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GenomeDx Biosciences Laboratory 10355 Science Center Dr. Suite 240, San Diego, CA 92121 Tel: 1-888-792-1601 | Fax: 1-855-324-2768 [email protected] | www.genomedx.com Patient Details Order Information Patient Name: Order Date: GRID Analysis Patient Report! Specimen Received Date: Medical Record Number: Date of Birth: GenomeDx Accession ID: Patient Name: DEC1234 Date of Prostatectomy: ____________________________________________________________ !Report Date: Sept 21, 2015! Specimen ID: Ordering Physician: FOR RESEARCH USE ONLY*! Clinic/Hospital Name: Pathology Laboratory: Pathologist: Patient Details! Pathologist Address: Patient Name: SAMPLE! Clinical Date of Birth: NA!Details Pre-operative PSA (ng/mL): Date of Prostatectomy: NA! Gleason Score: Medical Record Number: NA! ! Your Decipher Result: Clinic/Hospital Address: RUO GRID information:! Additional Physician: Decipher® Accession ID: DEC1234! ! Ordering Dr. Urologist! EPE Physician: SVI SM+ LNI BCR Clinic/Hospital Name: Urology Inc! Other: Clinic/Hospital Address:! Genomic! high risk *Decipher GRID is a whole genome array analysis: This Report isrisk forresult: Research Use Only YourAnalysis Decipher genomic Independent of (RUO) and is not intended as an aid to clinical decision making ! clinical risk factors, your five year Decipher genomic RUO result – implicated markers*! Marker! Genomic Event! SPINK-1! CD274! Positive! Over-expression! risk of metastasis after radical prostatectomy is 21.8%. Your Decipher risk is 3.6 times the average* patient with adverse pathology. Interpretation: Clinical studies concluded that Decipher high risk men with adverse pathology have Implicated Pathway! a poor prognosis overall.1-3 These men may benefit from adjuvant or early salvage radiotherapy and consideration for clinical trials.4-6 EGFR ! PD-1 ! Relevant findings from published clinical studies: Patients with Decipher high risk had 77% 5 year metastasis-free survival and 70% 10 year cancer-specific survival.1,3 For these patients there was improved metastasis-free survival favoring adjuvant and early salvage postoperative radiotherapy.4-6 In patients with PSA rise or biochemical recurrence after surgery that received salvage radiotherapy, only 66.5% remained metastasis-free after 5 years.6 The Decipher risk reported here has a 95% confidence interval of 20.0% to 42.4%. References on reverse *Average clinical risk refers to the average cohort risk of clinically high-risk men post surgery, established in a cohort of 1,010 clinically high-risk patients that received radical prostatectomy as first line treatment at the Mayo Clinic between 2000 and 2006. The average incidence of metastasis was 6.0% at 5 years post radical prostatectomy. 5-year Predicted Probability of Clinical Metastasis: a genomic risk score is derived by measuring the RNA expression of 22 biomarkers in a primary prostate adenocarcinoma specimen (Erho et al., 2013). Decipher uses the genomic risk score to predict the 5-year probability for developing clinical metastasis; using a cox-proportional hazards survival model based upon a cohort of 1,010 clinically high-risk patients with 6.9 median years of follow-up (Karnes et al., 2013). Decipher probabilities range between 0% and 100%. Decipher risk categories are determined from an optimized statistical model, representing significantly distinct metastatic risk (hazard ratios) between the risk categories. Relative risk is calculated as a ratio of the patient’s Decipher probability as compared to the 6.0% average risk of clinical metastasis observed in this population of clinically high-risk men. GenomeDx Medical Director (Name & Signature) Medical Directors: Timothy J. Triche, MD PhD • Doug Dolginow, MD Date Disclaimer: The Decipher test was developed and its performance characteristics were determined by GenomeDx Biosciences Laboratory. The GenomeDx Biosciences