Loss Of Tumor Suppressor Dab2ip Correlates With Decreased Biochemical Recurrence-Free Survival In High-Risk Prostate Cancer Patients Treated With Radiation Therapy

DAB2IP loss has been associated with aggressive prostate cancer behavior. Preclinical data suggests that loss of DAB2IP plays a significant role in prostate cancer cell survival following exposure to ionizing radiation due to enhanced double strand break (DSB) repair, and resistance to apoptosis. Therefore, we performed a pilot study to determine whether DAB2IP status could serve as a novel biomarker indicative of radiation therapy (RT) effectiveness in high risk prostate cancer patients. Patients with high-risk disease (stage ≥ T3a, or Gleason score (GS) ≥ 8, or Prostate Specific Antigen (PSA) ≥ 20) treated with definitive RT between 2005-2011 at UT Southwestern were identified. Immuno-histochemistry (IHC) analysis for DAB2IP protein was performed on their biopsy specimens. DAB2IP status was scored in the tumors by an expert GU pathologist. Biochemical recurrence-free survival (BRFS) of patient cohorts with and without DAB2IP loss was determined using the Phoenix definition. Log rank test was used to correlate BRFS with DAB2IP levels. Univariate analysis of BRFS to pretreatment PSA, GS, stage, age, DAP2IP status was performed. Twenty-four patients treated for high risk prostate cancer were evaluated. DAB2IP loss was seen in 8 patients (33.3%) whereas 16 patients (66.7%) expressed DAB2IP. Median f/u for DAB2IP patients was 19.4 months (m) (range 8.2 to 57.8 m) and 23.9 m (range 8.8 to 74.0 m) for the DAB2IP deficient group. Patients expressing DAB2IP exhibited markedly improved BRFS compared to patients with loss of DAB2IP (p = 0.027; log-rank test). The estimated 2 yr BRFS was 90% and 68.5% respectively for the DAB2IP present and deficient groups. At 4 yrs BRFS was 90% and 34.3% for the present and deficient groups respectively. Univariate analysis demonstrated DAP2IP status as the only variable with significant association to BRFS at this point of follow up. In this initial study, DAB2IP deficiency in patients portended a significantly worse BRFS after definitive treatment with RT. This is the first clinical evidence suggesting the importance of DAB2IP deficiency as a potential biomarker for predicting radiation response in patients with high risk prostate cancer. Limitations of this study include small sample size and short duration of follow up. We plan to extend this study to remaining patients identified (expected n = 137 patients). Additional studies planned include performing IHC staining of Ki-67, and markers of DNA-DSB repair proteins (H2AX, ATM, DNA-PKcs, 53BP1) which will be correlated with DAB2IP status. Implications for developing therapeutic intervention strategies to enhance radiation response for patients found to have DAB2IP deficient prostate tumors will be discussed.