Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer
| العنوان: | Impact of DNA damage repair defects on response to radium-223 and overall survival in metastatic castration-resistant prostate cancer |
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| المؤلفون: | Sjoerd van Helvert, Niven Mehra, Samhita Pamidimarri Naga, Maren Bormann, Inge M. van Oort, Leonie I. Kroeze, Emmanuel S. Antonarakis, Peter H.J. Slootbeek, Winald R. Gerritsen, Maarten J. van der Doelen, Pedro Isaacsson Velho |
| المصدر: | European Journal of Cancer, 136, 16-24 European Journal of Cancer, 136, pp. 16-24 |
| بيانات النشر: | Elsevier BV, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Radium-223, Oncology, Cancer Research, medicine.medical_specialty, DNA Repair, DNA repair, DNA damage, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], DNA Mutational Analysis, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], medicine.disease_cause, Germline, Cohort Studies, 03 medical and health sciences, Prostate cancer, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Prostate, Internal medicine, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Biomarkers, Tumor, medicine, Humans, Neoplasm Metastasis, Aged, Retrospective Studies, Mutation, business.industry, High-Throughput Nucleotide Sequencing, Retrospective cohort study, Middle Aged, medicine.disease, Survival Analysis, Gene Expression Regulation, Neoplastic, body regions, Prostatic Neoplasms, Castration-Resistant, DNA Repair Enzymes, 030104 developmental biology, medicine.anatomical_structure, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], 030220 oncology & carcinogenesis, business, DNA Damage, Radium, medicine.drug |
| الوصف: | Purpose Radium-223 is a targeted alpha radiation therapy for metastatic castration-resistant prostate cancer. DNA damage repair (DDR) defective prostate cancers, specifically genetic aberrations leading to homologous recombination deficiency (HRD), accumulate irreparable DNA damage following genotoxic treatment. This retrospective study assessed DDR mutation status in patients treated with radium-223, investigating their association with efficacy and overall survival (OS). Patients and methods Included patients were treated with radium-223 and had results from primary or metastatic tumour tissue of a comprehensive next-generation sequencing panel of DDR genes, including canonical HRD genes. Patients were grouped by presence (DDR+) or absence (DDR−) of pathogenic somatic or germline aberrations in DDR genes. We evaluated OS, time to ALP progression (TAP), time to initiation of subsequent systemic therapy (TST) and biochemical responses between DDR groups. Results Ninety-three patients were included. Twenty-eight (30%) patients had DDR mutations, most frequently in ATM (8.6%), BRCA2 (7.5%) and CDK12 (4.3%) genes. DDR+ patients showed prolonged OS (median 36.3 versus 17.0 months; HR 2.29; P = 0.01). Median TAP and TST in the DDR+ and DDR− patients was 6.9 versus5.8 months (HR = 1.48; P = 0.15), and 8.9 versus7.3 months (HR = 1.58; P = 0.08), respectively. DDR+ patients more frequently completed radium-223 therapy (79% versus 47%; P = 0.05). No difference in biochemical responses were seen. Conclusion Patients harbouring DDR aberrations showed significant OS benefit, and more commonly completed radium-223 therapy. These findings need prospective confirmation and support strategies of genotoxic agents such as radium-223 in patients harbouring DDR defects. |
| وصف الملف: | application/pdf |
| تدمد: | 0959-8049 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8688c8108da1b18d253ac6e16f9309afTest https://doi.org/10.1016/j.ejca.2020.05.001Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8688c8108da1b18d253ac6e16f9309af |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 09598049 |
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