nccn guidelines genetic testing
Multigene panels to evaluate hereditary cancer risk: reckless or relevant? Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. N Engl J Med 2014;371:2488–2498. Given the considerable rate of predisposing mutations in patients with pancreatic cancer, as well as the fact that typical clinical factors (eg, young age of onset, family history of cancer) are poorly predictive for identifying mutation carriers, universal genetic testing for these individuals is warranted (see CRIT-3, page 384). J Natl Cancer Inst 2018;110:714–725. This activity is supported by educational grants from AstraZeneca; Celgene Corporation; Coherus BioSciences; Genentech, a member of the Roche Group; and TESARO, a GSK Company. J Clin Oncol 2009;27:433–438. Genetic counselors can be a good referral source, should there be a need for genetic testing. Hong YC, Liu HM, Chen PS, . For individuals in whom screening shows worrisome abnormalities, shorter screening intervals may be indicated. Zhen DB, Rabe KG, Gallinger S, . This activity is supported by a medical education grant from Exelixis, Inc. Accessed February 28, 2020. PALB2 mutations in European familial pancreatic cancer families. Tran SD, Pillemer SR, Dutra A, . CA Cancer J Clin 2012;62:118–128. Vadaparampil ST, Scherr CL, Cragun D, . Individuals Who Provided Content Development and/or Authorship Assistance: Testing Criteria for High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes, Evaluating the Source of Genetic Testing Information, NCCN CATEGORIES OF EVIDENCE AND CONSENSUS, NCCN.org/disclosures/guidelinepanellisting.aspx, https://www.eeoc.gov/laws/statutes/gina.cfm. The most recent Genetic/Familial High-Risk Assessment: Breast and Ovarian NCCN guidelines has a new section on multi-gene genetic testing. JAMA 2018;319:2401–2409. Myra J. Wick, MD, PhD, Panel Member, has disclosed that she has no relevant financial relationships. Weitzel JN, Chao EC, Nehoray B, . Differentiation of human bone marrow-derived cells into buccal epithelial cells in vivo: a molecular analytical study. ... along with genetic counseling. Therefore, germline testing for PRSS1, SPINK1, and other genes associated with pancreatitis is generally not recommended unless the individual’s personal or family history is suggestive of hereditary pancreatitis.85 Pancreas cancer screening is recommended in individuals harboring one of these variants only in the presence of a clinical phenotype consistent with hereditary pancreatitis. © 2021 MJH Life Sciences and Contemporary OB/GYN. Litton JK, Rugo HS, Ettl J, . Mutations in different genes can cause the same type of cancer. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Chaffee KG, Oberg AL, McWilliams RR, . The prevalence of BRCA2 mutations in familial pancreatic cancer. Jones S, Hruban RH, Kamiyama M, . Some NCCN treatment guidelines for BRCA-related cancers now recommend treatment with PARP inhibitors for patients with germline or somatic BRCA1/2 mutations, because PARP inhibitors have been shown to be active in these patients. Cancer Res 2011;71:2222–2229. There are 2 additional revisions of note to the testing criteria for high-penetrance genes associated with breast and/or ovarian cancer susceptibility. Canto MI, Almario JA, Schulick RD, . Genet Med 2018;20:1515–1521. Cancer 2015;121:4382–4388. Projecting the supply and demand for certified genetic counselors: a workforce study. Hereditary pancreatitis for the endoscopist. Hu C, Hart SN, Polley EC, . Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. Badalato L, Kalokairinou L, Borry P. Third party interpretation of raw genetic data: an ethical exploration. Swisher EM, Lin KK, Oza AM, . The updated NCCN "Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic" are available from the NCCN website. Science 2009;324:217. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. There is also the potential for impact on mortality rates, although long-term studies are needed in this area. Renaux-Petel M, Charbonnier F, Théry JC, . Simard EP, Ward EM, Siegel R, . However, the panel raised concerns about the demand on genetic counseling resources, the preparedness of healthcare professionals to provide cancer genetic counseling and management, and participants’ fears and concerns about testing, including those regarding privacy, stigmatization, and the need for appropriate medical and/or surgical management in patients and family members found to have a founder mutation. Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women, Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing, Next-generation sequencing for inherited breast cancer risk: counseling through the complexity, Increased reach of genetic cancer risk assessment as a tool for precision management of hereditary breast cancer, Counselling framework for moderate-penetrance cancer-susceptibility mutations, Routine use of gene panel testing in hereditary breast cancer should be performed with caution, Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory, Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients, The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience, Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel, Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared with limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer, Age-related clonal hematopoiesis associated with adverse outcomes, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence, Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors, Genetic Information Nondiscrimination Act of 2008. . 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. