Elena Castro1,2, Nuria Romero-Laorden1,3, Angela Del Pozo4, Rebeca Lozano1,5, Ana Medina6, Javier Puente7, Josep Maria Piulats8, David Lorente9, Maria Isabel Saez5,10, Rafael Morales-Barrera11, Enrique Gonzalez-Billalabeitia12, Ylenia Cendón1,13, Iciar García-Carbonero14, Pablo Borrega15, M José Mendez Vidal16, Alvaro Montesa5,10, Paz Nombela1, Eva Fernández-Parra17, Aránzazu Gonzalez Del Alba18, José Carlos Villa-Guzmán19, Kristina Ibáñez4, Alejo Rodriguez-Vida20, Lorena Magraner-Pardo1, Begoña Perez-Valderrama21, Elena Vallespín4, Enrique Gallardo22, Sergio Vazquez23, Colin C Pritchard24, Pablo Lapunzina4, David Olmos1,5. 1. 1 Prostate Cancer Clinical Unit, Spanish National Cancer Research Center, Madrid, Spain. 2. 2 Hospital Universitario Quiron, Madrid, Spain. 3. 3 Hospital Universitario La Princesa, Madrid, Spain. 4. 4 Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, and CIBERER Instituto de Salud Carlos III, Madrid, Spain. 5. 5 CNIO_IBIMA Genitourinary Cancer Research Unit, Institute of Biomedical Research in Málaga, Málaga Spain. 6. 6 Centro Oncológico de Galicia, Coruña, Spain. 7. 7 Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain. 8. 8 Institut Català d'Oncologia, Bellvitge Biomedical Research Institute, Barcelona, Spain. 9. 9 Hospital Universitario La Fe, Valencia, Spain. 10. 10 Hospitales Universitarios Virgen de la Victoria y Regional de Málaga, Málaga, Spain. 11. 11 Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain. 12. 12 Hospital Morales Messeguer-IMIB, UCAM, Murcia, Spain. 13. 13 Universidad Autónoma de Madrid, Madrid, Spain. 14. 14 Hospital Virgen de la Salud, Toledo, Spain. 15. 15 Hospital San Pedro de Alcántara, Cáceres, Spain. 16. 16 Hospital Universitario Reina Sofia, Córdoba, Spain. 17. 17 Hospital Universitario de Valme, Seville, Spain. 18. 18 Hospital Universitario Son Espases, Palma de Mallorca, Spain. 19. 19 Hospital General Universitario de Ciudad Real, Ciudad Real, Spain. 20. 20 Hospital del Mar, Barcelona, Spain. 21. 21 Hospital Universitario Virgen del Rocío, Seville, Spain. 22. 22 Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain. 23. 23 Hospital Universitario Lucus Augusti, Lugo, Spain. 24. 24 University of Washington Medical Center, Seattle, WA.
Abstract
PURPOSE: Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes. PATIENTS AND METHODS: Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored. RESULTS: We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio [HR], 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers. CONCLUSION: g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.
PURPOSE: Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes. PATIENTS AND METHODS: Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored. RESULTS: We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio [HR], 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers. CONCLUSION: g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.
Authors: Melissa A Reimers; Steven M Yip; Li Zhang; Marcin Cieslik; Mallika Dhawan; Bruce Montgomery; Alexander W Wyatt; Kim N Chi; Eric J Small; Arul M Chinnaiyan; Ajjai S Alva; Felix Y Feng; Jonathan Chou Journal: Eur Urol Date: 2019-10-20 Impact factor: 20.096
Authors: Siddhartha Yadav; Steven N Hart; Chunling Hu; David Hillman; Kun Y Lee; Rohan Gnanaolivu; Jie Na; Eric C Polley; Fergus J Couch; Manish Kohli Journal: JCO Precis Oncol Date: 2019-09-17
Authors: Goutam Chakraborty; Joshua Armenia; Ying Z Mazzu; Subhiksha Nandakumar; Konrad H Stopsack; Mohammad O Atiq; Kazumasa Komura; Lina Jehane; Rahim Hirani; Kalyani Chadalavada; Yuki Yoshikawa; Nabeela A Khan; Yu Chen; Wassim Abida; Lorelei A Mucci; Gwo-Shu Mary Lee; Gouri J Nanjangud; Philip W Kantoff Journal: Clin Cancer Res Date: 2019-12-03 Impact factor: 12.531