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

Abstract

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.

Figure 1. Comprehensive landscape of somatic AR and TP53 perturbations in liquid biopsies from patients with mCRPC at baseline (n=108), follow-up (n=31) or at progression (n=49) on abiraterone or enzalutamide.

Samples are grouped according to sample type. Upper: TP53 panel with copy-number, mutation and structural rearrangement status. Lower: AR panel, encompassing a CNV panel: AR copy number stratified according to amplification status. SNV panel: hotspot mutations within the ligand-binding domain of AR. GSR panel: genomic structural rearrangements across the AR gene. ARV panel: Presence of absence of AR splice variant expression. CNV denotes copy number variation. SNV denotes single nucleotide variation. GSR denotes genomic structural rearrangements. ARV denotes AR splice variants. LOH denotes loss-of-heterozygosity. MT denotes mutant. SSV denotes significant structural variant. AMP denotes amplified. MT denotes mutant. DEL denotes deletion. DUP denotes duplication. INV denotes inversion. TRA denotes translocation. ARv45 denotes structural variant deletion AR exon 1, which may result in AR45 expression. SVUS denotes structural variant of unknown significance. SSV denotes significant structural variant. Pos denotes positive. WT denotes wild-type.

Figure 2. AR splice variant expression in circulating tumour cells, detection of genomic AR and TP53 perturbations in plasma cell-free DNA, progression-free survival and PSA response on abiraterone or enzalutamide.

Kaplan-Meier (KM) analysis of progression-free survival (upper) and waterfall plots (WF) of prostate-specific antigen (PSA) responses after 10-12 weeks (or before in case of early disease progression) on therapy (lower), stratified according to outcome-associated ARV expression in CTCs (A), genomic AR (B) or TP53 (C) perturbations in plasma cfDNA at baseline. p-value in KM plot is calculated via logrank test. In WF plots: * denotes PFS < 10-12 weeks, ¶ denotes PSA increase > 200% and dashed blue horizontal lines represent 50% decrease in PSA.

Figure 3. Development and validation of a three stratum risk stratification system using clinical features and molecular profiling.

A) Multivariable Cox regression analysis (hazard ratio (confidence interval)) of progression-free survival using baseline clinical characteristics, ctDNA fraction estimate and TP53 status in patients with mCRPC. B) Multi-level landscape of cox coefficient-adjusted variable values (bottom), calculated clinical progression (i.e. PFS) score (middle) and progression-free survival (top). Patients are grouped according to the PFS score category (i.e. < Q1, Q1-Q3 and > Q3 level) and ordered according to increasing progression-free survival. Horizontal dashed lines represent 12- and 6-month landmarks. C) Kaplan-Meier analysis of progression-free survival, stratified according to clinical progression score category at baseline for the current study (i.e. training cohort, n=143) and Vancouver Prostate Centre study (i.e. testing cohort, n=201). p-value is calculated via logrank test. D) Performance characteristics of the three stratum risk stratification system, comparing risk group prevalences, median PFS times and Cox hazard ratios.