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Review| Volume 146, P30-47, March 2021

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing

Open AccessPublished:February 09, 2021DOI:https://doi.org/10.1016/j.ejca.2020.12.023
Clinical practice guidelines for BRCA1 and BRCA2 genetic testing
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      Highlights

      • •
        Provide update clinical recommendations for BRCA testing for preventive purpose.
      • •
        Offer testing clinical guidelines for personalised management of early and metatstatic breast cancer.
      • •
        Actualize germline and tumor testing indications for PARPi-approved therapies.
      • •
        Address the issues of rapid process and tumor analysis.

      Abstract

      BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed.
      The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis.
      An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer.
      These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.

      Keywords

      1. Introduction

      BRCA1 and BRCA2 genes (BRCA) analysis is increasingly being used to detect pathogenic variants for both preventive and therapeutic issues. Several guidelines on BRCA testing are available worldwide, but recent therapeutic advances in breast cancer management and approved therapies with poly(ADP)ribose polymerase inhibitor (PARPi) agents in breast, ovarian, prostate and pancreatic cancers, as well as the specific rapid germline and tumour testing process, deserve a comprehensive and integrative update to optimise BRCA testing in clinical practice.
      BRCA pathogenic or likely pathogenic variants (mutations, BRCAm) account for most identifiable hereditary breast and ovarian cancer (HBOC) syndromes. For women who carry a BRCAm, the cumulative risk for developing breast or ovarian cancer by age 70 years is 45%–66% and 11%–41%, respectively [
      • Antoniou A.
      • Pharoah P.D.P.
      • Narod S.
      • Risch H.A.
      • Eyfjord J.E.
      • Hopper J.L.
      • et al.
      Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.
      Am J Hum Genet. 2003; 72: 1117-1130
      ,
      • Kuchenbaecker K.B.
      • Hopper J.L.
      • Barnes D.R.
      • Phillips K.-A.
      • Mooij T.M.
      • Roos-Blom M.-J.
      • et al.
      Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
      JAMA. 2017; 317: 2402-2416
      ]. Validation of screening and preventive strategies in BRCAm carriers and increased awareness of their benefit by population and healthcare providers has led to a continuous increase in BRCA testing over the last two decades [
      • Pujol P.
      • Lyonnet D.S.
      • Frebourg T.
      • Blin J.
      • Picot M.C.
      • Lasset C.
      • et al.
      Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.
      Breast Canc Res Treat. 2013; 141: 135-144
      ,
      • Guo F.
      • Hirth J.M.
      • Lin Y.-L.
      • Richardson G.
      • Levine L.
      • Berenson A.B.
      • et al.
      Use of BRCA mutation test in the U.S., 2004–2014.
      Am J Prev Med. 2017; 52: 702-709
      ,
      • Liede A.
      • Mansfield C.A.
      • Metcalfe K.A.
      • Price M.A.
      • Snyder C.
      • et al.
      Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
      Preferences for breast cancer risk reduction among BRCA1/BRCA2 mutation carriers: a discrete-choice experiment.
      Breast Canc Res Treat. 2017; 165: 433-444https://doi.org/10.1007/s10549-017-4332-3
      ]. Thus, we need to update and prioritise the main indications for BRCA testing for breast and ovarian cancer risk assessment based on a rational analysis of the likelihood of BRCAm (lBRCAm).
      The major benefit of PARPi therapy for newly diagnosed ovarian cancer combined with improved progression-free survival in advanced ovarian, breast, prostate and pancreatic cancers [
      • Konstantinopoulos P.A.
      • Norquist B.
      • Lacchetti C.
      • Armstrong D.
      • Grisham R.N.
      • Goodfellow P.J.
      • et al.
      Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline.
      J Clin Oncol. 2020; 38: 1222-1245
      ,
      • Neviere Z.
      • De La Motte Rouge T.
      • Floquet A.
      • Johnson A.
      • Berthet P.
      • Joly F.
      How and when to refer patients for oncogenetic counseling in the era of PARP inhibitors.
      Ther Adv Med Oncol. 2020; 12 (1758835919897530)
      ] has prompted the development of BRCAm detection for targeted therapies. In some situations, such as ovarian cancer or prostate cancer, detecting somatic mutations has been effective for identifying PARPi-sensitive patients [
      • Capoluongo E.
      • Scambia G.
      • Nabholtz J.-M.
      Main implications related to the switch to 1/2 tumor testing in ovarian cancer patients: a proposal of a consensus.
      Oncotarget. 2018; 9: 19463-19468
      ]. In breast and pancreatic cancer, only germline mutations can drive an approved PARPi treatment to date. Thus, germline BRCA (gBRCA) and tumour BRCA (tBRCA) mutational analyses are being used for selecting patients who could benefit from a PARPi. In addition, in newly diagnosed breast cancer and metastatic breast cancer, BRCAm status can also lead to a major change in management such as personalised surgery or chemotherapy regimen. These clinical decisions based on BRCAm status need to be performed quickly, guided by tumour type and disease stage. Thus, we need specific guidelines that take into account the clinical applications of BRCAm analysis, as well as tumour and fast-track testing processes.
      More than 30 guidelines on BRCA testing are available worldwide [
      • Neviere Z.
      • De La Motte Rouge T.
      • Floquet A.
      • Johnson A.
      • Berthet P.
      • Joly F.
      How and when to refer patients for oncogenetic counseling in the era of PARP inhibitors.
      Ther Adv Med Oncol. 2020; 12 (1758835919897530)
      ,
      • Forbes C.
      • Fayter D.
      • de Kock S.
      • Quek R.G.W.
      A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer.
      Canc Manag Res. 2019; 11: 2321-2337https://doi.org/10.2147/cmar.s189627
      ,
      • Tung N.M.
      • Garber J.E.
      BRCA1/2 testing: therapeutic implications for breast cancer management.
      Br J Canc. 2018; 119: 141-152
      ]. In the United States, the US National Comprehensive Cancer Network [
      • Daly M.B.
      • Pilarski R.
      • Yurgelun M.B.
      • Berry M.P.
      • Buys S.S.
      • Dickson P.
      • et al.
      NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.
      J Natl Compr Canc Netw. 2020; 18: 380-391
      ], the American Society of Clinical Oncology [
      • Konstantinopoulos P.A.
      • Norquist B.
      • Lacchetti C.
      • Armstrong D.
      • Grisham R.N.
      • Goodfellow P.J.
      • et al.
      Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline.
      J Clin Oncol. 2020; 38: 1222-1245
      ,
      • Tung N.M.
      • Boughey J.C.
      • Pierce L.J.
      • Robson M.E.
      • Bedrosian I.
      • Dietz J.R.
      • et al.
      Management of hereditary breast cancer: American society of clinical oncology, American society for radiation oncology, and society of surgical oncology guideline.
      J Clin Oncol. 2020; 38: 2080-2106
      ] and the US Preventive Services Task Force [
      • Owens D.K.
      • Davidson K.W.
      • Krist A.H.
      • Barry M.J.
      • Cabana M.
      • et al.
      US Preventive Services Task Force
      Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US preventive Services Task Force recommendation statement.
      JAMA. 2019; 322: 652-665
      ] have published policy statements for genetic testing for BRCA-related cancer. Sixteen different guidelines exist in Europe [
      • Neviere Z.
      • De La Motte Rouge T.
      • Floquet A.
      • Johnson A.
      • Berthet P.
      • Joly F.
      How and when to refer patients for oncogenetic counseling in the era of PARP inhibitors.
      Ther Adv Med Oncol. 2020; 12 (1758835919897530)
      ,
      • Forbes C.
      • Fayter D.
      • de Kock S.
      • Quek R.G.W.
      A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer.
      Canc Manag Res. 2019; 11: 2321-2337https://doi.org/10.2147/cmar.s189627
      ,
      • Tung N.M.
      • Garber J.E.
      BRCA1/2 testing: therapeutic implications for breast cancer management.
      Br J Canc. 2018; 119: 141-152
      ]. However, most guidelines do not represent international consensus, differ from each other in the lBRCAm threshold retained (10% [
      • Runowicz C.D.
      • Leach C.R.
      • Lynn Henry N.
      • Henry K.S.
      • Mackey H.T.
      • Cowens-Alvarado R.L.
      • et al.
      American cancer society/American society of clinical oncology breast cancer survivorship care guideline.
      J Clin Oncol. 2016; 34: 611-635https://doi.org/10.1200/jco.2015.64.3809
      ,
      Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. London: National Institute for Health and Care Excellence, UK)2020
      ] or 5% [
      • Daly M.B.
      • Pilarski R.
      • Yurgelun M.B.
      • Berry M.P.
      • Buys S.S.
      • Dickson P.
      • et al.
      NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.
      J Natl Compr Canc Netw. 2020; 18: 380-391
      ]) and may not integrate the recent need for BRCA genotyping for PARPi treatment and personalised breast cancer management.
      Integrated and updated guidelines would optimise and harmonise healthcare offerings of the BRCA testing and the identification of BRCAm carriers for both preventive and therapeutic purposes. Thus, we developed BRCA testing guidelines at an international level with a specific methodology of evaluating the lBRCAm for a given set of criteria. The methodology was based on a combined approach of literature review, expert evaluation and risk model assessment, taking into account newly developed PARPi agents, as well as personalised management of breast cancer.

