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.
INTRODUCTION
Massively parallel sequencing technologies have transformed testing practices for hereditary breast cancer (BC) and breast and ovarian cancer (BOC) predisposition. Currently, several multigene panels are available that include from < 10 to > 100 known or candidate cancer susceptibility genes, which are tested for diagnostic or research purposes. Some panels are targeted at diverse cancers (pan-cancer panels), whereas others target specific cancers only (disease-specific panels).
The ability to run multigene panels at affordable prices has expanded the eligibility criteria and increased the demand for testing.1-5 However, the rapid pace at which candidate risk genes are moving from research based to clinical diagnostic testing has its drawbacks. Consequently, diagnostic laboratories are making inferences and clinicians are making decisions based on limited data. The rate of variants of uncertain significance (VUS) has increased proportionally to the extent of the sequenced genome.5-7 Moreover, many genes currently included on multigene panels have imprecise cancer risk estimates, and there is no consensus on when to test for a given gene or how to manage a reported (likely) pathogenic variant.8,9
The aim of this study was to describe a snapshot of the landscape of international genetic testing practices and risk management approaches for BC and BOC susceptibility genes beyond BRCA1 and BRCA2. A survey was conducted among members of the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), an international consortium focused on determining the clinical significance of variants in BRCA1, BRCA2, and other (ascertained or suspected) BC and BOC susceptibility genes, providing expertise to global database and classification initiatives, and exploring optimal avenues of communication of such information at the provider and patient levels. Additional information was collected via country networks in the United Kingdom and in Italy, from centers that were not directly involved in ENIGMA research at the time of study initiation.
In total, respondents represented cancer genetic experts from 61 centers across 20 countries. To our knowledge, this is the first study to describe international testing practices and risk management guidelines for non-BRCA1/2 genes implicated in BC and BOC susceptibility.
METHODS
This study was submitted for approval to the ethics committees of the two coordinating sites, the University of Chicago and Maastricht University. Both concluded that review by the institutional review board/official committee approval was not required, because the study was determined to be nonhuman subject research. A survey about genetic testing practices for non-BRCA1/2 BC and BOC susceptibility genes was developed by ENIGMA Clinical Working Group (CWG) leaders during 2016 (Appendix Table A1). ENIGMA members were invited to complete the survey if they had a clinical genetic testing or diagnostic laboratory affiliation and were involved in ordering, performing, or interpreting DNA tests for inherited susceptibility to BC/BOC at their center. An ENIGMA member is currently defined as a researcher or research group (consortium) who is willing to work collaboratively toward classification of variants by contributing data from families and/or conducting statistical analysis or laboratory-based assays within a working group framework. There is no requirement for ENIGMA members to state their primary role (clinician, genetic counselor, laboratory scientist, basic researcher), but all members by definition have a research interest in the topic of gene/variant classification.
Individuals from the same center could work on the survey together or choose a designated representative to complete it, so only one survey per center was counted. Specific questions were asked about 16 BC/BOC genes with published evidence of risk association commonly included on commercial BC panels at the time of the survey: ATM, BARD1, BRIP1, CDH1, CHEK2, MRE11A, NBN, NF1, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and MEN1 (which is considered a [candidate] BC susceptibility gene in the Netherlands10).
Information about testing and management approaches at individual sites, formulated as multiple-choice questions with a discrete number of options, was obtained through both in-person surveys (during conference session) and paper/electronic surveys, which included additional open-ended questions (Appendix Table A1).
The survey process is outlined in Figure 1. In brief, an in-person survey of members of the CWG, consisting mainly of laboratory and clinical scientists from academic centers, was conducted during the ENIGMA consortium meeting in Limassol, Cyprus, in January 2017. A total of 30 centers from 17 countries participated.
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.
A more detailed version of the survey was then distributed by e-mail (paper/electronic survey) to the same 30 centers that participated in the in-person survey and to additional ENIGMA-affiliated centers worldwide. This allowed collection of information from an additional eight centers and three countries.
Both in-person and paper/electronic survey data were reviewed for consistency and completeness. Participants were sent a copy of their answers and asked to verify them or to clarify any discrepancies.
Notably, in Italy and in the United Kingdom, the paper/electronic version of the survey was also distributed, via country networks, to centers that were not actively involved in ENIGMA research. This provided the opportunity to carry out additional subanalyses (ENIGMA v non-ENIGMA; described in Results). In Italy, all submissions were coordinated by A.D.N., as a liaison for the Network of Italian Collaborators to ENIGMA Studies and Trials. The effort comprised both the ENIGMA-affiliated Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori (Milan) and the Santa Chiara University Hospital (Pisa), which were counted among the 38 participating ENIGMA centers, and 14 additional centers, which were not directly affiliated with ENIGMA at the time of the survey (henceforth referred to as non-ENIGMA; Fig 1, lower right). Of the 14 Italian non-ENIGMA centers, five were dedicated to diagnostic testing only, and nine were dedicated to both diagnostics and research; moreover, half of them were university affiliated, and half were not.
