Peter A Fasching1, Siddhartha Yadav2, Chunling Hu3, Marius Wunderle1, Lothar Häberle1,4, Steven N Hart5, Matthias Rübner1, Eric C Polley5, Kun Y Lee3, Rohan D Gnanaolivu5, Peyman Hadji6, Hanna Hübner1, Hans Tesch7, Johannes Ettl8, Friedrich Overkamp9, Michael P Lux10,11, Arif B Ekici12, Bernhard Volz13, Sabrina Uhrig1, Diana Lüftner14, Markus Wallwiener15, Volkmar Müller16, Erik Belleville17, Michael Untch18, Hans-Christian Kolberg19, Matthias W Beckmann1, André Reis12, Arndt Hartmann20, Wolfgang Janni21, Pauline Wimberger22,23,24,25,26,27, Florin-Andrei Taran28, Tanja N Fehm29, Diethelm Wallwiener30, Sara Y Brucker30, Andreas Schneeweiss31, Andreas D Hartkopf30, Fergus J Couch3,5. 1. Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany. 2. Department of Oncology, Mayo Clinic, Rochester, MN. 3. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. 4. Biostatistics Unit, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany. 5. Department of Health Sciences Research, Mayo Clinic, Rochester, MN. 6. Frankfurt Center of Bone Health, Frankfurt, Germany. 7. Oncology Practice at Bethanien Hospital Frankfurt, Frankfurt, Germany. 8. Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 9. Oncologianova GmbH, Recklinghausen, Germany. 10. Klinik für Gynäkologie und Geburtshilfe Frauenklinik St Louise, Paderborn, St Josefs-Krankenhaus, Salzkotten, Germany. 11. Kooperatives Brustzentrum Paderborn, Paderborn, Germany. 12. Institute of Human Genetics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. 13. Ansbach University of Applied Sciences, Ansbach, Germany. 14. Department of Hematology, Oncology and Tumour Immunology, Charité University Hospital, Berlin, Campus Benjamin Franklin, Berlin, Germany. 15. Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany. 16. Department of Gynecology, Hamburg-Eppendorf University Medical Center, Hamburg, Germany. 17. ClinSol GmbH & Co KG, Würzburg, Germany. 18. Department of Gynecology and Obstetrics, Helios Clinics Berlin Buch, Berlin, Germany. 19. Marienhospital Bottrop, Bottrop, Germany. 20. Institute of Pathology, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. 21. Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany. 22. Department of Gynecology and Obstetrics, Carl Gustav Carus Faculty of Medicine and University Hospital, Technical University of Dresden, Dresden, Germany. 23. National Center for Tumor Diseases (NCT), Dresden, Germany. 24. German Cancer Research Center (DKFZ), Heidelberg, Germany. 25. Carl Gustav Carus Faculty of Medicine and University Hospital, Technical University of Dresden, Dresden, Germany. 26. Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany. 27. German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. 28. Department of Obstetrics and Gynecology, University Hospital Freiburg, Freiburg, Germany. 29. Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany. 30. Department of Obstetrics and Gynecology, University of Tuebingen, Tuebingen, Germany. 31. National Center for Tumor Diseases, Heidelberg University Hospital, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract
PURPOSE: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
PURPOSE: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS: Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
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