Genomic-based personalized treatment for organ-confined Prostate Cancer

Transcription

1 Genomic-based personalized treatment for organ-confined Prostate Cancer Kosj Yamoah, M.D, Ph.D. Radiation Oncology and Cancer Epidemiology Moffitt Cancer Center & Research Institute Tampa, FL

2 Prostate Cancer Pathogenesis Prensner, et, al. Sci. Trans. Med., 2012

3 Question What percentage of clinicians in Florida state use biomarkers in the management of their patients with prostate cancer. A.<10% B.25% C.50% D.70% E.100%

4 What percentage of clinicians in Florida state use biomarkers in the management of their patients with prostate cancer. A.<10% B.25% C.50% D.70% E.100% Answer

5 Oldest PCa Biomarker PSA Derivatives Age-specific PSA thresholds Free PSA PSA isoforms (propsa) PSA density PSA kinetics PSA velocity (PSAV) PSA doubling time (PSADT)

6 PSA clinical course RT +/- RT RT +/- Prensner, et, al. Sci. Trans. Med., 2012

7 The PCa Biomarker List Blood Urine Tissue Pre biopsy 4K PHI PCA3 Post biopsy re-biopsy 4K PHI TMPRSS2:ERG Post biopsy prognosis Prolaris Oncotype Dx Decipher Post surgery Decipher

8 PSA clinical course RT +/- RT RT +/- PHI 4K PCA3 TMPRSS2-ERG OncotypeDx:GPS/Genomic Health Prolaris/ Myriad Genetics Decipher/Genomedx AR-V7 Prensner, et, al. Sci. Trans. Med.,

9 PHI 4K PCA3 TMPRSS2-ERG OncotypeDX Prolaris Decipher Decipher Prensner, et, al. Sci. Trans. Med., 2012

10 Case 1 65 year old male with: PSA 6 (4.5 last year) negative DRE Doesn t want a biopsy

11 Prostate Health Index

12 Epstein Sig Cancer Gleason Men PSA 4-10 Only 5% African American Men Loeb J Urol 2014

13 4K Score 4 Kallikriens PSA fpsa ipsa hk2 DRE Prior biopsy information

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15 4K: >7.5% 4K: < 7.5% Reduction of biopsy by 38% Stattin Eur Urol 2015

16 4K vs PHI Nordstrom Eur Urol 2015

17 Urine Testing PCA-3 TMPRSS2-ERG

18 Prostate Cancer Antigen 3 (PCA3) Nucleic Acid Amplification Test DD3 (PCA3- noncoding RNA) overexpressed in PCa compared to benign tissue (Bussemakers Cancer Res 1999) Outperforms PSA AUC (vs PSA ) PPV ~52% (37-75%) Men with negative PCA3 unlikely to have PCa, but still have false positives Does not increase with volume or prostatitis Urine assays available Collect following vigorous DRE (3 strokes/lobe)

19 PCA3 Crawford JU 2010

20 TMPRSS2:ERG Gene Fusion Discovered in 2005 at the University of Michigan Gene fusion between TMPRSS2 and ERG Overexpressed in 50-60% of PSA-screened PCa Detectable in urine Only present when PCa is present not seen in normal tissue and any other cancers My Prostate Score now available combines urine PCA3, urine TMPRSS2:ERG as well as PSA and the PCPT risk assessment tool to provide a risk score.

21 TMPRSS2:ERG

22 Case 2 65 year old male with: PSA 6 (4.5 last year) negative DRE Biopsy 3/12 (10-20% avg.) cores Gleason 6 (3+3)

23 TREATMENT OPTIONS Active Surveillance OR- Surgery OR- External beam radiation therapy Brachytherapy (seed implantation) Cryotherapy & HIFU

24 Biomarkers Markers for Risk Stratification Oncotype Dx (GPS) Genomic Health Prolaris Myriad Genetics Decipher GenomeDx

25 Oncotype DX SCREENING PSA DRE DIAGNOSIS Biopsy Gleason Stage TREATMENT DECISION Active Surveillance OR Immediate Treatment Very low to low-intermediate risk Oncotype DX /GPS when combined with other clinical factors, can further clarify risk Confirmation that tumor is low risk and confined to prostate

26 Oncotype DX qrt-pcr 12 Cancer Related Genes 5 Reference Genes

27 Genetic Prostate Score (GPS) Oncotype DX Predicts High-grade pathology High-stage pathology Klein Eu Urol 2014

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30 GPS - Risk Refinement

31 Prolaris Myriad Genetics 31 Cell Cycle Progression (FOXM1, CDC20, CDKN3, CDC2, KIF11, KIAA0101, NUSAP1, CENPF, ASPM, BUB1B, RRM2, DLGAP5, BIRC5, KIF20A, PLK1, TOP2A, TK1, PBK, ASF1B, C18orf24, RAD54L, PTTG1, CDCA3, MCM10, PRC1, DTL, CEP55, RAD51, CENPM, CDCA8, and ORC6L ) 15 House Keeping Genes

32 Cell Cycle Progression Score Prolaris Bishoff JU :409

33 Cell Cycle Progression Score Prolaris Strong predictor per score unit of Biochemical recurrence Univar. HR 1.60 Multivar. HR 1.47 Metastatic disease Univar. HR 5.35 Multivar HR 4.19 Bishoff JU :409

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36 Case 3 65 year old male with: PSA 6 (4.5 last year) negative DRE Biopsy 5/12 (40% avg.) cores Gleason 7 (3+4)

37 TREATMENT OPTIONS Active Surveillance Radical Prostatectomy OR- Radiation Therapy External Beam- IMRT alone IMRT +Brachytherapy IMRT + ST-ADT Cryotherapy & HIFU

38 Decipher Genome Dx 22 RNA Biomarkers (1.4 million) Scores 0-1

39 Genomic Assay Decipher 70% of high-risk patients had low genomic classifier (GC) with good prognosis High GC scores had high risk of metastasis (>25%) Karnes et al, JU 2013

40 Klein et al. Urology 2016

41 Decipher Biopsy

42 Decipher Biopsy Decipher Biopsy predicts likelihood of: High grade disease (Gleason grade 4 or 5) 5 year metastasis 10 year PCSM

43 Same Patient: 65 year old male with: PSA 6 (4.5 last year) negative DRE Biopsy 5/12 (40% avg.) cores Gleason 7 (3+4) s/p RP Now has 1mm + margins, + PNI, +LVI, Gleason upgraded 8 (4+4) PSA undetectable

44 TREATMENT OPTIONS Observation OR- Radiation Therapy Adjuvant RT (immediate RT) OR- Salvage RT (with PSA rise: Early vs Late) RT + ADT (particularly for LN+ disease)

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46 Post op XRT Den Int J Rad Onc Bio Phy 2014

47 Den et al, JCO 2014

48 Den et al, JCO 2014

49 Clinical pathway with genomic integration

50 Conclusions New Markers provide improved sensitivity over PSA alone one for every step along the way Unknown which is better limited/no head to head Cost more? Not necessarily Bundled payment and comprehensive care model- improve delivery while decreasing cost.

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52 References Development and validation of a multivariate model combining cell cycle progression score with CAPRA to predict prostate cancer mortality in a conservatively. MK Brawer, MR Cooperberg, S Freedland. J Clin, 2013 A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. EA Klein, MR Cooperberg, C Magi-Galluzzi, JP Simko. - European urology, Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. RB Den, K Yousefi, EJ Trabulsi - Journal of Clinical jco.ascopubs.org.

53 THANK YOU