The Who s of Genomic Markers: Whom to Biopsy?

Transcription

1 The Who s of Genomic Markers: Whom to Biopsy? :20-7:40 AM E. David Crawford, M.D. Professor of Surgery/Urology/ Radiation Oncology University of Colorado

2 WSJ

3 Recent Advances in Prostate Cancer: 1. Prostate Cancer Markers (PCMs) 2. Next Generation Sequencing (NGS) Sequencing Panels 3. New Therapeutics for Advanced CaP 3

4 Prostate Cancer Clinical Needs 1. Screening: Primary Care Physicians (PCPs) need a simple message 2. Early Detection: Identify patients with clinically significant PCa earlier 3. Reduce Unnecessary repeat prostate biopsies 4. Enhance risk stratification: Surveillance vs. Interventional Therapy 5. Germline Mutations-Role of Urologist 4

5 Prostate Cancer Marker (PCM) Tissue Blood What is a PCM? A molecule that can be found in blood, tissue or body fluids that is a sign of a normal or abnormal process Urine 5

6 PCM Buckets Ini/al Biopsy: Iden/fy Significant PCa Nega/ve Biopsy: Whom to Rebiopsy Whom to offer Gene/c Tes/ng: Who to offer Interven/onal Therapy vs Ac/ve Surveillance Whom to treat or not treat post- prostatectomy: SelectMDx phi 4kscore ConfirmMDx SelectMDx phi Ambry GeneOcs Myriad GeneOcs GeneDx OncotypeDx Prolaris Decipher Prolaris Decipher 4kscore Invitae Promark

7 Message from USPSTF and Other Organizations Following the Lead PSA screening is a D recommendation Do Not Order Shared Decision Making Supported by AAFP and other organizations Moyer VA, et al. Ann Intern Med Jul 17;157(2): AAFP, USPSTF Issue Final RecommendaOon Against RouOne PSA- based Screening for Prostate Cancer 7

8 PSA: 0.84 (ng/ml) Shared Decision?

9 Beyond PSA: Prostate Cancer Challenges PSA Screening Poor specificity Too many negative prostate biopsies Over detection/treatment of insignificant Disease False Negative Biopsies Incorrect Risk Stratification for treatment decision making Over-treatment of tumors with prolonged natural history >>>>> life expectancy of patient

10 Beyond PSA Using PSA alone to guide prostate biopsy decisions should for the most part end Tools are needed to provide better risk assessment to detect clinically meaningful cancers Reduce unnecessary biopsies Reduce over-detection of indolent disease

11 Biomarker Tests for Molecularly Targeted Therapies- The Key to Unlocking Precision Medicine New England Journal of Medicine 375;1, July 7, 2016 Precision medicine Genomics Proteomics Metabolomics Personalized diagnosis and therapy Gary H. Lyman, M.D., M.P.H., and Harold L. Moses, M.D. 11

12 What Percent of all of the PSA s ordered in the US are by Urologists? 12

13 What Percent of all of the PSA s ordered in the US are by Urologists? 1.3 We need to educate those who are ordering and interpreong PSAs Internal Medicine Family Medicine Urology Hem/Onc 64.9% 23.7% 6.1% 1.3% Aslani A, et al. J Urol. 2013;do: /j.juro

14 Ways Forward With PCPs: Don t Confuse them Educate those who order PSAs: PCPs There Confused Velocity Density Age Specific % Free PSA Complex PSA Define a PSA level with little risk Who/when to refer to urologist? Phi PCA3 SelectMDx 4kscore HELP! 14

15 Defining an Appropriate PSA Level Patients and Methods: 350,000 HMO-Henry Ford System Men in system 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% Men Eligible: 21,502 15

16 5-year Diagnosis Rates Based on Initial PSA Level Percent developing prostate cancer 12% 10% 8% 6% 4% 2% 0% 0.51% PSA < 1.5ng/mL 15- fold Increase in risk 7.85% 19- fold Increase in risk for African Americans PSA 1.5-4ng/mL 10.39% Overall Study PopulaOon (21,500) Percent developing prostate cancer Maximum sensiovity and specificity at PSA 1.5 ng/ml EsOmated Area C= Specificity ROC Curve for All PaOents Crawford ED, et al. BJU Int. 2011;108(11):