Similarly, in the United Kingdom, D.M.E. completed the survey for her own ENIGMA-affiliated center (one of the 38 participating ENIGMA centers) and also coordinated, with the assistance of Y.W., the distribution of the survey through SurveyMonkey via the Association for Clinical Genetic Science mailing list to cancer genetic leads from diagnostic laboratories providing genetic testing for the publicly funded National Health Service (NHS). The original ENIGMA survey was modified to encompass questions that were considered most relevant to NHS laboratories (Appendix Table A1, far-right column). Nine laboratories responded (anonymously), representing approximately half of the active NHS laboratories in the United Kingdom (also henceforth referred to as non-ENIGMA; Fig 1, lower left).
Comparisons were made between individual centers, US and non-US ENIGMA centers, and ENIGMA and non-ENIGMA centers.
RESULTS
In total, 61 centers from 20 countries participated in the survey. The recruitment flowchart and the global distribution of participants are illustrated in Figure 1.
Clinical Utility
To get a preliminary idea of the participants’ opinions about the clinical utility of the 16 genes on which the survey focused, the CWG members present at the 2017 ENIGMA meeting in Cyprus were asked to answer the following questions relating to each of them: Should every patient with BC/OC who qualifies for (BRCA1/2) genetic testing (by criteria that we recognize may differ by country/center) be tested for the gene? and Do you agree that the cancer risk associated with (pathogenic variants in) the gene is high enough to inform clinical management? All participants (n = 23 at this specific session) stated that they would test every qualifying patient with BC (as defined in the question) for PALB2 and every qualifying patient with OC (as defined) for BRIP1, RAD51C, and RAD51D. No participant stated that he or she would test every qualifying patient with BC for NBN, MRE11A, or RAD50. Results for the other nine genes were variable (Appendix Fig A1A).
With regard to clinical management, all participants agreed that PALB2, TP53, CDH1, PTEN, and STK11 along with BRIP1, RAD51C, and RAD51D were associated with high enough (BC or OC) risk to alter clinical management. Many participants felt that the risk associated with CHEK2 and ATM pathogenic variants could also alter clinical management. NF1, BARD1, MEN1, MRE11A, NBN, and RAD50 were deemed by most of the participants as genes that currently do not affect clinical management of BC risk (Appendix Fig A1B). Please note that 95% CIs for this figure and for all the following figures are provided in Appendix (Tables A2-A10).
Testing Practices
Participants were also asked (via in-person and/or paper/electronic surveys) if and how frequently they tested each gene, the method (single gene v gene panel) and purpose of testing (clinical v research), and the practices of reporting (likely) pathogenic variants and VUS to patients. The aggregate of the responses is presented here.
Purpose and setting.
Figure 2 shows the absolute number and proportion of the ENIGMA centers that tested for a specified gene (for clinical or research purposes) and that tested the gene regularly (ie, ordered the test for > 50% of patients who qualified for genetic testing, by criteria that we recognize may differ by center/country). Even though each gene was tested by > 50% of the centers (range, 52% to 100%), only PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1 were tested regularly by > 50% of centers.
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.
Testing in a research setting in addition to the clinical setting was common for ENIGMA centers (Appendix Fig A2). The genes that were most frequently tested (ie, tested by at least > 30% of centers) for research purposes only were: NBN, BARD1, RAD50, and MRE11A. All the other genes were tested clinically by at least two thirds of the ENIGMA centers. No center tested TP53 solely for research purposes.
Focusing only on clinical testing, a majority of ENIGMA centers used multigene panels (Fig 3). Single-gene testing was performed by a number of centers, varying from one to 21, for: TP53, PTEN, CDH1, STK11, PALB2, CHEK2, NF1, ATM, MEN1, and NBN (in decreasing order of frequency), often based on a specific phenotype (eg, PTEN hamartoma syndrome or neurofibromatosis type 1), or these genes were tested as a reflex only when BRCA1/2 testing was noninformative. Notably, these methods were not mutually exclusive. Seven centers from four countries (Belgium, Brazil, the Netherlands, and Spain) testing CHEK2 only tested for the 1100delC variant.
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.
Regarding the types of gene panels used, US respondents typically ordered broad cancer panels from commercial laboratories, although the specific panels varied depending on patient preferences, insurance considerations, and clinical scenarios. The non-US ENIGMA centers used a combination of commercial and custom in-house panels.
