Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer

Guru Sonpavde; Neeraj Agarwal; Gregory Russell Pond; Rebecca J. Nagy; Roberto H. Nussenzveig; Andrew W. Hahn; Oliver Sartor; Theodore Stewart Gourdin; Lakshminarayanan Nandagopal; Elisa M. Ledet; Gurudatta Naik; Andrew J. Armstrong; Jue Wang; Mehmet Asim Bilen; Shilpa Gupta; Petros Grivas; Sumanta K. Pal; Richard B. Lanman; Amir Ali Talasaz; Michael B. Lilly

doi:10.1002/cncr.31959

Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer

Guru Sonpavde, Neeraj Agarwal, Gregory Russell Pond, Rebecca J. Nagy, Roberto H. Nussenzveig, Andrew W. Hahn, Oliver Sartor, Theodore Stewart Gourdin, Lakshminarayanan Nandagopal, Elisa M. Ledet, Gurudatta Naik, Andrew J. Armstrong, Jue Wang, Mehmet Asim Bilen, Shilpa Gupta, Petros Grivas, Sumanta K. Pal, Richard B. Lanman, Amir Ali Talasaz, Michael B. Lilly

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions: ctDNA frequently was detected in this large cohort of “real-world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

Original language	English (US)
Pages (from-to)	1459-1469
Number of pages	11
Journal	Cancer
Volume	125
Issue number	9
DOIs	https://doi.org/10.1002/cncr.31959
State	Published - May 1 2019

Bibliographical note

Funding Information:
Guru Sonpavde has received grants from Boehringer-Ingelheim, Bayer, Onyx-Amgen, and Celgene to his institution for a trial; has acted as paid consultant and received research support from Pfizer, Merck, Janssen, and Sanofi (fees/year comply with institution’s guidelines); has acted as a paid consultant for Bayer, Argos, Genentech, Novartis, Sanofi, Exelixis, EMD Serono, Amgen, and Eisai (fees/year comply with institution’s guidelines); has acted as a paid consultant for and member of the steering committee for a trial sponsored by Agensys/Astellas; has received continuing medical education lecture fees from Clinical Care Options; has acted as a paid consultant (fees/year comply with institution’s guidelines) for and member of the data safety monitoring board of a trial funded by and steering committee of a trial sponsored by AstraZeneca; has been the author of an educational chapter/review for UptoDate; has acted as a paid consultant for (fees/year comply with institution’s guidelines) and member of the steering committee of a trial sponsored by Bristol-Myers Squibb; has acted as a consultant to develop a biomarker for the National Comprehensive Cancer Network (fees/year comply with institution’s guidelines); has acted as a CME-certified conference speaker for Physicians Education Resource; has acted as a conference speaker for OncLive; has acted as a speaker in an educational meeting for Research to Practice; and has acted as a member of the steering committee of a trial sponsored by Bavarian Nordic for work performed outside of the current study. Neeraj Agarwal has acted as a paid consultant for and received honoraria from Pfizer, Novartis, Merck, Genentech, Eisai, Exelixis, Clovis, EMD Serono, Bristol-Myers Squibb, AstraZeneca, Astellas, Eli Lilly, Bayer, and Pharmacyclics and has received research funding to his institution from Active Biotech, AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, Calithera, Celldex, Eisai, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, New link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Sanofi, Takeda, and Tracon for work performed outside of the current study. Gregory Pond has acted as a member of the Data Monitoring Committee for Takeda and has acted as a paid consultant for Merck for work performed outside of the current study and has a close family member who works for Roche Canada. Rebecca J. Nagy is an employee of and shareholder in Guardant Health Inc. Roberto H. Nussenzveig has acted as a paid member of the advisory board for Tempus Labs Inc. Oliver Sartor has acted as a paid consultant for Advanced Accelerator Applications, Astellas, Bavarian-Nordic, Bellicum, Blue Earth Diagnostics Inc, Celgene, EMD Serono, Myovant Sciences, Pfizer, and Teva; has received grants from and acted as a paid consultant for AstraZeneca, Bayer, Constellation, Dendreon, Endocyte, Johnson & Johnson, Progenics, and Sanofi; and has received grants from Bristol-Myers Squibb, Innocrin, Invitae, Merck, Roche, and Sotio for work performed as part of the current study. Andrew J. Armstrong has acted as a paid consultant for and received research support to Duke University from Dendreon and Janssen; has acted as a member of the speakers’ bureau of, as a paid consultant for, and received research support to Duke University from Pfizer, Astellas, and Bayer; and has received research support to Duke University from Sanofi Aventis, Genentech/Roche, Bristol-Myers Squibb, and Merck for work performed as part of the current study and has received a grant from Novartis for work performed outside of the current study. Mehmet A. Bilen has acted as a member of the advisory boards of Exelixis and Sanofi; has acted as a member of the advisory board of and received research support from Nektar; and has received research support from Bristol-Myers Squibb, AstraZeneca, Incyte, Seattle Genetics, Pfizer, Tricon, and Research for work performed outside of the current study. Shilpa Gupta has acted as a member of the advisory boards of Exelixis, Janssen, Merck, Genentech, Pfizer, and Armo Biosciences; has acted as a member of the advisory board of and Speakers Bureau for and received a research grant from Bristol-Myers Squibb; and received research grants from Seattle Genetics and Astellas for work performed as part of the current study. Petros Grivas has received fees for consulting and to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Bayer, Merck, and AstraZeneca; fees to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Mirati and OncoGenex; fees for consulting unrelated to this study and to the Cleveland Clinic Foundation and University of Washington for clinical trial conduction (unrelated to this study) from Pfizer; fees for consulting unrelated to this study from and participated in an educational, unbranded, and not product-related speaker’s program (after providing direct input for slides content) for and received fees to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Genentech and Bristol-Myers Squibb; has acted as a paid consultant for Dendreon, Exelixis, Biocept, EMD Serono, Seattle Genetics, Foundation Medicine, Driver Inc, QED Therapeutics, Heron Therapeutics, and Janssen; and has received fees for consulting (unrelated to this study) and fees to the University of Washington for an unrelated clinical trial from Clovis Oncology and Bavarian Nordic for work performed outside of the current study. Sumanta K. Pal has acted as a paid consultant for and received research funding from Pfizer, Novartis, Bristol-Myers Squibb, Astellas, and Medivation and has acted as a paid consultant for AVEO, Myriad Genetics, Genentech, and Exelixis. Richard B. Lanman is an employee and stockholder of Guardant Health Inc and a stockholder and board member of Biolase Inc. AmirAli Talasaz is an employee and stockholder of Guardant Health Inc. Michael B. Lilly has received research support from Bavarian Nordic Immunotherapeutics and Bayer and acted as a paid consultant for Senex and Proveri Inc for work performed outside of the current study.

