Advances in Diagnostic and Molecular Testing in Prostate...
Transcript of Advances in Diagnostic and Molecular Testing in Prostate...
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September 24, 2015 1
Ashley E. Ross MD PhD Assistant Professor Urology, Oncology, Pathology Johns Hopkins School of Medicine
Advances in Diagnostic and Molecular Testing in Prostate Cancer
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Disclosures
• Relevant Financial Disclosure – Previous Consultant, now Collaborative
Researcher: GenomeDX • Produces DecipherTM test for post prostatectomy risk
assessment
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Localized Prostate Cancer – Urologists Perspective
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Surveillance
Treatment
Prostatectomy, Radiation
Adjuvant/Salvage TherapySurveillance
Decision Making Complexity• High Prevalence• Broad Spectrum of
Localized Disease• Relatively Long Natural
History (Competing Risks)
• Morbidity of Diagnosis and Treatment
Screening and
Diagnosis
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PART 1: SCREENING AND DIAGNOSIS
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Screening and Diagnosis – Reducing Over Diagnosis
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• Strategies— – Evidence based screening
• Decrease intensity of screening (particularly when the screening test is suboptimal)
– Develop superior tests • The ideal test would be able to identify clinically
significant prostate cancer
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Evidence Based Screening– AUA Statement 2013
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• No screening in men under age 40 – Low prevalence
• Routine screening not recommended for men 40-54 – Screening can be considered on an individualized basis i.e. men
at risk (AAM, +FamHx)
• Shared decision making for screening for men age 55-69 – Consider routine screening intervals of 2 years or more for men
who opt to be screened (PLCO)
• No routine screening in men with <10-15 year life expectancy
• Consider discontinuation of screening at 70
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Emerging Approaches for Prostate Cancer Screening / Detection – FDA Approved Tests
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• Prostate Health Index (PHI) – Serum test – Approved for use in men 50 and over with PSAs of
4-10 and negative DREs, to help determine if biopsy is indicated
• PCA3 – Urine test – Approved for use in decision making for repeat biopsy
after a prior negative biopsy (scores <25 protective)
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Emerging Approaches for Prostate Cancer Screening/Detection – PHI
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• PHI – Prostate Health Index – Blood test based on total PSA (tPSA), free
PSA (fPSA) and the PSA isoform [-2]proPSA
– [−2]proPSA/fPSA × √PSA = PHI – proPSA is expressed at greater levels in
the peripheral zone (where prostate cancer develops) and also at greater levels from prostate cancer tissue
– hK2 may be over-expressed in malignancy – Increases specificity over a range of
sensitivities compared to PSA – Cost effective = relatively cheap! BJU International���
Volume 112, Issue 6, pages 717-728, 3 JUL 2012 DOI: 10.1111/j.1464-410X.2012.11329.x���http://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2012.11329.x/full#bju11329-fig-0001
Catalona J Urol 2011, Stephan Clin Chem 2013, Nichol MB BJUI 2012
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Emerging Approaches for Prostate Cancer Screening/Detection – PHI
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BJU International���Volume 112, Issue 3, pages 313-321, 4 JUL 2013 DOI: 10.1111/bju.12217���http://onlinelibrary.wiley.com/doi/10.1111/bju.12217/full#bju12217-fig-0001
Catalona et al. The Journal of Urology, Volume 185, Issue 5, 2011, 1650 - 1655
PHIPHI
PSA PSA
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PHI-- Association with RP Features
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Guazzoni , European Urology, Volume 61, Issue 3, 2012, 455 - 466
Above, 350 consecutive RP patients Similar analysis of ~450 RP patients showed patients with pT3 and GS > 7 have PHI of 64.9 vs 42.9 for those who don’t (p<0.0001) (Fossati et al 2014)
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PHI in AAM
• Limited studies • JHH institutional database
– 80 AAM who underwent PHI testing and had RP
– 30 AAM with elevated PSA who underwent PHI testing
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PHI in AAM Undergoing RRP
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050
100
150
PH
I sco
re
pT2 pT3a (ECE) pT3b (SVI)Pathologic tumor stage on RP (pT stage)
050
100
150
PH
I sco
re
Gleason score 6 Gleason score 7-10Pathologic Gleason score
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PHI in AAM – Men Undergoing Screening
• 30 AAM presenting with elevated PSA – 22 opted not to undergo biopsy
• Median PHI 19.1 (17-27.5)
– 8 Underwent prostate biopsy • Median PHI 43 (37.5-93.4)
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PHI in AAM – Men Undergoing Screening (red = GS 7-10)
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4060
8010
012
0PH
I sco
re
No cancer CancerBiopsy result
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• PCA3 – Urine based test for a prostate cancer
specific non-coding transcript – FDA approved in 2012 for decision making
about repeat biopsy in a man with 1 or more negative biopsies
• Bradley et al J Urol 2013: – A comparative effectiveness review of PCA3
vs PSA commissioned by the US Agency for Healthcare Quality and Research
• Conclusion: PCA3 provides higher accuracy than total PSA and independent information. Evidence is insufficient that PCA3 testing improves health outcomes
Emerging Approaches for Prostate Cancer Screening/Detection – PCA3
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Emerging Approaches for Prostate Cancer Screening/Detection – 4K Score
• Similar to PHI • Blood test • Free PSA, Intact PSA, Total PSA, hK2 • AUC increased for any PCa or High Grade vs
tPSA (0.79 and 0.82 vs 0.63 and 0.74) • Prospective screening study is underway • Most evaluations in European Patients
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Bryant et al JNCI 2015
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Emerging Approaches for Prostate Cancer Screening/Detection – Urinary TMPRSS2:ERG
• Chromosomal rearrangement between TMPRSS2 and ETS family members (most notably ERG) seen in ~50% of prostate cancer cases – However only ~30% of AAM cases
• Rearrangement produces a unique transcript (tissue based specificity 99.9%)
• Can be analyzed in urine similar to PCA3 • Increases AUC for detection of PCa and High
grade disease September 24, 2015 17
Tomlins Science 2005 Tomlins Eur Urol 2015
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Emerging Approaches for Screening/Detection Multi-Parametric Prostate MRI
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Multi-Parametric Prostate MRI
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PI- RADS
1 Most Probable Benign
2 Probable Benign
3 Indeterminate
4 Probably Malignant
5 Highly Suspicious
Portalez et al, E Urol 2012
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mpMRI of the Prostate May Play A Significant Role for AAM
• Anterior tumors may be more common among AAM
• mpMRI is imperative for AAM considering AS
• mpMRI may play an important role in prostate cancer screening
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Sundi et al. J Urol 2014
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Multi-Parametric Prostate MRI
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Pokomy et al, E Urol 2014
• Allowed +DRE • Allowed PSA >10 • 57% PCA on biopsy
• 36% Reduction Unnecessary Biopsies
• 6% Un-diagnosed Gleason 7 Dz (3+4=7)
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Clinical Trial of Augmented PSA Screening
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Conclusions Part 1
• PHI, PCA-3, 4K Score, T2:ERG, mpMRI all present opportunities for reduction of over-diagnosis – Dedicated studies in AA populations are needed, PHI
appears promising – mpMRI is imperative for AAM considering AS
• Use in primary unscreened populations is unclear and needs study
• Thresholds for biopsy utilizing new tests needs study • Comparisons between biomarkers needs study
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PART 2: MOLECULAR TISSUE TESTING AFTER DIAGNOSIS
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Tissue Based Advances
• Molecular understanding of localized prostate cancer has increased
• We have increased facility to obtain molecular information from routinely collected and stored formalin-fixed paraffin embedded tissue
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Molecular Events of Early Prostate Cancer– T2:ERG, Cell Cycle, PTEN Loss
26 Baca et al. Cell 2013
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Genomic Level Pathology of AAM Prostate Cancer May Differ
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Genomic Level Pathology of AAM Prostate Cancer May Differ
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Differential Prediction of pT3 Disease in AAM and EAM
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AA menEA men
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Genomic Level Signatures Maintain Predictive Power
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Conclusions Part 2
• Molecular testing of tissue represents an emerging technique to aid in clinical decision making – PTEN, OncotypeDX GPS, Promark: AS or Treatment – Ki-67, Prolaris: WW vs Treatment – Decipher: Adjuvant Radiation
• Molecular basis of prostate cancer may differ by race • Validation in African American populations is needed
and development of ethnicity specific signatures is warranted
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