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

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d5070476e573">Purpose</h5> <p id="P2">To infer the prognostic value of simultaneous androgen receptor ( <i>AR</i>) and <i>TP53</i> profiling in liquid biopsies from metastatic castration-resistant prostate cancer (mCRPC) patients starting a new line of <i>AR</i> signalling inhibitors (ARSi). </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d5070476e587">Experimental design</h5> <p id="P3">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 <i>AR</i> splice variants (ARVs). Low-pass whole-genome and targeted gene-body sequencing of <i>AR</i> and <i>TP53</i> 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. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d5070476e601">Results</h5> <p id="P4">Overall, no single <i>AR</i> 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. <i>TP53</i> 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 <i>AR</i> alterations. Using Cox coefficient analysis of clinical parameters and <i>TP53</i> status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs 7.51 vs 2.62 months, p &lt; 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 &lt; 0.0001). </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d5070476e618">Conclusions</h5> <p id="P5">In an all-comer cohort, tumour burden estimates and <i>TP53</i> outperform any <i>AR</i> perturbation to infer prognosis. </p> </div>