Publisher Copyright:
© 2019 American Cancer Society

Keywords

castration resistant
circulating tumor DNA (ctDNA)
failure-free survival
genomic profiling
metastatic
prostate cancer
survival

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1002/cncr.31959

OpenUrl availability

Full text

Cite this

Sonpavde, G., Agarwal, N., Pond, G. R., Nagy, R. J., Nussenzveig, R. H., Hahn, A. W., Sartor, O., Gourdin, T. S., Nandagopal, L., Ledet, E. M., Naik, G., Armstrong, A. J., Wang, J., Bilen, M. A., Gupta, S., Grivas, P., Pal, S. K., Lanman, R. B., Talasaz, A. A., & Lilly, M. B. (2019). Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer. Cancer, 125(9), 1459-1469. https://doi.org/10.1002/cncr.31959

Sonpavde, G, Agarwal, N, Pond, GR, Nagy, RJ, Nussenzveig, RH, Hahn, AW, Sartor, O, Gourdin, TS, Nandagopal, L, Ledet, EM, Naik, G, Armstrong, AJ, Wang, J, Bilen, MA, Gupta, S, Grivas, P, Pal, SK, Lanman, RB, Talasaz, AA & Lilly, MB 2019, 'Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer', Cancer, vol. 125, no. 9, pp. 1459-1469. https://doi.org/10.1002/cncr.31959

@article{69a42711d12c4aac864db69dde235467,

title = "Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer",

abstract = "Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions: ctDNA frequently was detected in this large cohort of “real-world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.",

keywords = "castration resistant, circulating tumor DNA (ctDNA), failure-free survival, genomic profiling, metastatic, prostate cancer, survival",

author = "Guru Sonpavde and Neeraj Agarwal and Pond, {Gregory Russell} and Nagy, {Rebecca J.} and Nussenzveig, {Roberto H.} and Hahn, {Andrew W.} and Oliver Sartor and Gourdin, {Theodore Stewart} and Lakshminarayanan Nandagopal and Ledet, {Elisa M.} and Gurudatta Naik and Armstrong, {Andrew J.} and Jue Wang and Bilen, {Mehmet Asim} and Shilpa Gupta and Petros Grivas and Pal, {Sumanta K.} and Lanman, {Richard B.} and Talasaz, {Amir Ali} and Lilly, {Michael B.}",