      2. Methods

      2.1 Guideline development and composition of the working group

      These guidelines were commissioned by the French Society of Predictive and Personalised Medicine (SFMPP) from September 2019 to June 2020, and a guideline chair was selected (supplementary data). The SFMPP is an independent non-profit learned society with public funding that aims to provide guidelines for genetic testing [
      • Pujol P.
      • Vande Perre P.
      • Faivre L.
      • Sanlaville D.
      • Corsini C.
      • Baertschi B.
      • et al.
      Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.
      Eur J Hum Genet. 2018; 26: 1732-1742
      ,
      • Pujol P.
      • De La Motte Rouge T.
      • Penault-Llorca F.
      From targeting somatic mutations to finding inherited cancer predispositions: the other side of the coin.
      Diagnostics. 2019; 9https://doi.org/10.3390/diagnostics9030083
      ,
      • Pujol P.
      • Fodil-Chérif S.
      • Mandel J.L.
      • Baertschi B.
      • Sanlaville D.
      • Zarca D.
      • et al.
      Réflexions éthiques sur le dépistage génétique préconceptionnel en population générale : le débat français et l’avis de la Société Française de Médecine Prédictive et Personnalisée.
      Ethics, Medicine and Public Health. 2020; 12: 100439https://doi.org/10.1016/j.jemep.2019.100439
      ]. A Guideline Development Group (GDG) was selected to ensure a wide range of expertise across all relevant disciplines in different countries. Members of the GDG completed a Declaration of Conflict of Interests (CoIs) form (supplementary data), which was reviewed and vetted by the SFMPP. A scoping meeting was held on 5 October 2019 to develop key priorities and validate the methodology described below. Key questions to cover included What are the current indications for BRCA testing in clinical practice? What is the place for BRCA tumour testing and a fast-track process for personalised treatment of BRCA-related cancer? The specific guidelines process is described in supplementary data and based on published data on lBRCAm and their respective levels of evidence, evaluation of lBRCAm by risk model assessment and expert estimation, and the therapeutic value of BRCAm for managing breast cancer and treating BRCA-related cancer with PARPi agents.
      The GDG consisted of a group of 48 multidisciplinary experts from Belgium, England, France, Germany, Italy, Israel, Scotland, Spain, and Switzerland, who were divided into two working subgroups: preventive and therapeutic (supplementary data). The preventive subgroup included medical geneticists and genetic counsellors, organ specialists, oncologists, surgeons, patient representatives, ethicist experts, psychologists and lawyers. The group also included a methodologist with expertise in evidence appraisal and guideline development. This group provided guidelines and ethical reflection for updating BRCA testing for preventive purposes. The therapeutic subgroup included medical, radiation and surgical oncologists; organ specialists; clinicians and molecular geneticists; pathologists; and patient representatives and provided an independent evaluation of the indication for a PARPi and personalised management of breast cancer.
      Experts from the preventive and therapeutic subgroups were invited to evaluate the level of evidence and to estimate by quotation the lBRCAm independently, as described below (Table 1a, Table 1b, Table 1ca, 1b and 1c ). Eight teleconference/webinar meetings were organised to develop this formal consensus and achieve expert agreement. Fourteen additional international experts (listed in supplementary data) reviewed and proofread recommendations. The overall guideline-development process, including the funding of the work, panel formation, management of CoIs, internal and external review and organisational approval, was guided by procedures derived from the Guidelines International Network–McMaster Guideline Development Checklist [

      Guideline development checklist n.d. http://cebgrade.mcmaster.ca/guidecheck.html [accessed 1 September 2020].

      ] and was intended to meet recommendations by the Guidelines International Network [

      Welcome to G-I-N — guidelines international Network n.d. https://g-i-n.net/ [accessed 1 September 2020].

      ].
      Table 1aLikelihood of BRCA1 or BRCA2 mutation.
      ClasslBRCAm
      A≥10%
      B≥7.5 to <10%
      C≥5 to <7.5%
      D≥2.5 to <5%
      E<2.5%
      lBRCAm, likelihood of BRCA1 or BRCA2 pathogenic or likely pathogenic variant.
      Table 1bLevel of evidence.
      LevelDefinitionCommentary
      IConcordant data on the lBRCAm available in level 1 publicationLevel 1 publication: prospective or large retrospective studies, cohort studies with control, pooled studies
      IIData available in level 2 publication or discordant data in the literatureLevel 2 publication: cohort study with non-contemporaneous control, case–control series, subgroup analysis
      IIIData available in level 3 publicationLevel 3 publication: case series without control, small series, series with selection bias
      IVNo data available in the literatureOnly model assessment of risk available
      Table 1cGrade of recommendations.
      GradeDefinitionRecommendation
      AHigh lBRCAm (≥7.5%, supported by LOE I/II) and/or therapeutic valueRecommended
      BModerate lBRCAm (2.5–7.5%) and no therapeutic valueConsidered
      CLow lBRCAm (<2.5%) and no therapeutic valueNot routinely proposed
      LOE, level of evidence.

      2.2 Parameters evaluated

      The lBRCAm for a given criterion was based on a combined approach of literature review, expert quotation and risk model assessment as defined below. The process of development of the guidelines is presented in supplementary data. Current clinical criteria for genetic testing were obtained from existing guidelines (for review, see Refs. [
      • Neviere Z.
      • De La Motte Rouge T.
      • Floquet A.
      • Johnson A.
      • Berthet P.
      • Joly F.
      How and when to refer patients for oncogenetic counseling in the era of PARP inhibitors.
      Ther Adv Med Oncol. 2020; 12 (1758835919897530)
      ,
      • Forbes C.
      • Fayter D.
      • de Kock S.
      • Quek R.G.W.
      A systematic review of international guidelines and recommendations for the genetic screening, diagnosis, genetic counseling, and treatment of BRCA-mutated breast cancer.
      Canc Manag Res. 2019; 11: 2321-2337https://doi.org/10.2147/cmar.s189627
      ,
      • Tung N.M.
      • Garber J.E.
      BRCA1/2 testing: therapeutic implications for breast cancer management.
      Br J Canc. 2018; 119: 141-152
      ]). Criteria were divided into four categories: (1) personal, (2) family or personal and family combined, and (3) theragnostic and (4) personalised management of breast cancer. Whenever possible, a given criterion was evaluated by subcategories (i.e., age at diagnosis: <35, <40, <45, <50 years, any age), and respective data on lBRCAm were collected from the literature. A theragnostic indication was defined as an approved use of PARPi in BRCA-related cancer by continental drug agencies in the United States (US Food and Drug Administration [FDA]) and Europe (European Medicines Agency [EMA]).

      2.3 Literature selection process

      The search strategy is given in supplementary data. The PubMed database was searched for English language studies published in English from January 1995 to May 2020 by using the following query of terms related to BRCA clinical testing: ((gene, BRCA 1[MeSH]) OR (gene, BRCA 2[MeSH]) OR (BRCA 1 gene[MeSH]) OR (BRCA 2[MeSH]) OR (BRCA1 2[MeSH]) OR (breast cancer 1 gene[Tw]) OR (breast cancer 2 gene[tw]) OR (BRCA1/2[MeSH])) AND ((genetic testing[MeSH]) OR (genetic counselling[MeSH]) OR (genetic risk[MeSH]) OR (breast cancer[MeSH]) OR (ovarian cancer[MeSH]) OR (prostate cancer[MeSH]) OR (pancreatic cancer[MeSH]) OR (melanoma[MeSH]) OR (cholangiocarcinoma[MeSH]) OR (familial risk[Tw]) OR (prevalence[MeSH]) OR (unselected[Tw]) OR (general population[Tw]) OR (early onset[Tw]) OR (triple negative breast cancer[Tw]) OR (bilateral breast cancer[Tw]) OR (male breast cancer[Tw]) OR (founder effect[Tw]) OR (parp inhibitor[Tw]) OR (poly-adp-ribose polymerase inhibitor[Tw]) OR (polyadenosine diphosphate-ribose polymerase inhibitor[Tw]) OR (platinum sensitive[Tw]) OR (breast cancer management[Tw]) OR (rapid testing[Tw]) OR (fast testing[Tw]) OR (fast track process[Tw]) OR (tumour testing[Tw]) OR (somatic testing[Tw])) AND (English[Language]) AND (‘1995/01/01’[Date - Publication]: ‘2020/06/20’[Date - Publication]) NOT (case reports[Publication Type]) NOT (case reports[Tiab]) NOT (mice[Tw]).
      The literature search used variations and Boolean connectors of key terms. Results of database searches were supplemented with bibliographies of seminal articles or reviews and contributions from expert panel members. For guidelines, the websites of associations, colleges and learned societies listing various recommendations were also searched.
      A total of 4725 results were found. From these, 603 records were retrieved, including 277 publications retained for estimating lBRCAm and 32 publications or electronic links to guidelines (Supplementary data).

      2.4 Criteria of evaluation

      Criteria for BRCA testing were obtained from existing guidelines and divided into three categories: personal criteria, family or personal and family combined criteria and therapeutic criteria. For each retained criterion, the reported lBRCAm was searched in the literature (as an independent variable or from subgroup analysis). Classes a-e were considered and corresponded to lBRCAm ≥10%, ≥7.5 to <10%, ≥5 to <7.5%, ≥2.5 to <5%, and <2.5%, respectively (Table 1a). The working group defined the level of evidence (LOE) as I, concordant data on the lBRCAm available in level 1 publications; II, data on the lBRCAm available in level 2 publications or discordant data in the literature; III, data on the lBRCAm available in level 3 publications; or IV, no data available, risk model assessments of lBRCAm (Table 1b). The level of publication was defined as 1, prospective or large retrospective studies, cohort studies with control, pooled studies; 2, cohort study with non-contemporaneous control, case–control series, subgroup analysis; or 3, case series without control, small series, series with selection bias (Table 1b).