Laboratory is certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ‘88) to perform high complexity testing. This test has not been cleared or approved by the U.S. Food and Drug Administration. Summary of surgical pathology report is provided for convenience of Ordering Physician. Please refer to Referring Pathologist’s original pathology report to guide treatment decisions. *A complete list of the markers assayed & their researchCopyright implications can be found © GenomeDx Biosciences Inc. on page 2 of this report! CLIA ID# 05D2055897 Page 1 of 2 Page 1 of 2! GenomeDx Biosciences Laboratory 10355 Science Center Dr. Suite 240, San Diego, CA 92121 Tel: 1-888-792-1601 | Fax: 1-855-324-2768 [email protected] | www.genomedx.com Patient Details Order Information Patient Name: Order Date: GRID Analysis Patient Report! Specimen Received Date: Medical Record Number: Date of Birth: Marker! Patient Name: Date of Prostatectomy: ____________________________________________________________ Biological Pathology Laboratory: Context! Pathologist: Genomic Event*! SPINK1! Pathologist Intrinsic Address: Subtype! Positive! Clinical Details Pre-operative PSA (ng/mL): Gleason Score: CD274! Immune ! Specimen ID: !Report Date: ! Ordering Physician: Percentile Rank**! NA! GenomeDx Accession ID: Relevant Research Findings! Clinic/Hospital Name: Clinic/Hospital Address: Over-expression of SPINK1 has been shown to be associated Additional Physician: with poor outcome in ERG- prostate cancer patients, especially in men with African-American ancestry. In vitro studies suggest that SVI SPINK1SM+ positive prostate cancer growth EPE LNI BCR is sensitive to EGFR inhibitors such as cetuximab6! Other: Over- 93rd! PD-L1/PD-1-mediated T cell co-inhibition is involved in Your Decipher Result: Genomic Checkpoint! expression! immune high evasion risk in prostate cancer. Over-expression of PDL1 by cancer cells may enable tumors to evade T cell immune responses. Over-expression of PDL1 is correlated to greater Your genomic 12! risk result: Independent of responses to Decipher anti-PD1 therapy clinical risk factors, your five year Decipher genomic risk of metastasis after radical prostatectomy is 21.8%. Your Decipher risk is 3.6 times the average* patient with adverse pathology. Interpretation: Clinical studies concluded that *Intrinsic subtypes are defined by outlier expression (e.g., either positive or negative). High or low expression areadverse defined bypathology 1 standard deviation Decipher high risk men with have greater or lower than the mean of the GRID population (n=1,683).! a poor prognosis overall.1-3 These men may benefit **Percentile rank indicates the percentage of patient tumors in the GRID (n=1,683) with lower scores than your tumor’s expression! Genomic markers assayed in Decipher GRID! from adjuvant or early salvage radiotherapy and consideration for clinical trials.4-6 Relevant findings from published clinical studies: Patients with Decipher highbelow risk had 77% 5 yearthe metastasis-free and Decipher GRID analyses ~44,000 coding and non-coding genes. The list represents biomarkerssurvival currently 70% 10 year cancer-specific survival.1,3 For these patients there evaluated for their prognostic & predictive power in prostate cancer. Decipher GRID will be updated as new markers was improved metastasis-free survival favoring adjuvant and early are studied and evaluated.! salvage postoperative radiotherapy.4-6 Proliferation! Metastasis/ Invasion! Intrinsic Subtypes! In patients withNeuroendocrine PSA rise or biochemical recurrence after surgery Androgen / Immune that received Small salvage radiotherapy, only Checkpoint! 66.5% remained Signaling! Cell! 6 Ki-671,2! SChLAP13.4! ERG1,2,6! 8! AR1! The Decipher risk NEAT1 B7-H32,11! reported here has a 95% confidence interval of TOP2A1,2! SPARCL15! ETV12,6! PSA2! Cyclin D19! PD112! ETV46,7! NKX3-11! pRB1,10! PDL112! 