note = "Funding Information: Guru Sonpavde has received grants from Boehringer-Ingelheim, Bayer, Onyx-Amgen, and Celgene to his institution for a trial; has acted as paid consultant and received research support from Pfizer, Merck, Janssen, and Sanofi (fees/year comply with institution{\textquoteright}s guidelines); has acted as a paid consultant for Bayer, Argos, Genentech, Novartis, Sanofi, Exelixis, EMD Serono, Amgen, and Eisai (fees/year comply with institution{\textquoteright}s guidelines); has acted as a paid consultant for and member of the steering committee for a trial sponsored by Agensys/Astellas; has received continuing medical education lecture fees from Clinical Care Options; has acted as a paid consultant (fees/year comply with institution{\textquoteright}s guidelines) for and member of the data safety monitoring board of a trial funded by and steering committee of a trial sponsored by AstraZeneca; has been the author of an educational chapter/review for UptoDate; has acted as a paid consultant for (fees/year comply with institution{\textquoteright}s guidelines) and member of the steering committee of a trial sponsored by Bristol-Myers Squibb; has acted as a consultant to develop a biomarker for the National Comprehensive Cancer Network (fees/year comply with institution{\textquoteright}s guidelines); has acted as a CME-certified conference speaker for Physicians Education Resource; has acted as a conference speaker for OncLive; has acted as a speaker in an educational meeting for Research to Practice; and has acted as a member of the steering committee of a trial sponsored by Bavarian Nordic for work performed outside of the current study. Neeraj Agarwal has acted as a paid consultant for and received honoraria from Pfizer, Novartis, Merck, Genentech, Eisai, Exelixis, Clovis, EMD Serono, Bristol-Myers Squibb, AstraZeneca, Astellas, Eli Lilly, Bayer, and Pharmacyclics and has received research funding to his institution from Active Biotech, AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, Calithera, Celldex, Eisai, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, New link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Sanofi, Takeda, and Tracon for work performed outside of the current study. Gregory Pond has acted as a member of the Data Monitoring Committee for Takeda and has acted as a paid consultant for Merck for work performed outside of the current study and has a close family member who works for Roche Canada. Rebecca J. Nagy is an employee of and shareholder in Guardant Health Inc. Roberto H. Nussenzveig has acted as a paid member of the advisory board for Tempus Labs Inc. Oliver Sartor has acted as a paid consultant for Advanced Accelerator Applications, Astellas, Bavarian-Nordic, Bellicum, Blue Earth Diagnostics Inc, Celgene, EMD Serono, Myovant Sciences, Pfizer, and Teva; has received grants from and acted as a paid consultant for AstraZeneca, Bayer, Constellation, Dendreon, Endocyte, Johnson & Johnson, Progenics, and Sanofi; and has received grants from Bristol-Myers Squibb, Innocrin, Invitae, Merck, Roche, and Sotio for work performed as part of the current study. Andrew J. Armstrong has acted as a paid consultant for and received research support to Duke University from Dendreon and Janssen; has acted as a member of the speakers{\textquoteright} bureau of, as a paid consultant for, and received research support to Duke University from Pfizer, Astellas, and Bayer; and has received research support to Duke University from Sanofi Aventis, Genentech/Roche, Bristol-Myers Squibb, and Merck for work performed as part of the current study and has received a grant from Novartis for work performed outside of the current study. Mehmet A. Bilen has acted as a member of the advisory boards of Exelixis and Sanofi; has acted as a member of the advisory board of and received research support from Nektar; and has received research support from Bristol-Myers Squibb, AstraZeneca, Incyte, Seattle Genetics, Pfizer, Tricon, and Research for work performed outside of the current study. Shilpa Gupta has acted as a member of the advisory boards of Exelixis, Janssen, Merck, Genentech, Pfizer, and Armo Biosciences; has acted as a member of the advisory board of and Speakers Bureau for and received a research grant from Bristol-Myers Squibb; and received research grants from Seattle Genetics and Astellas for work performed as part of the current study. Petros Grivas has received fees for consulting and to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Bayer, Merck, and AstraZeneca; fees to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Mirati and OncoGenex; fees for consulting unrelated to this study and to the Cleveland Clinic Foundation and University of Washington for clinical trial conduction (unrelated to this study) from Pfizer; fees for consulting unrelated to this study from and participated in an educational, unbranded, and not product-related speaker{\textquoteright}s program (after providing direct input for slides content) for and received fees to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Genentech and Bristol-Myers Squibb; has acted as a paid consultant for Dendreon, Exelixis, Biocept, EMD Serono, Seattle Genetics, Foundation Medicine, Driver Inc, QED Therapeutics, Heron Therapeutics, and Janssen; and has received fees for consulting (unrelated to this study) and fees to the University of Washington for an unrelated clinical trial from Clovis Oncology and Bavarian Nordic for work performed outside of the current study. Sumanta K. Pal has acted as a paid consultant for and received research funding from Pfizer, Novartis, Bristol-Myers Squibb, Astellas, and Medivation and has acted as a paid consultant for AVEO, Myriad Genetics, Genentech, and Exelixis. Richard B. Lanman is an employee and stockholder of Guardant Health Inc and a stockholder and board member of Biolase Inc. AmirAli Talasaz is an employee and stockholder of Guardant Health Inc. Michael B. Lilly has received research support from Bavarian Nordic Immunotherapeutics and Bayer and acted as a paid consultant for Senex and Proveri Inc for work performed outside of the current study. Publisher Copyright: {\textcopyright} 2019 American Cancer Society",