      2.5 Model estimation of lBRCAm and expert quotation

      The estimation of the lBRCAm was based ideally on existing literature taking into account the level of publication defined above. In some situations, data from the literature were available from studies, including a small number of cases with possible selection bias. Subgroup analysis and model assessment of lBRCAm provided an additional estimation of the lBRCAm. In this study, we used the risk models BRCAPRO [

      BRCAPRO n.d. https://projects.iq.harvard.edu/bayesmendel/brcapro [accessed 31 August 2020].

      ,
      • Berry D.A.
      • Iversen E.S.
      • Gudbjartsson D.F.
      • Hiller E.H.
      • Garber J.E.
      • Peshkin B.N.
      • et al.
      BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
      J Clin Oncol. 2002; 20: 2701-2712https://doi.org/10.1200/jco.2002.05.121
      ], BOADICEA [

      BOADICEA web application - centre for cancer genetic epidemiology n.d. https://ccge.medschl.cam.ac.uk/boadicea/boadicea-web-application/ [accessed 31 August 2020].

      ,
      • Antoniou A.C.
      • Pharoah P.P.D.
      • Smith P.
      • Easton D.F.
      The BOADICEA model of genetic susceptibility to breast and ovarian cancer.
      Br J Canc. 2004; 91: 1580-1590https://doi.org/10.1038/sj.bjc.6602175
      ], and PennII [
      • Couch F.J.
      • DeShano M.L.
      • Anne Blackwood M.
      • Calzone K.
      • Stopfer J.
      • Campeau L.
      • et al.
      BRCA1Mutations in women attending clinics that evaluate the risk of breast cancer.
      N Engl J Med. 1997; 336: 1409-1415https://doi.org/10.1056/nejm199705153362002
      ], and their updated versions to estimate the lBRCAm. The estimations were computed with the same fictional pedigree, representative of an average family, described and previously published [
      • Pujol P.
      • Lyonnet D.S.
      • Frebourg T.
      • Blin J.
      • Picot M.C.
      • Lasset C.
      • et al.
      Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.
      Breast Canc Res Treat. 2013; 141: 135-144
      ] (also see supplementary data for ‘standard’ pedigree). Data are available in supplementary data.
      Experts were invited to estimate the grade of lBRCAm (A-C; see below) in their field of expertise in light of data from the literature by using the a-e classification of the lBRCAm and risk model estimations. The lBRCAm for each criterion was assigned a quotation by at least three independent experts. Experts were also invited to determine the LOE and evaluate the level of publication. Discrepancies in the evaluation were discussed with the steering committee.

      2.6 Theragnostic value, treatment personalisation

      For PARPi, the criteria for recommendations were (1) approval by the EMA and/or FDA and (2) temporary authorisation for use in European countries and breakthrough therapy designation by the FDA. Recommendations for addressing metastatic cancer (platinum-containing regimen, PARPi, BRCA testing) were based on guidelines from the ABC global alliance in Europe (ABC4 [
      • Cardoso F.
      • Senkus E.
      • Costa A.
      • Papadopoulos E.
      • Aapro M.
      • André F.
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      Ann Oncol. 2018; 29: 1634-1657
      ], ABC5 [

      OncologyPRO. Making a difference for advanced breast cancer patients n.d. https://oncologypro.esmo.org/meeting-resources/eso-esmo-advanced-breast-cancer-fifth-international-consensus-conference-abc5/making-a-difference-for-advanced-breast-cancer-patients [accessed 1 September 2020].

      ]) and US ASCO guidelines [
      • Tung N.M.
      • Boughey J.C.
      • Pierce L.J.
      • Robson M.E.
      • Bedrosian I.
      • Dietz J.R.
      • et al.
      Management of hereditary breast cancer: American society of clinical oncology, American society for radiation oncology, and society of surgical oncology guideline.
      J Clin Oncol. 2020; 38: 2080-2106
      ].

      2.7 Grading recommendations

      Guidelines were divided into three grades: grade A, for patients for whom testing should be offered, given a high lBRCAm (≥7.5% with LOE I or II and/or established therapeutic value); grade B, for patients for whom testing should be considered, given a moderate lBRCAm (2.5–7.5%); and grade C, for patients for whom testing should not be routinely offered, given a low lBRCAm (<2.5%) (Table 1c).
      In this work, the cutoff for a high lBRCAm was set at 7.5%, whereas some guidelines used a threshold of 10% (ASCO [
      • Konstantinopoulos P.A.
      • Norquist B.
      • Lacchetti C.
      • Armstrong D.
      • Grisham R.N.
      • Goodfellow P.J.
      • et al.
      Germline and somatic tumor testing in epithelial ovarian cancer: ASCO guideline.
      J Clin Oncol. 2020; 38: 1222-1245
      ], NICE [
      Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. London: National Institute for Health and Care Excellence, UK)2020
      ]) and others 5% (NCCN [
      • Daly M.B.
      • Pilarski R.
      • Yurgelun M.B.
      • Berry M.P.
      • Buys S.S.
      • Dickson P.
      • et al.
      NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.
      J Natl Compr Canc Netw. 2020; 18: 380-391
      ]). With a cutoff of 10%, most of the family criteria would not be considered at high risk (see results section) and most of the criteria analysed to give a lBRCAm of 5%–10%, so the GDG retained the intermediate cutoff of 7.5%. In some subgroups, although the lBRCAm could be above this cutoff, a grade B recommendation was attributed when the LOE was III or IV or when only one study was available.

      3. Results

      3.1 Single or personal criteria related to breast cancer

      Personal criteria related to breast cancer, including age at disease onset, triple-negative breast cancer (TNBC) phenotype, bilaterality, male breast cancer and founder effect, have been extensively studied, and the lBRCAm are given by subgroups (Table 2a ). Only three criteria featured a lBRCAm ≥7.5% with both LOE I and expert quotation of grade A: age ≤40, TNBC ≤60 and male breast cancer. The criterion ‘bilateral breast cancer with first cancer at age ≤50’ was also associated with lBRCAm ≥7.5%, with LOE II and expert quotation grade A. Risk model estimation is in supplementary data (Table S7a).
      Table 2alBRCAm according to individual criteria related to breast cancer.
      CriterialBRCAm
      lBRCAm, likelihood to detect BRCA pathogenic of likely pathogenic variant; LOE, level of evidence; TNBC, triple-negative breast cancer.
      (%)      		ReferencesGuidelinesLOEQuotation
      lBRCAm, likelihood to detect BRCA pathogenic of likely pathogenic variant; LOE, level of evidence; TNBC, triple-negative breast cancer.
      Age
       ≤356–201,2,3,4,5,6,7,8,9,10,11,1213,14,15,16,17,18IA
       ≤403.8–235,19,20,21,22,23,24,25,26,27,28,29,3031,32,33,16,33,34,35IA
       ≤451.6–12.25,23,36,37,38,39,4041,42,43IIB
       ≤504–12.426,27,44,45,46,47,4841,49,50,51IIB
       ≤5525IIIC
       >501.252,53,54IIIC
       Any age0.4–7.555,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,27,54,71,36,72,73,74,75,76,48NoneIIC
      TNBC
       ≤4023–3677,20,7831,18IA
       ≤507.6–27.679,80,81,77,8283,16IA
       ≤6011.4–16.880,7842,41,84,49,15,14,50IIA
       >604.9–5.780,85,78,86IIB
       Any age2.9–17.536,87,78,82,8843IIB
      Bilateral
       1st ≤ 4026.7–33.325,89,90,2416IIA
       1st ≤ 509–22.791,6,9232,41,31,33,14,15IIA
       1st ≤ 6015.3 (<55)9343,49IIIC
       Any age6.6–346,94,20,95,25,96,97,98,89,9033,99,31,50IIIC
       Male7.4–33100,101,102,103,104,105,106,107,108,109,110,11141,32,43,99,112,31,50,18,14IA
      ∗ lBRCAm, likelihood to detect BRCA pathogenic of likely pathogenic variant; LOE, level of evidence; TNBC, triple-negative breast cancer.
      Table 2blBRCAm according to founder effects.
      CriterialBRCAm
      lBRCAm, likelihood to detect BRCA pathogenic of likely pathogenic variant; LOE, level of evidence; BC, breast cancer; FH, family history; OC, ovarian cancer.
      (%)      		ReferencesGuidelinesLOEQuotation
      Ashkenazi heritage
       No cancer1.1–2.91,2,3,4,5,6,7,8,9,10,11,12IC
       Unselected breast cancer4.5–2513,14,15,16,17,18,19,20,21,22,2324,25,26,27,28,29,30,31,32,33IB
       Early onset ≤4019.5–43.314,15,17,18,21,34,35,36IA
       ≤508.7–18.714,3738IA
       Male BC6.4–19.137,39,40,41IA
       Ovarian cancer35.7–6218,42,43IIA
      Icelandic heritage
       No cancer0.4–0.644,45IIC
       Unselected BC7.7–10.444,45,46,47,4829IIB
       Male BC38–4046,47,49IIA
      Polish heritage
       No cancer0.25–0.450,51IIIC
       Unselected BC3.151IIIB
       BC age >508.350IIIB
       BC age <506–1352,50IIIB
       TNBC9.953IIIB
       Unselected ovarian cancer6.3–2154,55,56,57,58,59IIA
      French-Canadian heritage
       No cancer0.260,61IIC
       Unselected BC3.1–3.860,63IIB
       BC age < 401364IIA
       BC age < 459.360IIIB
       BC age < 504.7–5.161,62IIB
       BC and FH4565IIA
       Unselected OC7.7–866,67,68IIA
      Hungarian heritage69,70
       BC3.6IIIB
       BC and FH18IIIB
       OC11IIA
      Mexican heritage71,72
       TNBC <5023IIIB
       BC and FH6IIIB
      ∗ lBRCAm, likelihood to detect BRCA pathogenic of likely pathogenic variant; LOE, level of evidence; BC, breast cancer; FH, family history; OC, ovarian cancer.
      Age at breast cancer onset <45 or <50 years was associated with a wide range of lBRCAm depending on the study (from 1.6% to 12.2% and 4% to 12.4%, respectively). The LOE for these criteria was II and expert quotation grade B.
      In women from populations with a small spectrum of founder mutation, with a founder effect (e.g., Ashkenazi, Icelandic, Polish and French-Canadian), the lBRCAm in the literature varied widely when breast cancer was diagnosed at any age. In women with Ashkenazi or Icelandic heritage, the lBRCAm was 4.5%–11.7% and 7.7%–10.3%, respectively. However, most of these studies did not reach LOE I, and the effect of family history or age in women undergoing a genetic test could not be ruled out. lBRCAm was significantly higher when comparing subgroups of early-onset and male breast cancer with other populations (Ashkenazi heritage, 19.5%–43% and 6.4%–19.1% for early-onset and male breast cancer, respectively; Icelandic heritage, 7.7%–10.3% and 40%, respectively). For Ashkenazi women, breast cancer at age ≤50 years was associated with a lBRCAm of 8.7%–18.7% with LOE II and expert quotation grade A.

