..biomarkers, running the gauntlet..

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1 The long and winding round for the clinical introduction of a biomarker Molecular diagnostic of prostate cancer based on non invasive liquid biopsies..biomarkers, running the gauntlet.. Prof dr Jack A Schalken Radboudumc, Nijmegen, NL

2 The biomarker identity crisis I think I am a biomarker Therefore I am a biomarker I think Freely adapted from Descartes cogito ergo sum

3 Biomarkers 1 : classification Diagnostic Prognostic (natural biological potential) Predictive (therapy response) Therapy monitoring (effectiveness) 1 Note; A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

4 Molecular profiling: DD3...DD3 PCA3 PCA3 PCA3 DD3 (Bussemakers et al., Cancer Res. 59: , 1999) Overexpressed in >90% of PrCa T B N T N T N T N M M (kb) 4.0 DD

5 history.. Development of the liquid biopsy concept 1996 PCA3 discovery 2002 liquid biopsy concept 2003 proof of concept 2007 PCA3 launch 12 september 2002

6 2002; do prostate cancer cells shed in urine? Cells in prostatic urethra Digital Rectal Exam (DRE)

7 Simple, non-invasive, urine specimen collected post-dre 7 days/ambient temperature Groskopf J, et al. Clin Chem 2006;52:

8 Development of the Liquid Biopsy Concept PCA3 Discovery Proof of Concept PCA3 Launch Liquid Biopsy Concept Integrate All Experience/ Expertise in NovioGendix, Radboudmc Spin Off history 12 september 2002

9 The basis for Progensa PCA3 Tissue gene expression of PCA PCA3 prototypical high fold change/high p value NP BPH LG HG CRPC Meta

10 PCA3 in some GS 8 cancers, CRPCs and mets No/limited prognostic value Confirmed in > 10,000 cases Mohammed Alshalalfa, Gerald W. Verhaegh et al Oncotarget, 2017 Limitations PCA3

11 New approach Design a study where the end point is a clinical product, rather than merely a scientific product..

12 Requirements Requirement What question(s) are we answering? Analytical Validity Does the test provide accurate, reliable results? Clinical Validity How accurately does the test determine presence of disease and predict patient outcomes? Clinical Utility Health Economics Do the test results impact medical decisionmaking, leading to improved patient outcomes? Is the test cost-effective, and does it increase Quality-Adjusted Life Years?

13 Identification of biomarkers for prostate cancer

14 Identification of a gene panel

Prospective multicenter study 358 subjects 6 urology clinics in the Netherlands: Radboud University Nijmegen Medical Centre, Academic

biopsies Analysis performed on blinded urine samples obtained preceding a prostate biopsy Identification of a candidate Gene Panel for the

15 Prospective multicenter study 358 subjects 6 urology clinics in the Netherlands: Radboud University Nijmegen Medical Centre, Academic Medical Centre Amsterd Ziekenhuis group Twente (ZGT Hengelo), Canisius Wilhelmina Hospital Nijmegen, Scheper Ziekenhuis Emmen, St Elisabeth Hospital Tilburg. Identification of Biomarkers for PCa in tissue Validation of biomarkers in urinary sediments Predict risk of high grade cancer in prostate biopsies Analysis performed on blinded urine samples obtained preceding a prostate biopsy Identification of a candidate Gene Panel for the early diagnosis of Prostate Cancer. Leijten G., Hessels D., Smit F., Jannink S., de Jong H., Melchers W., Cornel E., de Reijke T., Vergunst H., Kil P., Knipsch Hulsbergen-van de Kaa C., Mulders P., van Oort I., Schalken J. Clinical Cancer Research 21(13) , 2015

16 Biomarker Selection HOXC6-DLX1

17 High grade PCa upon biopsy (%) HOXC6-DLX1 correlates with High-grade PCa in biopsy < HOXC6-DLX1 score

18 Urinary HOXC6-DLX1 outperforms PCA3 for diagnosis of Gleason score 7-10

19 Area under the curve Diagnostic performance of HOXC6-DLX1 0,8 0,75 0,7 0,65 0,6 0,55 0,5 spsa <6 spsa <8 spsa <10 All spsa HOXC6-DLX1 score

