Clinical and Radiographic Correlates of Canonical Cancer Pathway Deregulation in Malignant Intraprostatic Lesions

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Volume 96  Number 2S  Supplement 2016 T stage (TNM 2009 classification). Preoperative PSA level clinical T stage (T2a/b, T2c, T3a, T3b), and biopsy Gleason score (5 to 6, 3+4 Z 7, 4 + 3 Z 7, 8 to 10) were recorded as preoperative predictors. These predictors were used in multivariable logistic regression analysis based nomograms to estimate the probabilities of extraprostatic extension, positive margin(s), Gleason Score 8-10 after RP, respectively. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Analyses were performed with open-source statistical software (version 3.2.1). Results: Preoperatively, 41% of patients had a PSA level between 10 and 20 ng/mL, 80% had T2, and 50% had biopsy Gleason score 7; postoperatively, 47% had extraprostatic extension disease, 36% had positive margin, and 22% had Gleason Score 8-10. Nomograms were developed for the predicted probabilities of having the indications of adjuvant radiation therapy (pathologically extraprostatic extension disease or positive margin(s), or Gleason Score 8-10, respectively). The calibration curve for probabilities showed good agreement between prediction by nomogram and actual observation. The C-index of the nomograms for predicting for extraprostatic extension disease, or positive margin(s), or Gleason Score 810 were 0.707, 0.659, 0.897, respectively. The risk of having one of the indications of adjuvant radiation therapy increased with increases in predictors except for clinical T stage for predicting Gleason Score 8-10 (P Z 0.25). Conclusion: Using clinic-pathological information, we produced nomograms which may accurately predict the probabilities of having indications for adjuvant radiation therapy after RP. This nomogram may help individualize initial treatment options. Author Disclosure: M. Ma: None. X. Gao: None. M. Xie: None. Z.G. Zhou: None. B. Zhao: None. D. Wang: None.

most significant differential gene expression with 117-fold decrease in GS 8+ IPLs (P<0.001). Central gland IPLs had higher Notch deregulation than peripheral zone IPLs (P Z 0.04). PI-RADS 5 IPLs had higher TGFB (P Z 0.04) and CC (P Z 0.02) deregulation. PI-RADS score strongly correlated with both TGFB and CC pathway score (r Z 0.5, P<0.05). Degree of contrast enhancement strongly correlated with Wnt (r Z 0.52), TGFB (r Z 0.5), RAS (r Z 0.53), and CC (r Z 0.55) pathway scores. Last, PSA strongly correlated with DNA Repair pathway score (r Z 0.85, P<0.05). Conclusion: This study demonstrates the feasibility of cancer pathway profiling of targeted prostate biopsy specimens and reveals demonstrable differences between GS6 and GS 8+ IPLs. Changes in tumor biology also strongly correlate with PSA, tumor location, and MRI findings. These findings merit further study to correlate disease-driving molecular changes and clinical and radiographic characteristics. Author Disclosure: C. Dulaney: None. S. Rais-Bahrami: Consultant; Philips InVivo. D. Della Manna: None. J. Gordetsky: None. J. Nix: Consultant; Philips InVivo. E.S. Yang: Honoraria; NanoString. Advisory Board Member; NanoString.

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Purpose/Objective(s): Prostate cancers patient management has been enhanced with several commercially available genomic prognostic tests such as the DecipherÒ prostate cancer classifier. These tests are useful for making local therapy treatment decision-making. In addition to being the most validated predictor of metastasis in prostate cancer, Decipher is also a genome-wide assay that measures the expression of many druggable targets that are of clinical utility to match patients to clinical trials. Materials/Methods: Decipher GRID (Genomic Resource Information Database), was queried to assess the expression patterns of 15 genes from 5 biological pathways (Table 1) in 2,111 radical prostatectomy patients from prospective Decipher commercial cases. The frequency of high (or low) expression of each gene was ascertained using the median absolute deviation (MAD) metric. High and low gene expression was defined by median +/- 1.5*1.48*MAD.

