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A blood test taken before the first tablet identified the men whose disease would resist both standard hormone drugs, which the clinical variables could not do.
Two hundred and two men with treatment-naive metastatic castration-resistant prostate cancer were randomised to abiraterone or enzalutamide and had whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA before therapy. Time to progression was similar for the two agents, which had never been directly compared. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and of circulating tumour DNA abundance. Somatic alterations in TP53, previously linked to reduced tumour dependency on androgen receptor signalling, were also independently associated with rapid resistance. Detection of AR amplification did not outperform standard prognostic biomarkers, but AR gene structural rearrangements truncating the ligand-binding domain were identified in several men with primary resistance.
It shows that the useful information in a castration-resistant plasma sample is in the repair genes and TP53 rather than in the androgen receptor finding that dominates the report, and it is the closest thing the field has to a head-to-head comparison of abiraterone against enzalutamide.
Shares AR amplification (gene and upstream enhancer), Circulating tumour DNA fraction (and what a negative plasma result means), ATM, Cell-free DNA (cfDNA).
Shares ATM, Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC).
Shares ATM, Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC).
Shares Cancer Discovery, Cell-free DNA (cfDNA), Double-strand break repair: HR versus end joining, Resistance routes: how a blocked pathway comes back.
Shares Androgen receptor signalling, Castration-resistant prostate cancer (CRPC), p53 / RB / cell-cycle checkpoint, Drug resistance (primary and acquired).
Shares AR amplification (gene and upstream enhancer), Androgen receptor signalling, Double-strand break repair: HR versus end joining, Castration-resistant prostate cancer (CRPC).
Shares Circulating tumour DNA fraction (and what a negative plasma result means), ATM, Cell-free DNA (cfDNA), Double-strand break repair: HR versus end joining.
Shares Circulating tumour DNA fraction (and what a negative plasma result means), Cell-free DNA (cfDNA), Androgen receptor signalling, Androgen receptor.