Title |
TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer
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Published in |
Clinical Cancer Research, March 2019
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DOI | 10.1158/1078-0432.ccr-18-1943 |
Pubmed ID | |
Authors |
Bram De Laere, Steffi Oeyen, Markus Mayrhofer, Tom Whitington, Pieter-Jan van Dam, Peter Van Oyen, Christophe Ghysel, Jozef Ampe, Piet Ost, Wim Demey, Lucien Hoekx, Dirk Schrijvers, Barbara Brouwers, Willem Lybaert, Els G. Everaert, Daan De Maeseneer, Michiel Strijbos, Alain Bols, Karen Fransis, Nick Beije, Inge E. de Kruijff, Valerie van Dam, Anja Brouwer, Dirk Goossens, Lien Heyrman, Gert G. Van den Eynden, Annemie Rutten, Jurgen Del Favero, Mattias Rantalainen, Prabhakar Rajan, Stefan Sleijfer, Anders Ullén, Jeffrey Yachnin, Henrik Grönberg, Steven J. Van Laere, Johan Lindberg, Luc Y. Dirix |
Abstract |
To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from metastatic castration-resistant prostate cancer (mCRPC) patients starting a new line of AR signalling inhibitors (ARSi). Between March 2014 and April 2017, we recruited mCRPC patients (n=168) prior to ARSi in a cohort study encompassing 10 European centres. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA). Targeted CTC RNA-seq allowed the detection of eight AR splice variants (ARVs). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss-of-heterozygosity, mutations and structural rearrangements in ctDNA. Clinical or radiological progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox-regression models. Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumour burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value (HR 1.88, 95%CI 1.18-3.00, p = 0.008), and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs 7.51 vs 2.62 months, p < 0.0001), which was validated in an independent mCRPC cohort (n=202) starting first-line ARSi (median, 14.3 vs 6.39 vs 2.23 months, p < 0.0001). In an all-comer cohort, tumour burden estimates and TP53 outperform any AR perturbation to infer prognosis. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 7 | 21% |
United Kingdom | 6 | 18% |
Belgium | 4 | 12% |
Switzerland | 1 | 3% |
Canada | 1 | 3% |
Korea, Republic of | 1 | 3% |
Japan | 1 | 3% |
Germany | 1 | 3% |
Australia | 1 | 3% |
Other | 0 | 0% |
Unknown | 11 | 32% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 18 | 53% |
Scientists | 13 | 38% |
Practitioners (doctors, other healthcare professionals) | 3 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 134 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 22 | 16% |
Student > Bachelor | 21 | 16% |
Student > Ph. D. Student | 18 | 13% |
Student > Master | 14 | 10% |
Other | 9 | 7% |
Other | 14 | 10% |
Unknown | 36 | 27% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 37 | 28% |
Biochemistry, Genetics and Molecular Biology | 29 | 22% |
Agricultural and Biological Sciences | 5 | 4% |
Nursing and Health Professions | 4 | 3% |
Immunology and Microbiology | 3 | 2% |
Other | 14 | 10% |
Unknown | 42 | 31% |