Active surveillance: Shrinking the grey zone. Sommerakademi e Munich, June Who is the Right Patient and what is the right Protocol?

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1 Active surveillance: Who is the Right Patient and what is the right Protocol? Active surveillance: Shrinking the grey zone Sommerakademi e Munich, June Or: Shrinking the Gray Zone IPCU 2017

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 Gleason 3: Molecular genetics resembles normal cells in most cases Metastatic potential ~ zero. Vs Gleason 4: molecular hallmarks of cancer Achilles Heel of active surveillance strategies relates to pathologic miss of co-existent higher grade cancer True biological grade progression is uncommon Pre-histologic adverse genetic alterations exist MRI and molecular biomarkers enhance diagnostic accuracy and are complementary

4 Genomic alterations quantitatively, not qualitatively different between grades. Rubin M et al, Eur Urol 2016; 69(4):557-60

5 PTEN loss and chromosome 8 alterations in Gleason grade 3 cores predicts the presence of un-sampled grade 4 tumor: implications for AS. Trock B et al, Modern Path April PTEN loss, MYC/8q gain or LPL/ 8p loss in a Gl 3 core is a strong indicator of co-existent Gl 4. More common in Gl3 cores from Gl 4+3 than 3+4. Gl 3 sampled from a Gl.7 cancer is often biologically distinct from Gl 3 from a Gl 6 tumor

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

7 Implications of Extracellular Vesicle (EV) Transfer on Cellular Heterogeneity in Cancer: Zomer A, Cancer Res Apr 15;76(8): EVs released by highly malignant cells are taken up by less malignant cells within the same and distant tumors These carry mrna involved in migration and metastasis. RNA from more aggressive cells is incorporated and induces aggressive behavior in the indolent cells

8 There are virtually no well documented cases of pathologically proven Gleason 6 cancers that have metastasized 12,000 Gleason 6 cancers treated with RP with 20 year follow up (Eggener S, J Urol 2011) Pca mortality 0.2% at 20 years Re-review of these showed higher grade Ca 14,123 cases of pathologic Gleason 6 at RP (Ross HM, Am J Surg Path 2012) 22 with positive nodes (era of limited node dissection) All were upgraded on re-review

9 Most guidelines differentiate between very low risk and low risk based on cancer volume If Gleason pattern 3 doesn t metastasize, why does volume of Gleason 3 cancer matter? Answer: High volume is a marker for the presence of higher grade cancer

10 Predicting disease reclassification during AS PSA Density Race Core involvement

11 Selection Criteria for AS Programme T stage Gleason Pos Cores Max % Ca PSA PSAD Other Sunnybrook Klotz Hopkins Tosoian Goteborg Godtman T1c, T2a < 0.15 T2a 6 10 UCSF Welty T2a 6 33% 10 Marsden Selvadurai T % 15 Age Age > 65 Australia Thompson Copenhagen Thomsen T2a 6 30% < T2a 6 3 < Miami Soloway T2 6 2 < Age < 80 PRIAS Bul T < 0.2

12 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

13 Stricter AS criteria for PCa do not result in significantly better outcomes: A comparison of protocols. Komisarenko M, Finelli A. J Urol Jun 24 Intervention rates between groups

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

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

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

17 Recursive partitioning analysis: Metastasis free survival by risk group

18 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

19 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%

20 MRI targeting: Gleason 4+3 after prior biopsy showed 1 pos core 10% Gleason 3+3 Gl 4+3 Gl 3+3

21 Can Clinically Significant Prostate Cancer Be Detected with MRI? Study year N Ca Dx rate % Accura cy % Sens % Spec % PPV % Abd-Alazeez Chamie Sonn NR NR NR NR Abd-Alazeez NPV % Arumainayagam Kasivisvanathan Hoeks NR NR NR NR Rais-Bahrami NR Rouse Thompson Wysock NR NR NR NR Salami NR NR NR NR Pannebianco

22 ASIST study 273 men on AS < 1 year randomized between systematic Bx vs MRI with targeted and systematic Bx MRI with targeted Bx vs systematic Bx: No difference in rate of upgrading (21.2 vs 22.8%) Median # cores: 2 vs 12 PPV for Pirads 5 for Gleason >=7: 33% PPV for Pirads 4 for Gleason >=7: 37% NPV for Pirads 1-2: 85%

