Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer

Matti Annala, Gillian Vandekerkhove, Daniel Khalaf, Sinja Taavitsainen, Kevin Beja, Evan W. Warner, Katherine Sunderland, Christian Kollmannsberger, Bernhard J. Eigl, Daygen Finch, Conrad D. Oja, Joanna Vergidis, Muhammad Zulfiqar, Arun A. Azad, Matti Nykter, Martin E. Gleave, Alexander W. Wyatt, Kim N. Chi

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. SIGNIFICANCE: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.

Original languageEnglish
Pages (from-to)444-457
Number of pages14
JournalCancer Discovery
Volume8
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

Cite this

Annala, M., Vandekerkhove, G., Khalaf, D., Taavitsainen, S., Beja, K., Warner, E. W., ... Chi, K. N. (2018). Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. Cancer Discovery, 8(4), 444-457. https://doi.org/10.1158/2159-8290.CD-17-0937
Annala, Matti ; Vandekerkhove, Gillian ; Khalaf, Daniel ; Taavitsainen, Sinja ; Beja, Kevin ; Warner, Evan W. ; Sunderland, Katherine ; Kollmannsberger, Christian ; Eigl, Bernhard J. ; Finch, Daygen ; Oja, Conrad D. ; Vergidis, Joanna ; Zulfiqar, Muhammad ; Azad, Arun A. ; Nykter, Matti ; Gleave, Martin E. ; Wyatt, Alexander W. ; Chi, Kim N. / Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. In: Cancer Discovery. 2018 ; Vol. 8, No. 4. pp. 444-457.
@article{d82cb0bd29874ddbbded0cb0ae88c23f,
title = "Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer",
abstract = "Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-na{\"i}ve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. SIGNIFICANCE: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.",
author = "Matti Annala and Gillian Vandekerkhove and Daniel Khalaf and Sinja Taavitsainen and Kevin Beja and Warner, {Evan W.} and Katherine Sunderland and Christian Kollmannsberger and Eigl, {Bernhard J.} and Daygen Finch and Oja, {Conrad D.} and Joanna Vergidis and Muhammad Zulfiqar and Azad, {Arun A.} and Matti Nykter and Gleave, {Martin E.} and Wyatt, {Alexander W.} and Chi, {Kim N.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1158/2159-8290.CD-17-0937",
language = "English",
volume = "8",
pages = "444--457",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research",
number = "4",

}

Annala, M, Vandekerkhove, G, Khalaf, D, Taavitsainen, S, Beja, K, Warner, EW, Sunderland, K, Kollmannsberger, C, Eigl, BJ, Finch, D, Oja, CD, Vergidis, J, Zulfiqar, M, Azad, AA, Nykter, M, Gleave, ME, Wyatt, AW & Chi, KN 2018, 'Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer' Cancer Discovery, vol. 8, no. 4, pp. 444-457. https://doi.org/10.1158/2159-8290.CD-17-0937

Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer. / Annala, Matti; Vandekerkhove, Gillian; Khalaf, Daniel; Taavitsainen, Sinja; Beja, Kevin; Warner, Evan W.; Sunderland, Katherine; Kollmannsberger, Christian; Eigl, Bernhard J.; Finch, Daygen; Oja, Conrad D.; Vergidis, Joanna; Zulfiqar, Muhammad; Azad, Arun A.; Nykter, Matti; Gleave, Martin E.; Wyatt, Alexander W.; Chi, Kim N.

In: Cancer Discovery, Vol. 8, No. 4, 01.04.2018, p. 444-457.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer

AU - Annala, Matti

AU - Vandekerkhove, Gillian

AU - Khalaf, Daniel

AU - Taavitsainen, Sinja

AU - Beja, Kevin

AU - Warner, Evan W.

AU - Sunderland, Katherine

AU - Kollmannsberger, Christian

AU - Eigl, Bernhard J.

AU - Finch, Daygen

AU - Oja, Conrad D.

AU - Vergidis, Joanna

AU - Zulfiqar, Muhammad

AU - Azad, Arun A.

AU - Nykter, Matti

AU - Gleave, Martin E.

AU - Wyatt, Alexander W.

AU - Chi, Kim N.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. SIGNIFICANCE: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.

AB - Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers. SIGNIFICANCE: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.

UR - http://www.scopus.com/inward/record.url?scp=85046680807&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-17-0937

DO - 10.1158/2159-8290.CD-17-0937

M3 - Article

VL - 8

SP - 444

EP - 457

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 4

ER -