The main issues that emerged regarding barriers to panel testing, among ENIGMA centers and non-ENIGMA Italian centers, were lack of knowledge of cancer risk/penetrance and of management guidelines (hence, lack of actionability); concerns about VUS; validation of testing method; and need for “robust, carefully curated, and constantly updated international databases” and for “global data sharing.” Separately, the nine United Kingdom NHS laboratories were asked, “If you currently only report BRCA genes but might report broader panels in the future, what issues are major barriers/problems to overcome?” Responses were chosen from a menu of nine options plus “other,” and the four main reasons selected (by half or more of respondents) were no request by the oncologists (of note, NHS oncologists can ask directly for BRCA1 and BRCA2 testing but not for multigene panels), lengthy and laborious process of variant interpretation, lack of standardization of reporting, and lack of demand for testing.
Reporting practices and cascade testing.
For genes analyzed through clinical testing, > 90% of ENIGMA centers reported (likely) pathogenic variants to patients (for CHEK2 and NBN, the percentages were slightly lower, at 88% and 71%, respectively; Fig 4). Some centers reported these variants only if the patient met criteria for the associated syndrome (eg, hereditary diffuse gastric cancer for CDH1, neurofibromatosis type 1 for NF1). Almost all centers (67% to 81% for NBN, RAD50, MRE11A, and BARD1 and > 90% for the other genes) offered cascade testing to family members if a (likely) pathogenic variant was identified (data not shown). Notably, participants from the Netherlands reported that they only tested first-degree relatives for CHEK2 1100delC variant when the estimated risk based on family history was lower than the risk conferred by having the variant, so testing for the variant had clinical utility because it would change surveillance recommendations.11
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.
A high percentage (50% to 82%) of ENIGMA centers reported VUS to patients (Fig 4). Most of these centers reported that they would not offer cascade testing for VUS unless it was in a research setting for cosegregation purposes to aid variant (re)classification (data not shown).
Variant Classification Systems
All respondents reported using the International Agency for Research on Cancer five-tier classification system,12 and many also used American College of Medical Genetics and Genomics13 classification criteria. Sources cited for (qualitative) variant classification were literature and public databases including ClinVar,14 the Breast Cancer Information Core database,15 and the Leiden Open Variant Database.16 Respondents were also asked, “Who takes responsibility for interpreting the clinical significance of the variants identified?” This question was answered by 39 centers (including ENIGMA and non-ENIGMA centers) with the following responses: the clinical team (ie, a medical geneticist or oncologist specialized in genetics; n = 16), the laboratory team (n = 11), a combination of the two (n = 10), and a bioinformatic pipeline (n = 2).
Clinical Management Practices and Guidelines
Most ENIGMA centers (≥ 80%) had risk management guidelines for a majority of non-BRCA1/2 genes considered reportable to patients (Fig 5). Exceptions were BARD1, RAD50, and MRE11A, for which ≤ 30% of centers had guidelines.
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).
Although most ENIGMA centers reported having some type of management guidelines for all genes except BARD1, RAD50, and MRE11A, after review, only 10 of 20 countries had national guidelines for (some of) these genes (Table 1). Furthermore, in some countries (Denmark and Germany), the national guidelines were not gene specific (ie, they were broken down by high- and moderate-risk categories rather than by specific gene). Other guidelines were local (center or region specific) or international (meaning national guidelines from another country were used). Review of management guidelines disclosed both similarities and substantial differences in country-specific guidelines available for BC risk management according to gene (Table 1). Ten countries had national guidelines for high-risk cancer syndrome–associated genes such as TP53, CDH1, and PTEN (with the exception of Belgium not having guidelines for CDH1). National guidelines were limited for other BC genes considered clinically actionable, including PALB2. The primary differences between countries were the starting age and type of diagnostic imaging (mammography v magnetic resonance imaging [MRI] v sonography) and the policy on risk-reducing mastectomy. For instance, there was no consensus on the age to begin mammograms/MRI for carriers of pathogenic variants in NF1, MEN1, PALB2 (age 25 v 30 years), or TP53 (age 20 v 25 years). The United Kingdom guidelines differed from all others in that breast MRI was not the standard imaging technique for carriers of pathogenic variants in other gene carriers (except for TP53). Guidelines for risk-reducing mastectomy in carriers of PALB2 pathogenic variants ranged among accepted (n = 1), consider depending on personal/family history (n = 5), and not enough evidence to recommend (n = 1). For PTEN and CDH1, the guidelines that commented on preventive surgery (four of the seven and five of the eight national guidelines, respectively) mentioned risk-reducing mastectomy as a possible option. There were no national management guidelines for BARD1, RAD50, or MRE11A pathogenic variant carriers, which is consistent with the indeterminate evidence for BC or OC risk associated with these genes.
Table 1.
National Guidelines for BC Management
For the OC susceptibility genes BRIP1, RAD51C, and RAD51D, the US-based National Comprehensive Cancer Network and the Dutch guidelines recommended risk-reducing salpingo-oophorectomy (RRSO) from age 45 to 50 years; RRSO was recommended only for RAD51C and RAD51D by the German Hereditary Breast and Ovarian Cancer Consortium. Before RRSO, the Czech Republic guidelines also advised sonography starting from age 30 years.