      3.2 Family and combined criteria

      For family and combined criteria, most available data on lBRCAm were noted in the subgroup analysis of cohort and retrospective studies. In many situations, owing to the complexity and a high number of combinations of criteria, data are lacking. The LOE was III or IV for most family or combined criteria, except for ‘the number of cases of breast cancer in ≥2 relatives’, with LOE II (Table 3a). Risk model estimation is in supplementary data. In several situations, models could not discriminate the specific lBRCAm with combined criteria. In women with breast cancer and a relative with grade A personal criteria (such as early-onset, male breast cancer and ovarian cancer), prediction of lBRCAm by models and expert opinion favoured a grade A recommendation for the first-degree relative and grade B recommendation for second- or third-degree relatives. For any family or combined criteria, Ashkenazi or Icelandic heritage should be taken into account because studies found an increased risk with this heritage. The lBRCAm in women with breast cancer and a relative with prostate or pancreatic cancer varied widely by study and model, with LOE III-IV and expert estimate grade B.
      Table 3aPBRCA in according to family and combined criteria.
      Family/combined£ criterialBRCAm literature (%)lBRCAm models∗(%)ReferencesExisting guidelinesLOEQuotation
      1 case of BC with 2 cases of BC in a CR∗∗1,2,3,4,5,6,7,8,9,10IIA
      Any CR3.8–10.611,12,13,14
       1st/1st130.2–10.512IIIA
       1st/2nd60.1–712IIIB
       2nd/2nd4<0.1–612IIIB
      1 case of BC and 1 of BC in CR with one age ≤ 504–2211,12,13,15,16,17,182,19,20,21,22,6IIA
       1st0.2–3.8
       2nd<0.1–3.8
      1 case of BC and bilateral BC in a CR12.8–21 (age <50)11,1319 (first age <50),20,23 (both age <60)IIIA
       1st5–8
       2nd1.1
      1 case of BC and a CR with ovarian cancer4.3–5511,12,13,14,15,16,1821,20,9,23,19,24,22,2,3,25,5,6,26IIA
       1st0.4–8
       2nd<0.1–4.
      1 case of BC and a CR with one male BC16.5112,19,24,20,23,22,9,6,27,28IIA
       1st1.2–14
       2nd0.3–7
      1 case of BC and a CR with prostate cancer13.6–190.1–72924 (prostate age <60 and BC age <50), 2,3 (Gleason score ≥7), 4,5 (prostate age <55)IIIB
      1 case of BC and a CR with pancreatic cancer19.7–37.50.1–1230,31,32,33,343,4, (BC age <50), 2IIIB
      1 case of BC and an FDR with individual grade A criteria and no possibility for testing ∗∗∗theoretically >50% of lBRCAm of FDRIIA
      Asymptomatic person with individual grade A criteria in an FDRtheoretically 50% of lBRCAm of FDRIIB
      £ Combined, personal and family criteria; LOE, level of evidence; CR, close relative, first-degree or second-degree relative; FDR, first-degree relative; 1st/1st: two first-degree relatives; ∗ BOADICEA, BRCAPRO, PENN II (see Table 5 bis//supplementary data); ∗∗ in the paternal or maternal side; ∗∗∗ death or other reason.

      3.3 Treatment personalisation of breast cancer

      For women with a recent diagnosis of primary breast cancer and those with metastatic breast cancer, the knowledge of BRCA mutation status could significantly influence the medical or surgical decision-making. Table 4 summarises the situations in which rapid testing could have meaningful clinical application.
      Table 4Rapid BRCA testing for treatment personalisation of primary or metastatic breast cancer.
      Treatment personalisationOptionTreatment phaseCriteria for rapid testingPersonalisationReferences
      Putative impact on surgery for women considering preventive surgerymastectomy versus conservative surgeryprior surgery

      neoadjuvant chemotherapy
      • age <40
      • TNBC
      • high lBRCAm
      • newly diagnosed cancer in a family with a known mutation
      		breast conservative surgery or radical preventive surgery (ipsilateral or bilateral). Both acceptable options.1

      2

      3,4,5,6,7,8
       Putative impact on radiation therapy for women considering preventive surgeryno radiation therapy versus radiation therapyafter ipsilateral or bilateral mastectomyhigh lBRCAm with age >35, T1/T2, N0, HR+ and HER2-
      • •
        no PMRT if age >40, HR + Her 2-grade I/II, no LVI, pT1 pN0
      • •
        PMRT required if age <35, or pN + T3/T4 HER2+ M+
      • •
        PMRT multidisciplinary discussion if intermediate risk
      		9

      2
       Putative impact on chemotherapyplatinumneoadjuvantno evidence of benefitno recommendations2

      5

      6
      platinum versus taxanemetastatic in platinum-naive patientTNBC or hormone resistantplatinum-containing regimen10

      11,6
      Putative impact on targeted therapyPARPineoadjuvantno evidence of benefitongoing trial12
      PARPimetastaticTNBC or hormone resistantolaparib, talazoparib13,6,14,2,5
      PMRT, post-mastectomy radiation therapy; PARPi, poly(ADP)ribose polymerase inhibitor; HR+, hormone receptor-positive; TNBC, triple-negative breast cancer.
      For women with primary breast cancer and high lBRCAm, the knowledge of the mutation status may be critical in the surgical options offered, specifically when the patient is a candidate for total mastectomy (uni- or bilateral) because of increased risk of a second ipsi- and/or contralateral cancer. Women with putative hereditary risk, particularly in the context of a strong family history, TNBC, young age at disease onset, or known BRCA mutation in a relative and willing to consider preventive surgery, should receive complete information delivered by a surgeon, oncologist and genetics counsellor to guide their autonomous choice. Prognostic factors of breast cancer, age, comorbidities and psychological aspects should be taken into account, as stated in currently available guidelines (NCCN [
      • Daly M.B.
      • Pilarski R.
      • Yurgelun M.B.
      • Berry M.P.
      • Buys S.S.
      • Dickson P.
      • et al.
      NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.
      J Natl Compr Canc Netw. 2020; 18: 380-391
      ], French Institut National du Cancer 2017 [
      • Tung N.M.
      • Boughey J.C.
      • Pierce L.J.
      • Robson M.E.
      • Bedrosian I.
      • Dietz J.R.
      • et al.
      Management of hereditary breast cancer: American society of clinical oncology, American society for radiation oncology, and society of surgical oncology guideline.
      J Clin Oncol. 2020; 38: 2080-2106
      ,

      Institut National Du Cancer. Thésaurus - Femmes porteuses d’une mutation de BRCA1 ou BRCA2/Détection précoce du cancer du sein et des annexes et stratégies de réduction du risque - ref : RECOBRCATHES17 n.d. http://www.e-cancer.fr/ [accessed 28 August 2020].

      ]). The working group recommended proposing the test in a rapid turnaround time after information on the benefit and risk of prophylactic surgery is given by a multidisciplinary team, including a surgeon, geneticist and medical oncologist if the patient actively opts for this analysis. For patients with newly diagnosed breast cancer and high lBRCAm, breast conservative surgery is also an option [
      • Tung N.M.
      • Boughey J.C.
      • Pierce L.J.
      • Robson M.E.
      • Bedrosian I.
      • Dietz J.R.
      • et al.
      Management of hereditary breast cancer: American society of clinical oncology, American society for radiation oncology, and society of surgical oncology guideline.
      J Clin Oncol. 2020; 38: 2080-2106
      ]. Thus, conservative surgery and uni- or bilateral risk-reducing mastectomy should be discussed and balanced in discussion with the patient, considering the increased risk of a second cancer (ipsi- or contralateral), the physical and psychological burden of surgery and taking into account prognostic factors, age and comorbidities with respect to the autonomous choice of the patient.
      For women with breast cancer at low risk of recurrence, such as age at onset >40 years and N0, T1/T2, hormone-receptor–positive (HR+), and human epidermal growth factor receptor–negative (HER2-) tumours, radiation therapy could be omitted when the patient opts for mastectomy rather than conservative surgery for preventive action. In contrast, a risk-reducing mastectomy that follows conservative surgery plus radiation therapy may negatively affect the cosmetic results and increase surgery complications.
      In the metastatic setting, for patients with HER2 negative tumours requiring chemotherapy, gBRCA testing is recommended because a platinum treatment should be preferred to taxane in platinum-naive patients [
      • Tung N.M.
      • Boughey J.C.
      • Pierce L.J.
      • Robson M.E.
      • Bedrosian I.
      • Dietz J.R.
      • et al.
      Management of hereditary breast cancer: American society of clinical oncology, American society for radiation oncology, and society of surgical oncology guideline.
      J Clin Oncol. 2020; 38: 2080-2106
      ,
      • Cardoso F.
      • Senkus E.
      • Costa A.
      • Papadopoulos E.
      • Aapro M.
      • André F.
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      Ann Oncol. 2018; 29: 1634-1657
      ,

      OncologyPRO. Making a difference for advanced breast cancer patients n.d. https://oncologypro.esmo.org/meeting-resources/eso-esmo-advanced-breast-cancer-fifth-international-consensus-conference-abc5/making-a-difference-for-advanced-breast-cancer-patients [accessed 1 September 2020].

