Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition

Abstract

Purpose: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). Results: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. Conclusions: Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.

Genomic Features of Lung-Recurrent Hormone-Sensitive Prostate Cancer

“…TF for WES was estimated using manually fitted ploidy models for copy number and heterozygous SNP deviation, as described previously. 25…”

“…Targeted DNA sequencing was performed on all samples using an established targeted panel capturing the exons of 73 prostate cancer-relevant genes, according to the published methodology. [23][24][25] Whole-exome sequencing (WES) was performed on 28 tumor samples (and matched gDNAs) using the same protocol as for targeted DNA sequencing except that hybridization capture was carried out with the Roche Nimblegen SeqCap EZ MedExome kit. A detailed description of somatic and germline mutation calling and copy number evaluation is given in the Data Supplement.…”

Androgen receptor genomic alterations and treatment resistance in metastatic prostate cancer

“…In castration‐resistant disease, AR gene amplification is the dominant genomic mechanism contributing to increased AR expression 11,14 . More recently, whole genome sequencing has helped define the existence of a critical transcriptional enhancer 600−700 kb upstream of the AR gene body, with coamplification of both the AR gene body and associated enhancer representing the most common genomic pattern observed in mCRPC clinical samples 13,15,20–22 …”

Liquid Biopsy, ctDNA Diagnosis through NGS

“…Another study exploiting dynamic ctDNA analysis to monitor genetic evolutions during ensartinib treatment in NSCLC showed that TP53 mutations promoted tumor evolution and accelerated occurrence of resistance, thus indicating TP53 mutations at baseline were independently correlated with worse clinical outcomes [87]. Deep targeted and whole-exome sequencing of ctDNA in metastatic castration-resistant prostate cancer patients for comparison of base-line and posttreatment showed that the dominant androgen receptor (AR) genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance [88].…”