Subanalyses: ENIGMA-US Versus ENIGMA-Other Centers and Versus Non-ENIGMA Centers
Responses from the seven ENIGMA centers in the United States (ENIGMA-US) were compared with those of the other 31 ENIGMA centers (ENIGMA-other). In addition, responses from 14 non-ENIGMA centers in Italy and nine non-ENIGMA laboratories in the United Kingdom were compared with those from 38 ENIGMA centers across all countries.
Results of these comparisons are summarized in Appendix Figs A3 and A4. Briefly, the ENIGMA-US centers were more likely to regularly test all genes, particularly through multigene panels, compared with ENIGMA-other centers (Appendix Figs A3 and A4). A much smaller proportion of non-ENIGMA centers from Italy and the United Kingdom tested each gene compared with ENIGMA-affiliated centers (Appendix Fig A3).
Management guidelines were more likely to be available in the US-based ENIGMA centers compared with the other ENIGMA centers for all genes except BARD1, RAD50, MRE11A, and MEN1. Only a small proportion of the Italian and United Kingdom non-ENIGMA centers had management guidelines for the 16 genes. Non-ENIGMA United Kingdom centers reported guidelines to be available for TP53 (71% of centers) and CHEK2 (14%), whereas the non-ENIGMA Italian centers reported available guidelines for PALB2 (19% of centers), TP53 (50%), PTEN (19%), CDH1 (38%), STK11 (19%), CHEK2 (13%), and ATM (6%).
DISCUSSION
We surveyed a total of 61 cancer genetic centers across 20 countries asking about their genetic testing and management practices relating to 16 BC and BOC predisposition genes. Our global survey demonstrated that only a few genes are routinely analyzed beyond BRCA1/2; most centers clinically test them through multigene panels and report (likely) pathogenic variants (and VUS, to a slightly lesser extent) to patients; and gene-specific guidelines for BC and OC risk management are limited and differ between countries, especially in regard to starting age and type of imaging and risk-reducing surgery recommendations.
With falling costs of sequencing and more genes being identified that are associated with increased BC and BOC risk, multigene (panel) testing is becoming the norm. The results of our survey confirm this trend, showing that genes that are commonly offered on commercial panels were tested by > 50% of the surveyed centers.
Nevertheless, the value of multigene panel testing continues to be debated in the context of three main areas: limited additional yield of pathogenic variants in genes other than BRCA1/2 coupled with significantly increased interpretation workload, reliability of penetrance estimates for moderate- or uncertain-risk genes (clinical validity), and evidence for informing management recommendations to improve patient outcomes (clinical utility).9 Our international survey demonstrates that the use of panel testing varies widely among countries. US centers were early adopters of multigene testing, which is generally ordered more liberally (if insurance criteria are met), with broader gene panels. Moreover, differences were observed when comparing ENIGMA-affiliated centers with non-ENIGMA Italian and United Kingdom centers (with the latter testing non-BRCA1/2 genes less than one third of the time). Conceivably, because ENIGMA is a research consortium, centers that are ENIGMA members are more involved in research and might become aware of, and hence implement, novel technologies before they become mainstream. Conversely, national/universal health service providers may require a higher threshold of benefit before adopting new tests.
The insufficient evidence in support of clinical validity and/or utility (hence, actionability) of the genes included on panels was the most common concern raised by the participating centers. Easton et al8 asserted that “a genomic test should not be offered until its clinical validity is established”8(p2); however, the utility of a gene needs to be continuously reconsidered as more data become available, and this can only be done by analyzing results from large cohorts of individuals who have been tested. Concerns about the rates of VUS were frequently expressed by the study participants, but just as variant rates have significantly decreased over the years for BRCA1/2 as a result of concerted classification efforts, the same trend will likely occur for other susceptibility genes, arguably at a faster pace as (and provided that) more laboratories worldwide contribute their testing data to population and peer-reviewed databases.5,28,29 Despite the establishment of such databases, survey participants felt that “robust, constantly updated international databases” and “global data sharing” are still lacking. They also expressed the need for robust software that could help with annotation and real-time classification of each variant. This is a worthy goal, but expert judgment in variant classification methods is still required, because fully automated approaches to variant classification that apply guidelines are not ready for clinical practice.6
At a basic level, some centers reported validation of the testing method as a barrier. Therefore, it is important to recognize the technologic barriers in certain countries, although the transition to massively parallel sequencing is ultimately expected to increase throughput and optimize diagnosis without significantly elevating costs.30
There were also nonmedical barriers to implementing routine testing of many of these surveyed genes. Insurance can be a major barrier in the United States, where, for example, Medicare (a US federal health insurance program for people who are age ≥ 65 years and for certain younger people with disabilities) will only cover testing for individuals with a BC or OC diagnosis, and many insurers will not cover multigene panel testing if the patient has already had prior genetic testing. Confounding matters, direct-to-consumer testing is becoming increasingly common in the United States. In many other countries, particularly those with national (ie, universal) health care, testing is approved on a gene-by-gene basis or as a package if research-derived evidence is considered robust enough to change clinical management.