17 Serum PSA 1.5ng/mL Predicting Enlargement & Risk of Progression Prostate volume (ml) PSA of 1.5 surrogate for enlarged prostate 65 Age (years) Risk of progression* Adapted from Roehrborn CG et al. Urology. 1999;53: *Crawford ED et al. J Urol. 2006;175: Serum PSA (ng/ml) 17

18 PSA 1.5 Indicator for BPH Progression Male patient: Age 55, 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.

19 Prostate Size and Urinary Symptoms 19

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22 Top Manuscript Top Stories in Urology: Prostate Cancer Screening PracticeUpdate 12/18/16, 4)12 PM (/) Channels Search PracticeUpdate " FEATURED Published in Urology (/explore/channel/urology/sp3) Expert Opinion / Commentary November 08, Top Stories in Urology: Prostate Cancer Screening Written by (/author/alan-partin/80) Alan W Partin MD, PhD An approach using PSA levels of 1.5 ng/ml as the cutoff for prostate cancer screening in primary care This paper, recently published in Urology and highlighted as the Story of the Week in PracticeUpdate Urology, addresses a major until now unanswered question in medicine 1 related to early detection of prostate cancer. The discussion and recommendations made by this esteemed group of authors and the comments provided by Dr. Laurence Klotz outline the potential impact of this manuscript not only urologists but for general practitioners as well ( ( Page 1 of 5 22

23 What percent of men have an initial PSA > 1.5 ng/ml? Patients (age 40 to 75) with 1 PSA result in the past 12 months 217,000 patients Results from 0.01 to 5,000 Eliminate extreme results 215,613 patients Results from 0.01 to 10.0

24 Result Distribution 73% PSA < 1.5 ng/ml

25 Early Detection a Way Forward Vital signs and many tests routinely performed by PCPs before informed decision Informed decision when tests are abnormal Why not PSA? 73% of men require no discussion PSA treated like other lab tests: lipids electrolytes weight BP- rouone Men s health broader issue > 1.5 ng/ml surrogate for BPH, Prosta//s, Prostate Cancer Roehrborn CG et al. Urology. 1999;53:

26 A Way Forward: PSA > 1.5 ng/ml Surrogate for: 1. BPH-most common 2. Prostate Cancer 3. Long term PCa risk 4. Evaluate-Don t Biopsy everyone with > 1.5 ng/ml!!!! 5. Use PCMs to help determine whom to biopsy

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28 The Goal in 2016 Gleason 6 Active Surveillance What PCM helps us identify patient harboring high risk cancers?

29 PCM Buckets Ini/al Biopsy: Iden/fy Significant PCa Nega/ve Biopsy: Whom to Rebiopsy Whom to offer Gene/c Tes/ng: Who to offer Interven/onal Therapy vs Ac/ve Surveillance Whom to treat or not treat post- prostatectomy: SelectMDx phi 4kscore ConfirmMDx SeleMDx phi Ambry GeneOcs Myriad GeneOcs GeneDx OncotypeDx Prolaris Decipher Prolaris Decipher 4kscore Invitae Promark

30 phi 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 (%) <30 n= n= n= n= n=86 83 >70 n= >80 n=69 ([- 2] propsa/fpsa)* tpsa phi score phi 30

31 Results: phi Risk Stratifies Significant PCa * p =.0016 p =.041 p = * n=72 Slide 31

32 PCA3 Does Not Discriminate High from Low Grade PCa 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): Measure PCA3 and PSA mrna from cells PCA3 score = PCA3/PSA mrna x

33 4Kscore Prostate Bx for aggressive PCa 4Kscore 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 33

34 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 < 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 = PosiOve PredicOve Value 34