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. If this is not possible, buccal cells may be considered as an alternative source for DNA15; however, one study reported that over time, buccal epithelial cells are replaced by donor-derived cells in allogeneic HSCT recipients.16 Therefore, genetic testing using buccal swab samples may be limited given this known risk of donor DNA contamination. Multi-gene panel testing is when someone undergoes genetic testing for more than one or two genes. Because some pathogenic or likely pathogenic variants are associated with rare autosomal recessive conditions (eg, Fanconi anemia or constitutional mismatch repair deficiency), testing the partner of a carrier of a pathogenic or likely pathogenic variant may be considered to inform reproductive decision-making.51. Any family members who received genetic testing should also be noted, as well as test results. Manchanda R, Patel S, Gordeev VS, . Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. J Med Genet 2018;55:173–180. N Engl J Med 2018;379:753–763. Couch FJ, Johnson MR, Rabe KG, . The above table presents the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing. 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. Therefore, larger long-term studies are needed to further determine the risks and benefits of routine pancreas screening in high-risk individuals, as well as the threshold for surgical intervention and biopsy.80, With the exception of CDKN2A and STK11, pancreas screening in individuals who have a pathogenic or likely pathogenic variant associated with increased risk of exocrine pancreatic cancer is not recommended unless there is additional family history of pancreatic cancer (at least 1 first- or second-degree relative).81 If family history criteria are met, then pancreas screening may be considered at age 50 years, or 10 years younger than the earliest pancreatic cancer diagnosis in the family, whichever is earlier.81 For carriers of a CDKN2A or STK11 pathogenic or likely pathogenic variant, no additional family history is needed to warrant screening. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Somatic TP53 variants frequently confound germ-line testing results. Major dilemmas regarding multigene testing are that there are limited data and a lack of clear guidelines regarding degree of cancer risk associated with some of the genes assessed and how to communicate and manage risk among carriers of these genes.33–37 This issue is compounded by the low incidence rates of hereditary disease, leading to difficulty in conducting adequately powered studies.33 Multigene tests often include low- to moderate-penetrance genes, for which there are few available data regarding degree of cancer risk and guidelines for risk management.29,34,38–40 Furthermore, it is possible that the risks associated with these genes may not entirely be due to that gene only, but may be influenced by gene/gene or gene/environment interactions. Therefore, the specific laboratory and multigene test should be chosen carefully.29 In addition, pathogenic or likely pathogenic variants identified for more than one gene add complexity that may lead to difficulty in making risk management recommendations.32 A management plan based on genetic test results should only be developed for identified pathogenic or likely pathogenic variants that are clinically actionable. Incidental germline findings discovered through other sources (eg, participation in a research study) should be reviewed by a genetics professional.25 Confirmatory testing in these cases may be recommended, especially if the reporting laboratory is not appropriately certified. Lancet Oncol 2019;20:636–648. Hall MJ, Forman AD, Pilarski R, . Pre-test genetic counseling services for hereditary breast and ovarian cancer delivered by non-genetics professionals in the state of Florida. The criteria have been reorganized into 3 sections: (1) testing is clinically indicated, (2) testing may be considered, and (3) low probability of testing results having documented clinical utility. van Marcke C, De Leener A, Berlière M, . Br J Cancer 2013;109:777–779. Kurian AW, Hare EE, Mills MA, . Vasen H, Ibrahim I, Ponce CG, . Tandy-Connor S, Guiltinan J, Krempely K, . Genetic testing results will impact medical management AND Individual meets genetic testing criteria, NCCN Guidelines® or other published clinical diagnostic criteria, for at least one hereditary cancer syndrome (e.g. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Jaiswal S, Fontanillas P, Flannick J, . American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. Susan D. Darlow, PhD, Oncology Scientist/Medical Writer, NCCN, has disclosed that she has no relevant financial relationships. Lesions detected through routine screening may not always require resection (eg, sporadic branch duct intraductal papillary mucinous neoplasms). In that case, the genetic testing laboratory can limit the search for pathogenic or likely pathogenic variants in additional family members to the same location in the gene. Fibroblasts are also indicated when testing individuals with active or recent hematologic malignancies.17, A counseling dilemma is posed by the finding of a variant of unknown significance (VUS), a genetic alteration that may actually represent a benign polymorphism unrelated to an increased cancer risk or may indicate an increased cancer risk. Eccles DM, Mitchell G, Monteiro AN, . NCCN guidelines help providers identify appropriate candidates for counseling and testing. Humphris JL, Johns AL, Simpson SH, . Dr. Lockwood, Editor-in-Chief, is Dean