Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer

Santosh Gupta, Daniel H. Hovelson, Gabor Kemeny, Susan Halabi, Wen Chi Foo, Monika Anand, Jason A. Somarelli, Scott A. Tomlins, Emmanuel S. Antonarakis, Jun Luo, Ryan V. Dittamore, Daniel J. George, Colin Rothwell, David M. Nanus, Andrew J. Armstrong, Simon G. Gregory

Research output: Contribution to journalArticlepeer-review

Abstract

Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.

Original languageEnglish (US)
Pages (from-to)225-239
Number of pages15
JournalGenes Chromosomes and Cancer
Volume59
Issue number4
DOIs
StatePublished - Apr 1 2020
Externally publishedYes

Bibliographical note

Funding Information:
We wish to acknowledge support from the Prostate Cancer Foundation and Bayer Pharmaceuticals. We wish to thank the Prostate Cancer Foundation and Movember for their financial support of this Global Treatment Sciences Challenge Award, and the US Department of Defense Prostate Cancer Clinical Trial Consortium for infrastructural support for this multicenter study. Dr. Armstrong was supported by a Prostate Cancer Foundation grant and the DCI P30 CA014236 as well as Duke Cancer Institute shared resources for biostatistics, Flow Cytometry, and Sequencing and Genomic Technologies. This work was partially funded by Department of Defense grants W81XWH‐13‐PCRP‐CCA, W81XWH‐17‐2‐0021 and W81XWH‐14‐2‐0179 (DJG/AJA, Duke). J.A.S. acknowledges support from the Department of Defense (PC170316). We acknowledge Dr Emmanuel Antonarakis MD and Jun Luo PhD for their contribution of CTC AR‐V7 testing at Johns Hopkins, under W81XWH‐16‐PCRP‐CCRSA (E.S.A, Johns Hopkins). We acknowledge Drs David Nanus and Scott Tagawa for their enrollment of patients at Weill Cornell Medical College under W81XWH‐14‐2‐0159 (DMN, Weill Cornell). We wish to thank the study coordinators at Weill Cornell, Duke University, Johns Hopkins, University of Chicago, and Memorial Sloan Kettering Cancer Center and the DOD Prostate Cancer Clinical Trials Consortium (DOD PCCTC). We wish to acknowledge the dedication of our patients to provide blood samples at no clear benefit to them but for the benefits of all patients with prostate cancer. We acknowledge support from the Duke Cancer Institute Center for Prostate and Urologic Cancers. We would like to acknowledge the assistance of the Duke Molecular Physiology Institute Molecular Genomics core for the generation of data for the manuscript.

Funding Information:
We wish to acknowledge support from the Prostate Cancer Foundation and Bayer Pharmaceuticals. We wish to thank the Prostate Cancer Foundation and Movember for their financial support of this Global Treatment Sciences Challenge Award, and the US Department of Defense Prostate Cancer Clinical Trial Consortium for infrastructural support for this multicenter study. Dr. Armstrong was supported by a Prostate Cancer Foundation grant and the DCI P30 CA014236 as well as Duke Cancer Institute shared resources for biostatistics, Flow Cytometry, and Sequencing and Genomic Technologies. This work was partially funded by Department of Defense grants W81XWH-13-PCRP-CCA, W81XWH-17-2-0021 and W81XWH-14-2-0179 (DJG/AJA, Duke). J.A.S. acknowledges support from the Department of Defense (PC170316). We acknowledge Dr Emmanuel Antonarakis MD and Jun Luo PhD for their contribution of CTC AR-V7 testing at Johns Hopkins, under W81XWH-16-PCRP-CCRSA (E.S.A, Johns Hopkins). We acknowledge Drs David Nanus and Scott Tagawa for their enrollment of patients at Weill Cornell Medical College under W81XWH-14-2-0159 (DMN, Weill Cornell). We wish to thank the study coordinators at Weill Cornell, Duke University, Johns Hopkins, University of Chicago, and Memorial Sloan Kettering Cancer Center and the DOD Prostate Cancer Clinical Trials Consortium (DOD PCCTC). We wish to acknowledge the dedication of our patients to provide blood samples at no clear benefit to them but for the benefits of all patients with prostate cancer. We acknowledge support from the Duke Cancer Institute Center for Prostate and Urologic Cancers. We would like to acknowledge the assistance of the Duke Molecular Physiology Institute Molecular Genomics core for the generation of data for the manuscript.

