Chromodomain Helicase DNA Binding Protein 5 (CHD5) Is Associated With Improved Overall Survival in Patients Undergoing Adjuvant Therapy for Resected Pancreatic Adenocarcinoma

Abstract

investigated the role of DAB2IP and/or EZH2 as prognostic biomarkers following radiation therapy (RT) in high-risk PCa patients. Materials/Methods: Immunohistochemistry was performed and scored by an expert genitourinary pathologist. Freedom from biochemical failure (FFBF) was determined using the Phoenix definition. Castrate resistancefree survival (CRFS) was determined when 2 episodes of rising prostatespecific antigen (PSA) occurred while on standard hormone therapy. Distant metastasis-free survival (DMFS) was determined from clinical data review. Log-rank test and Cox regression were used to determine significance of DAB2IP and EZH2 levels with clinical outcome. Results: Fifty-four patients with high-risk PCa (stage T3a, or Gleason score 8, or PSA 20) treated with RT from 2005-2012 at UT Southwestern were evaluated. 28.3% (13/46) of patients revealed DAB2IPreduction while 71.7% (33/46) retained DAB2IP. Nearly all patients expressed EZH2 (97.9%), supporting prior reports that EZH2 expression precedes DAB2IP reduction. For EZH2, the intensity level was grade (G) 0 in 1 (2.1%), G1 in 9 (18.8%), G2 in 29 (60.4%), and G3 in 9 (18.8%) patients. Median follow-up was 34.0 months (mos) (range, 6.7-76.1 mos) for DAB2IP-reduced patients, 29.9 mos (range, 6.1-84.6 mos) for DAB2IP-retained patients, and 32.6 m (range, 2.8-84.6 mos) for the EZH2 study. Patients with reduced DAB2IP demonstrated worse outcome compared to patients retaining DAB2IP, including FFBF (2-year Z 73% vs 93%; 4-yearZ 37% vs 89%; p Z 0.04; HR Z 3.65), DMFS (2-yearZ 90% vs 97%; 4-year Z 36% vs 97%; p Z 0.05), and CRFS (4-year Z 50% vs 90%; p Z 0.02). Intensity of EZH2 expression trended toward significance for worse FFBF and CRFS (p Z 0.07). Patients with reduced DAB2IP or highest intensity (G3) EZH2 expression exhibited even worse FFBF (p Z 0.03; HR Z 5.65). Six of the 7 patients that developed CRPC had reduced DAB2IP or G3 EZH2. Even with modest follow-up and after controlling for duration of hormone therapy, DAB2IP remains significant. Conclusions: This study suggests that DAB2IP loss is a potent biomarker for identifying high-risk PCa patients that portends worse outcome despite definitive RT. EZH2 is expressed in most high-risk PCa tumors evaluated, and is a less potent discriminator of outcome in this group of patients. DAB2IP status in combination with degree of EZH2 expression may be useful for determining patients with worse outcome within the high-risk patient population. Author Disclosure: C. Jacobs: None. P. Kapur: None. J. Yan: None. V. Tumati: None. X. Xie: None. D. Pistenmaa: None. M. Bhuiyan: None. J. Hsieh: None. D. Saha: None. D. Kim: None.