Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer

Manish Kohli; Winston Tan; Tiantian Zheng; Amy Wang; Carlos Montesinos; Calven Wong; Pan Du; Shidong Jia; Siddhartha Yadav; Lisa G. Horvath; Kate L. Mahon; Edmond M. Kwan; Heidi Fettke; Jianjun Yu; Arun A. Azad

doi:10.1016/j.ebiom.2020.102728

Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer

Manish Kohli, Winston Tan, Tiantian Zheng, Amy Wang, Carlos Montesinos, Calven Wong, Pan Du, Shidong Jia, Siddhartha Yadav, Lisa G. Horvath, Kate L. Mahon, Edmond M. Kwan, Heidi Fettke, Jianjun Yu, Arun A. Azad

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

11 Scopus citations

Abstract

Background: Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer. Methods: In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group. Findings: cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13–4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC. Interpretation: ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management. Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

Original language	English (US)
Article number	102728
Journal	EBioMedicine
Volume	54
DOIs	https://doi.org/10.1016/j.ebiom.2020.102728
State	Published - Apr 2020

Keywords

Circulating tumor DNA
Genomic alterations
Metastatic prostate cancer

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.ebiom.2020.102728

Cite this

Kohli, M., Tan, W., Zheng, T., Wang, A., Montesinos, C., Wong, C., Du, P., Jia, S., Yadav, S., Horvath, L. G., Mahon, K. L., Kwan, E. M., Fettke, H., Yu, J., & Azad, A. A. (2020). Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer. EBioMedicine, 54, [102728]. https://doi.org/10.1016/j.ebiom.2020.102728

Kohli, M, Tan, W, Zheng, T, Wang, A, Montesinos, C, Wong, C, Du, P, Jia, S, Yadav, S, Horvath, LG, Mahon, KL, Kwan, EM, Fettke, H, Yu, J & Azad, AA 2020, 'Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer', EBioMedicine, vol. 54, 102728. https://doi.org/10.1016/j.ebiom.2020.102728

@article{bca97dd5976c4cdd83344d01231904b7,

title = "Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer",

abstract = "Background: Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer. Methods: In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group. Findings: cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13–4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC. Interpretation: ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management. Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.",

keywords = "Circulating tumor DNA, Genomic alterations, Metastatic prostate cancer",

author = "Manish Kohli and Winston Tan and Tiantian Zheng and Amy Wang and Carlos Montesinos and Calven Wong and Pan Du and Shidong Jia and Siddhartha Yadav and Horvath, {Lisa G.} and Mahon, {Kate L.} and Kwan, {Edmond M.} and Heidi Fettke and Jianjun Yu and Azad, {Arun A.}",

note = "Funding Information: This study was supported by: NHMRC Postgraduate Scholarship (to Edmond M Kwan); Movember/ Prostate Cancer Foundation of Australia Clinical Scientist Fellow ( CSA 0515 ; to Kate Mahon); the Astellas Investigator-Initiated Grant, Cancer Institute NSW Translational Program Grant ( 2018/TPG001 ; to Lisa G Horvath); the NHMRC Project Grant, Victorian Cancer Agency Clinical Research Fellowship- CRF14009 , Astellas Investigator-Initiated Grant, NHMRC Project Grant - GNT1098647 (to Arun A Azad); and the National Institute of Health - RO1-CA212097 (to Manish Kohli). Funding Information: We thank Paul Fletcher and Daley Drucker (Moffitt Cancer Center) for editorial assistance. They were not compensated beyond their regular salaries. This study was based on a non-commercial collaboration between academic institutions. No funding was received from Predicine, Inc. during the conduct of the study. This study was supported by: NHMRC Postgraduate Scholarship (to Edmond M Kwan); Movember/Prostate Cancer Foundation of Australia Clinical Scientist Fellow (CSA 0515; to Kate Mahon); the Astellas Investigator-Initiated Grant, Cancer Institute NSW Translational Program Grant (2018/TPG001; to Lisa G Horvath); the NHMRC Project Grant, Victorian Cancer Agency Clinical Research Fellowship-CRF14009, Astellas Investigator-Initiated Grant, NHMRC Project Grant - GNT1098647 (to Arun A Azad); and the National Institute of Health- RO1-CA212097 (to Manish Kohli). Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = apr,

doi = "10.1016/j.ebiom.2020.102728",

language = "English (US)",

volume = "54",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

}

TY - JOUR

T1 - Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer

AU - Kohli, Manish

AU - Tan, Winston

AU - Zheng, Tiantian

AU - Wang, Amy

AU - Montesinos, Carlos

AU - Wong, Calven

AU - Du, Pan

AU - Jia, Shidong

AU - Yadav, Siddhartha

AU - Horvath, Lisa G.

AU - Mahon, Kate L.

AU - Kwan, Edmond M.

AU - Fettke, Heidi

AU - Yu, Jianjun

AU - Azad, Arun A.

N1 - Funding Information: This study was supported by: NHMRC Postgraduate Scholarship (to Edmond M Kwan); Movember/ Prostate Cancer Foundation of Australia Clinical Scientist Fellow ( CSA 0515 ; to Kate Mahon); the Astellas Investigator-Initiated Grant, Cancer Institute NSW Translational Program Grant ( 2018/TPG001 ; to Lisa G Horvath); the NHMRC Project Grant, Victorian Cancer Agency Clinical Research Fellowship- CRF14009 , Astellas Investigator-Initiated Grant, NHMRC Project Grant - GNT1098647 (to Arun A Azad); and the National Institute of Health - RO1-CA212097 (to Manish Kohli). Funding Information: We thank Paul Fletcher and Daley Drucker (Moffitt Cancer Center) for editorial assistance. They were not compensated beyond their regular salaries. This study was based on a non-commercial collaboration between academic institutions. No funding was received from Predicine, Inc. during the conduct of the study. This study was supported by: NHMRC Postgraduate Scholarship (to Edmond M Kwan); Movember/Prostate Cancer Foundation of Australia Clinical Scientist Fellow (CSA 0515; to Kate Mahon); the Astellas Investigator-Initiated Grant, Cancer Institute NSW Translational Program Grant (2018/TPG001; to Lisa G Horvath); the NHMRC Project Grant, Victorian Cancer Agency Clinical Research Fellowship-CRF14009, Astellas Investigator-Initiated Grant, NHMRC Project Grant - GNT1098647 (to Arun A Azad); and the National Institute of Health- RO1-CA212097 (to Manish Kohli). Publisher Copyright: © 2020 The Author(s)

PY - 2020/4

Y1 - 2020/4

N2 - Background: Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer. Methods: In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group. Findings: cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13–4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC. Interpretation: ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management. Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

AB - Background: Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer. Methods: In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group. Findings: cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13–4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC. Interpretation: ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management. Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

KW - Circulating tumor DNA

KW - Genomic alterations

KW - Metastatic prostate cancer

UR - http://www.scopus.com/inward/record.url?scp=85082756699&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85082756699&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2020.102728

DO - 10.1016/j.ebiom.2020.102728

M3 - Article

C2 - 32268276

AN - SCOPUS:85082756699

VL - 54

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 102728

ER -

Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this