Circulating tumor cell chromosomal instability and neuroendocrine phenotype by immunomorphology and poor outcomes in men with mCRPC treated with abiraterone or enzalutamide

Landon C. Brown, Susan Halabi, Joseph D. Schonhoft, Qian Yang, Jun Luo, David M. Nanus, Paraskevi Giannakakou, Russell Z. Szmulewitz, Daniel C. Danila, Ethan S. Barnett, Emily A. Carbone, Jimmy L. Zhao, Patrick Healy, Monika Anand, Audrey Gill, Adam Jendrisak, William R. Berry, Santosh Gupta, Simon G. Gregory, Richard WenstrupEmmanuel S. Antonarakis, Daniel J. George, Howard I. Scher, Andrew J. Armstrong

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose: While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance. Experimental Design: PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY). Results: We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2–4.0 and HR 3.8; 95% CI, 1.2–12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n ¼ 173; HR, 5.7; 95% CI, 2.6–12.7). Conclusions: A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions.

Original languageEnglish (US)
Pages (from-to)4077-4088
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number14
DOIs
StatePublished - Jul 15 2021
Externally publishedYes

Bibliographical note

Funding Information:
L.C. Brown reports personal fees from Seattle Genetics outside the submitted work. S. Halabi reports grants from Epic Sciences outside the submitted work. J.D. Schonhoft reports other from Epic Sciences during the conduct of the study, as well as other from Epic Sciences outside the submitted work. J. Luo has served as a paid consultant/advisor for Sun Pharma, Janssen, Tolero, and Sanofi. J. Luo has received research funding to his institution from Orion, Astellas, Sanofi, Constellation, Calibr, Pandomedx, Trovagene, and Gilead, and is a co-inventor of a technology that has been licensed to Tokai, Qiagen, and A&G. D.M. Nanus reports grants from Prostate Cancer Foundation during the conduct of the study. P. Giannakakou reports grants from Weill Cornell Medicine during the conduct of the study. R.Z. Szmulewitz reports personal fees from Astellas/Pfizer during the conduct of the study, as well as personal fees from Merck and other from Corcept Therapeutics outside the submitted work. D.C. Danila reports grants from Prostate Cancer Foundation during the conduct of the study. D.C. Danila also reports research support from U.S. Department of Defense, American Society of Clinical Oncology, Prostate Cancer Foundation, Stand Up 2 Cancer, Janssen Research & Development, Astellas, Medivation, Agensys, Genentech, and CreaTV; D.C. Danila is consultant for Angle LLT, Axiom LLT, Janssen Research & Development, Astellas, Medivation, Pfizer, Genzyme, and Agensys. A. Gill reports other from Epic Sciences during the conduct of the study, as well as other from Epic Sciences outside the submitted work. A. Jendrisak reports other from Epic Sciences during the conduct of the study. R. Wenstrup reports other from Epic Sciences during the conduct of the study, as well as other from Epic Sciences outside the submitted work. E.S. Antonarakis reports grants and personal fees from Bristol Myers Squibb, Amgen, Eli Lilly, Bayer, Curium, Constellation, Clovis, AstraZeneca, Merck, Astellas, and Janssen outside the submitted work; in addition, E.S. Antonarakis has a patent for an AR-V7 biomarker technology issued, licensed, and with royalties paid from Qiagen. D.J. George reports personal fees from AACR, Axess Oncology, Capio Biosciences, Constellation Pharma, Flatiron, Merck, Millennium Med Pub, Modra Pharma, Myovant Sciences, NCI Genitourinary, Nektar Thera, Physician Education Resource, Propella Therapeutics, RevHealth, UroGPO, and Vizuri Health Sciences; grants and personal fees from Astellas, AstraZeneca, BMS, and Janssen Pharma; grants from Calithera, Novartis, and Pfizer; personal fees and other from Bayer and Michael J Hennessey Assoc; other from EMD Serono, Ipsen, and UroToday; and grants, personal fees, and other from Exelixis and Sanofi outside the submitted work. H.I. Scher reports grants from Epic Sciences during the conduct of the study. H.I. Scher also reports personal fees and nonfinancial support from Ambry Genetics Corp and Konica Minolta, Inc; nonfinancial support from Amgen, ESSA Pharmaceuticals, Janssen Research & Development, Janssen Biotech, Inc, and Menarini Silicon Biosystems; personal fees from Bayer, Pfizer Inc., Sun Pharmaceuticals Industries, Inc., WCG Oncology, and Asterias Biotherapeutics; and grants from Illuminia, Inc., Janssen, Menarini Silicon Biosystems, and Thermo Fisher Scientific outside the submitted work. A.J. Armstrong reports grants and personal fees from Merck, BMS, Astellas, Dendreon, Bayer, AstraZeneca, Janssen, and Pfizer; personal fees from Clovis; and grants from Genentech, Constellation, and Beigene outside the submitted work. No disclosures were reported by the other authors.

Funding Information:
We wish to thank the Prostate Cancer Foundation and Movember for their financial support of this Global Treatment Sciences Challenge Award (A.J. Armstrong, Duke University), and the U.S. Department of Defense Prostate Cancer Clinical Trial Consortium for infrastructural support for this multicenter study. A.J. Armstrong was supported by a Prostate Cancer Foundation grant, an NIH R01 (1R01CA233585-01), and the Duke Cancer Institute (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 (D.J. George, A.J. Armstrong, Duke University), W81XWH-15-1-0467 (S. Halabi, Duke University), W81XWH-18-1-0278 (S. Halabi, Duke Univesity), W81XWH-14-2-0159 (D.M. Nanus, Weill Cornell Medical College), W81XWH-15-2-0018 (R.Z. Szmulewitz, University of Chicago), W81XWH-15-2-0018 (H.I. Scher, Memorial Sloan Kettering Cancer Center), and W81XWH-16-PCRP-CCRSA (E.S. Antonarakis, Johns Hopkins University). D.C. Danilla and H.I. Scher were also supported in part by NCI grants P30CA008748 and the MSKCC Sidney Kimmel Center for Prostate and Urologic Cancers. J.L. Zhao is supported by an ASCO Conquer Cancer Young Investigator Award, a K12 Paul Calabresi Career Development Award for Clinical Oncology, and a Prostate Foundation Young Investigator Award. This research was supported in part by NCI grant NIH T32CA062948 and the CTSC UL1 TR002384-01 (Weill Cornell Medical College). We wish to thank the study coordinators at Weill Cornell Medical College, Duke University, Johns Hopkins University, University of Chicago, and Memorial Sloan Kettering Cancer Center. 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.

Publisher Copyright:
© 2021 American Association for Cancer Research.

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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