European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer
I Vergote, A González-Martín, I Ray-Coquard, P Harter, N Colombo, P Pujol, D Lorusso, M R Mirza, B Brasiuniene, R Madry, J D Brenton, M G E M Ausems, R Büttner, D Lambrechts, European experts’ consensus group, I Vergote, M Ausems, B Brasiuniene, J Brenton, R Büttner, N Colombo, A González-Martín, P Harter, D Lambrechts, D Lorusso, R Madry, M R Mirza, P Pujol, I Ray-Coquard, M Abreu, S Balboni, S Banerjee, M Barberis, M P Barretina Ginesta, J-F Baurain, M Bignami, L Bjorge, P Blecharz, I Bruchim, M Capilna, N Cerana, A Cicchetti, D Collins, N Concin, M D'Incalci, B Davidson, T de la Motte Rouge, P De Iaco, F Demirkiran, H Denys, T Doerk, A Dorum, A Ferrero, A P Fidalgo, M Genuardi, L Gladieff, R Glasspool, C Grimm, M Gultekin, E Hahnen, A Hasenburg, A Hegmane, V Heinzelmann, E Hogdall, R Janavicius, S Jarmalaite, R Kalachand, R Kaneva, S Kilickap, R Kocian, D Kolencik, R Kristeleit, A Kryzhanivska, A Leary, B Lemley, M Ligtenberg, J A López-Guerrero, C J Lord, E Avall-Lundqvist, J Maenpaa, S Mahner, F Marmé, C Marth, I McNeish, S Merkelbach-Bruse, M Mourits, N Normanno, A Oaknin, K Ojamaa, C Papdimitriou, F Penault-Llorca, A M Perrone, S Pignata, E Pikarsky, E Rouleau, M Rubio, A Sapino, B Schmalfeldt, J Sehouli, R Shapira, K D Steffensen, V Sukhin, J Syrios, Z Szallasi, C Taskiran, M Terzic, M Tischkowitz, I Toth, K Van de Vijver, M A Vardar, B Wasag, P Wimberger, E Witteveen, I Vergote, A González-Martín, I Ray-Coquard, P Harter, N Colombo, P Pujol, D Lorusso, M R Mirza, B Brasiuniene, R Madry, J D Brenton, M G E M Ausems, R Büttner, D Lambrechts, European experts’ consensus group, I Vergote, M Ausems, B Brasiuniene, J Brenton, R Büttner, N Colombo, A González-Martín, P Harter, D Lambrechts, D Lorusso, R Madry, M R Mirza, P Pujol, I Ray-Coquard, M Abreu, S Balboni, S Banerjee, M Barberis, M P Barretina Ginesta, J-F Baurain, M Bignami, L Bjorge, P Blecharz, I Bruchim, M Capilna, N Cerana, A Cicchetti, D Collins, N Concin, M D'Incalci, B Davidson, T de la Motte Rouge, P De Iaco, F Demirkiran, H Denys, T Doerk, A Dorum, A Ferrero, A P Fidalgo, M Genuardi, L Gladieff, R Glasspool, C Grimm, M Gultekin, E Hahnen, A Hasenburg, A Hegmane, V Heinzelmann, E Hogdall, R Janavicius, S Jarmalaite, R Kalachand, R Kaneva, S Kilickap, R Kocian, D Kolencik, R Kristeleit, A Kryzhanivska, A Leary, B Lemley, M Ligtenberg, J A López-Guerrero, C J Lord, E Avall-Lundqvist, J Maenpaa, S Mahner, F Marmé, C Marth, I McNeish, S Merkelbach-Bruse, M Mourits, N Normanno, A Oaknin, K Ojamaa, C Papdimitriou, F Penault-Llorca, A M Perrone, S Pignata, E Pikarsky, E Rouleau, M Rubio, A Sapino, B Schmalfeldt, J Sehouli, R Shapira, K D Steffensen, V Sukhin, J Syrios, Z Szallasi, C Taskiran, M Terzic, M Tischkowitz, I Toth, K Van de Vijver, M A Vardar, B Wasag, P Wimberger, E Witteveen
Abstract
Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition.
Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive.
Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.
Keywords: BRCA1/2; PARP inhibition; genetic counselling; homologous recombination deficiency; mainstream genetic testing; ovarian cancer.