year = "2019",

month = may,

day = "1",

doi = "10.1002/cncr.31959",

language = "English (US)",

volume = "125",

pages = "1459--1469",

journal = "Cancer",

issn = "0008-543X",

publisher = "John Wiley and Sons Inc.",

number = "9",

}

TY - JOUR

T1 - Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer

AU - Sonpavde, Guru

AU - Agarwal, Neeraj

AU - Pond, Gregory Russell

AU - Nagy, Rebecca J.

AU - Nussenzveig, Roberto H.

AU - Hahn, Andrew W.

AU - Sartor, Oliver

AU - Gourdin, Theodore Stewart

AU - Nandagopal, Lakshminarayanan

AU - Ledet, Elisa M.

AU - Naik, Gurudatta

AU - Armstrong, Andrew J.

AU - Wang, Jue

AU - Bilen, Mehmet Asim

AU - Gupta, Shilpa

AU - Grivas, Petros

AU - Pal, Sumanta K.

AU - Lanman, Richard B.

AU - Talasaz, Amir Ali

AU - Lilly, Michael B.

N1 - Funding Information: Guru Sonpavde has received grants from Boehringer-Ingelheim, Bayer, Onyx-Amgen, and Celgene to his institution for a trial; has acted as paid consultant and received research support from Pfizer, Merck, Janssen, and Sanofi (fees/year comply with institution’s guidelines); has acted as a paid consultant for Bayer, Argos, Genentech, Novartis, Sanofi, Exelixis, EMD Serono, Amgen, and Eisai (fees/year comply with institution’s guidelines); has acted as a paid consultant for and member of the steering committee for a trial sponsored by Agensys/Astellas; has received continuing medical education lecture fees from Clinical Care Options; has acted as a paid consultant (fees/year comply with institution’s guidelines) for and member of the data safety monitoring board of a trial funded by and steering committee of a trial sponsored by AstraZeneca; has been the author of an educational chapter/review for UptoDate; has acted as a paid consultant for (fees/year comply with institution’s guidelines) and member of the steering committee of a trial sponsored by Bristol-Myers Squibb; has acted as a consultant to develop a biomarker for the National Comprehensive Cancer Network (fees/year comply with institution’s guidelines); has acted as a CME-certified conference speaker for Physicians Education Resource; has acted as a conference speaker for OncLive; has acted as a speaker in an educational meeting for Research to Practice; and has acted as a member of the steering committee of a trial sponsored by Bavarian Nordic for work performed outside of the current study. Neeraj Agarwal has acted as a paid consultant for and received honoraria from Pfizer, Novartis, Merck, Genentech, Eisai, Exelixis, Clovis, EMD Serono, Bristol-Myers Squibb, AstraZeneca, Astellas, Eli Lilly, Bayer, and Pharmacyclics and has received research funding to his institution from Active Biotech, AstraZeneca, Bavarian Nordic, Bristol-Myers Squibb, Calithera, Celldex, Eisai, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Medivation, Merck, New link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Sanofi, Takeda, and Tracon for work performed outside of the current study. Gregory Pond has acted as a member of the Data Monitoring Committee for Takeda and has acted as a paid consultant for Merck for work performed outside of the current study and has a close family member who works for Roche Canada. Rebecca J. Nagy is an employee of and shareholder in Guardant Health Inc. Roberto H. Nussenzveig has acted as a paid member of the advisory board for Tempus Labs Inc. Oliver Sartor has acted as a paid consultant for Advanced Accelerator Applications, Astellas, Bavarian-Nordic, Bellicum, Blue Earth Diagnostics Inc, Celgene, EMD Serono, Myovant Sciences, Pfizer, and Teva; has received grants from and acted as a paid consultant for AstraZeneca, Bayer, Constellation, Dendreon, Endocyte, Johnson & Johnson, Progenics, and Sanofi; and has received grants from Bristol-Myers Squibb, Innocrin, Invitae, Merck, Roche, and Sotio for work performed as part of the current study. Andrew J. Armstrong has acted as a paid consultant for and received research support to Duke University from Dendreon