of the Morsani College of Medicine and Senior Vice President of USF Health, University of South Florida, Tampa. Moore KN, Secord AA, Geller MA, . In an interview with Targeted Oncology during the 2019 Prostate Cancer Consensus Conference, James L. Mohler, MD, explained the reasons for changes to the NCCN guidelines on genetic testing and counseling in prostate cancer. Posttest counseling includes disclosure of results, a discussion of the associated medical risks, an assessment of the impact of the results on the individual’s emotional state, a discussion of the impact of the results on the medical management of the individual, and determination of how and where the patient will be screened for cancer risk.14 Counseling should include information on any available resources, such as disease-specific support groups, high-risk clinics, advocacy groups, and research studies.50 Probands should be advised regarding possible inherited cancer risk to relatives and available options for risk assessment and management. Addressing the Cervical Cancer Screening Disparities Gap, Advances in the Testing for Preterm Premature Rupture of Membrane, Cervical Cancer Screening: Protecting and Improving Health Outcomes of Women, Combination Regimen of Estradiol and Progesterone, Enhanced Recovery for Cesarean Deliveries in the United States: Perspectives From the Front Lines – Part 1. N Engl J Med 2017;377:523–533. Carriers of a pathogenic or likely pathogenic variant should be encouraged to participate in clinical trials or genetic registries. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry. Ann Oncol 2015;26:2057–2065. This activity is supported in part by an educational grant from Bayer Healthcare Pharmaceuticals. Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Rebours V, Lévy P, Ruszniewski P. An overview of hereditary pancreatitis. Genetic testing for cancer susceptibility. Testing should be considered in individuals for whom there is a personal or family history suggesting genetic cancer susceptibility and for whom results will aid in risk management and treatment. Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. Genetic testing in PCa patients may inform prognosis, treatment options, and have implications for family counseling. If a patient meets criteria for germline testing for a given gene, then confirmatory germline testing should be considered despite tumor profiling results. Gut 2020;69:7–17. Vail PJ, Morris B, van Kan A, . Genetic predisposition accounts for 5–10% of all breast cancers (BC) diagnosed. Robert Pilarski, MS, LGC, Panel Vice Chair, has disclosed that he has no relevant financial relationships. Individuals who have received allogeneic hematopoietic stem cell transplantation (HSCT) should not have molecular genetic testing performed on blood samples, because the blood cells would represent donor-derived DNA. Your credit cannot be reported without this information. Cancer Res 2004;64:2634–2638. Unaffected patients should be informed that testing an affected relative first, whenever possible, is more informative than undergoing testing themselves. Multigene panels to evaluate hereditary cancer risk: reckless or relevant? Robson ME, Bradbury AR, Arun B, . Clin Genet 2015;87:473–477. It’s important for all pancreatic cancer patients to explore genetic testing with their healthcare teams. A pragmatic testing-eligibility framework for population mutation screening: the example of BRCA1/2. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. Kurian AW, Ward KC, Hamilton AS, . The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) provide the healthcare community with current guidelines and best practices for the treatment and management of various types of cancer. Yurgelun MB, Chittenden AB, Morales-Oyarvide V, . The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 1.2020 contains several updates—including new and expanded sections on risk assessment and management related to three major cancer types—while also maintaining a more conservative approach toward testing practices where the evidence is still … J Genet Couns 2018;27:16–20. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. The guidelines have also strengthened recommendations around somatic (tumor tissue) testing. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. Best AF, Tucker MA, Frone MN, . These companies do not provide comprehensive genetic analysis that includes gross deletion or duplication analysis. Surg Clin North Am 2008;88:705–721. Testing typically used by companies providing ancestry information directly to consumers is microarray-based single-nucleotide polymorphism (SNP) testing that has not been validated for clinical use. N Engl J Med 2014;371:2477–2487. Included genes may change with emerging clinical data. Cancer Epidemiol Biomarkers Prev 2019;28:293–302. Thats according to new guidelines established by the National Comprehensive Cancer Network (NCCN), a group of 27 expert cancer centers throughout the U.S. that provides recommendations called Clinical Practice Guidelines for the treatment of some 30 different cancer types. Tung N, Battelli C, Allen B, . Almost 25% of women with breast cancer have a family history of the disease and, those who do have a higher risk of developing cancer. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. Conflicting interpretation of genetic variants and cancer risk by commercial laboratories as assessed by the prospective registry of multiplex testing. Multigene testing may detect pathogenic or likely pathogenic variants not found in single-gene testing.26–28 Multigene testing may be most useful when more than one gene can explain an inherited cancer syndrome. Uptake, results, and outcomes of germline multiple-gene sequencing after diagnosis of breast cancer. Genet Med 2019;21:213–223. Roberts NJ, Jiao Y, Yu J, . Lucas AL, Shakya R, Lipsyc MD, . Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. All rights reserved. Robson M, Im SA, Senkus E, . ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. Accessed February 28, 2020. Counselors should recommend genetic counseling and testing for at-risk relatives. Gastroenterology 2015;148:556–564. J Genet Couns 2013;22:155–163. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Klein AP, Brune KA, Petersen GM, . Walsh T, Casadei S, Coats KH, . Third-party services are available to assist patients with interpreting their raw data, but these services are not government-regulated. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. Dig Liver Dis 2012;44:8–15. March 22, 2019. J Clin Oncol 2014;32:2001–2009. A comparison of the detection of BRCA mutation carriers through the provision of Jewish population-based genetic testing compared with clinic-based genetic testing. These patients should be considered for referral to research studies that aim to define the functional impact of the gene variant, such as variant reclassification programs through clinical laboratories or registries. Multigene panel testing detects equal rates of pathogenic BRCA1/2 mutations and has a higher diagnostic yield compared with limited BRCA1/2 analysis alone in patients at risk for hereditary breast cancer. Patel MR, Eppolito AL, Willingham FF. Bombard Y, Bach PB, Offit K. Translating genomics in cancer care. Blazer KR, Slavin T, Weitzel JN. Tumor profiling can be considered complementary to germline testing. Mary A. Dwyer, MS, CGC, Director, Guidelines Operations, NCCN, has disclosed that she has no relevant financial relationships. If you have any questions, please e-mail education@nccn.org. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. For most families in whom the presence of a pathogenic or likely pathogenic variant is unknown, it is best to consider testing an affected family member first, especially a family member with early-onset disease, bilateral disease, or multiple primaries, because that individual has the highest likelihood of a positive test result. Concerns about underutilization of genetic testing have spurred interest in broader peri-diagnostic testing. Updates include an expansion of genetic testing criteria to take into account other genes besides BRCA1/2 that are associated with an increased risk of breast and/or ovarian cancer, streamlined organization of these testing criteria, revisions to testing criteria related to Ashkenazi Jewish ancestry, genetic testing for the purpose of systemic therapy decision-making, an increased focus on phenotypically directed multigene panel tests, and the addition of information regarding pancreas screening and genes with associated pancreatic cancer. First, Ashkenazi Jewish ancestry without a personal cancer history is now included as a scenario for which genetic testing may be considered. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. Genovese G, Kähler AK, Handsaker RE, . UAN: JA4008196-0000-20-005-H01-P. All clinicians completing this activity will be issued a certificate of participation. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Gene panel testing for inherited cancer risk. Deleterious germline mutations are a risk factor for neoplastic progression among high-risk individuals undergoing pancreatic surveillance. Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. J Natl Cancer Inst 2003;95:1548–1551. ATM mutations in patients with hereditary pancreatic cancer. Cragun D, Camperlengo L, Robinson E, . Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour. The testing criteria listed are for breast and/or ovarian cancer susceptibility genes with strong or moderate evidence of actionability (eg, BRCA1/2, CDH1, and PALB2; testing criteria for Li-Fraumeni syndrome and Cowden syndrome continue to be presented in their own dedicated sections). Reports regarding germline findings that may impact medical management should come from laboratories that are certified by the College of American Pathologists (CAP) and CLIA, with some US states (eg, New York) having additional reporting requirements. JCO Precis Oncol 2017;1:1–10. N Engl J Med 2019;381:317–327. Kari B. Wisinski, MD, Panel Member, has disclosed that she has received honoraria from Genomic Health, Inc., and grant/research support from Pfizer Inc. Matthew B. Yurgelun, MD, Panel Member, has disclosed that he has received consulting fees from and is a scientific advisor for Janssen. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. 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/87059; and (3) view/print certificate. Clin Cancer Res 2013;19:3396–3403. J Genet Couns 2007;16:241–260. Upon completion of this activity, participants will be able to: 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. 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. Rainville IR, Rana HQ. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. Concerns about underutilization of genetic testing have spurred interest in broader peri-diagnostic testing. Almost 25% of women with breast cancer have a family history of the disease, and women with an affected first-degree relative have a 1.75-fold higher risk of developing cancer.1 That risk increases to 2.5-fold with two or more affected first-degree relatives. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.