Conflict of interest statement
Disclosure IV: Consulting (2019-2021): Aksebio (2021); Amgen (Europe) GmbH (2019); AstraZeneca (2019-2022); BMS (2021); Clovis Oncology Inc. (2019-2019); Carrick Therapeutics (2019); Deciphera Pharmaceuticals (2020-2021); Eisai (2021); Elevar Therapeutics (2020); F. Hoffmann-La Roche Ltd (2019-2021); Genmab (2019-2021); GSK (2019-2021); Immunogen Inc. (2019-2022); Jazzpharma (2021-2022); Karyopharm (2021); Mersana (2020); Millennium Pharmaceuticals (2019); MSD (2019-2022); Novocure (2020-2022); Novartis (2021); Octimet Oncology NV (2019); Oncoinvent AS (2019-2022); Sotio a.s. (2019-2022); Verastem Oncology (2020); Zentalis (2020). Contracted research: Oncoinvent AS (2019-2020); Genmab (2019-2021). Corporate sponsored research: Amgen (2019-2020); Roche (2019-2020). AG-M: Consulting (2019-2021): Amgen (Europe) (2019); AstraZeneca (2019-2021); Clovis Oncology Inc. (2019-2021); Eisai (2021); F. Hoffmann-La Roche Ltd (2019-2021); Genmab (2019-2020); GSK (2019-2021); Immunogen Inc. (2019-2021); Mersana (2020); MSD (2019-2021); Novocure (2020); Novartis (2021); Oncoinvent AS (2019-2021); Sotio (2019-2021). Contracted research: La Roche (2019-2021); GSK (2019-2021).IR-C: Consulting (2019-2021): Amgen (2019-2021); AstraZeneca (2019-2021); Clovis Oncology Inc. (2019-2021); Eisai (2021); F. Hoffmann-La Roche Ltd (2019-2021); Genmab (2019-2020); GSK (2019-2021); Mersana (2020-2021); Merck Serono (2020-2021); MSD (2019-2021); Novocure (2021); Novartis (2021); OnxEo (2020-2021); Pharmamar (2019-2021); Deciphera (2019-2021). Contracted research: BMS (2019-2021); MSD (2019-2021).PH: Honoraria: Amgen, AstraZeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis. Advisory board: AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD/Merck. Research funding (institute): AstraZeneca, Roche, GSK, Genmab, Immunogen, Clovis. NC: Consulting: AstraZeneca; BIOCAD; Clovis Oncology; Eisai; GlaxoSmithKline; Immunogen; Mersana; MSD; Oncxerna; Pharmamar; Pfizer; Roche; Tesaro. Promotional speaker: AstraZeneca; Clovis; Eisai; GlaxoSmithKline; MSD; Novartis; Tesaro. PP: AstraZeneca (2019-2021); Exact Science (2019-2021); GSK (2019-2021); HEDERADx (2021); MSD (2019-2021); Novartis (2020); Onco DNA (2019-2021); Pfizer (2019-2021); Predilife (2019-2021); Seqone (2019-2021).DL: Consulting (2019-2021): Amgen (2020); AstraZeneca (2019-2021); Clovis Oncology Inc. (2019-2021); Eisai (2021); F. Hoffmann-La Roche Ltd (2019-2020); Genmab (2019-2021); GSK (2019-2021); Immunogen Inc. (2019-2021); MSD (2019-2021); Novartis (2021); Merck Serono (2020-2021); Pharmamar (2019-2021). Contracted research: MSD (2019-2021); GSK (2019-2021); Clovis Oncology (2019-2021). MRM: Consulting and lectures: AstraZeneca; Biocad; GSK; Karyopharm; Merck; Roche; Zailab. Contracted research: Apexigen; AstraZeneca; GSK; Ultimovacs. Other: Karyopharm & Sera Prognistics (Member of Board of Directors); Deciphera (Trial Chair). BB: Consulting (2019-2021): F. Hoffmann-La Roche (2019-2020); AstraZeneca (2019-2020); Merck Serono (2019-2020); Pharmaswiss (2019-2020); GSK (2019); Novartis (2019-2021). Contracted research: AstraZeneca (2020-2021); F. Hoffmann-La Roche (2019-2020). RM: Consulting (2019-2021): AstraZeneca (2019-2021); F. Hoffmann-La Roche Ltd (2019-2020); GSK (2019-2021). JDB: Consulting (2020-2021): AstraZeneca. Contracted research: Clovis Oncology (2019); Aprea (2019-21); Tailor Bio (2020-21); Other: Co-founder and shareholder Inivata (2019-2021); Co-founder and shareholder Tailor Bio (2019-2021). MGEMA: Consulting (2019-2020): MSD. Contracted research: Pfizer (2020); AstraZeneca (2020). RB: Consulting and lectures (2019-2021): AbbVie; AstraZeneca; Bayer; BMS; Boehringer-Ingelheim; Janssen; Illumina; Lilly; MSD; Novartis; Qiagen; Pfizer; Roche. Other (2019-2021): Testifying Advisor for MSD in GBA-assessment for Pembrolizumab, Advisor for Durvalumab. Co-Founder and CSO for Targos Molecular Pathology, Kassel/Germany until April 2021. DL: Consulting (2019-2021): AstraZeneca (2019-2021); BMS (2019); Boehringer Ingelheim (2019); Montis Biosciences (2021); MSD (2019-2021). Contracted research: Montis Biosciences (2021).
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Source: PubMed