HSD3B1 (1245A>C) germline variant and clinical outcomes in metastatic castration-resistant prostate cancer patients treated with abiraterone and enzalutamide: results from two prospective studies
| Autor: | D.J. Khalaf, I.M. Aragón, M. Annala, R. Lozano, S. Taavitsainen, D. Lorente, D.L. Finch, N. Romero-Laorden, J. Vergidis, Y. Cendón, C. Oja, M.I. Pacheco, M. Zulfiqar, M.E. Gleave, A.W. Wyatt, D. Olmos, K.N. Chi, E. Castro, E. Almagro, J.Á. Arranz, E.G. Billalabeitia, P. Borrega, J.A. Contreras, M. Domenech, R. Escribano, E. Fernández-Parra, E. Gallardo, I. García-Carbonero, R. García, J. Garde, A. González del Alba, B. González, A. Hernández, S. Hernando, P. Jiménez, N. Laínez, R. Luque, E. Martínez, A. Medina, M.J. Méndez-Vidal, A. Montesa, R. Morales, null Olmos David, J.L. Pérez-Gracia, B. Pérez-Valderrama, Á. Pinto, J. Piulats, J. Puente, R. Querol, A. Rodríguez-Vida, M.I. Sáez, S. Vázquez, E. Vélez, J.C. Villa-Guzmán, R. Villatoro, C. Zambrana |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Male medicine.medical_specialty therapeutic response biomarker Abiraterone Acetate 03 medical and health sciences Prostate cancer chemistry.chemical_compound 0302 clinical medicine Prednisone Multienzyme Complexes Internal medicine abiraterone Genotype Nitriles Phenylthiohydantoin medicine HSD3B1 Enzalutamide genetic polymorphism Humans Prospective Studies Prospective cohort study enzalutamide Proportional hazards model business.industry Hazard ratio Androgen Antagonists Hematology Prostate-Specific Antigen medicine.disease Prostatic Neoplasms Castration-Resistant 030104 developmental biology Germ Cells Treatment Outcome chemistry metastatic castration-resistant prostate cancer 030220 oncology & carcinogenesis Cohort Benzamides Androstenes business medicine.drug |
| Popis: | Background A common polymorphism (1245A>C) in the HSD3B1 gene is associated with increased de novo synthesis of androgens and worse outcomes in men treated with androgen-deprivation therapy for metastatic castration-sensitive prostate cancer. The objective of the study was to determine whether this polymorphism is associated with outcomes for metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone or enzalutamide. Patients and methods A total of 547 patients treated with abiraterone or enzalutamide from two prospective cohorts were evaluated. The HSD3B1 genotype was determined by targeted sequencing and/or TaqMan single-nucleotide polymorphism genotyping. In cohort 1, patients were randomized to receive abiraterone + prednisone or enzalutamide. In cohort 2, patients received either agent according to investigator's choice. Prostate-specific antigen (PSA) response rate, time to PSA progression (TTPP), time to progression (TTP) and overall survival were determined. Associations between HSD3B1 genotypes and outcomes were evaluated via univariate Cox regression. Multivariable Cox model was used to determine the independent association of each covariate. Results The HSD3B1 variant genotype (CC) was present in 15% of patients and was associated with worse TTP [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.02–1.67, P = 0.032] and PSA response rates (48% for CC versus 62% and 65% for AA and AC, respectively [P = 0.019]), with no significant difference in TTPP (HR 1.28, 95% CI 0.99–1.66, P = 0.064). The effect of genotype was similar for treatment with abiraterone or enzalutamide with a negative test for interaction for TTPP (P = 0.997) and TTP (P = 0.749). Multivariable analysis did not show a significant association between genotype and TTP or TTPP. Conclusions The HSD3B1 (CC) genotype was associated with shorter TTP and lower PSA response rate in patients with mCRPC treated with abiraterone or enzalutamide. However, the CC genotype did not provide prognostic information beyond that conferred by standard clinical variables, suggesting that it may not be a suitable stand-alone biomarker in mCRPC. |
| Databáze: | OpenAIRE |
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