TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer

Clin Cancer Res. 2019 Mar 15;25(6):1766-1773. doi: 10.1158/1078-0432.CCR-18-1943. Epub 2018 Sep 12.


Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). 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 radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models.

Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (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).

Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Androgen Receptor Antagonists / pharmacology*
  • Androgen Receptor Antagonists / therapeutic use
  • Androstenes / pharmacology
  • Androstenes / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzamides
  • Biomarkers, Tumor / blood*
  • Circulating Tumor DNA / blood
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Follow-Up Studies
  • Humans
  • Kaplan-Meier Estimate
  • Liquid Biopsy / methods
  • Male
  • Neoplastic Cells, Circulating / pathology
  • Nitriles
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / pharmacology
  • Phenylthiohydantoin / therapeutic use
  • Predictive Value of Tests
  • Prognosis
  • Progression-Free Survival
  • Prostatic Neoplasms, Castration-Resistant / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / mortality
  • RNA-Seq
  • Receptors, Androgen / blood
  • Receptors, Androgen / metabolism
  • Tumor Suppressor Protein p53 / blood*


  • AR protein, human
  • Androgen Receptor Antagonists
  • Androstenes
  • Antineoplastic Agents
  • Benzamides
  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • Nitriles
  • Receptors, Androgen
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Phenylthiohydantoin
  • enzalutamide
  • abiraterone