Elucidating Prostate Cancer Behaviour During Treatment via Low-pass Whole-genome Sequencing of Circulating Tumour DNA
| Autor: | Stephen J. Pettitt, Antje Neeb, Lorna Pope, Jane Goodall, Suzanne Carreira, Joe Baxter, Pasquale Rescigno, Harry Parr, Diletta Bianchini, Claudia Bertan, Stéphane Oudard, Christine Geffriaud-Ricouard, Christopher J. Lord, Sandrine Macé, Oliver Sartor, Ayse Ozatilgan, Rossitza Christova, Gemma Fowler, Maryou B. Lambros, Wei Yuan, Ines Figueiredo, Niven Mehra, Joaquin Mateo, Jan Rekowski, Penelope Flohr, George Seed, Mario A. Eisenberger, Semini Sumanasuriya, Adam Sharp, Mustapha Chadjaa, Johann S. de Bono |
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| Přispěvatelé: | Institut Català de la Salut, [Sumanasuriya S] The Institute of Cancer Research, University of London, London, UK. The Royal Marsden Hospital, London, UK. [Seed G, Parr H, Christova R, Pope L, Bertan C] The Institute of Cancer Research, University of London, London, UK. [Mateo J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Male 030232 urology & nephrology Docetaxel Tumour fraction Other subheadings::Other subheadings::/drug therapy [Other subheadings] Circulating Tumor DNA Prostate cancer chemistry.chemical_compound Cell-free DNA 0302 clinical medicine Prospective Studies cfDNA Elements genètics mòbils Cabazitaxel Otros calificadores::Otros calificadores::/genética [Otros calificadores] Prostate Cancer Hazard ratio DNA Neoplasm mCRPC Prostatic Neoplasms Castration-Resistant Cell-free fetal DNA Pharmaceutical Preparations 030220 oncology & carcinogenesis Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] Pròstata - Càncer - Aspectes genètics medicine.drug medicine.medical_specialty lpWGS Urology Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] Context (language use) nucleótidos y nucleósidos de ácidos nucleicos::ácidos nucleicos::ácidos nucleicos libres de células::ADN tumoral circulante [COMPUESTOS QUÍMICOS Y DROGAS] 03 medical and health sciences Taxanes Internal medicine medicine Other subheadings::Other subheadings::/genetics [Other subheadings] Enzalutamide Humans Taxane Nucleic Acids Nucleotides and Nucleosides::Nucleic Acids::Cell-Free Nucleic Acids::Circulating Tumor DNA [CHEMICALS AND DRUGS] business.industry ctDNA medicine.disease Pròstata - Càncer - Tractament Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms Male::Prostatic Neoplasms::Prostatic Neoplasms Castration-Resistant [DISEASES] Metastatic castration-resistant prostate cancer chemistry neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata::neoplasias prostáticas resistentes a la castración [ENFERMEDADES] Low-pass whole-genome sequencing business |
| Zdroj: | Scientia European Urology European Urology, 80, 2, pp. 243-253 European Urology, 80, 243-253 |
| ISSN: | 0302-2838 |
| Popis: | Background Better blood tests to elucidate the behaviour of metastatic castration-resistant prostate cancer (mCRPC) are urgently needed to drive therapeutic decisions. Plasma cell-free DNA (cfDNA) comprises normal and circulating tumour DNA (ctDNA). Low-pass whole-genome sequencing (lpWGS) of ctDNA can provide information on mCRPC behaviour. Objective To validate and clinically qualify plasma lpWGS for mCRPC. Design, setting, and participants Plasma lpWGS data were obtained for mCRPC patients consenting to optional substudies of two prospective phase 3 trials (FIRSTANA and PROSELICA). In FIRSTANA, chemotherapy-naïve patients were randomised to treatment with docetaxel (75 mg/m2) or cabazitaxel (20 or 25 mg/m2). In PROSELICA, patients previously treated with docetaxel were randomised to 20 or 25 mg/m2 cabazitaxel. lpWGS data were generated from 540 samples from 188 mCRPC patients acquired at four different time points (screening, cycle 1, cycle 4, and end of study). Outcome measurements and statistical analysis lpWGS data for ctDNA were evaluated for prognostic, response, and tumour genomic measures. Associations with response and survival data were determined for tumour fraction. Genomic biomarkers including large-scale transition (LST) scores were explored in the context of prior treatments. Results and limitations Plasma tumour fraction was prognostic for overall survival in univariable and stratified multivariable analyses (hazard ratio 1.75, 95% confidence interval 1.08–2.85; p = 0.024) and offered added value compared to existing biomarkers (C index 0.722 vs 0.709; p = 0.021). Longitudinal changes were associated with drug response. PROSELICA samples were enriched for LSTs (p = 0.029) indicating genomic instability, and this enrichment was associated with prior abiraterone and enzalutamide treatment but not taxane or radiation therapy. Higher LSTs were correlated with losses of RB1/RNASEH2B, independent of BRCA2 loss. Conclusions Plasma lpWGS of ctDNA describes CRPC behaviour, providing prognostic and response data of clinical relevance. The added prognostic value of the ctDNA fraction over established biomarkers should be studied further. Patient summary We studied tumour DNA in blood samples from patients with prostate cancer. We found that levels of tumour DNA in blood were indicative of disease prognosis, and that changes after treatment could be detected. We also observed a “genetic scar” in the results that was associated with certain previous treatments. This test allows an assessment of tumour activity that can complement existing tests, offer insights into drug response, and detect clinically relevant genetic changes. Take Home Message Tumour fraction, independent from cell-free DNA concentration and other clinical variables, is prognostic, with low-pass whole-genome sequencing profiles detecting abiraterone/enzalutamide-induced emerging genomic instability that is likely to be acquired as a result of tumour development. |
| Databáze: | OpenAIRE |
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