Development and validation of a prostate cancer genomic signature that predicts early adt treatment response following radical prostatectomy

Robert Jeffrey Karnes, Vidit Sharma, Voleak Choeurng, Hussam Al Deen Ashab, Nicholas Erho, Mohammed Alshalalfa, Bruce Trock, Ashley Ross, Kasra Yousefi, Harrison Tsai, Shuang G. Zhao, Jeffrey J. Tosoian, Zaid Haddad, Mandeep Takhar, S. Laura Chang, Daniel E. Spratt, Firas Abdollah, Robert Brian Jenkins, Eric A. Klein, Paul L. Nguyen & 6 others Adam P. Dicker, Robert B. Den, Elai Davicioni, Felix Y. Feng, Tamara L. Lotan, Edward M. Schaeffer

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT. Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n ¼ 232; set II, n ¼ 435; set III, n ¼ 612). The primary endpoint of the analysis was postoperative metastasis. Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR ¼ 0.18, Pinteraction ¼ 0.009; set II: HR ¼ 0.25, Pinteraction ¼ 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P ¼ 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P ¼ 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction ¼ 0.035). Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery.

Original languageEnglish (US)
Pages (from-to)3908-3916
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number16
DOIs
StatePublished - Aug 15 2018

Fingerprint

Prostatectomy
Androgens
Prostatic Neoplasms
Therapeutics
Neoplasm Metastasis
Propensity Score
Risk Reduction Behavior
Group Psychotherapy
Transcriptome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Development and validation of a prostate cancer genomic signature that predicts early adt treatment response following radical prostatectomy. / Karnes, Robert Jeffrey; Sharma, Vidit; Choeurng, Voleak; Ashab, Hussam Al Deen; Erho, Nicholas; Alshalalfa, Mohammed; Trock, Bruce; Ross, Ashley; Yousefi, Kasra; Tsai, Harrison; Zhao, Shuang G.; Tosoian, Jeffrey J.; Haddad, Zaid; Takhar, Mandeep; Chang, S. Laura; Spratt, Daniel E.; Abdollah, Firas; Jenkins, Robert Brian; Klein, Eric A.; Nguyen, Paul L.; Dicker, Adam P.; Den, Robert B.; Davicioni, Elai; Feng, Felix Y.; Lotan, Tamara L.; Schaeffer, Edward M.

In: Clinical Cancer Research, Vol. 24, No. 16, 15.08.2018, p. 3908-3916.

