FAP), and MUTYH–associated polyposis (MAP),2,8 and rare inherited syndromes, including juvenile polyposis syndrome (JPS), Cowden syndrome/PTEN hamartoma tumor syndrome (PHTS), and Peutz-Jeghers syndrome (PJS).9,10 Some syndromes are still being further characterized, such as the I1307K polymorphism in APC11,12 and polymerase proofreading–associated polyposis secondary to germline mutations in POLE and POLD1.13,14 In addition, there are other syndromes that do not yet have a clearly identified pathogenic variant, such as serrated polyposis syndrome.15
Hereditary cancer risk assessment is essential to identifying individuals and families at risk for developing certain types of cancers and provides targeted surveillance and management for affected individuals.6 High-risk individuals may be identified based on phenotypic criteria, including family history and patient-specific factors, such as age at diagnosis and tumor phenotype. The presence of a genetic mutation may then be confirmed with single or multigene testing.7 With the capacity to analyze several genes at the same time, multigene testing allows for the inclusion of multiple susceptibility genes simultaneously.7 This is important to note because emerging evidence suggests a role for newly identified genes included on multigene panels that may be associated with increased risk of CRC or adenomatous polyposis.16,17 However, an underrecognition of clinical criteria used to identify individuals with hereditary CRC syndromes may lead to incomplete risk assessments and subsequent inappropriate or insufficient surveillance recommendations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk syndromes. These NCCN Guidelines Insights highlight important updates and summarize criteria for the evaluation of hereditary CRC syndromes, including colorectal polyposis syndromes and Lynch syndrome, and considerations for the use of multigene testing in the assessment of hereditary CRC syndromes.
Assessment of Risk for Hereditary CRC Syndromes
The NCCN Genetic/Familial High-Risk Assessment: Colorectal Panel recommends a stepwise approach to risk assessment for hereditary CRC syndromes (see HRS-1, facing page), which should include genetic counseling and patient education by a professional who has expertise and experience in cancer genetics if the assessment identifies factors associated with increased risk. The 2019 update included a section on principles of cancer risk assessment and counseling for individuals with potentially increased risk, which can guide shared decision-making regarding the need for genetic testing (see the complete version of these guidelines at NCCN.org).
Criteria for Evaluation of Polyposis Syndromes
Previously identified polyposis syndromes include FAP, attenuated FAP (AFAP), MAP, and other rare genetic causes of multiple adenomatous polyps. Emerging data suggest that alterations in several other genes, including AXIN2, GREM1, NTHL1, POLE, POLD1, and MSH3, may contribute to some cases of adenomatous polyposis and increase CRC risk.16 If there is no personal or family history of a known pathogenic variant in a colorectal polyposis or cancer gene, the patient’s personal or family history of any of the following should trigger evaluation for a possible polyposis syndrome:
>10 adenomatous polyps in a lifetime
≥2 hamartomatous polyps
≥5 serrated polyps proximal to the sigmoid colon
The panel recommends that individuals meeting any of the above criteria undergo detailed risk assessment and genetic evaluation for potential polyposis syndromes (see HRS-2, page 1036). The presence of >10 adenomas may be linked to FAP, AFAP, MAP, and rare genetic causes of multiple adenomatous polyps; the presence of ≥2 hamartomatous polyps may be associated with PJS, JPS, or Cowden syndrome/PHTS; and the presence of ≥5 serrated polyps proximal to the sigmoid colon may be associated with serrated polyposis syndrome.
Criteria for Evaluation of Lynch Syndrome
Lynch syndrome is one of the most common genetically determined predisposition syndromes, accounting for 2% to 4% of all CRC cases8,18–20 and 2% to 3% of endometrial cancer cases.21,22 Lynch syndrome results from a germline mutation in 1 of 4 DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2).23 Deletions in the EPCAM gene, which lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing, also cause Lynch syndrome.24,25 Individuals with Lynch syndrome are at increased risk for metachronous colon cancer and metachronous or synchronous extracolonic Lynch syndrome–related cancers. In addition to colon cancer, endometrial and ovarian cancers are the most common Lynch syndrome–associated cancers; less common associated cancers include gastric, pancreatic, biliary tract, ureter and renal pelvis, small intestine, and brain (usually glioblastoma), as well as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas, as seen in the Muir-Torre syndrome variant. Data are still emerging on whether Lynch syndrome consistently increases risk for breast and prostate cancer.26–29 Identification of Lynch syndrome offers an opportunity for optimizing therapy and managing future risk for individuals with CRC or endometrial cancer, and for early detection and prevention of cancer for asymptomatic carriers of Lynch syndrome–associated mutations.