      ,
      • Tutt A.
      • Tovey H.
      • Cheang M.C.U.
      • Kernaghan S.
      • Kilburn L.
      • Gazinska P.
      • et al.
      Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial.
      Nat Med. 2018; 24: 628-637
      ]. In the neoadjuvant setting, because available studies are not conclusive, the use of a platinum-containing regimen is not routinely recommended outside clinical trials (Table 4).

      3.4 Theragnostic value for PARPi

      The use of PARPi and the lBRCAm in breast, ovarian, prostate and pancreatic cancer are summarised in Table 5, Table 6. In ovarian cancer, the benefits of various PARPi therapies (olaparib, niraparib rucaparib, and veliparib) on progression-free survival in phase III randomised trials are highly significant and approved by the EMA and FDA (Table 5). In the absence of gBRCAm, BRCAm should be screened in any non-mucinous high-grade epithelial ovarian carcinoma at the germline and tumour level because PARPi has been found efficacious in exclusive tumour mutation, and thus, approved by drug agencies (for review, see Ref. [
      • Neviere Z.
      • De La Motte Rouge T.
      • Floquet A.
      • Johnson A.
      • Berthet P.
      • Joly F.
      How and when to refer patients for oncogenetic counseling in the era of PARP inhibitors.
      Ther Adv Med Oncol. 2020; 12 (1758835919897530)
      ]). Personal or family criteria could not discriminate against women with BRCAm because up to 40% of women carrying a BRCA1 or BRCA2 mutation do not present a discernible family history or meet NCCN [
      • Daly M.B.
      • Pilarski R.
      • Yurgelun M.B.
      • Berry M.P.
      • Buys S.S.
      • Dickson P.
      • et al.
      NCCN guidelines insights: genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 1.2020.
      J Natl Compr Canc Netw. 2020; 18: 380-391
      ] or other testing criteria (Table 6).
      Table 5Rapid BRCA testing process for PARPi.
      OrganStateRapid testingDrugGermline or tumour BRCAm, HRDApprovalStudy/Reference
      Ovary ∗Maintenance (after first line)Platinum sensitive

      High-grade serous      		olaparibTumour or germlineFDA, EMASOLO11 (NCT01844986)

      PAOLA2 (NCT02477644)
      Platinum sensitive

      High-grade serous or endometrioid      		olaparib plus bevacizumabTumour or germline

      HRD      		FDA, EMA
      Platinum sensitive

      High-grade serous or endometrioid      		niraparibAll-comersFDA, EMAPRIMA3 (NCT02655016)
      Front line and maintenanceHigh grade serous or endometrioidveliparibTumour or germline, HRDFDA UR

      EMA UR      		VELIA4 (NCT02470585)
      RecurrencePlatinum sensitive

      High-grade serous or endometrioid      		olaparibTumour or germline

      All-comers      		FDA, EMA

      FDA, EMA      		5 (NCT00753545),6 (NCT00753545), SOLO7 (NCT01874353),

      STUDY 198 (NCT00753545)
      Platinum sensitive

      High-grade serous or endometrioid      		rucaparibAll-comersFDA, EMAARIEL 39,10 (NCT01968213), (NCT01968213)
      Platinum sensitiveniraparibAll-comersEMA FDANOVA11 (NCT01847274)

      QUADRA12 (NCT02354586)
      Recurrence >2 linesIn patients intolerant to platinumrucaparibTumour or germlineEMA URARIEL 2 (NCT01891344)
      ProstateMetastaticCastration resistant (who received taxane and abiraterone/enzalutamide)olaparibTumour or germline, HRDFDA EMAPROfound13 (NCT02987543)
      rucaparibTumour or germlineFDATRITON 214 (NCT02952534)
      niraparibTumour or germlineFDA BTDGALAHAD15 (NCT02854436)
      talazoparibAll-comersNATALAPRO 1/216,17 (NCT03148795), (NCT03395197)
      PancreasMetastatic

      Maintenance      		Platinum sensitive (with no progression at 16 weeks)olaparibGermlineFDA, EMAPOLO18 (NCT02184195)
      BreastMetastatic or locally advancedTNBC or HR + HER2- hormone-resistantolaparib talazoparibGermline

      Germline      		EMA FDA

      EMA FDA      		OlympiAD19 (NCT02000622)

      EMBRACA20 (NCT01945775)
      HRD, homologous recombination deficiency; BTD Breakthrough Therapy Designation; ∗epithelial non-mucinous non-borderline ovarian cancer, tubal or peritoneal carcinoma. UR, Under review; NA, not available.
      Table 6Likelihood of germline BRCAm in unselected BRCA-related cancer.
      Site/StageBRCA 1 (%)BRCA 2 (%)BRCA 1/2 (%)ReferencesgBRCAm found although unmet testing criteria∗ (%)References
      Breast Cancer
      Any disease stage0.2–4.10.8–2.51.6–10.71,2,3,4,5,6,7,820–772,9,3,4,5,6,7
      Metastatic only1.1–2.01.0–2.93.0–4.310,11,12––
      Prostate Cancer
      Any disease stage0–1.251.1–4.71.0–5.913,14,15,1637–6415,17
      Metastatic0–1.34.2–94.2–1013,18,19,20,21,22,23,24,25,26,27,2844–5322,23
      Pancreatic Cancer
      Any disease stage0–1.41.3–4.21.8–7.129,30,31,32,33,34,35,36,37,38,39,4012–5729,31,33,41,39,40
      Metastatic1.51.53–7.513,42,43,44––
      Ovarian Cancer
      Any disease stage4–13.30.6–85.8–25.88,45,46,47,48,49,50,51,52,53,54,55,56,57,58,598–7748,49,47,46,55,51,56,58
      gBRCAm, germline BRCA mutation; ∗Testing criteria vary according to the publication, NCCN criteria, family criteria, Ontario criteria, etc.; -, No data available.
      For women with metastatic breast cancer, olaparib and talazoparib improved both progression-free survival and quality of life as compared with chemotherapy in two phase III randomised trials ([
      • Robson M.
      • Im S.-A.
      • Senkus E.
      • Xu B.
      • Domchek S.M.
      • Masuda N.
      • et al.
      Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.
      N Engl J Med. 2017; 377: 523-533
      ,
      • Litton J.
      • Rugo H.S.
      • Ettl J.
      • Hurvitz S.
      • Gonçalves A.
      • Lee K.-H.
      • et al.
      Abstract GS6-07: EMBRACA: a phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician's choice of therapy in patients with advanced breast cancer and a germline BRCA mutation. General Session Abstracts.
      American Association for Cancer Research, 2018
      ]). Overall survival was not significantly improved in these studies [

      Program Planner n.d. https://www.abstractsonline.com/pp8/#!/9045/presentation/10773 [accessed 1 September 2020].

      ,
      • Robson M.
      • Domchek S.
      Broad application of multigene panel testing for breast cancer susceptibility-Pandora’s box is opening wider.
      JAMA Oncol. 2019; https://doi.org/10.1001/jamaoncol.2019.4004
      ]. Screening for BRCAm in the metastatic setting is recommended for any TNBC or hormone-resistant breast cancer because personal or family criteria predicting mutation are lacking in 20%–70% of patients (Table 6). In the neoadjuvant setting, PARPi agents are under investigation (ClinicalTrials.gov: NCT03499353) and are not currently recommended outside of the clinical research field.
      In metastatic prostate cancer, the PARPi agents, olaparib, rucaparib, niraparib and talazoparib, were found to be effective in phase II or III trials (Table 5). Because almost 50% of BRCA cases occur in patients who do not present family criteria for testing, BRCA testing should be proposed to any person with metastatic castrate-resistant prostate cancer (Table 6). A fast track process should be proposed to patients with castration-resistant prostate cancer who have already received taxane and abiraterone or enzalutamide because a PARPi, in this case, provides a superior response as compared with other agents, given the results of clinical trials (Table 5, [
      • Giri V.N.
      • Knudsen K.E.
      • Kelly W.K.
      • Cheng H.H.
      • Cooney K.A.
      • Cookson M.S.
      • et al.
      Implementation of germline testing for prostate cancer: philadelphia prostate cancer consensus conference 2019.
      J Clin Oncol. 2020; 38: 2798-2811
      ]). BRCA tumour genotyping could be proposed as a first approach if coupled with complete information on family and preventive consequences of a germline finding.
      In metastatic pancreatic cancer, BRCA testing should be offered to all patients with platinum-sensitive cancer given the results of the POLO study, in which olaparib improved progression-free survival and quality of life of patients with advanced pancreatic cancer, with no disease progression at 16 weeks after platinum initiation [
      • Golan T.
      • Hammel P.
      • Reni M.
      • Van Cutsem E.
      • Macarulla T.
      • Hall M.J.
      • et al.
      Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
      N Engl J Med. 2019; 381: 317-327https://doi.org/10.1056/nejmoa1903387
      ,
      • Hammel P.
      • Kindler H.L.
      • Reni M.
      • Van Cutsem E.
      • Macarulla Mercade T.
      • Hall M.J.
      • et al.
      POLO: health-related quality of life (HRQoL) of olaparib maintenance treatment versus placebo in patients with a germline BRCA mutation and metastatic pancreatic cancer (mPC).
      Ann Oncol. 2019; 30: v254-v255https://doi.org/10.1093/annonc/mdz247.003
      ]. Given the rapid evolution of pancreatic cancer, BRCA testing may be proposed as soon as the diagnosis is given. Family criteria could not be used to select patients for BRCA genotyping because 10%–60% of germline mutation carriers with pancreatic cancer do not fit the NCCN criteria (Table 6). Further studies are needed to evaluate whether molecular profiling at the time of diagnosis, including BRCAm status, would help decide the first-line chemotherapy (e.g., platinum-containing regimen).