6! metastasis-free after 5 years. 20.0% to 42.4%. References on reverse 1,2,7! 2! PCA3 Chromogranin A patients that received radical prostatec*Average clinical risk refers to the average cohortETV5 risk of clinically high-risk men post surgery, established in a cohort of 1,010 clinically high-risk tomy as first line treatment at the Mayo Clinic between 2000 and 2006. The average incidence of metastasis was 6.0% at 5 years post radical prostatectomy. SPINK16! 5-year Predicted Probability of Clinical Metastasis: a genomic risk score is derived by measuring the RNA expression of 22 biomarkers in a primary prostate adenocarcinoma specimen (Erho et al., 2013). Decipher uses the genomic risk score to6 predict the 5-year probability for developing clinical metastasis; using a cox-proportional hazards survival model based upon FLI1 a cohort of 1,010 clinically high-risk patients with 6.9 median! years of follow-up (Karnes et al., 2013). Decipher probabilities range between 0% and 100%. Decipher risk categories are determined from an optimized statistical model, representing significantly distinct metastatic risk (hazard ratios) between the risk categories. Relative risk is calculated as a ratio of the GenomeDx References:! patient’s Decipher probability as compared to the 6.0% average risk of clinical metastasis observed in this population of clinically high-risk men. 1. Yamoah, et al. Novel biomarker signature that may predict aggressive disease in African-American men with prostate cancer. Journal of Clinical Oncology, 2015; DOI: 10.1200/JCO.2014.59.8912.! 2. Erho, N., et al., Discovery and Validation of a Prostate Cancer Genomic Classifier that Predicts Early Metastasis Following PLoS One. 2013 Jun 24;8(6):e66855.! Disclaimer: The DecipherRadical test wasProstatectomy. developed and its performance characteristics were determined by 3. Prensner, et al. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional analysis of SChLAP1,Lancet Oncology,is2014, GenomeDxhigh-throughput Biosciences Laboratory. The GenomeDx Biosciences Laboratory certified15(13):1469-80! under the Clinical Laboratory Improvementcomplex, Amendments of 1988 (CLIA ‘88)2013, to perform high complexity testing. This test has 4. Prensner, et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF Nature Genetics, 45(11):1392-8! not beenprostate cleared orcancers approvedand by the U.S. Food and Summary of surgical 5. Hurley, et al., Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive is prognostic forDrug poorAdministration. clinical outcome, PNAS, 2012,pathology 109(37): Date 14977-82! GenomeDx Medical Director (Name & Signature) report is provided for convenience of Ordering Physician. Please refer to Referring Pathologist’s original 6. Tomlins, et al. Characterization of 1577 Primary Prostate Cancers Reveals Novel Biological and Clinicopathologic Insights into Molecular Subtypes, Eur Urology, 2015! pathology report to guide treatment decisions. Medical Directors: 7. Aytes, et al. ETV4 promotes metastasis in response to activation of PI3-kinase and Ras signaling in a mouse model of advanced prostate cancer. PNAS, 2013,110(37):E3506-15 ! Timothy J. Triche, MD PhD • Doug Dolginow, MD 8. Chakravaty, et al. The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer, Nature Comm , 2014, 21;5:5383! 9. Tsai, et al., Cyclin D1 Loss Distinguishes Prostatic Small Cell Carcinoma from Most Prostatic Adenocarcinomas, Clinical Cancer Research, 2015,! CLIA ID# 05D2055897 10. Tan,et al., Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma, Clinical Cancer Research, 2014, 20(4):890-903! Page 1 of 2 11. Chavin, et al. Expression of immunosuppresive B7-H3 ligand by hormone-treated Copyright prostate cancer tumors Biosciences and metastases. © GenomeDx Inc. Clinical Cancer Research, 2009,15(6):2174-80! 12. Zitvogel and Kroemer, Targeting PD-1/PD-L1 interactions for immunotherapy, Oncoimmunology, 2012,1(8):1223-1225 ! Page 2 of 2!