35 4Kscore FINAL REPORT D O C T O R USA Acct #: (1234) P: P A T I E N T DOB:04/30/1938 Age:76 Y Sex:M ddress:, USA P: S A M P L E Specimen ID: Date Of Report: 04/19/2015 Date Collected: 04/18/2015 Time Collected: 00:00 Date Received: 04/18/2015 Time Received: Interpretation LOW RISK There is a 95% probability that the patient will not have aggressive disease on a prostate biopsy. For a patient aged 60 years or older with a total PSA 3 ng/ml and a 4Kscore <7.5%, the probability of not developing distant metastases within the next 10 years is 99.8%. 4Kscore Test Results Low Risk Moderate Risk High Risk 4Kscore: Clinical Information 5% 1% 2% 3% 4% 5% 6% 7.5% 10% 12% 14% 16% 18% 20% 4Kscore Test Result 30% 40% 50% 60% 70% 80% >90% Digital Rectal Exam (DRE): Normal Prior Biopsy Status: Yes - Negative Test Information The 4Kscore result is the prediction of the individual s risk of aggressive prostate cancer of Gleason score 7 or higher if a prostate biopsy is performed. The 4Kscore is calculated from the results of four immunoassays: Total PSA, Free PSA, Intact PSA, and Human Kallikrein-2 (hk2), plus patient age, reported DRE result, and history of prior negative biopsy. Based on the 4Kscore US validation study, prostate biopsy should be considered in most men with a 4Kscore of 7.5% or higher. However, patient management should be based on clinical judgment and shared decision-making about undergoing biopsy. In a landmark study by Stattin et al. 12,542 men were followed for up to 20 years in Västerbotten, Sweden to determine the risk of prostate cancer metastases. Men who had a suspicious PSA and a 4Kscore of 7.5% or less had a low risk (<1%) of having metastatic prostate cancer within 20 years. References: 1. Parekh, DJ, Punnen S, Sjoberg DD, et al. Eur Urol Sep;68(3): Gupta A, Roobol J, Savage CJ, et al. Br J Cancer Aug;103(5): Stattin P, Vickers AJ, Sjoberg DD, et al. Eur Urol Aug;68(2): Note: This test was evaluated and its performance characteristics determined by BioReference Laboratories. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. BioReference Laboratories is certified under the Clinical Laboratory Improvement Act of 1988 (CLIA) as qualified to perform high complexity clinical testing. BioReference Laboratories, Inc. James Weisberger, M.D. Clinical Page 1 of Edward H. Ross Dr Elmwood Park, NJ (800) Laboratory Director Printed 05/16/14 10:04 AM GenPath is a business unit of BioReference Laboratories, Inc.

36 SelectMDx for Prostate Cancer: * Risk Stratification for Clinically Significant PCa For patients being considered for prostate biopsy Increased Risk for GS 7 PCa Consider Biopsy PCP/Urologist PSA>1.5 Urologist Repeat PSA, DRE SelectMDx Very Low Risk for GS 7 PCa Avoid Biopsy * 2 genes associated with aggressive CaP- Urine Assay Very Low Risk 99.6% NPV for GS 8 98% NPV for GS 7 36

37 SelectMDx Clinical Validation of a Risk Profile for the Detection of High Grade Cancer SelectMDx for Prostate Cancer: Strongest predictor of high-grade disease compared to traditional clinical risk factors 98% NPV for GS 7 cancer 99% NPV for GS 8 cancer European Urology 2016 Van Neste et al., European Urology

38 SelectMDx Outperforms PCA3 & PCPT Risk Calculator for Detection of High Grade Cancer ROC Curve for Clinically Significant Cancer Correlation with Gleason Score SensiOvity SelectMDx 0.77 PCPTRC 2.0 SelectMDx Risk Profile p<0.001 p< PCA Specificity No PCa GS 6 GS 7 98% NPV for GS 7 Van Neste L, Hendriks RJ, Schalken JA et al; Detection of High-grade Prostate Cancer Using a Urinary Molecular Biomarker Based Risk Score, Eur Uro 2016 Accepted

39 SelectMDx Sample Patient Report Identification of Men for Prostate Bx: 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 Risk for CS PCa Very Low Risk Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer. Leyten et al. Clin Cancer Res, 2015

40 SelectMDx Correlation with Mapping Biopsies (needle prostatectomy) Results* Statistical Formula Value 95% CI Disease prevalence:17.39% (9.32% to 28.41%) Sensitivity: 100% (73.54% to %) Negative Predictive Value: 100% (91.40% to %) SelectMDx has 100% sensi/vity and 100% NPV (if we use cutoff Gleason score as 4+3 and above and use 3+3 and 3+4 as non- significant) *n=73 Crawford et al., Abstract submitted 40

41 PCMs help eliminate Gleason 6 Ac/ve Surveillance

42 Tests in Bucket of who to biopsy 4 2 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 May ; 26(3): Requires Phlebotomist & Centrifuge Urine Sample - In Office Procedure Urine Sample - In Office Procedure

43 Thank you 43