An Approach to Early Detection of Significant Cancers

An Approach to Early Detection of Significant Cancers FDUS 9.11.16 E. David Crawford, M.D. University of Colorado Denver Aurora, CO

AUA State of Art 2

WSJ 5.10.16 3

Recent Advances in Prostate Cancer: E. David Crawford 1) PCMs (Prostate Cancer Markers): Molecular Markers and Genomic Assays 2) Multiple new therapeutics with different mechanisms of action advanced prostate cancer 4

Prostate Cancer Detection Challenges 1) Improve the interpretation of PSA, thus allow Primary Care Physicians to enhance referral efficiency for Urology evaluation 2) A test which will decrease unnecessary negative re-biopsies and enhance detection 3) A test to enhance risk stratification of newly diagnosed PCa patients who are best suited for surveillance vs interventional therapy 5

PCMs Tissue Blood What is a biomarker? A molecule that can be found in blood, 3ssue or body fluids that is a sign of a normal or abnormal process Urine 6

PCM Buckets

Message from USPSTF And Other Organizations Following the Lead PSA screening is a D recommendation Physicians should not order PSA screening unless they are prepared to engage in shared decision making that enables an informed choice by patients Supported by AAFP AAFP recommends against performing PSAbased screening for prostate cancer in asymptomatic men What to do? Moyer VA, et al. Ann Intern Med. 2012 Jul 17;157(2):120 34. AAFP, USPSTF Issue Final Recommenda3on Against Rou3ne PSA- based Screening for Prostate Cancer 8

Prostate Cancer: Current Needs Refine PSA Increase the likelihood of an initial positive biopsy Reduce unnecessary repeat biopsies, enhance distinguishing benign from malignant disease Stratify low risk from higher risk cancers Will PCMs (Prostate Cancer Markers) improve our management? 9

Change is Imperative! No One Size Fits All Genomics Proteomics Metabolomics Precision medicine Personalized diagnosis and therapy 10

What Percent of all of the PSA s ordered in the US are by Urologists 1. 6% 2. 25% 3. between 40-60% 4. around 70% 11

Who is Ordering PSA Tests in United States? 1.3 We need to educate those who are ordering and interpre3ng PSAs 23.7 6.1 64.9 Internal Medicine Family Medicine Urology Hem/Onc 64.9% 23.7% 6.1% 1.3% Aslani A, et al. J Urol. 2013;do:10.1016/j.juro.2013.12.010 12

Ways Forward Educate those who order PSAs PCPs Define a PSA level with little risk (age, family history, prostate gland volume, symptoms, DRE) Identify those who need further evaluation by a Urologist 13

Defining PSA Levels and Improving Performance Patients and Methods: 350,000 HMO-Henry Ford System Men in system 1997-2008 Initial PSA between 1-5ng/ml Minimum 5 years follow-up No 5 ARIs Results: Mean age -55 years Mean PSA 1.0 African American 29% Detected Cancer: 2% 21,502 men eligible 14

5-year Diagnosis Rates Based on Initial PSA Level Percent developing prostate cancer 12% 10% 8% 6% 4% 2% 0% Overall Study Popula<on (21,500) 0.51% PSA < 1.5ng/mL 15- fold increase in risk 7.85% PSA 1.5-4ng/mL African Americans 19- fold increase in risk 10.39% Receiver Opera<ng Characteris<c Curve for All Pa<ents Percent developing prostate cancer 1.0 0.8 0.6 0.4 0.2 0 Maximum sensi3vity and specificity at PSA 1.5 ng/ml Es3mated Area C=0.87251 0 0.2 0.4 0.6 0.8 1.0 1- Specificity A first PSA test threshold of 1.5-4.0 ng/ml, represents the Early- Warning PSA Zone Pa<ents with PSA 1.5 ng/ml have an increased risk of developing PC Crawford ED, et al. BJU Int. 2011;108(11):1743-9 15

Serum PSA 1.5ng/mL Predicting Enlargement & Risk of Progression Prostate volume (ml) 65 60 55 50 45 40 35 PSA of 1.5 surrogate for enlarged prostate 65 Age (years) Risk of progression* 30 1 2 3 4 5 6 7 Adapted from Roehrborn CG et al. Urology. 1999;53:581 589. *Crawford ED et al. J Urol. 2006;175:1422 1427. Serum PSA (ng/ml) 16

Natural History of Untreated BPH Progression Male patient, age 55 years: symptomatic EP, PSA = 1.5 ng/ml, negative for prostate cancer Age 55 yrs 60 yrs 65 yrs 70 yrs PV 30 ml >40 ml >50 ml >61 ml PSA 1.5 ng/ml Figure based on Roehrborn C, et al. J Urol. 2000;163:13 20.

