Corbin Jacobs1, Vasu Tumati1, Payal Kapur2, Jingsheng Yan3, David Hong1, Manzerul Bhuiyan1, Xian-Jin Xie3, David Pistenmaa4, Lan Yu1, Jer-Tsong Hsieh5, Debabrata Saha4, D W Nathan Kim6. 1. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas. 2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. 3. Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas. 4. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, Dallas, Texas. 5. Simmons Cancer Center, Dallas, Texas; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. 6. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, Dallas, Texas. Electronic address: Nathan.Kim@utsouthwestern.edu.
Abstract
PURPOSE: This pilot study investigates the role of DOC-2/DAB2 Interacting Protein (DAB2IP) and enhancer of zeste homolog 2 (EZH2) as prognostic biomarkers in high-risk prostate cancer patients receiving definitive radiation therapy. METHODS AND MATERIALS: Immunohistochemistry was performed and scored by an expert genitourinary pathologist. Clinical endpoints evaluated were freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Log-rank test and Cox regression were used to determine significance of biomarker levels with clinical outcome. RESULTS: Fifty-four patients with high-risk prostate cancer (stage ≥ T3a, or Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with radiation therapy from 2005 to 2012 at our institution were evaluated. Nearly all patients expressed EZH2 (98%), whereas 28% of patients revealed DAB2IP reduction and 72% retained DAB2IP. Median follow-up was 34.0 months for DAB2IP-reduced patients, 29.9 months for DAB2IP-retained patients, and 32.6 months in the EZH2 study. Reduction in DAB2IP portended worse outcome compared with DAB2IP-retained patients, including FFBF (4-year: 37% vs 89%, P=.04), CRFS (4-year: 50% vs 90%, P=.02), and DMFS (4-year: 36% vs 97%, P=.05). Stratified EZH2 expression trended toward significance for worse FFBF and CRFS (P=.07). Patients with reduced DAB2IP or highest-intensity EZH2 expression exhibited worse FFBF (4-year: 32% vs 95%, P=.02), CRFS (4-year: 28% vs 100%, P<.01), and DMFS (4-year: 39% vs 100%, P=.04) compared with the control group. CONCLUSION: Loss of DAB2IP is a potent biomarker that portends worse outcome despite definitive radiation therapy for patients with high-risk prostate cancer. Enhancer of zeste homolog 2 is expressed in most high-risk tumors and is a less potent discriminator of outcome in this study. The DAB2IP status in combination with degree of EZH2 expression may be useful for determining patients with worse outcome within the high-risk prostate cancer population.
PURPOSE: This pilot study investigates the role of DOC-2/DAB2 Interacting Protein (DAB2IP) and enhancer of zeste homolog 2 (EZH2) as prognostic biomarkers in high-risk prostate cancerpatients receiving definitive radiation therapy. METHODS AND MATERIALS: Immunohistochemistry was performed and scored by an expert genitourinary pathologist. Clinical endpoints evaluated were freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Log-rank test and Cox regression were used to determine significance of biomarker levels with clinical outcome. RESULTS: Fifty-four patients with high-risk prostate cancer (stage ≥ T3a, or Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with radiation therapy from 2005 to 2012 at our institution were evaluated. Nearly all patients expressed EZH2 (98%), whereas 28% of patients revealed DAB2IP reduction and 72% retained DAB2IP. Median follow-up was 34.0 months for DAB2IP-reduced patients, 29.9 months for DAB2IP-retained patients, and 32.6 months in the EZH2 study. Reduction in DAB2IP portended worse outcome compared with DAB2IP-retained patients, including FFBF (4-year: 37% vs 89%, P=.04), CRFS (4-year: 50% vs 90%, P=.02), and DMFS (4-year: 36% vs 97%, P=.05). Stratified EZH2 expression trended toward significance for worse FFBF and CRFS (P=.07). Patients with reduced DAB2IP or highest-intensity EZH2 expression exhibited worse FFBF (4-year: 32% vs 95%, P=.02), CRFS (4-year: 28% vs 100%, P<.01), and DMFS (4-year: 39% vs 100%, P=.04) compared with the control group. CONCLUSION: Loss of DAB2IP is a potent biomarker that portends worse outcome despite definitive radiation therapy for patients with high-risk prostate cancer. Enhancer of zeste homolog 2 is expressed in most high-risk tumors and is a less potent discriminator of outcome in this study. The DAB2IP status in combination with degree of EZH2 expression may be useful for determining patients with worse outcome within the high-risk prostate cancer population.
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