Clinical and Radiographic Correlates of Canonical Cancer Pathway Deregulation in Malignant Intraprostatic Lesions C. Dulaney, S. Rais-Bahrami, D. Della Manna, J. Gordetsky, J. Nix, and E.S. Yang; University of Alabama at Birmingham, Birmingham, AL Purpose/Objective(s): Management of prostate cancer classically relies on histopathologic evaluation with little understanding of underlying tumor biology. The purpose of this study was to characterize and compare cancer pathway deregulation in malignant intra-prostatic lesions (IPLs) sampled by targeted magnetic resonance imaging/trans-rectal ultrasound (MRI/TRUS) fusion biopsy and to explore clinical and radiographic correlates of tumor biology. Materials/Methods: Patients who had targeted MRI/TRUS fusion biopsy of IPLs with either low risk (Gleason score (GS) 6 and PSA < 10) or high risk (GS 8+) prostate cancer were identified. Multiparametric prostate MRIs were reviewed by urologists and radiologists. IPLs with suspicious T2 and diffusion weighted, contrast enhanced MRI findings were identified and a PI-RADS (MRI measure of prostate cancer suspicion, range 1-5) score was assigned. PSA at time of biopsy and location of each IPL were recorded. RNA was harvested from areas of tumor identified by the pathologist in the targeted biopsy specimens. Samples were analyzed using a cancer pathway-based gene expression profiling platform. Advanced analysis of gene expression and cancer pathway signature data was then performed. Primary outcome was differences in pathway deregulation scores for GS6 and 8+ IPLs. Secondary outcomes were differences in pathway scores based on clinical and imaging characteristics. Pathway score significance was calculated using t-test. Results: Biopsies from 12 discrete IPLs were identified in 11 patients. Seven were GS 6 and 5 GS 8+. PSA ranged from 2.95 to 15.2. DNA Repair, Wnt, Notch, Cell Cycle (CC), PI3K, and RAS pathways had the highest global significance scores when comparing GS 6 and 8+ IPLs. Apoptosis pathway had the highest differential deregulation in GS 8+ IPLs (P Z 0.04). In the apoptosis pathway, GS 8+ was associated with 2.6-fold increase in BAD gene expression (P Z 0.01) and 5.3-fold increase in PIK3CB expression (P Z 0.01). Overall, MAP2K6 had the

2611 The Frequency of Druggable Targets in Localized Prostate Cancer: Initial Analysis From a Commercially Available Genomic Expression Database in Urologic Cancer R.B. Den,1 E. Davicioni,2 M. Takhar,2 N.G. Erho,2 L. Lam,2 H.A.D.M. Ashab,2 A. Olson,2 M. Dillon,2 K. Yousefi,2 P. Wood,2 and M. Alshalafa2; 1Sidney Kimmel Medical College at Thomas Jefferson University, Sidney Kimmel Cancer Center, Philadelphia, PA, 2GenomeDx Biosciences, Vancouver, BC, Canada

Abstract 2611; Table 1.

Gene

Pathway

Ki67 TOP2A AR

Proliferation Androgen Signaling

KLK2 KLK3 CCND1 Neuroendocrine CHGA AURKA PD1 Immune Checkpoint PDL1 B7H3 MET Growth Factor Receptors EGFR HER2 VEGFR2

Frequency (%)

High/Low Expression Assoc. Clinical Significance

Low Expression n (%)

High Expression n (%)

High High Low

3(0.1%) 1(0.0%) 38(1.8%)

158(7.5%) 195(9.2%) 55(2.6%)

Low Low Low High High High

103(4.9%) 120(5.7%) 39(1.8%) 11(0.5%) 11(0.5%) 47(2.2%)

43(2%) 34(1.6%) 44(2.1%) 130(6.2%) 76(3.6%) 34(1.6%)

High High High

33(1.6%) 48(2.3%) 0(0.0%)

58(2.7%) 52(2.5%) 97(4.6%)

High High High

19(0.9%) 17(0.8%) 4(0.1%)

72(3.4%) 52(2.5%) 134(6.3%)