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

Alexander W. Wyatt, Matti Annala, Rahul Aggarwal, Kevin Beja, Felix Feng, Jack Youngren, Adam Foye, Paul Lloyd, Matti Nykter, Tomasz M. Beer, Joshi J. Alumkal, George V. Thomas, Robert E. Reiter, Matthew B. Rettig, Christopher P Evans, Allen C Gao, Kim N. Chi, Eric J. Small, Martin E. Gleave

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume109
Issue number12
DOIs
StatePublished - Dec 1 2017
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Biopsy
DNA
Neoplasms
Castration
Mutation
Genome
Exome
DNA Fingerprinting
Plasma Cells
Phosphatidylinositol 3-Kinases
DNA Sequence Analysis
Genes
Biomarkers
Alleles

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wyatt, A. W., Annala, M., Aggarwal, R., Beja, K., Feng, F., Youngren, J., ... Gleave, M. E. (2017). Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer. Journal of the National Cancer Institute, 109(12). https://doi.org/10.1093/jnci/djx118

Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer. / Wyatt, Alexander W.; Annala, Matti; Aggarwal, Rahul; Beja, Kevin; Feng, Felix; Youngren, Jack; Foye, Adam; Lloyd, Paul; Nykter, Matti; Beer, Tomasz M.; Alumkal, Joshi J.; Thomas, George V.; Reiter, Robert E.; Rettig, Matthew B.; Evans, Christopher P; Gao, Allen C; Chi, Kim N.; Small, Eric J.; Gleave, Martin E.

In: Journal of the National Cancer Institute, Vol. 109, No. 12, 01.12.2017.

Research output: Contribution to journalArticle

Wyatt, AW, Annala, M, Aggarwal, R, Beja, K, Feng, F, Youngren, J, Foye, A, Lloyd, P, Nykter, M, Beer, TM, Alumkal, JJ, Thomas, GV, Reiter, RE, Rettig, MB, Evans, CP, Gao, AC, Chi, KN, Small, EJ & Gleave, ME 2017, 'Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer', Journal of the National Cancer Institute, vol. 109, no. 12. https://doi.org/10.1093/jnci/djx118
Wyatt, Alexander W. ; Annala, Matti ; Aggarwal, Rahul ; Beja, Kevin ; Feng, Felix ; Youngren, Jack ; Foye, Adam ; Lloyd, Paul ; Nykter, Matti ; Beer, Tomasz M. ; Alumkal, Joshi J. ; Thomas, George V. ; Reiter, Robert E. ; Rettig, Matthew B. ; Evans, Christopher P ; Gao, Allen C ; Chi, Kim N. ; Small, Eric J. ; Gleave, Martin E. / Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer. In: Journal of the National Cancer Institute. 2017 ; Vol. 109, No. 12.
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AU - Annala, Matti

AU - Aggarwal, Rahul

AU - Beja, Kevin

AU - Feng, Felix

AU - Youngren, Jack

AU - Foye, Adam

AU - Lloyd, Paul

AU - Nykter, Matti

AU - Beer, Tomasz M.

AU - Alumkal, Joshi J.

AU - Thomas, George V.

AU - Reiter, Robert E.

AU - Rettig, Matthew B.

AU - Evans, Christopher P

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N2 - 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.

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