Active surveillance: Shrinking the grey zone. Sommerakademi e Munich, June rd FOIUS Tel Aviv, July 2016

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1 Active surveillance: Shrinking the grey zone Active surveillance: 3 rd FOIUS Tel Aviv, July 2016 Shrinking the grey zone Sommerakademi e Munich, June

2 Active Surveillance for low risk PCa What has changed? (since Klotz, Choo J Urol 167: 1664, 2002) Greater recognition of overtreatment problem, acceptance of concept Nature of occult high grade disease Predictive value of baseline parameters Flaws of PSA kinetics as trigger Multiparametric MRI New modelling studies Randomized data on role of 5 ARIs Longer follow up,, ~2000 publications

3 2016: What we know Molecular genetics of Gleason pattern 3 resembles normal cells in most cases; pattern 4 has many molecular hallmarks of cancer Metastatic potential of Gleason 3 ~ zero. The major limitation of current active surveillance strategies relates to pathologic miss of coexistent higher grade cancer True biological grade progression occurs, but is uncommon Pre-histologic adverse genetic alterations exist MRI and molecular biomarkers enhance diagnostic accuracy (complementary)

4 Gleason 3 lacks hallmarks of cancer Characteristic/Pathway Gleason 3 Gleason 4 Expression of pro-proliferation embryonic, neuronal, hematopoietic stem cell genes, EGF, EGFR No Overexpressed AKT pathway: MAP2K4, RALA, PHLPP, PML No Aberrant HER2/neu No Amplified Antigrowth signal insensitivity (Cyclin D2, CKDN1β) Expressed Absent Resisting apoptosis: DAD1 Negative Strong Exp BCL2 Mostly Neg. Upregulated Absence of senescence: TMPRSS2-ERG ERG normal Increased Sustained angiogenesis: VEGF Low Increased Expression of other pro-angiogenic factors Normal Increased Tissue invasion/metastasis markers (CXCR4, others) Normal PTEN loss 10% > 90% Overexpressed Clinical evidence of metastasis/mortality Absent Present

5 The clonal origin of lethal prostate cancer Haffner M, Yegasubramanian et al, JCI, epub Oct

6 In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior Zomer A, Cell 2015, 161, Extra-cellular vesicles released by malignant tumor cells taken up by less malignant cells located within the same and within distant tumors These EVs carry mrnas involved in migration and metastasis. The RNA from more aggressive cells is incorporated and induces aggressive behavior in the indolent cells

7 Toronto Surveillance Cohort 993 patients, median f/u of 8.9 years ( years) Serial PSA, biopsy (no MRI until 2012) 78% low risk 22% patients intermediate risk (G7 or PSA > 10) 38% of these < 70 years Intervention for PSA DT < 3 years (until 2010), upgrading to Gleason 3 + significant 4 30 patients have developed metastases 15 died of prostate cancer 4 died other causes, 11 alive with mets

8 Intervention free survival in active surveillance Klotz et al JCO 33(3):

9 OS Survival with AS Klotz et al JCO 33(3): CSS

10 HR % 51% OS and CSS: Low vs Intermediate risk (Gleason 3+4, PSA >10) Overall Survival Cause Specific Survival 97% HR %

11 Intermediate risk group: Baseline Gleason score, not PSA, predicted for mets Baseline PSA >10 vs GS 7, Met free survival 93% 77%

12 Recursive partitioning analysis: Metastasis free survival by risk group

13 Hopkins AS long term outcome: Overall mortality and Pca mortality Tosoian J, Carter B et al. JCO.2015 Pca mortality 0.5% at 15 years

14 Long term outcome of surveillance reflects inclusion criteria and intervention strategy Eligibility Sunnybrook All Gleason 6, PSA <=15, and selected Gleason 3+4 Johns Hopkins NCCN low risk (<= 2 pos cores, <50% core involvement, PSAD < 0.15 Intervention Gleason 4+3 NCCN low risk (volume progression or any Gleason 4) Proportion of Pca patients eligible 15 year Pca mortality 50% 20% 5% (mostly baseline Gl. 7) 0.5%

15 Current Paradigm Initial Bx and risk categorization Comorbidity and life expectancy Patient preference Re biopsy to improve accuracy of risk classification Periodic re-evaluation for change in risk Intervention: Change in risk category PSA anxiety Patient preference Active surveillance Image based/ Molecular paradigm Reduce uncertainty of eligibility determination MRI/biomarker instead of 2 nd biopsy Improved patient selection: MRI negative/favorable score : The new very low risk MRI target/high score: greater acceptance of treatment Serial imaging/molecular monitoring with modulated interval More rational decision for intervention

16 PCa: Traditional large grey zone T1a Gleason 6, PSA < 10 Everything else

17 The new black, white, and grey zones AS: Gleason 6, non-extensive disease, nonsuspicious MRI, low PSA density Gleason >= 7 with > 10% Gleason 4 The grey zone : Extensive Gleason 6 Gleason 6 in men < 50 yrs Gleason 7 with < 10% Gleason 4 PiRADS 4-5 with low grade cancer on targeted biopsy, high PSAD

18 Conclusions: Gleason pattern 3 is a non-metastasizing lesion lacking most hallmarks of cancer Presence of any Gleason 4 at baseline confers significant increased risk of metastasis at 15 years The grey zone has shifted and shrunk Small volume Gleason 6 no longer grey zone Today: High volume Gleason 6 in young patient Gleason 3+ pattern 4 < 10% Small volume Gleason 3+4 with negative MRI or genomic assay Most Gleason 7 should be treated