PURPOSE: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. METHODS: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. RESULTS: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. CONCLUSION: Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

Aalborg University Hospital Aalborg Denmark

Athens Medical Center

Azienda Ospedaliera di Cosenza Cosenza

Barretos Cancer Hospital Barretos São Paulo Brazil

Catalan Institute of Oncology and CIBERONC Barcelona

Charles University Prague Czech Republic

City of Hope Duarte CA

Copenhagen University Hospital Rigshospitalet Copenhagen

Cyprus Institute of Neurology and Genetics Nicosia Cyprus

Dana Farber Cancer Institute Boston MA

Fondazione IRCCS Istituto Nazionale dei Tumori Milan

Ghent University Hospital Ghent Belgium

Hong Kong Sanatorium and Hospital Hong Kong Special Administrative Region People's Republic of China

Hospital Clinico San Carlos and Centro de Investigación Biomédica en Red de Cáncer Madrid

IEO European Institute of Oncology IRCCS

Institute of Biomolecular Chemistry National Research Council Sassari

Institute of Cancer Research and Royal Marsden National Health Service Foundation Trust London

Instituto Português de Oncologia do Porto Francisco Gentil Porto Portugal

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS Meldola

Keio University School of Medicine Tokyo Japan

King Edward Memorial Hospital Perth Western Australia

Kuwait University and Genatak Center for Genomic Medicine Safat Kuwait

Leiden University Medical Centre Leiden the Netherlands

Lund University Lund Sweden

Maastricht University Medical Center Maastricht

Mayo Clinic Rochester MN

Memorial Sloan Kettering Cancer Center New York NY

Moffitt Cancer Center Tampa FL

National Centre for Scientific Research Demokritos Athens Greece

Normandy University Cancer Center F Baclesse and Unicancer Genetic Group Caen France

Odense University Hospital Odense

Ohio State University Columbus OH

Ospedale Cremona Azienda Socio Sanitaria Territoriale di Cremona Cremona

Ospedale di Circolo ASST dei Sette Laghi Varese

Ospedale Policlinico San Martino IRCCS per l'Oncologia Genoa

Prince of Wales Hospital and Community Health Randwick New South Wales

QIMR Berghofer Medical Research Institute Brisbane Queensland Australia

Radboud University Medical Center Nijmegen

Santa Chiara University Hospital Pisa

Sapienza University of Rome and Sant'Andrea Hospital Rome

The University of Chicago Center for Clinical Cancer Genetics Chicago IL

Toma Advanced Biomedical Assays Busto Arsizio

Universidad de Santiago de Compostela Santiago de Compostela Spain

Université Paris Descartes and Unicancer Genetic Group Paris

University Hospital Cologne and German Consortium of Hereditary Breast and Ovarian Cancer Cologne Germany

University Hospital of Parma Parma

University of Brescia Brescia

University of Buenos Aires Buenos Aires Argentina

University of Florence Florence

University of Modena and Reggio Emilia Modena

University of Pennsylvania Philadelphia PA

University of Rome Tor Vergata

University of Southampton Southampton

University of Utah School of Medicine Salt Lake City UT

Vall d'Hebron Institute of Oncology and University Hospital of Vall d'Hebron Barcelona

Veneto Institute of Oncology IOV IRCCS Padua Italy

Women's and Children's NHS Foundation Trust Birmingham United Kingdom

Zobrazit více v PubMed

Walsh T, Lee MK, Casadei S, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA. 2010;107:12629–12633. PubMed PMC

Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol. 2014;32:2001–2009. PubMed PMC

Kurian AW, Kingham KE, Ford JM. Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. Curr Opin Obstet Gynecol. 2015;27:23–33. PubMed

Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33:304–311. PubMed PMC

LaDuca H, Stuenkel AJ, Dolinsky JS, et al. Utilization of multigene panels in hereditary cancer predisposition testing: Analysis of more than 2,000 patients. Genet Med. 2014;16:830–837. PubMed PMC

Maxwell KN, Hart SN, Vijai J, et al. Evaluation of ACMG-guideline-based variant classification of cancer susceptibility and non-cancer-associated genes in families affected by breast cancer. Am J Hum Genet. 2016;98:801–817. PubMed PMC

Domchek SM, Bradbury A, Garber JE, et al. Multiplex genetic testing for cancer susceptibility: Out on the high wire without a net? J Clin Oncol. 2013;31:1267–1270. PubMed

Easton DF, Pharoah PD, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med. 2015;372:2243–2257. PubMed PMC