Available strategies for identification of Lynch syndrome have evolved over time. Historically, the Amsterdam criteria (I and II) were used to identify individuals who warrant further genetic testing (Table 1). These criteria are very stringent, however, and miss as many as 68% of patients with Lynch syndrome.32 Subsequently, the Bethesda Guidelines were developed to provide a broader clinical criteria for screening33 (see Table 1). One study reported that MLH1 and MSH2 mutations were detected in 65% of patients with MSI of colon cancer tissue who met the Bethesda criteria.34 Another study reported on the accuracy of the revised Bethesda criteria, concluding that the guidelines were useful for identifying patients who should undergo further testing.35 Patients fulfilling the revised Bethesda criteria had an odds ratio for carrying a germline mutation in MLH1 or MSH2 of 33.3 (95% CI, 4.3–250; P=.001). Still, a considerable number of patients with Lynch syndrome fail to meet even the revised Bethesda criteria.20 Indeed, the Amsterdam30,36 and Bethesda31,33 criteria, based on family and personal history of cancer alone, are limited as diagnostic tools for Lynch syndrome due to their relatively low sensitivity.20,32,35,37,38
Revised Clinical/Pathologic Criteria to Identify Lynch Syndrome
To improve detection of individuals with Lynch syndrome, an alternative strategy, referred to as “universal tumor screening,” is available in which all individuals newly diagnosed with CRC have either tumor-based MSI or immunohistochemistry testing for absence of DNA MMR proteins.39–41 This approach provides a sensitivity of 100% (95% CI, 99.3%–100%) and specificity of 93.0% (95% CI, 92.0%–93.7%) for identifying individuals with Lynch syndrome.39 An alternative approach is to test all patients with CRC diagnosed prior to age 70 years plus those diagnosed at older ages who meet the Bethesda criteria.39 This approach gave a sensitivity of 95.1% (95% CI, 89.8%–99.0%) and specificity of 95.5% (95% CI, 94.7%–96.1%). This alternative approach had improved sensitivity compared with the revised Bethesda criteria, and improved specificity compared with universal screening regardless of age. Expanding universal screening to include endometrial cancers has also been shown to improve the detection of Lynch syndrome.42 Cost-effectiveness of universal screening has been established and has been endorsed by the Evaluation of Genomic Applications in Practice and Prevention Working Group at the CDC, the US Multi-Society Task Force on Colorectal Cancer, and ESMO.43–47 With minor qualifications, ASCO also endorses the ESMO guidelines.48 Based on this considerable evidence and consensus to support implementation, the NCCN panel recommends universal tumor testing of individuals with CRC or endometrial cancer as a primary strategy for screening for Lynch syndrome. To complement this approach, the NCCN panel also identifies personal and family history criteria that can help identify individuals at increased risk for Lynch syndrome. Specific strategies recommended by the NCCN panel for identifying individuals with Lynch syndrome, based on either universal screening or personal/family cancer history criteria, are outlined.
Personal and Family History of CRC, Endometrial, or Other Lynch Syndrome–Associated Cancer
The panel recommends universal screening of all patients with CRC or endometrial cancer at any age with tumor showing evidence of MMR deficiency, either by MSI or loss of MMR protein expression, to maximize sensitivity for Lynch syndrome detection and simplify care processes.
Further genetic testing is recommended based on results of MSI and/or immunohistochemistry for DNA MMR proteins, as well as family and personal history of cancer (see LS-1 and LS-A 4 of 5, pages 1038 and 1039). The panel emphasized the importance of implementing a program for universal screening that includes a systematic method to identify those who are eligible for Lynch syndrome screening, a process for providing pretest counseling, standard methods for administering the tests and reporting their results, and a mechanism for follow-up of the results so that appropriate cancer prevention recommendations based on the test results, family history, and personal history are provided. Successful universal Lynch syndrome screening programs may require an interdisciplinary team that includes a cancer genetics expert along with the relevant specialty providers, including those from primary care, gastroenterology, surgery, oncology, pathology, and potentially others.49
Among individuals with a personal history of CRC or endometrial cancer, the panel provided the following additional criteria for the evaluation of Lynch syndrome (see HRS-3, above):
An individual with CRC or endometrial cancer and any of the following:
► Diagnosed at age <50 years
► Another synchronous or metachronous Lynch syndrome–related cancer
► ≥1 first- or second-degree relatives with Lynch syndrome–related cancer diagnosed at age <50 years
► ≥2 first- or second-degree relatives with Lynch syndrome–related cancers, regardless of age
An individual with colorectal tumor with histology typically associated with MSI-high (ie, presence of tumor-infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern)
Among individuals with a family history of CRC, endometrial, or other Lynch syndrome–associated cancer, the following are recommended as criteria for the evaluation of Lynch syndrome (see HRS-3, above):
≥1 first-degree relative with CRC or endometrial cancer diagnosed at age <50 years
≥1 first-degree relative with CRC or endometrial cancer and another synchronous or metachronous Lynch syndrome–related cancer
≥2 first- or second-degree relatives with Lynch syndrome–related cancer, including ≥1 diagnosed at age <50 years
≥3 first- or second-degree relatives with Lynch syndrome–related cancers, regardless of age