In terms of risk magnitudes, PALB2 and TP53 are the only BC genes, in addition to BRCA1/2, that consistently fall into the high-risk category across studies (ie, confer levels of risk greater than four times that in the general population)8; the remainder have conflicting evidence regarding the risk category into which they fit.8,9,31-33 Our survey confirmed that ENIGMA centers test PALB2 and TP53 relatively frequently and regard them as clinically actionable genes. These two genes were tested much less consistently by non-ENIGMA centers, evidencing the lack of consensus, even for genes that are generally regarded as high risk. These differences in testing approaches may be, however, more directly linked to how health care is paid (ie, if certain genes have been approved or not for testing through the national/universal health care system).
Large-scale studies have become recently available that address the penetrance of moderate-risk (ie, two to four times the risk compared with the general population) BC/BOC genes and the risk magnitudes of the genes included in multigene panels.8,9,31,32 These studies are providing a broader perspective of risk, particularly for genes like CHEK2 or NBN, for which previous risk estimates were based primarily on studies of founder variants only.8 However, most of these studies are based on predominantly white European populations, and therefore, the evidence may not be generalizable.
BRIP1, RAD51C, and RAD51D are ever more accepted as OC but not BC risk predisposition genes (two to five times the risk compared with the general population).15,32 Notably, many respondents agreed that every patient with OC should be tested for these three genes (in addition to BRCA1/2). Although there is currently no indication that OC treatment for a carrier of a pathogenic variant in one of these three genes would differ from that for a noncarrier, carriers may benefit from RRSO at menopause.
The uncertainties and inconsistencies regarding risk and testing practices are magnified when it comes to syndromic cancer genes like PTEN, CDH1, STK11, NF1, NBN, and MEN1, as well as genes conferring an uncertain risk such as BARD1, RAD50, and MRE11A. Although there is significant evidence for elevated BC risk and lobular BC risk in carriers of pathogenic variants in PTEN and in CDH1, respectively,34-36 it is likely that these BC risks (and those from the other syndromic genes) are overestimated and therefore unreliable, because they were derived from patients whose histories were consistent with these rare syndromes rather than from unselected patients.8
More robust and replicable penetrance estimates from large-cohort and population studies are certainly needed to further define risks. In addition, better understanding of gene-gene and gene-environment interactions that affect risk is required. However, on the basis of both the evidence available from the literature and the results of our survey, which incorporate an international clinical perspective, the 16 genes can be grouped into five categories: high BC risk: PALB2, TP53, PTEN, and CDH1; moderate BC risk: ATM and CHEK2; BC risk of unclear magnitude (but established risk for other cancer types): STK11, NF1, NBN, and MEN1; moderate OC risk: BRIP1, RAD51C, and RAD51D; and insufficient evidence for BC or OC risk: BARD1, RAD50, and MRE11A.
The clinical utility of multigene panel testing is assessed based on the improved outcomes of those managed by evidence-based surveillance or prevention approaches. Management guidelines are largely based on expert opinion. Easton et al8 reviewed guidelines across various countries, but they were specific to women with a family history of BC or with BRCA1/2 mutations. A framework for management of moderate-risk BC/BOC genes has been extensively reviewed by Tung et al9 and includes a comparison of surveillance guidelines among the United States, United Kingdom, and Germany. Our survey offers a more extensive comparison of management guidelines among several countries for non-BRCA1/2 risk genes. Results from the survey show that many countries do not yet have their own guidelines, and/or they use National Comprehensive Cancer Network guidance. There are limited national guidelines available even for genes such as PALB2, BRIP1, RAD51C, and RAD51D, which most participants felt should always be tested because they are clinically actionable. Most importantly, when management guidelines are available, they are largely based on expert opinion rather than being evidence based. This explains why the guidelines often differ in important aspects such as indication for risk-reducing surgery and type of diagnostic imaging recommendations.
Our study was initiated to provide a snapshot of ENIGMA clinical practice for non-BRCA1/2 genes. It included countries and centers with ENIGMA affiliation and also a small subset of centers with no direct link to the ENIGMA consortium at the time of the survey. It provides a global, yet incomplete, picture of testing practices in the world. Indeed, countries like Poland and Israel, with founder pathogenic variants in some of these genes, did not participate in the survey. Because panel testing is currently being implemented in large regions of the world like Asia, Africa, and South America, similar surveys will need to be redistributed once more countries have established testing protocols. Even at the time of the survey, testing protocols and surveillance recommendations were in flux in some countries, and broader gene panels were expected to be offered within a short time. We acknowledge that our sampling of non-ENIGMA centers was limited, and we aim to survey a more diverse collection of US, Canadian, and other worldwide regional or community practices in future studies.