Using PSA as an Aid to Diagnose BPH The PSA value is more accurate than a DRE in estimating prostate size when trans-rectal ultrasound is not available 1 The DRE tends to underestimate prostate size, and the degree of underestimation correlates with increasing prostate size 1 PSA 1.5 ng/ml suggests a prostate volume >30 ml 2 Prostate volume (ml) 65 60 55 50 45 40 35 30 1 2 3 4 5 6 Serum PSA (ng/ml) 75 70 65 60 55 50 Age (years) Error roughly 5 ml Figure adapted from Roehrborn C, et al. Urology. 1999;53:581-589. 1. Bosch J, et al. Eur Urol. 2004;46:753-759. 2. Kaplan S. Weill Medical College of Cornell University Reports on Men s Urologic Health. 2006;1(1):1 8.

A Practical Algorithm for the Treatment of BPH in Primary Care Man >50 years old presents with urinary symptoms No Determine if patient has Enlarged Prostate ( 30 ml): DRE PSA 1.5 ng/ml Yes Treat symptoms Treat symptoms and reduce prostate size -blocker 5ARI Combination 5ARI plus -blocker Reassess periodically Adapted from Figure 3, entitled Practical Algorithm for the treatment of EP in primary care: in Kaplan S. Weill Medical College of Cornell University Reports on Men s Urologic Health.

Prostate Size and Urinary Symptoms 20

Early Detection A Way Forward PSA treated like other lab tests, lipids, electrolytes, weight, and BP-routine Informed decision when tests are abnormal 70% of men require no discussion-based on our screening data on 150,000 men Men s health broader issue > 1.5 ng/ml surrogate for BPH, Prostatitis, Prostate Cancer Roehrborn CG et al. Urology. 1999;53:581 589. 21

Pa3ent Presents for Screening (PCP) PSA Test PSA < 1.5 PSA > 1.5 Do Nothing Repeat PSA Provider CaP Evalua.on Algorithm with PCMs PCP Evalua3on Urologist Evalua3on PCMs Biopsy Result Final Recommenda3on Urologist Repeat DRE and PSA Norm al Regular Screening Abnorma l Monitor Nega3ve Biopsy * Select MDx PCA3 PHI 4K Posi3ve Who to biopsy? Know Error specimen provenance Adopted from Crawford et al. (PMID: 24701701) Who to rebiopsy? Avoid Rebiopsy Confirm MDx PCA3 Select MDx 4K PCMT Rebiopsy Indeterminat e ASAP HGPIN Atypia Ac3ve Surveillance *Consider Targe3ng MRI/US Fusion Biopsy Oncotype Dx Prolaris PTEN- ERG ProMark Who to treat? Indolent vs aggressive cancer? Interven3on - RP - Cryo - IMRT - ADT - Brachy Decipher Prolaris?AR- V7? HSD3B1 further therapy?

Prostate Cancer Diagnostic Pathway: Role for Genomic Tests and Biomarkers Pa3ent Presents SCREENING PSA Test PSA < 1.5 PSA > 1.5 Phi 4K SelectMDx PCA3 Urologist Repeat PSA/DRE Conduct Biopsy Normal Abnormal Monitor Nega3ve ConfirmMDx PCA3 4K phi Avoid Re- biopsy Re- biopsy Copyright Neal Shore, MD 2015 Indeterminate ASAP HGPIN ATYPIA Re- Bx Ac3ve Surveillance Posi3ve OncotypeDX ProMark PTEN / ERG Prolaris Indolent vs. aggressive cancer Interven3on Decipher Prolaris Know Error 23 CRPC CTC s AR- V7

Prostate Cancer Diagnostic Pathway: Role for Biomarkers Pa3ent Presents SCREENING PSA Test PSA < 1.5 PSA > 1.5 PHI 4K score PHI SELECTMDx PCA3 Urologist Repeat PSA/DRE Conduct Biopsy Normal Abnormal Monitor 24