In addition to these criteria, the panel has recommended that individuals with increased risk for Lynch syndrome based on clinical prediction models should also receive further evaluation. Statistical models that predict risk for carrying a mutation in a DNA MMR gene are an additional commonly applied clinical approach to identifying individuals at risk for Lynch syndrome.32,50–52 These models provide probabilities of mutations and/or of the development of future cancers based on family and personal history. The PREMM5 model can be applied online at https://premm.dfci.harvard.edu/ and the MMRPredict model is available at hnpccpredict.hgu.mrc.ac.uk/. MMRpro is available for free download at www4.utsouthwestern.edu/breasthealth/cagene/. Using a cutoff of 5%, one study suggests that both PREMM5 and MMRPredict are effective at predicting an individual’s risk of carrying MMR mutations, but they may be less effective at identifying individuals with PMS2 mutations.53 A study evaluating the performance of the PREMM5 prediction model relative to the previous model, PREMM1,2,6, found that PREMM5 quantified the risk to an individual of carrying MMR gene mutations at a threshold of ≥2.5%, suggesting that testing can be performed based on this score threshold.54 It is worth noting that at a threshold of ≥2.5%, there is an increase in sensitivity but a decrease in specificity. Furthermore, performance of the model in more usual care settings (eg, in consecutive primary care patients) has not been established, causing uncertainty as to whether sensitivity and particularly specificity would be similar to those observed in higher-risk populations. Regarding predictive models, the current criteria recommended by the panel for the evaluation of Lynch syndrome include (see HRS-3, page 1037) an individual with a ≥5% risk of having an MMR gene pathogenic variant based on predictive models (PREMM5,54 MMRpro, MMRPredict).
The panel notes that it is reasonable for testing to be conducted based on a PREMM5 score of ≥2.5% and clinical judgment. Individuals not meeting any of the outlined criteria may be considered to have average or moderate risk for CRC, based on family history of CRC or advanced adenomas in first-degree relatives. Increased risk warranting genetic evaluation may be indicated by, but not restricted to, personal or family history of congenital hypertrophy of the retinal pigment epithelium, osteomas, supernumerary teeth, desmoid tumor, cribriform variant of papillary thyroid cancer, brain cancer (typically medulloblastoma), and hepatoblastoma.
Conclusions and Future Considerations
Comprehensive hereditary assessment is needed to identify individuals who have pathogenic variants that contribute to increased CRC risk.7,55 The panel recommends a stepwise approach, which includes genetic counseling, using the outlined criteria based on the individual’s personal and family history. During the 2019 panel review, members discussed a number of important updates to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, including clarifying the initial approach to assessing hereditary CRC syndromes, the approach to identifying individuals with rare genetic causes of multiple adenomatous polyps, and the criteria for the evaluation of Lynch syndrome.
The panel recognized several future opportunities for research that might help inform and optimize future recommendations. Although the goal of universal tumor screening is to identify individuals at risk for Lynch syndrome, implementation of this practice has been slow, and risk assessment and referral for hereditary CRC syndromes is not widely used55–58; strategies to improve implementation are needed. It is also unclear whether all patients with a personal history of cancer should be offered multigene testing to screen for both Lynch syndrome and other potential hereditary causes. Research in this area is relevant now that the cost of multigene testing has become competitive with the cost of tumor-based testing (eg, with immunohistochemistry), because germline testing with blood or saliva may be convenient relative to organizing tumor-based testing, and because broader multigene testing might allow for increased opportunities for personalized prevention.59,60
Another area ripe for further development is whether less restrictive criteria should be used to refer patients for testing for Lynch syndrome and other causes of hereditary CRC risk. For example, for patients with a family history of CRC or endometrial cancer, the panel currently recommends evaluation for Lynch syndrome based on age of onset and number of cancers among family members. Less restrictive criteria (such as having any family history of CRC) might improve identification of pathogenic mutation carriers but would have broad public health implications, because up to 10% of the population has a family history of CRC. Similarly, a less restrictive threshold for recommending evaluation for Lynch syndrome based on clinical prediction models could be recommended, but the impact on the general population in terms of number who would have a score triggering further evaluation requires further study. The panel also recognized a need for more evidence to inform the threshold for recommending genetic testing for adenomatous polyposis syndromes (eg cumulative >10 vs >20 lifetime adenomas), and a need for more observational research on the natural history of cancer risk among carriers of more recently identified CRC risk genes.
Ultimately, future research has great potential to further clarify and optimize the best strategies for identifying individuals at increased hereditary risk for CRC, and the best approaches to cancer risk reduction for those with identified pathogenic variants and CRC syndromes.
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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.
The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2019. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