      3.5 Sequence analysis

      BRCA sequence analysis should be performed and reported according to laboratory guidelines such as the American College of Medical Genetics (ACMG) standards ([
      • Richards S.
      • Aziz N.
      • Bale S.
      • Bick D.
      • Das S.
      • et al.
      on behalf of the 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: 405-423
      ] for germline DNA sequencing [
      • Li M.M.
      • Datto M.
      • Duncavage E.J.
      • Kulkarni S.
      • Lindeman N.I.
      • Roy S.
      • et al.
      Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, American society of clinical oncology, and college of American pathologists.
      J Mol Diagn. 2017; 19: 4-23
      ]; for tumour DNA sequencing). For both germline and tumour DNA sequencing and interpretation of results, particular attention should be paid to coverage (at least 100% of exonic sequence and adjacent intronic sequence that may affect the splice site), read depth (at least 30× for germline single nucleotide variant (SNV) DNA sequencing, at least 200× for copy number variant (CNV) DNA sequencing, at least 300× for tumour DNA sequencing), use of the Human Genome Variation Society (HGVS [

      Describing sequence variants n.d. http://www.hgvs.org/mutnomen [accessed 1 September 2020].

      ]) unambiguous nomenclature for variant designation, and use of well-defined variant classification. For BRCA1 or BRCA2 germline variants, classification should be based on variant pathogenicity with respect to a hereditary cancer predisposition syndrome, such as the five-category classification of the ACMG: pathogenic, likely pathogenic, uncertain significance, likely benign, or benign [
      • Richards S.
      • Aziz N.
      • Bale S.
      • Bick D.
      • Das S.
      • et al.
      on behalf of the 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: 405-423
      ]. Standardised terminology and definitions for describing and reporting sequence variation have been set out by the recommendations of the ENIGMA consortium (PMID: 30962250 J Med Genet. 2019 Jun; 56(6):347–357. Towards controlled terminology for reporting germline cancer susceptibility variants: an ENIGMA report Amanda B Spurdle 1, Stephanie Greville-Heygate 2, Antonis C Antoniou 3, Melissa Brown 4, Leslie Burke 4, Miguel de la Hoya 5, Susan Domchek 6, Thilo Dörk 7, Helen V Firth 8, Alvaro N Monteiro 9, Arjen Mensenkamp 10, Michael T Parsons 1, Paolo Radice 11, Mark Robson 12, Marc Tischkowitz 13, Emma Tudini 1, Clare Turnbull 14 15, Maaike Pg Vreeswijk 16, Logan C Walker 17, Sean Tavtigian 18 19, Diana M Eccles 2).
      For BRCA1 and BRCA2 somatic variants, classification should focus on their significance in clinical decision-making with respect to the therapeutic issue (i.e., the 4-category classification of the ACMG: strong clinical significance, potential clinical significance, unknown clinical significance and benign or likely benign variants) [
      • Li M.M.
      • Datto M.
      • Duncavage E.J.
      • Kulkarni S.
      • Lindeman N.I.
      • Roy S.
      • et al.
      Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, American society of clinical oncology, and college of American pathologists.
      J Mol Diagn. 2017; 19: 4-23
      ]. Implementation of techniques and pipelines enabling both SNV and CNV detection should be preferred, optimally by next-generation sequencing. Implementation of identity monitoring should be guaranteed. For appropriate interpretation of tumour DNA sequencing results, specific consideration should be given to the cellularity of the tumour sample (<30% considered as low cellularity and <10% very low cellularity, increasing false-negative results), variant allele fraction, and variant detection in a normal matched control DNA sample if included.

      4. Guidelines bottom line

      4.1 Guideline questions

      What are the current indications for BRCA testing in clinical practice?
      What is the place for BRCA tumour testing and a fast-track process in treatment personalisation of BRCA-related cancer?

      4.2 Target population

      Individuals with a personal or family risk of a BRCAm (preventive purpose).

      4.3 Breast cancer patient

      Patient with a diagnosis of BRCA-related cancer sensitive to PARPi agents (ovarian, breast, prostate, pancreas).

      4.4 Target audience

      The target audience and intended users of these guidelines are health providers involved in BRCA-related cancers, including geneticists, medical and radiation oncologists, surgeons, organ specialists such as gynaecologists, urologists and gastroenterologists, general practitioners and genetic counsellors.

      4.5 Guideline aims

      Establish clinical guidelines on BRCA testing to (1) identify individuals who may benefit from risk-reducing strategies, (2) update recommendations of testing for theragnostic purposes with PARPi agents in BRCA-related cancer, (3) provide recommendations for testing for personalised management of early and metastatic breast cancer, and (4) define the place and role of a tumour testing approach and fast-track genotyping and counselling processes.

      4.6 Methods

      An expert panel consisting of clinical geneticists; medical, radiation and surgical oncologists; molecular geneticists; pathologists; genetic counsellors; patient representatives; ethicists; psychologists; lawyers; and methodologists developed clinical practice guideline recommendations for BRCA testing. These recommendations are based on a combined approach that included a systematic review of the medical literature, evaluation of the lBRCAm (from publications, evaluation by risk assessment models and expert opinion), the theragnostic value in BRCA-related cancer (based on treatment approval for PARPi agents in specific cancer types) and the impact of BRCAm knowledge on the management of early or advanced breast cancer. The overall guideline development process, including the funding of the work, panel formation, management of conflicts of interest, internal and external review, and organisational approval, was guided by procedures derived from the Guidelines International Network–McMaster Guideline Development Checklist [

      Guideline development checklist n.d. http://cebgrade.mcmaster.ca/guidecheck.html [accessed 1 September 2020].

      ].

      4.7 Recommendations

      • 1.
        Preventive
        • 1.1.
          For patients presenting a personal or family history of high lBRCAm (grade A, Table 7), BRCA testing should be offered after genetics information is provided and discussed with a specialist in genetics.
          Table 7Grade A BRCA testing criteria.
          Criteria
          Individual (BC)Age ≤ 40
          Age ≤ 50: bilateral£, founder effect$