Massively parallel sequencing represents a transformational technology that we must learn to apply appropriately in health care. Although the number of genes, other than BRCA1/2, associated with BC/BOC risk is growing, only a small subset of them have clinical utility at the moment. Our survey reveals lack of consensus among most countries regarding which genes to test, how to test them, how to most efficiently interpret variants, and how to manage patients carrying pathogenic variants. The goal of this study was to highlight the differences across countries and to determine what additional information and infrastructure are still needed to move toward more uniform testing practices and management guidelines internationally.
Our collected evidence suggests that the clinical usefulness of multigene panel testing for BC/BOC predisposition can be improved by a better definition of the cancer risks associated with genetic variation in cancer susceptibility genes and by the availability of evidence-based management guidelines. To this end, it is key that clinicians share clinical and genetic data, through ENIGMA and/or other international consortia focused on the clarification of the BC and OC risk associated with genetic variation, and that tested individuals are encouraged to participate in initiatives that collate genetic testing data and in long-term follow-up studies that evaluate intervention strategies. As ENIGMA CWG, we aim at promoting the use of internationally accepted, standard guidelines at the country level through sharing and discussion of all available management guidelines, and we will continue to evaluate testing practices and risk management recommendations periodically.
ACKNOWLEDGMENT
We thank D. Stoppa-Lyonet (Institute Curie, Paris, France) and A. Waha (Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology, University Hospital Cologne, Germany) for providing risk management guidelines and S. Gutiérrez-Enríquez (Oncogenetics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain) for her contributions. C.L. thanks the Catalan Institute of Oncology Hereditary Cancer Program team led by G. Capella.
Appendix
Additional colleagues involved in the NICEST (Network of Italian Collaborators to ENIGMA Studies and Trials) project, who contributed to this study: C. Barisani, M. Giacchè (Spedali Civili, Brescia), F. Dulcetti, A.M. Ruggeri (Toma Advanced Biomedical Assays, Busto Arsizio), S. Vaccarella (Azienda Ospedaliera di Cosenza, Cosenza), B. Riboli (Azienda Socio Sanitaria Territoriale [ASST] Cremona, Cremona), L. Papi, A.L. Putignano (University of Florence, Florence), C. Bruzzone, P. Buda (Ospedale Policlinico San Martino Istituto di Ricovero e Cura a Carattere Scientifico [IRCCS] per l’Oncologia, Genoa), D. Calistri, V. Zampiga (Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola), B. Bonanni, D. Bondavalli (IEO, European Institute of Oncology IRCCS), J. Azzollini, C. Zanzottera (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan), V. Medici, A. Toss (University of Modena and Reggio Emilia, Modena), M.A. Bella, B. Bortesi (University Hospital of Parma, Parma), G. Gambino, R. Scarpitta (Santa Chiara University Hospital, Pisa), A. Germani (Sapienza University of Rome and Sant’Andrea Hospital, Rome), M.R. D’Apice, L.B. Salehi (University Hospital Tor Vergata, Rome), G. Palmieri, G. Palomba (Institute of Biomolecular Chemistry, National Research Council, Sassari), and I. Carnevali (Ospedale di Circolo ASST Settelaghi, Varese, Italy).
Table A1.
Questions Included in the Surveys (by mode of distribution)
Table A2.
Frequency of Testing
Table A3.
Clinical Testing Methods
Table A4.
Reporting Practices of (likely) Pathogenic Variants and VUS to Patients
Table A5.
Sources of Management Guidelines From ENIGMA Centers
Table A6.
Clinical Utility: Every Patient With BC (or OC) Who Meets Criteria for Genetic Testing Should Be Tested for This Gene
Table A7.
Clinical Utility: Cancer Risks Associated With This Gene Are High Enough to Affect Clinical Management
Table A8.
Testing Setting: Clinical Versus Research
Table A9.
Genes Regularly Tested by ENIGMA-US Versus ENIGMA-Other Versus Italian and United Kingdom Non-ENIGMA Centers
Table A10.
Genes Tested Through Panel Testing by ENIGMA-US Versus ENIGMA-Other Centers
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.
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.
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.
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).
Footnotes
Supported by Grant No. KFAS No. 2011-1302-06 from the Kuwait Foundation for the Advancement of Sciences (F.A.-M.); by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development (FEDER) funds (Grants No. PI12/02585 and PI15-00355; O.D.); by funding from the European Union Horizon 2020 Research and Innovation Programme under Grant Agreement No. 634935 and ISCIII funding (Grant No. PI15/00059; M.d.l.H.); by Grants No. 15-27695A, 15-28830A, and 16-29959A from the Ministry of Health of the Czech Republic and Charles University Project No. PROGRES Q28/LF1 (P.K., J.S.); by the Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Carlos III Health Institute, Organismo Adscrito al Ministerio de Economía y Competitividad, FEDER, Catalan Health Institute, and Autonomous Government of Catalonia (Grants No. PI13/00285, PIE13/00022, PI16/00563, and 2009SGR283; C.L.); by the Netherlands Organization for Scientific Research, Mosaic Research Program Grant No. 017.008.022, and Van de Kampfonds from Leiden University Medical Centre (Grant No. 30.925; S. Moghadasi); by a National Council of Technological and Scientific Development scholarship and Barretos Cancer Hospital, Financiadora de Inovação Pesquisa CT-INFRA (February 2010), and Fundação de Amparo à Pesquisa do Estado de São Paulo Grant No. 2013/24633-2 (E.I.P.); by a National Health and Medical Research Council Senior Research Fellowship No. ID1061779 (A.B.S.); by funds from Italian citizens who allocated the 5 × 1,000 share of their tax payments in support of the Ospedale Policlinico San Martino Istituto di Ricovero e Cura a Carattere Scientifico per l’Oncologia Genova according to Italian laws (Institutional Projects 5 × 1000; L.V.); and by the Spanish Health Research Foundation, ISCIII, through the Research Activity Intensification Program (Contract Grant No. INT15/00070, INT16/00154, and INT17/00133) and through Centro de Investigación Biomédica en Red de Enferemdades Raras (Acciones Cooperativas y Complementarias Intramurales 2016 No. ER17P1AC7112/2018), Autonomous Government of Galicia (Consolidation and Structuring Program No. IN607B), and the Fundación Mutua Madrileña (call 2018; A.V.). NIH breast cancer Specialized Program of Research Excellence (SPORE; P50 CA116201) award to Mayo Clinic (F.J.C.).
AUTHOR CONTRIBUTIONS
Conception and design: Sarah M. Nielsen, Diana M. Eccles, Iris L. Romero, Amanda B. Spurdle, Arcangela De Nicolo, Encarna B. Gómez-García
Financial support: Fergus J. Couch, Olufunmilayo I. Olopade
Administrative support: Sophie Krieger, Olufunmilayo I. Olopade, Encarna B. Gómez-García
Provision of study material or patients: Diana M. Eccles, Fahd Al-Mulla, Michela Biancolella, Maria Adelaide Caligo, Mariarosaria Calvello, Gabriele Lorenzo Capone, T.L. Chris Chan, Kathleen B.M. Claes, Laura Cortesi, Simona De Toffol, Ros Eeles, Anna Efremidis, Florentia Fostira, Conxi Lázaro, Siranoush Manoukian, Nadia Naldi, Olufunmilayo I. Olopade, Nicholas S. Pachter, Edenir I. Palmero, Maria Piane, Marianna Puzzo, Maria Christina Sini, Angela Solano, Manuel Teixeira, Mads Thomassen, Amanda Toland, Therese Törngren, Liliana Varesco, Jeffrey Weitzel, Encarna B. Gómez-García
Collection and assembly of data: Diana M. Eccles, Iris L. Romero, Michela Biancolella, Rien Blok, Maria Adelaide Caligo, Mariarosaria Calvello, Gabriele Lorenzo Capone, Pietro Cavalli, T.L. Chris Chan, Kathleen B.M. Claes, Laura Cortesi, Fergus J. Couch, Simona De Toffol, Orland Diez, Susan M. Domchek, Ros Eeles, Anna Efremidis, Florentia Fostira, Andreas Hadjisavvas, Thomas v.O. Hansen, Akira Hirasawa, Claude Houdayer, Petra Kleiblova, Sophie Krieger, Conxi Lázaro, Maria Louizidou, Siranoush Manoukian, Arjen R. Mensenkamp, Luigi Mori, April Morrow, Nadia Naldi, Henriette R. Nielsen, Olufunmilayo I. Olopade, Nicholas S. Pachter, Edenir I. Palmero, Inge S. Pedersen, Maria Piane, Marianna Puzzo, Mark Robson, Maria Rossing, Maria Christina Sini, Angela Solano, Jana Soukupova, Gianluca Tedaldi, Manuel Teixeira, Mads Thomassen, Maria Grazia Tibiletti, Amanda Toland, Therese Törngren, Erica Vaccari, Liliana Varesco, Ana Vega, Barbara Wappenschmidt, Jeffrey Weitzel, Arcangela De Nicolo, Encarna B. Gómez-García