Research output: Contribution to journalArticle

Karnes, RJ, Sharma, V, Choeurng, V, Ashab, HAD, Erho, N, Alshalalfa, M, Trock, B, Ross, A, Yousefi, K, Tsai, H, Zhao, SG, Tosoian, JJ, Haddad, Z, Takhar, M, Chang, SL, Spratt, DE, Abdollah, F, Jenkins, RB, Klein, EA, Nguyen, PL, Dicker, AP, Den, RB, Davicioni, E, Feng, FY, Lotan, TL & Schaeffer, EM 2018, 'Development and validation of a prostate cancer genomic signature that predicts early adt treatment response following radical prostatectomy', Clinical Cancer Research, vol. 24, no. 16, pp. 3908-3916. https://doi.org/10.1158/1078-0432.CCR-17-2745
Karnes, Robert Jeffrey ; Sharma, Vidit ; Choeurng, Voleak ; Ashab, Hussam Al Deen ; Erho, Nicholas ; Alshalalfa, Mohammed ; Trock, Bruce ; Ross, Ashley ; Yousefi, Kasra ; Tsai, Harrison ; Zhao, Shuang G. ; Tosoian, Jeffrey J. ; Haddad, Zaid ; Takhar, Mandeep ; Chang, S. Laura ; Spratt, Daniel E. ; Abdollah, Firas ; Jenkins, Robert Brian ; Klein, Eric A. ; Nguyen, Paul L. ; Dicker, Adam P. ; Den, Robert B. ; Davicioni, Elai ; Feng, Felix Y. ; Lotan, Tamara L. ; Schaeffer, Edward M. / Development and validation of a prostate cancer genomic signature that predicts early adt treatment response following radical prostatectomy. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 16. pp. 3908-3916.
@article{3ae5043203b543169bcb15b593ea75e0,
title = "Development and validation of a prostate cancer genomic signature that predicts early adt treatment response following radical prostatectomy",
abstract = "Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT. Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n ¼ 232; set II, n ¼ 435; set III, n ¼ 612). The primary endpoint of the analysis was postoperative metastasis. Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR ¼ 0.18, Pinteraction ¼ 0.009; set II: HR ¼ 0.25, Pinteraction ¼ 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1{\%} vs. 31.0{\%}, P ¼ 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4{\%} vs. 29.2{\%}, P ¼ 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction ¼ 0.035). Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery.",
author = "Karnes, {Robert Jeffrey} and Vidit Sharma and Voleak Choeurng and Ashab, {Hussam Al Deen} and Nicholas Erho and Mohammed Alshalalfa and Bruce Trock and Ashley Ross and Kasra Yousefi and Harrison Tsai and Zhao, {Shuang G.} and Tosoian, {Jeffrey J.} and Zaid Haddad and Mandeep Takhar and Chang, {S. Laura} and Spratt, {Daniel E.} and Firas Abdollah and Jenkins, {Robert Brian} and Klein, {Eric A.} and Nguyen, {Paul L.} and Dicker, {Adam P.} and Den, {Robert B.} and Elai Davicioni and Feng, {Felix Y.} and Lotan, {Tamara L.} and Schaeffer, {Edward M.}",
year = "2018",
month = "8",
day = "15",
doi = "10.1158/1078-0432.CCR-17-2745",
language = "English (US)",
volume = "24",
pages = "3908--3916",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

TY - JOUR

T1 - Development and validation of a prostate cancer genomic signature that predicts early adt treatment response following radical prostatectomy

AU - Karnes, Robert Jeffrey

AU - Sharma, Vidit

AU - Choeurng, Voleak

AU - Ashab, Hussam Al Deen

AU - Erho, Nicholas

AU - Alshalalfa, Mohammed

AU - Trock, Bruce

AU - Ross, Ashley

AU - Yousefi, Kasra

AU - Tsai, Harrison

AU - Zhao, Shuang G.

AU - Tosoian, Jeffrey J.

AU - Haddad, Zaid

AU - Takhar, Mandeep

AU - Chang, S. Laura

AU - Spratt, Daniel E.

AU - Abdollah, Firas

AU - Jenkins, Robert Brian

AU - Klein, Eric A.

AU - Nguyen, Paul L.

AU - Dicker, Adam P.

AU - Den, Robert B.

AU - Davicioni, Elai

AU - Feng, Felix Y.

AU - Lotan, Tamara L.

AU - Schaeffer, Edward M.

PY - 2018/8/15

Y1 - 2018/8/15

N2 - Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT. Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n ¼ 232; set II, n ¼ 435; set III, n ¼ 612). The primary endpoint of the analysis was postoperative metastasis. Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR ¼ 0.18, Pinteraction ¼ 0.009; set II: HR ¼ 0.25, Pinteraction ¼ 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P ¼ 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P ¼ 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction ¼ 0.035). Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery.

AB - Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT. Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n ¼ 232; set II, n ¼ 435; set III, n ¼ 612). The primary endpoint of the analysis was postoperative metastasis. Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR ¼ 0.18, Pinteraction ¼ 0.009; set II: HR ¼ 0.25, Pinteraction ¼ 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P ¼ 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P ¼ 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction ¼ 0.035). Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery.

UR - http://www.scopus.com/inward/record.url?scp=85051441586&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85051441586&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-17-2745

DO - 10.1158/1078-0432.CCR-17-2745

M3 - Article

VL - 24

SP - 3908

EP - 3916

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 16

ER -