New Paradigm HIGH false-positive rate leading to unnecessary biopsy REDUCE over-diagnosis of men with GS 6 cancer REDUCE over-treatment of non-lethal disease 25

The Goal in 2016 Gleason 6 Ac<ve Surveillance

PSA Performance Beckman Coulter phi PSA Isoforms FDA Approved, 2012 For men with tpsa between 2 10 ng/ml and non suspicious DRE for PCa tpsa fpsa [- 2] propsa Posi<ve biopsy (%) 100 90 80 70 60 50 40 30 20 10 0 25 <30 n=212 36 30-39 n=204 49 40-49 n=166 69 73 50-59 n=123 60-69 n=86 83 >70 n=113 91 >80 n=69 ([- 2] propsa/fpsa)* tpsa phi score phi 27

PCA3 Prostate tumor Marker release from tumor DRE Cell shedding Blood sample Urine sample Measure PSA protein in serum PCA3 is FDA approved and has CMS reimbursement Adapted from Marks LS, Rev Urol. 2008;10(3):175 181. Measure PCA3 and PSA mrna from cells PCA3 score = PCA3/PSA mrna x10-3 28

Percent of Men with Positive Biopsy by PCA3 Score First Biopsy 80% 70% PCA3 Score (95% CI) 60% 50% 40% 30% 20% 10% 0% <5 5-19 20-34 35-50 50-100 >100 PCA3 Score (n=1914) Crawford ED et al. J Urol. 2012 Nov;188(5):1726-31. 29

PCA3: Report PROGENSA PCA3 Performing Site: Clinical Lab PATIENT INFORMATION SPECIMEN ID: 15AGS035437 Metamark, Inc Metamark, Inc. 100 Kestrel Drive, Collegeville, PA 19426 Phone 877-743-3338 www.metamark.us PATIENT INFORMATION SPECIMEN ID #: XXXXXXXXX PHYSICIAN Name: DOB: Patient #: Patient Name XX/XX/XXXX XXXXXXXXX Date Collected: Date Received: Date Reported: 4/28/2015 4/29/2015 4/30/2015 Primary Physician: Client: Client #: Physician Name XXXXXXXXXX XXXXXX 10 PROGENSA PCA3 DIAGNOSIS 1. A negative score is associated with a decreased likelihood of a positive biopsy for prostate cancer. 2. An adequate amount of PSA RNA was detected in the urine sample. The Progensa PCA3 test was developed and its performance characteristics determined by Hologic, Inc. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such approval is not necessary. This test is used for clinical purposes. It should not be regarded as investigational or for research. Metamark is certified under Clinical Laboratory Improvements Amendments of 1988 (CLIA) as qualified to perform high complexity clinical laboratory testing. REFERENCES Progensa PCA3 Assay Package Insert 502083 Rev. B. Hologic Inc. TEST CHARACTERISTICS Due to normal assay variability, specimens with PCA3 scores near the cut-off of 25 (i.e. 18-31) could yield a different overall interpretation of positive or negative upon repeat testing. PCA3 scores in the range from 18 to 31 should, therefore, be interpreted with caution. The testing method is target capture, transcriptionmediated amplification (TMA) and hybrid protection assay (HPA), manufactured by Hologic, Inc and performed using the Hologic, Inc Progensa assay kit. Dwight Mirmow, MD Final Report Electronically Signed on 4/30/2015 at 2:56 PM CPT Codes: 81313 _ CLIA #: 39D1089277 Copyright 2014 Metamark, Inc. All rights reserved 30

PSA PERFORMANCE : 4Kscore Prostate Bx for aggressive CaP 4Kscore Prostate Cancer Test Prostate cancer test Based on the following panel of kallikrein markers: Total PSA Free PSA Intact PSA Human Kallikrein 2 (HK2) + Age, DRE, and prior biopsy status 31

4Kscore test: Reports individual % risk of aggressive prostate cancer if prostate biopsy was performed The patient s 4Kscore Test result is 5% At a 4Kscore Test result of 5%, about 1 in 20 men biopsied would have high-grade prostate cancer. 4Kscore Test Result 1% 5% 10% 15% 20% 25% 30% 40% 50% 60% 70% 80% 90% 95% = 95% chance that the biopsy does not find a high-grade prostate cancer. 100 20 10 6.7 5 4 3.3 2.5 2 < 2 Number of men to biopsy to find one high-grade prostate cancer = 5% chance that the biopsy finds a high-grade prostate cancer. 4Kscore = Posi3ve Predic3ve Value 32