Tung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13:581–588. PubMed PMC

Dreijerink KM, Goudet P, Burgess JR, et al. Breast-cancer predisposition in multiple endocrine neoplasia type 1. N Engl J Med. 2014;371:583–584. PubMed PMC

Vereniging Klinische Genetica Nederland: Erfelijke tumoren. http://www.vkgn.org/vakinformatie/richtlijnen-en-protocollen/erfelijke-tumoren/

Plon SE, Eccles DM, Easton D, et al. Sequence variant classification and reporting: Recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat. 2008;29:1282–1291. PubMed PMC

Richards S, Aziz N, Bale S, et al. ACMG Laboratory Quality Assurance Committee: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–424. PubMed PMC

Landrum MJ, Lee JM, Benson M, et al. ClinVar: Public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 2016;44:D862–D868. PubMed PMC

National Human Genome Research Institute Breast cancer information core: An open access on-line breast cancer mutation. https://research.nhgri.nih.gov/bic/

Fokkema IF, Taschner PE, Schaafsma GC, et al. LOVD v.2.0: The next generation in gene variant databases. Hum Mutat. 2011;32:557–563. PubMed

Daly MB, Pilarski R, Berry M, et al. NCCN guidelines insights: Genetic/familial high-risk assessment—Breast and ovarian, version 2.2017. J Natl Compr Canc Netw. 2017;15:9–20. PubMed

Janatová M, Borecká M, Soukupová J, et al. PALB2 as another candidate gene for genetic testing in patients with hereditary breast cancer in Czech Republic [in Czech] Klin Onkol. 2016;29(suppl 1):S31–S34. PubMed

Cancer Institute NSW, eviQ: Cancer genetics: Risk management. https://www.eviq.org.au/cancer-genetics/risk-management.

Unicancer: Le Groupe génétique et cancer. http://www.unicancer.fr/recherche/les-groupes-recherche/groupe-genetique-et-cancer-ggc.

Llort G, Chirivella I, Morales R, et al. SEOM clinical guidelines in hereditary breast and ovarian cancer. Clin Transl Oncol. 2015;17:956–961. PubMed PMC

Robays J, Stordeur S, Hulstaert F, et al: Oncogenetic testing and follow-up for women with hereditary breast/ovarian cancer, Li Fraumeni syndrome and Cowden syndrome. https://kce.fgov.be/sites/default/files/page_documents/KCE_236Cs_Oncogenetic_testing_Abstract.pdf.

Robays J, Stordeur S, Hulstaert F, et al: Oncogenetic testing, diagnosis and follow-up in Birt-Hogg-Dubé syndrome, familial atypical multiple mole melanoma syndrome and neurofibromatosis 1 and 2. https://kce.fgov.be/sites/default/files/atoms/files/KCE_243_oncogenetic_testing_Neurofibromatosis_Report_0.pdf.

National Institute for Health and Care Excellence: Familial breast cancer: Classification, care and managing breast cancer and related risks in people with a family history of breast cancer. https://www.nice.org.uk/guidance/cg164/chapter/recommendations#surveillance-and-strategies-for-early-detection-of-breast-cancer. PubMed

German Consortium of Hereditary Breast and Ovarian Cancer: Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms. http://www.awmf.org/leitlinien/detail/ll/032-045OL.html.

Rhiem K, Schmutzler RK. Risk-adapted surveillance: Focus on familial breast and ovarian cancer [in German] Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2014;57:307–311. PubMed

Schmutzler RK. Konsensusempfehlung des Deutschen Konsortiums Familiärer Brust- und Eierstockkrebs zum Umgang mit Ergebnissen der Multigenanalyse. Geburtshilfe Frauenheilkd. 2017;77:733–739.

Lincoln SE, Kobayashi Y, Anderson MJ, et al. A systematic comparison of traditional and multigene panel testing for hereditary breast and ovarian cancer genes in more than 1000 patients. J Mol Diagn. 2015;17:533–544. PubMed

Kurian AW, Ford JM. Multigene panel testing in oncology practice: How should we respond? JAMA Oncol. 2015;1:277–278. PubMed

Castéra L, Krieger S, Rousselin A, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014;22:1305–1313. PubMed PMC

Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3:1190–1196. PubMed PMC

Kurian AW, Hughes E, Handorf EA, et al. Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precis Oncol PubMed

Antoniou AC, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497–506. PubMed PMC

Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18:400–407. PubMed PMC

Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12:3209–3215. PubMed

Pharoah PD, Guilford P, Caldas C. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001;121:1348–1353. PubMed

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk