Biomarkers for Prostate Cancer. Eric Wallen, MD Department of Urology

Transcription

1 Biomarkers for Prostate Cancer Eric Wallen, MD Department of Urology

2 Disclosure MDxHealth Scientific Advisor

3 55-year-old man: Poor Guy Risk of prostate cancer? 1 in 6 Risk of prostate cancer death? 1 in 40 Risk of biopsy related complications 1 in 25 If PSA elevated and biopsy (-), risk of repeat biopsy 1 in 2.5 If biopsy negative, risk of missed cancer 1 in 4 If diagnosed with NCCN low risk CaP, risk of upgrading/staging at surgery? 1 in 4 If surgery shows T3 disease, need for radiation? 1 in? Wouldn t it be great if there were some biomarkers that helped with these questions?

4 What is personalized medicine? Customization of healthcare based on rational use of an individual patient s unique disease features What is a biomarker? A measurable characteristic of the biology of a particular disease state Tissue, blood, serum, urine, EPS, MRI (?)

5 Is there a need for biomarkers in mgmt of prostate cancer? AUA guidelines 2007 and 2013 discuss in Research and Future Directions section 2007 development of biomarkers of aggressiveness is desirable 2013 many biomarkers, poor evidence Yes! We need more decision aids to provide actionable guidance Still in evolution

6 Bench to bedside DNA, RNA, epigenetic K. Chiam et al., Cancer Lett. (2012)

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8 Where can biomarkers help? 1. When to biopsy 2. When to re-biopsy 3. When to treat 4. When to treat adjuvant 5. Assess therapeutic response

9 Where can biomarkers help? 1. When to biopsy 2. When to re-biopsy 3. When to treat 4. When to treat adjuvant 5. Assess therapeutic response

10 From: Operating Characteristics of Prostate-Specific Antigen in Men With an Initial PSA Level of 3.0 ng/ml or Lower JAMA. 2005;294(1): doi: /jama Figure Legend: AUC indicates area under the receiver operating characteristic curve. Date of download: 4/20/2014 Copyright 2014 American Medical Association. All rights reserved.

11 Odds Ratios, While Attractive, Must Be Considered When Evaluating These Tests OR of 3 reclassifies 25% of results

12 When to Biopsy ( screen smarter ) Goals: Decrease unnecessary biopsies Decrease detection of low risk disease Currently: PSA, fpsa, PSAd, risk calculators Molecular Tests: Phi: Prostate Health Index (serum): PSA 2-10, nl DRE f/tpsa and propsa formula generates a score (Clin Chem 2013) Multiparametric MRI with MRI fusion biopsies (Rastinehad, JU, 2014) OPKO 4K test (serum) incl PSA and hk2 to generate risk score for GS 7 enose (urine) emission testing!

13 PHI Precursor forms of PSA elevated in PCa and measurable in serum Formula includes tpsa and fpsa, as well as (-2)proPSA Screening pts with PSA and nl DRE gives incr sens/spec (64/63) Using cutoff of 35, 26% of biopsies could be avoided FDA approved for PSA 4-10 Le, JU, 2010 Lazzeri, BJU, 2013

14 PHI ROC Sokoll, Cancer Epi Bio Prev 2010

15 MPMRI: Pre-biopsy Possibly selective detection of high grade lesions and lower detection of low grade lesions in patients Possibly a quantum leap However Not standardized yet. 3T or 1.5T? Endorectal or not? Biopsy in bore, fusion, or cognitive? ***radiologist dependent*** Costly Still has false negatives so is standard biopsy still warranted? Multi-institutional trials to come Bjurlin, UCNA, 2014 Siddiiqui, Eur Urol, 2013 Marks, Curr Op Urol 2013 Wysock, Eur Urol, 2013 Albertsen, Jurol, 2013

16 OPKO 4K Test 4 kallikreins: tpsa, fpsa, ipsa, hk2 measured in serum and used in nomogram with DRE and age to get probability score for prostate cancer When used in serum from ERSCP prostatectomies, good predictor of aggressive disease Prospective multi-institutional trial results presented by Daniel Lin at AUA2014. AUC.82 for prediction of GS 7 Cost: $400, currently available Carlsson, EurUrol, 2013 Voigt, The Prostate, 2013

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18 TMPRSS2-ERG ERG oncogene fusion with TMPRSS2 is an early change in prostate cancer TMPRSS2-ERG fusion can be measured in urine post DRE High specificity, low sensitivity U Mich group reported at AUA2014 a large study of T2ERG+PCA3+PSA that had AUC score of.73 in predicting GS 7 Prob will seek FDA approval in combination with PCA3 for screening Leyten, Eur Urol, 2014

19 PCA3 (not approved for screening, but ) Post prostatic massage urine test for RNA that is elevated in PCa, score generated Extensively studied, FDA approved for repeat bx only Most studies done are on patients already selected for biopsy (not screening) Strength appears to be specificity (75%) not sensitivity (50%) Score correlates with increasing grade Better than PSA for all grades of PCa, equivalent for GS 7 Prob won t be approved for screening (not selective for higher grade prostate cancer) but more studies pending, incl combinations with other biomarkers Chevli, Jurol, 2014

20 PCA3 for Screening: No Chevli, Jurol, 2014

21 Summary: Screening Smarter Use PCPT and/or ERSPC risk calculator Use online life expectancy calculator Consider molecular tests (PHI, 4K) but watch out for cost Consider MRI but you must have an experienced, trained radiologist (cost too) Minimize infection risk of biopsy

22 Where can biomarkers help? 1. When to biopsy 2. When to re-biopsy 3. When to treat 4. When to treat adjuvant 5. Assess therapeutic response

23 Repeat Biopsy: The Numbers 1.3M biopsies/yr 1M are negative 43% repeat biopsy within 3 yr Biopsies carry risk Infection Hospitalization Pinsky, BJUI, 2007 Loeb, Jurol, 2011, 2014

24 Tests To Help Decision to Re-Biopsy PCA3 (urine after prostate massage) RNA overexpressed in Pca ConfirmMDx: Epigenetic Test on negative biopsy tissue MATLOC, DOCUMENT (JU, 2013, JU 2014) NPV 90% Assesses epigenetic changes for 3 genes Mitomics (mitochondrial DNA testing on negative biopsy tissue)

25 PCA3 for Rebiopsy FDA approved for cutoff= 25 Sens/spec up to 90/50 Can help guide decision to rebiopsy May help avoid up to half of repeat biopsies Luo, Asian J Androl, 2014

26 ConfirmMDx: Epigenetic Changes Influence Gene Expression Without Changing the Genome Test detects an epigenetic field effect with the cancerization process at the DNA level The field effect around the cancer focus can be present despite the normal micro appearance of cells Detection of field effects extends the coverage of the biopsy helping to rule in, or rule out, occult cancers Cancer Field Effect Biopsy

27 ConfirmMDx clinical validation studies MATLOC and DOCUMENT Approx 500 patients who had 2 biopsies each All with negative first biopsy, biopsy tissue tested Approx 100 cancers seen on re-biopsy, NPV 90% Test identified 2/3 of these as positive, sensitivity/specificity 66% 1/3 of cancers Gleason >6 Could also decrease repeat biopsies significantly Stewart, JU, 2013

28 MPMRI for Rebiopsy Provides anatomic information Can help guide re-biopsy and detects PCa in up to 50% of pts MPMRI outperformed PCA3 and PHI in pts undergoing rebiopsy If MPMRI negative, repeat biopsy for ongoing concern yielded very few significant cancers NICE (English cost-effectiveness guidelines group): Consider pre-re-biopsy Intergroup study pending Needs to be done as techniques vary widely Bjurlin, J Urol., 2014, UCNA 2014 Porpiglia, J Urol, 2014 Hong, Diag Interv Rad, 2014

29 Where can biomarkers help? 1. When to biopsy 2. When to re-biopsy 3. When to treat 4. When to treat adjuvant 5. Assess therapeutic response

30 No. of patients (%) Active Surveillance is Underutilized WW RP Brachy EBRT Cryo PADT Cooperberg MR et al. J Clin Oncol Mar 1;28(7): CAPRA score: Increased score, increased risk 31

31 Aids in AS vs Treatment Prolaris: Cell cycle gene panel Oncotype DX: Mixed gene panel MPMPRI Cuzick, Lancet Oncol 2011

32 Prolaris Application: Predict BCR, metastasis, and risk of death Measures panel of cell cycle genes, which are increased in more aggressive disease Evaluated in prostatectomy specimens from pts with extended f/u, then extended to prostate biopsy specimens AUA2014: 3 clinical validation studies Improves upon age, GS, stage Predicts metastasis Improved dataset, not clear if this information would predict actual outcome in a modern cohort Prospective studies may be necessary to support adoption

33 Oncotype DX Application: Active surveillance candidates Seeks to predict adverse pathology: T3, GS>7 or primary 4 Tests cancer foci in biopsy for 17 genes found to be indicators of aggressiveness May reclassify pts in NCCN category Goal: Increase the number of patients and urologists who can feel reassured on AS, identifies a few who have aggressive features Predicts pathology, not clinical outcomes Klein, Eur Urol, 2014

34 Population-Based Clinical Risk Assessment VERY LOW RISK 10% (N=37) LOW RISK LOW-INTERMEDIATE 49% (N=191) 41% RISK (N=160) GPS Provides Biologic Risk Information 26% (N=100) 31% (N=119) 44% (N=169) GPS=8 84% GPS=25 75% GPS=51 57%

35 Where can biomarkers help? 1. When to biopsy 2. When to re-biopsy 3. When to treat 4. When to treat adjuvant 5. Assess therapeutic response

36 Tests for Prostatectomy Specimens Prolaris Increased score could help tip decision toward adjuvant therapy Decipher PTEN: FISH assessment of a common gene alteration in aggressive disease

37 CTC: Circulating Tumor Cells Measurement of CTC in CRPC trials Decrease during treatment highly predictive of treatment response and survival (Scher, Lancet Oncol, 2009)

38 Figure 1 Cumulative survival ROC curves comparing GC score and individual clinicopathological factors for predicting clinical metastasis 5 years after RP. GC showed noticeably higher discrimination than individual clinicopathological factors. Path, patho... R. Jeffrey Karnes, Eric J. Bergstralh, Elai Davicioni, Mercedeh Ghadessi, Christine Buerki, Anirban P. Mitra... Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population The Journal of Urology, Volume 190, Issue 6, 2013,

39 Considerations Prostate cancer is genetically complex Molecular tests are evolving rapidly Characteristics of a good test Answers a clinical question (utility) Is based on good evidence Is actionable changes a treatment Tests cannot be applied to all populations if not tested in them Rigorous validation with consistent methodology needed How costly will that be? Cost may limit development and evaluation of innovative tests Test must be applied to the specific and appropriate clinical context

40 Conclusions PSA screening identifies many non-aggressive cancers Uncertainty and fear cause patients and doctors to treat aggressively Before placing QOL at risk we need to better identify which patients need treatment, and the recent biomarker explosion seeks to do this Are the tests good enough yet? They are getting there If good enough, who pays for them? If used, are we and are patients going to abide by the result? If not, why order the test? If so, treatment will decrease significantly as we will flip the script on AS vs intervention