4K Medicare Letter Conclusion low grade prostate cancer (not on AS); there is significant difficulty equating the model used in the Swedish study to the presently proposed formula; and the incidence of clinically diagnosable prostate cancer in patients with low risk by the model/algorithm at 10 years is very concerning. Consequently, due to significant issues with assay validation and absence of clinical utility, 4Kscore testing is not reasonable and necessary and is not covered by Medicare. 33

Improved Risk Stratification for Clinically Significant Cancer Increased Risk for GS 7 PCa Consider Biopsy Routine Screening Elevated PSA, Abnormal DRE Select MDx Very Low Risk for GS 7 PCa Avoid Biopsy For pa<ents being considered for ini<al prostate biopsy Iden3fy men at high risk for aggressive cancer Assay performed on non- invasive, urine sample Very Low Risk 99.6% NPV for GS 8 98% NPV for GS 7 34

SelectMDx for Prostate Cancer Clinical Validation of a Risk Profile for the Detection of High Grade Cancer SelectMDx Risk Profile: Strongest predictor of high- grade disease 98% NPV for GS 7 cancer AUC of 0.89 (95% CI 0.85-0.95) European Urology 2016 Van Neste et al., European Urology 2016 35

SelectMDx Performance Outperforms PCA3 & PCPT Risk Calculator for Detection of High Grade Cancer ROC Curve for Clinically Significant Cancer Correlation with Gleason Score Sensi3vity 1. 0 0.8 0.6 0.4 0.2 0.89 SelectMDx 0.77 PCPTRC 2.0 SelectMDx Risk Profile 3 0 0 200 100 p<0.00 1 p<0.00 1 0.0 0.68 PCA3 1.0 0.8 0.6 0.4 0.2 0.0 Specificity No PCa GS 6 GS 7 Van Neste L, Hendriks RJ, Schalken JA et al; Detec3on of High- grade Prostate Cancer Using a Urinary Molecular Biomarker Based Risk Score, Eur Uro 2016 Accepted 36

Improves the Identification of Men for Prostate Biopsy: High Risk Increased risk for aggressive cancer Men who may benefit from biopsy Very Low Risk 98% NPV for aggressive cancer May avoid biopsy Return to routine screening Patient Report Sample Sample Patient Report Patient Name: Ken Sample Date of Birth: 12/27/1953 MRN/Patient#: 8979821 PSA: DRE: Patient Result: 8 ng/ml Normal The SelectMDx test result for this patient indicates a 85% likelihood of detecting prostate cancer, with a 50% probability for Gleason score 7, when performing a standard 12-core TRUS guided biopsy. Test Description: Disclaimer: MDxHealth is regulated under the Clinical Laboratory Improvement Amendments (CLIA) and the College of American Pathologists as an accredited laboratory to perform high complexity clinical testing. The SelectMDx for Prostate Cancer test was developed and its performance characteristics determined by MDxHealth. The test is intended for use as an aid to clinicians for patient management decisions about the need for a prostate biopsy on men with clinical factors suggesting an increased risk for prostate cancer. Use outside of this indication has not been validated by MDxHealth. Test results should be interpreted in conjunction with other laboratory and clinical data available to the clinician and relevant guidelines on the decision for biopsy. MDxHealth is certified by DEKRA for ISO 9001:2008 Quality Management System. This test was performed by MDxHealth Inc.,15279 Alton Parkway, Suite 100, California 92618. CLIA# 05D2033858; CAP# 80153999. General information about SelectMDx for Prostate Cancer can be found at www.mdxhealth.com. If you have any questions regarding this report, please contact MDxHealth Client Services at 866.259.5644 or clientservices@mdxhealth.com. Jess Savala, Jr., MD, Laboratory Director PATIENT Specimen#: 72389 Collection Date: 11/05/2015 Received Date: 11/07/2015 Report Date: 11/09/2015 Specimen Type: SPECIMEN Urine MDxH Accession#: PR-91322 Likelihood of prostate 85% cancer upon biopsy 50% Physician: Account: ACCOUNT Randolph Smith, MD. Urology Associates Address: 15279 Alton Drive Suite 100 City/State/Zip: Irvine, CA 92618 Likelihood of detecting Gleason score 7 SelectMDx for Prostate Cancer is a reverse-transcription PCR (RT-PCR) assay performed on urine specimens collected immediately following DRE from patients who are being considered for prostate biopsy. The test measures the urinary mrna levels of the DLX1 and HOXC6 biomarkers to aid in patient selection for prostate biopsy. Higher levels of DLX1 and HOXC6 mrna are associated with an increased probability for Gleason score 7 (GS 7) prostate cancer. A logistic regression model combining DLX1 and HOXC6 mrna levels with established clinical risk factors, including PSA, prostate volume, DRE, family history and age, is used to estimate the likelihood of detecting GS 7 prostate cancer upon biopsy, with an area under the curve (AUC) of 0.88 (95% CI: 0.85-0.91), in addition to the likelihood of no cancer or GS 6 disease. Performance is based on the presence of all relevant data elements; if all data are not available, or 5α-reductase inhibitors (5-ARIs) have been administered to decrease serum PSA values, results should be interpreted with caution and AUC of the test may vary. References: 1) Leyten et al; Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. Clin Cancer Res 2015. Jul 1;21 (13):3061-70 2) Hamid et al; The role of HOXC6 in prostate cancer development. The Prostate 2015. Dec;75 (16):1868-76. 15279 Alton Parkway Suite 100 Irvine, CA 92618 P:949.812.6979 866.259.5644 www.mdxhealth.com 2016 MDxHealth, Inc., All Rights Reserved. Inc. Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. Leyten et al. Clin Cancer Res, 2015 37

