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Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (And Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group

Sarah M Nielsen  1 Diana M Eccles  2 Iris L Romero  1 Fahd Al-Mulla  3 Judith Balmaña  4 Michela Biancolella  5 Rien Bslok  6 Maria Adelaide Caligo  7 Mariarosaria Calvello  8 Gabriele Lorenzo Capone  9 Pietro Cavalli  10 T L Chris Chan  11 Kathleen B M Claes  12 Laura Cortesi  13 Fergus J Couch  14 Miguel de la Hoya  15 Simona De Toffol  16 Orland Diez  4 Susan M Domchek  17 Ros Eeles  18 Anna Efremidis  19 Florentia Fostira  20 David Goldgar  21 Andreas Hadjisavvas  22 Thomas V O Hansen  23 Akira Hirasawa  24 Claude Houdayer  25 Petra Kleiblova  26 Sophie Krieger  27 Conxi Lázaro  28 Maria Loizidou  22 Siranoush Manoukian  29 Arjen R Mensenkamp  30 Setareh Moghadasi  31 Alvaro N Monteiro  32 Luigi Mori  33 April Morrow  34 Nadia Naldi  35 Henriette R Nielsen  36 Olufunmilayo I Olopade  1 Nicholas S Pachter  37 Edenir I Palmero  38 Inge S Pedersen  39 Maria Piane  40 Marianna Puzzo  41 Mark Robson  42 Maria Rossing  23 Maria Christina Sini  43 Angela Solano  44 Jana Soukupova  26 Gianluca Tedaldi  45 Manuel Teixeira  46 Mads Thomassen  36 Maria Grazia Tibiletti  47 Amanda Toland  48 Therese Törngren  49 Erica Vaccari  50 Liliana Varesco  51 Ana Vega  52 Yvonne Wallis  53 Barbara Wappenschmidt  54 Jeffrey Weitzel  55 Amanda B Spurdle  56 Arcangela De Nicolo  57 Encarna B Gómez-García  6
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Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (And Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group

Sarah M Nielsen et al. JCO Precis Oncol.

Abstract

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.

Figures

Fig A1.
Fig A1.
Opinions on clinical utility of non- BRCA1/2 breast (BC) and ovarian cancer (OC) risk genes. Participants who agree with the following statements (No. shown above each bar): (A) every patient with BC (or OC) who meets criteria for (BRCA1/2) genetic testing should be tested for this gene, and (B) cancer risks associated with this gene are high enough to affect clinical management. MRE11A, NBN, and RAD50 are candidate BC risk genes. These two questions were asked at a different time (during Evidence-Based Network for the Interpretation of Germline Mutant Alleles meeting in Cyprus in January 2017 compared with survey questionnaire). Therefore, only 23 centers answered these questions.
Fig A2.
Fig A2.
Testing setting: clinical versus research. Absolute No. of centers testing given gene through each method is shown above each bar. Only responses from those centers that reported they tested the gene were counted in the total, and the No. of centers that responded varied by gene (range, 14 to 37 centers). The centers that tested each gene through research only were compared with the proportion of centers that tested the gene only clinically and proportion of those that tested the gene for both clinical and research purposes. ENIGMA, Evidence-Based Network for the Interpretation of Germline Mutant Alleles.
Fig A3.
Fig A3.
Genes tested regularly by Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) centers in the United States (ENIGMA-US) versus other ENIGMA centers (ENIGMA-other) versus Italian and United Kingdom non-ENIGMA centers. Absolute No. of centers testing given gene regularly (defined as ordered for > 50% of patients eligible for genetic testing, by criteria that we recognize may differ by center/country) is shown above each bar. Of the seven total ENIGMA-US centers, the No. of centers that answered this question was four to seven, depending on the gene; of the 31 ENIGMA-other centers, a range of 22 to 30 centers answered this question. All 14 non-ENIGMA Italian centers answered this question; all nine non-ENIGMA United Kingdom centers answered this question. The United Kingdom version of the survey did not give “test regularly” as an option.
Fig A4.
Fig A4.
Genes tested through panel testing by Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) centers in the United States (ENIGMA-US) versus other ENIGMA centers (ENIGMA-other). Absolute No. of centers testing given gene through panel testing is shown above each bar. Only responses from those centers that reported they tested the gene were counted in the total, and the No. of centers that responded varied by gene (of the seven total ENIGMA-US centers, four to seven centers responded depending on the gene; of the remaining 31 ENIGMA-other centers, a range of 10 to 30 centers responded).
Fig 1.
Fig 1.
Survey distribution flow and global representation of participating centers. CWG, Clinical Working Group; ENIGMA, Evidence-Based Network for the Interpretation of Germline Mutant Alleles; NHS, National Health Service. (*) Via SurveyMonkey.
Fig 2.
Fig 2.
Frequency of testing. Absolute No. of centers testing given gene is shown above each bar. In total, there were 38 participating centers; however, the No. of centers that responded to the question varied by gene (range, 29 to 38 centers).Regularly was defined as ordered for 50% of eligible patients (ie, those who qualified for genetic testing, by criteria that we recognize may differ by center/country). ENIGMA, Evidence-Based Network for the Interpretation of Germline Mutant Alleles.
Fig 3.
Fig 3.
Clinical testing methods. Absolute No. of centers testing given gene through each method is shown above each bar. Only responses from those centers that reported they tested each gene were counted in the total, and the No. of centers that responded varied by gene (range, 14 to 38 centers). The three methods are not mutually exclusive; notably, the center in Kuwait performs whole-genome sequencing for all cases, which is not represented in the figure. ENIGMA, Evidence-Based Network for the Interpretation of Germline Mutant Alleles.
Fig 4.
Fig 4.
Reporting practices of (likely) pathogenic variants and variants of unknown significance (VUS; to patients). Absolute No. of centers reporting variants to patients is shown within each bar. Only responses from those centers that reported they clinically tested the given gene were counted in the total, and the No. of centers that responded varied by gene (range, 12 to 36 centers responding about reporting pathogenic variants; range, four to 20 centers responding about reporting VUS). ENIGMA, Evidence-Based Network for the Interpretation of Germline Mutant Alleles.
Fig 5.
Fig 5.
Sources of the management guidelines used by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) centers. Absolute No. of centers reporting existing management guidelines for each gene is shown within each bar. Only responses from centers that reported they performed clinical testing and reported (likely) pathogenic variants to patients were counted in the total, and the No. of centers that responded varied by gene (range, 10 to 31 centers). If management guidelines were available, centers were asked to specify the source of such guidelines (local, national, or international, such as National Comprehensive Cancer Network or National Institute for Health and Care Excellence).

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