Data analysis and interpretation: Sarah M. Nielsen, Diana M. Eccles, Iris L. Romero, Judith Balmaña, Susan M. Domchek, Alvaro N. Monteiro Amanda B. Spurdle, Arcangela De Nicolo, Encarna B. Gómez-García
Manuscript writing: All authors
Final approval of manuscript: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
Sarah M. Nielsen
No relationship to disclose
Diana M. Eccles
Honoraria: AstraZeneca, Pierre Fabre
Consulting or Advisory Role: AstraZeneca
Travel, Accommodations, Expenses: Pierre Fabre
Iris L. Romero
No relationship to disclose
Fahd Al-Mulla
No relationship to disclose
Judith Balmaña
Consulting or Advisory Role: AstraZeneca
Research Funding: AstraZeneca (Inst)
Travel, Accommodations, Expenses: AstraZeneca, PharmaMar
Michela Biancolella
No relationship to disclose
Rien Blok
No relationship to disclose
Maria Adelaide Caligo
Travel, Accommodations, Expenses: Technogenetics
Mariarosaria Calvello
No relationship to disclose
Gabriele Lorenzo Capone
No relationship to disclose
Pietro Cavalli
No relationship to disclose
T.L. Chris Chan
Employment: Hong Kong Sanatorium and Hospital
Kathleen B.M. Claes
Consulting or Advisory Role: AstraZeneca (Inst)
Laura Cortesi
No relationship to disclose
Fergus J. Couch
Consulting or Advisory Role: AstraZeneca
Research Funding: GRAIL
Other Relationship: Ambry Genetics
Miguel De La Hoya
No relationship to disclose
Simona De Toffol
No relationship to disclose
Orland Diez
No relationship to disclose
Susan M. Domchek
Honoraria: AstraZeneca, Clovis Oncology, Bristol-Myers Squibb
Research Funding: AstraZeneca (Inst), Clovis Oncology (Inst), PharmaMar (Inst)
Ros Eeles
Honoraria: Janssen-Cilag
Speakers’ Bureau: Janssen-Cilag
Anna Efremidis
No relationship to disclose
Florentia Fostira
No relationship to disclose
David Goldgar
No relationship to disclose
Andreas Hadjisavvas
No relationship to disclose
Thomas v.O. Hansen
No relationship to disclose
Akira Hirasawa
Research Funding: AstraZeneca
Claude Houdayer
No relationship to disclose
Petra Kleiblova
No relationship to disclose
Sophie Krieger
No relationship to disclose
Conxi Lázaro
No relationship to disclose
Maria Loizidou
No relationship to disclose
Siranoush Manoukian
No relationship to disclose
Arjen R. Mensenkamp
No relationship to disclose
Setareh Moghadasi
No relationship to disclose
Alvaro N. Monteiro
No relationship to disclose
Luigi Mori
No relationship to disclose
April Morrow
No relationship to disclose
Nadia Naldi
Travel, Accommodations, Expenses: AstraZeneca
Henriette R. Nielsen
No relationship to disclose
Olufunmilayo I. Olopade
Employment: CancerIQ (I)
Leadership: CancerIQ
Stock and Other Ownership Interests: CancerIQ, Tempus
Research Funding: Novartis (Inst)
Other Relationship: Tempus, Color Genomics, Roche/Genentech, Myriad Genetics, Bio Ventures for Global Health
Nicholas S. Pachter
No relationship to disclose
Edenir I. Palmero
No relationship to disclose
Inge S. Pedersen
No relationship to disclose
Maria Piane
No relationship to disclose
Marianna Puzzo
No relationship to disclose
Mark Robson
Honoraria: AstraZeneca
Consulting or Advisory Role: McKesson, AstraZeneca
Research Funding: AstraZeneca (Inst), Myriad Genetics (Inst), InVitae (Inst), Pfizer (Inst)
Travel, Accommodations, Expenses: AstraZeneca
Maria Rossing
No relationship to disclose
Maria Christina Sini
No relationship to disclose
Angela Solano
No relationship to disclose
Jana Soukupova
No relationship to disclose
Gianluca Tedaldi
No relationship to disclose
Manuel Teixeira
No relationship to disclose
Mads Thomassen
No relationship to disclose
Maria Grazia Tibiletti
No relationship to disclose
Amanda Toland
No relationship to disclose
Therese Törngren
Honoraria: Pfizer, AstraZeneca
Erica Vaccari
Consulting or Advisory Role: Color Genomics
Liliana Varesco
Consulting or Advisory Role: Pfizer
Ana Vega
No relationship to disclose
Yvonne Wallis
No relationship to disclose
Barbara Wappenschmidt
No relationship to disclose
Jeffrey Weitzel
No relationship to disclose
Amanda B. Spurdle
No relationship to disclose
Arcangela De Nicolo
No relationship to disclose
Encarna B. Gómez-García
No relationship to disclose
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