and Janssen; has acted as a member of the speakers’ bureau of, as a paid consultant for, and received research support to Duke University from Pfizer, Astellas, and Bayer; and has received research support to Duke University from Sanofi Aventis, Genentech/Roche, Bristol-Myers Squibb, and Merck for work performed as part of the current study and has received a grant from Novartis for work performed outside of the current study. Mehmet A. Bilen has acted as a member of the advisory boards of Exelixis and Sanofi; has acted as a member of the advisory board of and received research support from Nektar; and has received research support from Bristol-Myers Squibb, AstraZeneca, Incyte, Seattle Genetics, Pfizer, Tricon, and Research for work performed outside of the current study. Shilpa Gupta has acted as a member of the advisory boards of Exelixis, Janssen, Merck, Genentech, Pfizer, and Armo Biosciences; has acted as a member of the advisory board of and Speakers Bureau for and received a research grant from Bristol-Myers Squibb; and received research grants from Seattle Genetics and Astellas for work performed as part of the current study. Petros Grivas has received fees for consulting and to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Bayer, Merck, and AstraZeneca; fees to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Mirati and OncoGenex; fees for consulting unrelated to this study and to the Cleveland Clinic Foundation and University of Washington for clinical trial conduction (unrelated to this study) from Pfizer; fees for consulting unrelated to this study from and participated in an educational, unbranded, and not product-related speaker’s program (after providing direct input for slides content) for and received fees to the Cleveland Clinic Foundation for clinical trial conduction (unrelated to this study) from Genentech and Bristol-Myers Squibb; has acted as a paid consultant for Dendreon, Exelixis, Biocept, EMD Serono, Seattle Genetics, Foundation Medicine, Driver Inc, QED Therapeutics, Heron Therapeutics, and Janssen; and has received fees for consulting (unrelated to this study) and fees to the University of Washington for an unrelated clinical trial from Clovis Oncology and Bavarian Nordic for work performed outside of the current study. Sumanta K. Pal has acted as a paid consultant for and received research funding from Pfizer, Novartis, Bristol-Myers Squibb, Astellas, and Medivation and has acted as a paid consultant for AVEO, Myriad Genetics, Genentech, and Exelixis. Richard B. Lanman is an employee and stockholder of Guardant Health Inc and a stockholder and board member of Biolase Inc. AmirAli Talasaz is an employee and stockholder of Guardant Health Inc. Michael B. Lilly has received research support from Bavarian Nordic Immunotherapeutics and Bayer and acted as a paid consultant for Senex and Proveri Inc for work performed outside of the current study. Publisher Copyright: © 2019 American Cancer Society

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions: ctDNA frequently was detected in this large cohort of “real-world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

AB - Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions: ctDNA frequently was detected in this large cohort of “real-world” patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

KW - castration resistant

KW - circulating tumor DNA (ctDNA)

KW - failure-free survival

KW - genomic profiling

KW - metastatic

KW - prostate cancer

KW - survival

UR - http://www.scopus.com/inward/record.url?scp=85059666191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059666191&partnerID=8YFLogxK

U2 - 10.1002/cncr.31959

DO - 10.1002/cncr.31959

M3 - Article

C2 - 30620391

AN - SCOPUS:85059666191

SN - 0008-543X

VL - 125

SP - 1459

EP - 1469

JO - Cancer

JF - Cancer

IS - 9

ER -

Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer

Abstract

Bibliographical note

Keywords

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this