TY - JOUR
T1 - Development and validation of a prostate cancer genomic signature that predicts early adt treatment response following radical prostatectomy
AU - Karnes, R. 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 B.
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.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
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, P interaction ¼ 0.009; set II: HR ¼ 0.25, P interaction 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 (P interaction 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, P interaction ¼ 0.009; set II: HR ¼ 0.25, P interaction 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 (P interaction 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.
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U2 - 10.1158/1078-0432.CCR-17-2745
DO - 10.1158/1078-0432.CCR-17-2745
M3 - Article
C2 - 29760221
AN - SCOPUS:85051441586
SN - 1078-0432
VL - 24
SP - 3908
EP - 3916
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 16
ER -