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Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.

ABSTRACT: Background:Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. Methods:We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Results:Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Conclusions:Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.

SUBMITTER: Wyatt AW

PROVIDER: S-EPMC6440274 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.

Wyatt Alexander W AW Annala Matti M Aggarwal Rahul R Beja Kevin K Feng Felix F Youngren Jack J Foye Adam A Lloyd Paul P Nykter Matti M Beer Tomasz M TM Alumkal Joshi J JJ Thomas George V GV Reiter Robert E RE Rettig Matthew B MB Evans Christopher P CP Gao Allen C AC Chi Kim N KN Small Eric J EJ Gleave Martin E ME

Journal of the National Cancer Institute 20171201 12

<h4>Background</h4>Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sa ...[more]

PMID: 29206995

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Project description:PurposeCirculating tumor DNA (ctDNA) sequencing provides a minimally invasive method for tumor molecular stratification. Commercial ctDNA sequencing is increasingly used in the clinic, but its accuracy in metastatic prostate cancer is untested. We compared the commercial Guardant360 ctDNA test against an academic sequencing approach for profiling metastatic prostate cancer.Patients and methodsPlasma cell-free DNA was collected between September 2016 and April 2018 from 24 patients with clinically progressive metastatic prostate cancer representing a range of clinical scenarios. Each sample was analyzed using Guardant360 and a research panel encompassing 73 prostate cancer genes. Concordance of somatic mutation and copy number calls was evaluated between the two approaches.ResultsTargeted sequencing independently confirmed 94% of somatic mutations identified by Guardant360 at an allele fraction greater than 1%. AR amplifications and mutations were detected with high concordance in 14 patients, with only three discordant subclonal mutations at an allele fraction lower than 0.5%. Many somatic mutations identified by Guardant360 at an allele fraction lower than 1% seemed to represent subclonal passenger events or non-prostate-derived clones. Most of the non-AR gene amplifications reported by Guardant360 represented single copy gains. The research approach detected several clinically relevant DNA repair gene alterations not reported by Guardant360, including four germline truncating BRCA2/ATM mutations, two somatic ATM stop gain mutations, one BRCA2 biallelic deletion, 11 BRCA2 stop gain reversal mutations in a patient treated with olaparib, and a hypermutator phenotype in a patient sample with 42 mutations per megabase.ConclusionGuardant360 accurately identifies somatic ctDNA mutations in patients with metastatic prostate cancer, but low allele frequency mutations should be interpreted with caution. Test utility in metastatic prostate cancer is currently limited by the lack of reporting on actionable deletions, rearrangements, and germline mutations.

Project description:ImportanceDNA damage repair (DDR) gene mutations represent actionable alterations that can guide precision medicine strategies for advanced prostate cancer. However, acquisition of contemporary tissue samples for molecular testing can be a barrier to deploying precision medicine approaches. We hypothesized that most DDR alterations represent truncal events in prostate cancer and that primary tissue would faithfully reflect mutations found in cell-free circulating tumor DNA (ctDNA) and/or metastatic tissue.ObjectiveTo assess concordance in DDR gene alterations between primary prostate cancer and metastases or ctDNA specimens.Design, setting, and participantsPatients were included if a DDR pathway mutation was detected in metastatic tissue or ctDNA and primary tissue sequencing was available for comparison. Sequencing data from 3 cohorts were analyzed: (1) FoundationOne, (2) University of Washington clinical cases (University of Washington-OncoPlex or Stand Up to Cancer-Prostate Cancer Foundation International Dream Team sequencing pipelines), and (3) University of Washington rapid autopsy series. Only pathogenic somatic mutations were included, and more than 30 days between primary tumor tissue and ctDNA and/or metastatic tissue acquisition was required. Clonal hematopoiesis of indeterminate potential (CHIP) and germline events were adjudicated by an expert molecular pathologist and excluded.Main outcomes and measuresThe DDR gene alterations detected in primary prostate tissue matched with metastatic tissue and/or ctDNA findings.ResultsA total of 72 men with known DDR alterations were included in the analysis, and primary samples with paired ctDNA and/or metastatic tissue were sequenced. After excluding patients with ctDNA where only CHIP and/or germline events (n = 21) were observed, 51 patients remained and were included in the final analysis. The median (range) time from acquisition of primary tissue to acquisition of ctDNA or tumor tissue was 55 (5-193) months. Concordance in DDR gene mutation status across samples was 84% (95% CI, 71%-92%). Rates of concordance between metastatic-primary and ctDNA-primary pairs were similar when patients with CHIP events were excluded. Multiclonal BRCA2 reversion mutations associated with resistance to PARP inhibitors and platinum chemotherapy were detected in ctDNA from 2 patients.Conclusions and relevanceIn this genetic association study of 3 patient cohorts, primary prostate tissue accurately reflected the mutational status of actionable DDR genes in metastatic tissue, consistent with DDR alterations being truncal in most patients. After excluding likely CHIP events, ctDNA profiling accurately captured these DDR mutations while also detecting reversion alterations that may suggest resistance mechanisms.

Dataset Information

Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.

Publications

Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.

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