Genomics of lethal prostate cancer at diagnosis and castration resistance.
Joaquin Mateo,Joaquin Mateo,Joaquin Mateo,George Seed,Claudia Bertan,Pasquale Rescigno,Pasquale Rescigno,David Dolling,Ines Figueiredo,Susana Miranda,Daniel Nava Rodrigues,Bora Gurel,Matthew Clarke,Mark Atkin,Rob Chandler,Rob Chandler,Carlo Messina,Carlo Messina,Semini Sumanasuriya,Semini Sumanasuriya,Diletta Bianchini,Diletta Bianchini,Maialen Barrero,Maialen Barrero,Antonella Petermolo,Antonella Petermolo,Zafeiris Zafeiriou,Zafeiris Zafeiriou,Mariane Sousa Fontes,Mariane Sousa Fontes,Raquel Perez-Lopez,Raquel Perez-Lopez,Raquel Perez-Lopez,Nina Tunariu,Nina Tunariu,B. Fulton,Robert Jones,Ursula McGovern,Christy Ralph,Mohini Varughese,Omi Parikh,Suneil Jain,Tony Elliott,Shahneen Sandhu,Nuria Porta,Emma Hall,Wei Yuan,Suzanne Carreira,Johann S. de Bono,Johann S. de Bono +49 more
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TLDR
The genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers, with RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to m CRPC.Abstract:
The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.read more
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Journal ArticleDOI
Genomic and phenotypic heterogeneity in prostate cancer.
Michael C. Haffner,Michael C. Haffner,Michael C. Haffner,Wilbert Zwart,Martine Roudier,Lawrence D. True,William G. Nelson,Jonathan I. Epstein,Angelo M. De Marzo,Peter S. Nelson,Srinivasan Yegnasubramanian +10 more
TL;DR: This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient, and summarizes the manifestations of inter-tumoural and intra-t tumoural heterogeneity in primary and metastatic prostate cancer.
Journal ArticleDOI
First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors.
Timothy A. Yap,David S.P. Tan,Angelika Terbuch,Angelika Terbuch,Reece Caldwell,Christina Guo,Boon Cher Goh,Valerie Heong,Noor R. Md. Haris,Saira Bashir,Yvette Drew,David S. Hong,Funda Meric-Bernstam,Gary Wilkinson,Joseph Hreiki,Antje Margret Wengner,Friedhelm Bladt,Andreas Schlicker,Matthias Ludwig,Yinghui Zhou,Li Liu,Sonal Bordia,Ruth Plummer,Eleni Lagkadinou,Johann S. de Bono +24 more
TL;DR: The dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5-80 mg twice daily (BID) in 21 patients with advanced solid tumors is reported, finding it well tolerated with antitumor activity against cancers with certain DDR defects, including ATM loss.
Journal ArticleDOI
Oncogenic Genomic Alterations, Clinical Phenotypes, and Outcomes in Metastatic Castration-Sensitive Prostate Cancer.
Konrad H. Stopsack,Subhiksha Nandakumar,Andreas Wibmer,Samuel Haywood,Emily Weg,Ethan Barnett,Chloe J. Kim,Emily Carbone,Samantha E. Vasselman,Bastien Nguyen,Melanie Hullings,Howard I. Scher,Howard I. Scher,Michael J. Morris,Michael J. Morris,David B. Solit,Nikolaus Schultz,Philip W. Kantoff,Philip W. Kantoff,Wassim Abida,Wassim Abida +20 more
TL;DR: In this paper, the authors identify genomic features associated with prognosis in metastatic castration-sensitive prostate cancer that may aid in molecular classification and treatment selection, including DNA copy number alterations and alterations in predefined oncogenic signaling pathways.
Journal ArticleDOI
Genomic Analysis of Circulating Tumor DNA in 3,334 Patients with Advanced Prostate Cancer Identifies Targetable BRCA Alterations and AR Resistance Mechanisms
Hanna Tukachinsky,Russell Madison,Jon Chung,Ole Gjoerup,Eric Allan Severson,Lucas Dennis,Bernard Fendler,Samantha Morley,Lei Zhong,Ryon Graf,Jeffrey S. Ross,Jeffrey S. Ross,Brian M. Alexander,Wassim Abida,Simon Chowdhury,Charles J. Ryan,Karim Fizazi,Tony Golsorkhi,Simon Paul Watkins,Andrew Simmons,Andrea Loehr,Jeffrey M. Venstrom,Geoffrey R. Oxnard +22 more
TL;DR: In this paper, Hawkey et al. evaluated the landscape of targetable genomic alterations detected in ctDNA and assessed concordance with tissue-based CGP results, with a high level of agreement in detection of BRCA1/2 mutations.
Journal ArticleDOI
Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial
Thomas Powles,Kobe C. Yuen,Silke Gillessen,Edward E. Kadel,Dana E. Rathkopf,Nobuaki Matsubara,Charles G. Drake,Karim Fizazi,Josep M. Piulats,Piotr J. Wysocki,Gary L. Buchschacher,Boris Alekseev,Begoña Mellado,Boguslawa Karaszewska,Jennifer F. Doss,Grozdana Rasuo,Asim Datye,Sanjeev Mariathasan,Patrick Williams,Christopher Sweeney +19 more
TL;DR: The IMbassador250 trial as mentioned in this paper showed that patients with castration-resistant prostate cancer may benefit from program death ligand-1 (PD-L1) inhibition, especially with enzalutamide.
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