20 From Urine test to Risk Calculator (SelectMDx) Include clinical parameters (PSA, Prostate Volume etc)

2016 All rights reserved Valuable liquid biopsy test for patients and physicians The Product Non-Invasive urine test RNA PCR test The Urologist Part of routine examination

21 2016 All rights reserved Valuable liquid biopsy test for patients and physicians The Product Non-Invasive urine test RNA PCR test The Urologist Part of routine examination Identifies patient for MRI or biopsy A Non-invasive Test To Improve The Patient Selection For Initial Biopsy or MRI The Patient Non-invasive sample collection Easy to explain 21

22 What is SelectMDx? Molecular urine tests based risk classifer to guide biopsy decision

23 Validated in independent clinical cohort (multicenter, prospective) Urine test HOXC6/DLX1 Risk model/calculator

24 Risk model based on urine mrna (HOXC6/DLX1, spsa & Pvol), SelectMDx AUC= 0,90 for significant cancer!

25 HOXC6-DLX1 correlates with Gleason Score upon biopsy

26 Clinical Utility Old and New generation Urine PCa Tests 26 Area Under an ROC Curve Avoiding biopsies AUC % 98% 36% AUC 0.68 PCA3 SelectMDx NPV for high grade prostate cancer PCA3 SelectMDx

27 27 SelectMDx for Prostate Cancer Non-invasive, Liquid Biopsy to Identify Patients for Prostate Biopsy MRI and Biopsy routine PSA Elevated PSA DRE Urine Test Result Likely hood risk score Follow-up Discuss with patient Urine test for the prediction of histopathological outcome of prostate biopsy

28 SelectMDx Model high NPV NPV: number of patients for whom SelectMDx is negative and who do not have high-grade PCa SelectMDx has: 99.6% NPV for GS 8 Prostate Cancer 98 % NPV for GS 7 Prostate Cancer

29 Reporting - very low risk

30 Patient Report

31 Evidence for impact on clinical decision making (DCA)

32 Conclusions and perspectives Select MDx, a risk model based on the integration of a urine test with clinical parameters, accurately predicts clinically significant PrCa Decision Curve Analysis shows that SelectMDx can have a significant impact on clinical decision making (biopsy) SelectMDx is cost effective (Dijkstra et al, 2017, BJU) Combination with other diagnostic tools (mpmri) underway Initial data show that SelectMDx can be used to select men for whom mpmri is relevant

33 MDx studies supporting indication of SelectMDx for low PSA ranges Mapping biopsy study (UCHSC; Drs Crawford, de Lucia) o (near perfect) golden standard o GS 3+3 and GS 3+4 versus GS 4+3 and higher o Sensitivity to detect GS 4+3 and higher 100%, i.e. NPV 100 % o Opportunity SelectMDx for candidates for focal therapy o Science Evidence for Unique Selling Point of SelectMDx, i.e. test to identify men with significant PrCa o PrCa awarenes week PSA, 1 ng/ml o 0 % positive for SelectMDx o PrCa screening study-spain, Rubio Briones o All HG cancers positive for SelectMDx o Reduction in Bx by 80%!!

34 Studies with improved golden standard, mpmri mpmri in SelectMDx studies o SelectMDx correlates with PIRAD 4-5 o PIRAD score is radiologist s Gleason score; PIRAD 4-5 indication for biopsy 4M: Prospective multicenter study Dutch Cancer Foundation (Barentsz PI) o Recruitment completed Q (600) o Results; Q o Expected outcome; SelectMDx correlates with PIRAD 4-5

35 classical triage that leads to the diagnosis PrCa Serum PSA Ultrasound-guided biopsy Gleason grading Golden standard PrCa diagnosis 2.0 Serum PSA ánd Select MDx Multiparametric MRI guided biopsy Histopathology including a molecular classifier - Molecular classifier (eg Confirm and Inform Dx GPS, Decipher, Prolaris) MRI=magnetic resonance imaging PSA=prostate-specific antigen

The use of PCA3 in the diagnosis of prostate cancer

The use of PCA3 in the diagnosis of prostate cancer Daphne Hessels and Jack A. Schalken Abstract Although the routine use of serum PsA testing has undoubtedly increased prostate cancer detection, one of