          Age ≤ 60 triple negative
          Male
          Family historyBC with BC in two FDR∗
          BC with any of individual above criteria in a FDR∗∗
          Any relative of a known BRCA mutation carrier
          TheragnosticEpithelial ovarian cancer∗∗∗
          Metastatic HR and TN BC
          Metastatic HR prostate cancer
          Metastatic platinum-sensitive pancreatic cancer
          BC, breast cancer; FDR, first-degree relative; HR, hormone resistant; £bilateral BC with one ≤50 years; $ Ashkenazi Jewish or Icelandic heritages; ∗ within maternal or paternal side; ∗∗ anytime possible the affected relative would be the most relevant to test first; ∗∗∗ also fulfil individual preventive grade A criteria; non-mucinous, including primary peritoneal and fallopian tube; TN, triple negative.
        • 1.2.
          For patients with moderate lBRCAm (grade B, Table 8), testing should be considered taking into account specificities of the family history and personal criteria, and issues should be discussed with the patient in a dedicated and personalised genetic consultation.
          Table 8Grade B BRCA testing criteria.
          Criteria
          Individual (BC)
          • •
            Age 41-45
          • •
            TNBC age >60
          • •
            Bilateral (first after age 50)
          • •
            BC >50 with founder effect*
          • Family history or combined
          • •
            BC with 2 cases of BC in a second- or third-degree relative
          • •
            BC with individual grade A criteria (TNBC, age ≤ 40, male, ovarian cancer) in a second- or third-degree relative
          • •
            BC and 1 case of BC in first-degree relative with one age ≤ 50
          • •
            BC and a bilateral BC in first-degree relative (first after age 50)
          • •
            BC and 1 case of prostate cancer (Gleason score ≥ 7, metastatic or age ≤ 60) in an FDR
          • •
            BC and 1 case of pancreas cancer in an FDR
          • •
            BC with association of 2 cases of prostate (Gleason score ≥ 7, metastatic or age ≤ 60 years), pancreas or melanoma cancer in a CR
          • •
            Prostate or pancreatic cancer with AJ or Icelandic heritage
          • •
            Family history
            Association of two or more of these types of cancer in a CR on maternal or paternal side.
            of pancreatic and/or prostate cancer
          • •
            Person with an FDR with one of individual grade A criteria and no possibility for testing
            Death or other reason.
          CR, close relative; FDR, first-degree relative; If not specify BC, breast cancer any age. ∗ founder effect: Ashkenazi Jewish or Icelandic heritages.
          a Association of two or more of these types of cancer in a CR on maternal or paternal side.
          b Death or other reason.
        • 1.3.
          Independently of the lBRCAm, testing should be performed in a non-directive manner, and the patient’s autonomy and desire to know or to ignore the mutational status must be respected. The individual should make an informed decision with a written consent on whether they want to pursue genetic testing at the dedicated consultation.
        • 1.4.
          For patients with low lBRCAm (grade C) and for whom the mutational status does not have a proven therapeutic value, BRCA testing is not routinely recommended in clinical practice. However, the working group raised the question of the ethical issue of denying access to a BRCA genetic test for informed individuals with low lBRCAm who wish to be tested, given that up to 50% of breast cancer mutation carriers have low lBRCAm. In this situation, genetic counselling before and after the test is highly recommended. The test should be performed in a qualified laboratory fulfilling quality criteria for testing (see below). This option raises unsolved issues of cost-efficiency, medical benefit and testing reimbursement.
        • 1.5.
          Genetic counselling is highly recommended before and after a BRCA predictive test for a known familial mutation.
      • 2.
        Breast cancer treatment personalisation
        • 2.1.
          For patients with newly diagnosed breast cancer and meeting criteria of high lBRCAm, germline testing (gBRCA) should be considered when BRCAm status could affect the management of breast cancer (Table 4). For women with heredity-associated increased risk of a second cancer, particularly in the context of a cancer-dense family history, TNBC, young age or a relative with a known BRCAm, who are willing to consider the option of risk-reducing surgery, BRCA testing should be offered as a fast-track process after receiving complete information pertaining to the possible outcome of the test. The information should be given by a multidisciplinary team, including an oncologist, surgeon and genetic counsellor, to foster an autonomous choice and optimise the oncoplastic surgical decision and sequence. Appropriately trained non-geneticists involved in breast cancer such as oncologists and surgeons could give adequate information in coordination with genetic professionals.
        • 2.2.
          For metastatic breast cancer patients requiring chemotherapy, gBRCAm testing is recommended because platinum chemotherapy should be preferred to taxane in platinum-naive patients.
        • 2.3.
          In HER2-negative metastatic breast cancer, gBRCAm testing is recommended because olaparib or talazoparib should be offered as an alternative to first-to third-line chemotherapy for women with gBRCAm.
      • 3.
        PARPi
        • 3.1.
          BRCA testing should be offered for PARPi theragnostic purposes to patients with HER2-negative metastatic breast and castrate-resistant prostate cancer, platinum-sensitive metastatic pancreatic cancer and newly diagnosed FIGO stage III/IV or recurrent high-grade epithelial ovarian cancer in a fast-track process after specific genetic information is provided.
        • 3.2.
          For targeted therapy with PARPi agents, BRCA testing is recommended regardless of moderate or high lBRCAm criteria because 10%–75% of patients with breast, ovarian, prostate or pancreatic cancer, and gBRCAm do not fulfil these criteria (Table 6).
        • 3.3.
          Epithelial ovarian cancer fulfils criteria of high lBRCAm for risk-reducing purposes and major theragnostic value. Therefore, gBRCA testing should be offered to any woman with epithelial non-borderline non-mucinous ovarian cancer at the time of diagnosis in a fast-track process. Additional tumour testing should be proposed to ovarian cancer patients who do not carry gBRCAm.
        • 3.4.
          Appropriately trained non-geneticists involved in cancer care such as oncologists and surgeons could give adequate initial information in coordination with a multidisciplinary team, including geneticists.
      • 4.
        Tumour testing
        • 4.1.
          When tumour testing for theragnostic purposes is the preferred initial approach, the patient should be aware of inherited genetic aspects, including family and prevention issues that might emerge from genetic tumour testing, because most tumour BRCAm findings reflect a germline predisposition. Thus, genetic information and informed consent are required before any BRCA tumour testing. In case of therapeutic value, the information should be given by trained healthcare providers such as oncologists familiar with the genetic diagnosis and management of hereditary breast cancer, working in conjunction with a genetic consultation.
        • 4.2.
          For appropriate interpretation of tumour DNA sequencing results, specific consideration should be given to the cellularity of tumour sample, depth of coverage, ability to detect long-scale rearrangement and variant allele fraction. Techniques and pipelines enabling both SNV and CNV detection such as next-generation sequencing should be preferred
        • 4.3.
          Germline testing should be offered to any patient with an identified pathogenic or likely pathogenic tumour BRCA mutation.
        • 4.4.
          Educational programs should be developed to increase the awareness and training of healthcare providers in oncology, particularly oncologists, surgeons, organ specialists and patient advocacy representatives, to improve their skills to provide adequate explanations for BRCA testing for therapeutic purposes and personalised care according to the genetic results.
      • 5.
        General recommendations
        • 5.1.
          Clinical decisions, including preventive issues, management of breast cancer or PARPi treatment, should be based on pathogenic or likely pathogenic variants but not variants of unknown significance (VUS).
        • 5.2.
          BRCA sequence analysis should be performed and reported according to laboratory guidelines. For both germline and tumour DNA sequencing and interpretation of results, particular attention should be paid to sequence coverage (at least 100% of exonic sequence and intronic sequence adjacent to the splice site) and read coverage (at least 30× for SNV and 200× for CNV in germline DNA sequencing, at least 300× for tumour DNA sequencing). Results should use an unambiguous nomenclature for variant designation and classification (HGVS, ACMG).
        • 5.3.
          For germline or tumour BRCA genetic testing for theragnostic use, the information should be given by a clinician trained and aware of genetics, including the interpretation of results, regulations and risk-reducing strategies. The information given to the patient may include the medical implications of a positive, negative or non-informative result (i.e., VUS); the risk of transmission of genetic predisposition to offspring and family relatives (and according to regulations of certain countries in Europe, the legal obligation to transmit the information to close relatives); and the risk and benefit of risk-reducing strategies and the psychological consequences of knowing a genetic predisposition.