Funding Information:
Armstrong AJ reports research funding from consulting with Astellas/Pfizer, Janssen, Bayer, research support (to Duke) from Dendreon, Janssen, Astellas/Pfizer, Bayer, Constellation, Genentech, BMS, Merck, Astrazeneca. Speaker for Bayer and Dendreon. George DJ reports support from Acerta Pharmaceuticals – Research, American Association for Cancer Research – Sr Editor, Astellas – Consultant, Research, Advisory Board, Astrazeneca – Consultant, Advisory Board, Axess Oncology – Independent Contractor, Bayer H/C Pharmaceuticals – Research, Consultant, Speaker, Honorarium, Travel accommodations, SC, BMS – Consultant, Research, Steering Committee, Calithera – Research, Capio Biosciences – Scientific Advisory Board, EMD Serono – Honorarium, Exelixis, Inc – Research, Consultant, Speaker, Honorarium, Travel accommodations, Flatiron – Consultant, Ipsen – Honorarium, Janssen Pharmaceuticals – Research, Consultant, Independent Data Monitoring Committee (IDMC), Leidos Biomedical Research – Consultant, Merck Sharp & Dohme –Consultant, Michael J Hennessey Associates – Honorarium, Consultant, Millennium Medical Publishing, Clinical Advances in Hematology & Oncology –Co‐Editor‐in‐Chief, Modra Pharmaceuticals B.V. – Advisory Board, Myovant Sciences, Inc – Consultant, Nektar Therapeutics – Steering Committee, Novartis– Research, Physician Education Resource LLC – Consultant, Pfizer – Research, Consultant, Steering Committee, Honorarium, Sanofi – Research, Consultant, Speaker, Honorarium, Travel accommodations, UroGPO – Honorarium, UroToday –Honorarium, Travel accommodations, Vizuri Health Sciences, LLC – Consultant, and NCI – Steering Committee. Tomlins SA (SAT) reports that the University of Michigan has been issued patents on ETS gene fusions in prostate cancer, on which SAT is a co‐inventor. The diagnostic field of use was licensed to Hologic/Gen‐Probe Inc., which has sub‐licensed rights to Roche/Ventana Medical Systems. SAT has served as a consultant for and received honoraria from Janssen, AbbVie, Sanofi, Almac Diagnostics, and Astellas/Medivation. SAT has had sponsored research agreements with Astellas/Medivation and GenomeDX. SAT is an equity holder in, a prior consultant for, and current employee of Strata Oncology. Antonarakis ES is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Astra Zeneca, Bristol‐Myers Squibb, Clovis, and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers‐Squibb, AstraZeneca, Clovis, and Merck; and he is the co‐inventor of a biomarker technology that has been licensed to Qiagen. RV Dittamore is an employee at Epic Sciences. Nanus DM reports support from Genentech, Roche, and DSMB. Luo J has served as a paid consultant/advisor for Sun Pharma, Janssen, Tolero, and Sanofi; has received research funding to his institution from Orion, Mirati, Astellas, Sanofi, Constellation, Calibr, Pandomedx, and Gilead; and is a co‐inventor of a technology that has been licensed to Tokai, Qiagen, and A&G. Gupta S, Daniel HH, Gabor K, Halabi S, Foo WC, Monika A, Somarelli JA, Rothwell C, Gregory SG have declared no COI.

Publisher Copyright:
© 2019 Wiley Periodicals, Inc.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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