SelectMDx for Prostate Cancer Offers non-invasive, office based sample collection Improves detection of high grade cancer with patient-specific risk profile Helps identify men at Very Low Risk for aggressive cancer Outperforms standard clinical risk factors and other biomarkers alike Reasonable price offers cost-effective option to guide MRI & biopsy 38

Gleason 6 Ac<ve Surveillance

Tests in Bucket of who to biopsy 4 0 Assay Characteris<cs Company Beckman Coulter Opko Hologic MDxHealth Specimen Blood Blood Urine Urine Methodology Immuno assay Immuno assay qpcr qpcr 3 Protein biomarkers tpsa and fpsa, propsa 4 kallikriens biomarkers mrna test, 1 biomarker PSA, fpsa, Intact PSA, HK- 2 PCA3 2 mrna Biomarkers DLX1, HOXC6 Regulatory FDA/CE LDT/CLIA/CE FDA/CE LDT/CLIA/CE List price ($) $499 $1,900 $500 $500 Assay Performance (AUC) AUC 0.73 AUC 0.82 AUC 0.68 AUC 0.89 Comments Requires Phlebotomist 1) PCEC 2015, 2) Curr Opin Oncol. 2014 May ; 26(3): 259 264 Requires Phlebotomist & Centrifuge Urine Sample - In Office Procedure Urine Sample - In Office Procedure

Family Prac33oner Shared care Urologist Consider Tx PSA 5 years PSA <1.5 GS 4+3 + GS 6 or 3+4 Consider Tx High Risk TRUS Bx Genomic Markers Rou<ne Lab/PSA - Low Risk PSA >1.5 High Risk - ConfirmMDx + Ac<ve Surveillance PHI, MP MRI Consider referral to Urologist SelectMDxPCA3,4K Low Risk Copyright: E.D.Crawford

101 men with negative mpmri and correlation with RRP 42

Dare We Go Back to the Pre-PSA Era? With the introduc3on of PSA tes3ng, death from prostate cancer was reduced by 20%, whereas metasta3c disease was reduced by nearly half Welch, nejm 2015 373;18. Gomella, LG Celebra3ng the Death of PSA screening CJU December 2011

A Decision Aid for the Task Force

How to save the baby: screen smarter Start earlier Screen less frequently if baseline is low Focus on populations at highest risk Screen for high-risk prostate cancer, don t over-treat low-risk disease Embrace active surveillance Fix incentives Refer early and wisely Change nomenclature? Continue to develop novel biomarkers

Conclusions Screening saves lives, period. The USPSTF analysis downplays benefits, overestimates harms, and is predicated on far too short of a time horizon. Overtreatment is without question a major public health problem, and we have to fix it. But the answers lie in smarter screening and better treatment decisions, not in wholesale cessation of screening. To own the truth, own the data

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