      5. Discussion

      BRCA1 and BRCA2 gene mutations account for most actionable genetic breast cancer predispositions and are increasingly used for personalised breast cancer management and PARPi therapy of BRCA-related cancer. Thus, we propose updated guidelines for BRCA testing. Preventive and therapeutic indications are now overlapping in many situations, as in ovarian cancer or metastatic breast cancer. Thus, BRCA testing should be considered in a global and integrative way so that healthcare providers involved in both cancer care and genetics can clarify and standardise the appropriate process and timing of BRCA testing for all patients. With this aim, we introduce a methodology of recommendations based on expert consensus, integrating published data on lBRCAm and their respective levels of evidence, evaluation of lBRCAm by risk model assessment as well as the therapeutic value of BRCAm for managing BRCA-related cancer.
      Of note, epithelial ovarian cancer is the most powerful predictor of lBRCAm. Also, BRCAm in ovarian cancer offers the most actionable context for both preventive and therapeutic purposes. This point still needs to be universally communicated to healthcare providers and to professionals involved in managing ovarian cancer because recent data show a lack of testing in patients with ovarian cancer [
      • Dewdney S.
      • Potter D.
      • Haidle J.L.
      • Hulick P.J.
      • Riffon M.
      • Monzon F.A.
      • et al.
      Low rates of BRCA1 and BRCA2 testing for patients with ovarian cancer in ASCO's CancerLinQ, a real-world database.
      J Clin Oncol. 2020; 38 (6041–6041)https://doi.org/10.1200/jco.2020.38.15_suppl.6041
      ].
      Although the burgeoning knowledge of hereditary breast and ovarian cancer (HBOC) and the development of next-generation sequencing have prompted the use of multigene panels that include TP53, PALB2, PTEN, CDH1, and STK11, BRCA1 and BRCA2 gene mutations account for the vast majority of the actionable and identifiable hereditary syndromes [
      • Huang K.-L.
      • Mashl R.J.
      • Wu Y.
      • Ritter D.I.
      • Wang J.
      • Oh C.
      • et al.
      Pathogenic germline variants in 10,389 adult cancers.
      Cell. 2018; 173 (355–70.e14)
      ,
      • Buys S.S.
      • Sandbach J.F.
      • Gammon A.
      • Patel G.
      • Kidd J.
      • Brown K.L.
      • et al.
      A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes.
      Cancer. 2017; 123: 1721-1730
      ,
      • Couch F.J.
      • Shimelis H.
      • Hu C.
      • Hart S.N.
      • Polley E.C.
      • Na J.
      • et al.
      Associations between cancer predisposition testing panel genes and breast cancer.
      JAMA Oncol. 2017; 3: 1190-1196
      ]. Moreover, many other actionable genes involved in HBOC (i.e. TP53, PTEN, CDH1 and STK11) are often responsible for specific personal and family characteristics that differ from criteria for BRCA testing. Therefore, guidelines for BRCA testing should be clarified independently of other considerations. However, multigene panel genotyping is useful in BRCA-negative familial syndrome. Mutations of PALB2, RAD51C and other genes are currently under investigation to detect PARPi sensitivity but are not yet approved in BRCA-related cancer. The human recombination deficiency (HRD) that included tBRCAm and gBRCAm is approved as a predictive marker of PARPi sensitivity in ovarian cancer and studied with different approaches in other BRCA-related cancer. Further recommendations are needed for clinicians on HRD used as a predictive marker of PARPi sensitivity. Here, we focused on specific criteria that drive a clinical, non-systematic and personalised recommendation of BRCA testing for any individual with a family history or affected by BRCA-related cancer.
      From abundant literature, personal parameters related to breast cancer, such as TNBC, male breast cancer, early-onset breast cancer, or bilateral breast cancer, have been identified as predictors of a high probability of harbouring BRCA1 or BRCA2 mutations. The founder effect is another parameter that significantly increases the lBRCAm. For women with breast cancer who are of Ashkenazi or Icelandic heritage, the lBRCAm varies widely according to the study and population (from 4.5% to 25%; Table 2b). When considering subgroups of early-onset, TNBC and male breast cancer in individuals of Ashkenazi or Icelandic ethnicity, the lBRCAm is increased to more than 10%. Ashkenazi or Icelandic heritage in other situations received a grade B recommendation for testing outside these subgroups, except for Ashkenazi Jewish and Icelandic women with breast cancer diagnosed before age 50 years. Ashkenazi or Icelandic heritage in a woman with any grade B personal or family criteria should be considered for testing because this factor significantly increases the lBRCAm.
      Most combined and family criteria proposed in guidelines are based on clinical studies with a low level of evidence. For most of these criteria, only subgroup analyses of studies were available, and for some, no data were available in our search. Moreover, most published data are devoted to the selection bias of women referred for genetic counselling and undergoing BRCA testing. In situations of combined criteria for which clinical data are lacking, a risk assessment model could provide a helpful estimate of the lBRCAm. However, as reported previously, the estimation varies widely among models [
      • Panchal S.M.
      • Ennis M.
      • Canon S.
      • Bordeleau L.J.
      Selecting a BRCA risk assessment model for use in a familial cancer clinic.
      BMC Med Genet. 2008; 9: 116
      ] and may not be appropriate to discriminate some situations such as triple-negative phenotype, discrimination of risk according to relative closeness, ability to score single criteria, integrating prostate or pancreas cancer affecting relatives, etc. Because family or combined situations could not be exhaustively addressed by a literature search and/or estimates by models, lBRCAm >2.5% was assumed for some items such as ‘BC with ≥2 prostate, pancreatic or melanoma cancer cases in close relatives’ or ‘family history of pancreatic cancer and/or prostate cancer (≥2 cancer cases in first-, second- or third-degree relatives)’. With the complexity and a high number of combinations of parameters, the evaluation of lBRCAm in each situation should be addressed and discussed in a dedicated genetic and personalised consultation.
      Because of the clinical benefits of PARPi in BRCA-related cancer, the lack of timely identification of a BRCAm represents a lost opportunity for patients. Between 30% and 50% of patients with ovarian cancer or metastatic prostate, pancreatic or breast cancer do not fulfil personal or family criteria for preventive BRCA testing; thus, family history or personal criteria for testing cannot be retained to select patients who require testing. Of note, the incidence of BRCAm in metastatic prostate, pancreatic and breast cancer are in the range of grade B recommendations for testing for preventive purposes (2.5%–7.5%).
      In these guidelines, when the lBRCAm is estimated at <2.5% and the mutational status does not have therapeutic value, BRCA testing is not routinely recommended in clinical practice (expert agreement). The benefit of genetic testing is not established in women whose personal or family history suggest low risk for mutations in BRCA1 and BRCA2 genes, and the US Preventive Services Task Force found adequate evidence that this benefit is small to none (ref Task Force). However, in the study by Buchanan et al., some women with BRCA1 or BRCA2 mutation found in the UK genome projects without any personal/family criteria of testing benefitted from screening [
      • Manickam K.
      • Buchanan A.H.
      • Schwartz M.L.B.
      • Hallquist M.L.G.
      • Williams J.L.
      • Rahm A.K.
      • et al.
      Exome sequencing-based screening for BRCA1/2 expected pathogenic variants among adult biobank participants.
      JAMA Netw Open. 2018; 1e182140
      ]. Other studies suggest that screening may be beneficial in the general population or in women with breast cancer, particularly in populations with a high rate of predominant mutations [
      • King M.-C.
      • Lahad A.
      • Levy-Lahad E.
      Proposed shift in screening for breast cancer--reply.
      JAMA. 2015; 313: 525-526
      ,
      • Gabai-Kapara E.
      • Lahad A.
      • Kaufman B.
      • Friedman E.
      • Segev S.
      • Renbaum P.
      • et al.
      Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.
      Proc Natl Acad Sci U S A. 2014; 111: 14205-14210
      ]. The cost-effectiveness of BRCA testing is also debated in the low-risk or general population [
      • Sun L.
      • Brentnall A.
      • Patel S.
      • Buist D.S.M.
      • Bowles E.J.A.
      • Evans D.G.R.
      • et al.
      A cost-effectiveness analysis of multigene testing for all patients with breast cancer.
      JAMA Oncol. 2019; https://doi.org/10.1001/jamaoncol.2019.3323
      ,
      • Tuffaha H.W.
      • Mitchell A.
      • Ward R.L.
      • Connelly L.
      • Butler J.R.G.
      • Norris S.
      • et al.
      Cost-effectiveness analysis of germ-line BRCA testing in women with breast cancer and cascade testing in family members of mutation carriers.
      Genet Med. 2018; 20: 985-994
      ]. Further studies are required to state the medical benefit and cost-effectiveness of offering BRCA testing in populations with low lBRCAm and refining this cut-off. Overall, 20%–77% of BRCAm carriers in breast cancer do not fulfil testing criteria (Table 6), so strictly limiting access to genetic testing to people with high or moderate risk criteria and denying access to those with low risk who wish to be tested is questionable. The access of a person willing to undergo the test after genetic counselling and being given appropriate information about the benefits and risks of testing raises a host of unanswered questions in terms of ethics, regulation and economics. The Royal Marsden/ICR proposed that individuals not meeting any of the eligibility criteria could have a self-funded test. Other healthcare payers may be involved. The issue of testing low-risk individuals should be addressed in a personalised way according to the regional health regulations, funding and insurance policies. For testing low-risk patients, the working group recommended dedicated genetic consultation before and after the test, with complete information (including psychological impact, risk-reducing strategy and familial consequences of the test). Attention should be paid to the quality of the analysis, as described in our guidelines.
      Genetic counselling by a genetics professional genetics is recommended before and after a genetic test for an inherited breast/ovarian cancer syndrome related to BRCA and performed for preventive purposes. For theragnostic purposes, the information should be given by a clinician (physician or surgeon) who is trained, aware of genetics regulation, comfortable with interpreting results of a genetic test, and able to give appropriate information on risk-reducing strategies. The information should include the medical implications of a positive, negative or non-informative result (e.g., VUS); the risk of transmission of the genetic predisposition allele to an offspring and other family members (and according to regulations of certain countries in Europe, the juridical obligation to transmit the information to close relatives), the risk and benefit of risk-reducing strategies, and the psychological consequence of knowing the precise risk of genetic predisposition-associated cancer. Increasing numbers of surgeons and oncologists are becoming aware of these issues, and recent publications such as the ENGAGE results show that an oncologist-led BRCAm testing process in ovarian cancer is feasible [
      • Colombo N.
      • Huang G.
      • Scambia G.
      • Chalas E.
      • Pignata S.
      • Fiorica J.
      • et al.
      Evaluation of a streamlined oncologist-led BRCA mutation testing and counseling model for patients with ovarian cancer.
      J Clin Oncol. 2018; 36: 1300-1307
      ].
      If tumour testing for theragnostic purposes is preferred as the initial approach, the patient should be aware of the same family and prevention issues because most of the tumour mutation findings will be related to a germline predisposition [
      • Capoluongo E.
      • Scambia G.
      • Nabholtz J.-M.
      Main implications related to the switch to 1/2 tumor testing in ovarian cancer patients: a proposal of a consensus.
      Oncotarget. 2018; 9: 19463-19468
      ,
      • Pujol P.
      • De La Motte Rouge T.
      • Penault-Llorca F.
      From targeting somatic mutations to finding inherited cancer predispositions: the other side of the coin.
      Diagnostics. 2019; 9https://doi.org/10.3390/diagnostics9030083
      ]. Therefore, informed consent and genetic information are still required before any BRCA tumour testing, and patients should be aware that the results may have extra-therapeutic medical issues for themselves and their relatives. We and others previously reported clinical practice considerations and schemes for managing germline findings in somatic analysis, including written informed consent and a multidisciplinary approach involving an oncologist, molecular biologist/pathologist and geneticist for germline findings [
      • Capoluongo E.
      • Scambia G.
      • Nabholtz J.-M.
      Main implications related to the switch to 1/2 tumor testing in ovarian cancer patients: a proposal of a consensus.
      Oncotarget. 2018; 9: 19463-19468
      ,
      • Pujol P.
      • Vande Perre P.
      • Faivre L.
      • Sanlaville D.
      • Corsini C.
      • Baertschi B.
      • et al.
      Guidelines for reporting secondary findings of genome sequencing in cancer genes: the SFMPP recommendations.
      Eur J Hum Genet. 2018; 26: 1732-1742
      ,
      • Pujol P.
      • De La Motte Rouge T.
      • Penault-Llorca F.
      From targeting somatic mutations to finding inherited cancer predispositions: the other side of the coin.
      Diagnostics. 2019; 9https://doi.org/10.3390/diagnostics9030083
      ]. At any time of the somatic analysis, a patient may have access to a consultation with a geneticist if additional information is required. These recommendations should be regularly updated according to the knowledge evolution about cancer risk, target therapies with PARPi agents or other agents, and the level of evidence.
      These integrative and updated guidelines may help clinicians standardise and optimise BRCA testing practices for both preventive and therapeutic purposes.

      Conflicts of interest

      The development of these guidelines was wholly funded by SFMPP. The panelists received no payments. The complete CoI for researchers who contributed to the guidelines are provided in supplementary data. Categories for disclosure of CoI include employment; leadership; stock or other ownership; honoraria, consulting or advisory role; speaker’s bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships.

      Acknowledgements

      The authors acknowledge the contribution of patient advocacy from BRCA France and Sapins de noël des créateurs associations.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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      Article info

      Publication history

      Published online: February 09, 2021
      Accepted: December 14, 2020
      Received in revised form: December 9, 2020
      Received: October 23, 2020

      Footnotes

      ☆This work was commissioned and supported by the French Society of Predictive and Personalized Medicine (Société Française de Médecine Prédcitive et Personnalisée) (grant no. 11SFMPP201902), an independent nonprofit learned society.

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      DOI: https://doi.org/10.1016/j.ejca.2020.12.023

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