23 ASIST study: Results in MRI arm (N=127) Systematic Biopsies Total Gl 7 SB only Gleason No Cancer Targeted Biopsies (T1 to T4) No Cancer Total Gl 7 TB only (6%) (8%)

24 59 year old male, PSA 4.7, lesion left PZ, targeted biopsy Gleason 6. Lesion stable at 1 year T2 ADC DWI Baseline 1 year

25 Prostate Biomarkers: Who to treat and who to surveil Oncotype DMX Prolaris Promark Decipher The pipeline.mitomics, Telo, MIR, ExosomeDx, etc.

26 Intratumoral andi intertumoral genomic heterogeneity of multifocal localized Pca impacts molecular classifications and genomic prognosticators. Wei L, Eur Urol Jul 20. Whole-exome sequencing, single-nucleotide polymorphism arrays, and RNA sequencing in 4 representative patients.

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

28 Comparison of guidelines: US, Canada, UK Low risk Pca Intermediate risk Tests Other tests 5 ARI Cancer Care Ontario CUAJ 2015 AS preferred management Active treatment; AS for selected pts PSA q 3-6 mo DRE q 1 yr Systematic bx within 6-12 mo, then q 3-5 yrs MRI when clinical and path findings discordant May have a role ASCO JCO 2016 NICE 2016 Same 1 Same Same Other tests remain investigational Same Radical treatment for disease progression 2 PSA q 3-4 months, monitor kinetics, otherwise same MRI at enrollment No clear role

29 Trends in Active Surveillance: Utilization Ingimarsson JP (New Hampshire) Cancer Causes Control Jun;26(6):923-9 Womble PR (MUSIC): (Michigan) Eur Urol Jan;67(1):44-50 Weerakoon M (Australia): BJUI 2015: 115 S5, Cooperberg M et al, JAMA. 2015;314(1): <60 yr yr 0 >70 yr LR VLR IR Loeb S (Sweden): AS in 91% VLR and 74% LR, URS 2015 Timilshina N, Saad F. World J Urol Jul 22

30 Trends in Active Surveillance: Utilization Ingimarsson JP (New Hampshire) Cancer Causes Control Jun;26(6):923-9 Womble PR (MUSIC): (Michigan) Eur Urol Jan;67(1):44-50 Weerakoon M (Australia): BJUI 2015: 115 S5, Cooperberg M et al, JAMA. 2015;314(1): yr 0 >70 yr LR VLR IR Loeb S (Sweden): AS in 91% VLR and 74% LR, URS 2015 Timilshina N, Saad F. World J Urol Jul 22

31 Diagnosis of Pca and pursuit of active surveillance is not followed by weight loss: potential for a teachable moment. Liss MA, Thompson IM. Prostate Cancer Prostatic Dis Jul 19

32 Active Holistic Surveillance: Berg CJ, Habibian DJ, Katz AE, Kosinski KE, Corcoran AT, Fontes AS. J Nutr Metab. 2016;2016: Advice to patients: Dietary: Eliminate red meats, dairy products, fried foods, refined carbohydrates Increase poultry, fish, green tea, soy milk, red wine, flaxseed, cruciferous vegetables. Supplement```` BroccoProtect Omega mg/ day Zyflamend Vit D3 Genikinoko 1000 mg bid Active Hexose Correlated Compound (AHCC Lyocell Capsaicin Rationale Antioxidants ê Inflammation ê Inflammation, prolif Differentiation inducer Apoptosis, ê angiogen Boosts immunity Antioxidants ê proliferation

33 Potential mechanisms by which exercise delays the progression of prostate cancer Galvão, D. A. et al. (2016) Enhancing active surveillance of prostate cancer: the potential of exercise medicine Nat. Rev. Urol.

34 Web based lifestyle Web based diet, exercise Behavioral changes, BMI Name N Intervention Outcome Nordic lifestyle Vigorous exercise >= 3 x/wk, rye Pca progression Diet in Pca Dietary education and telephone counselling x 2 yrs Clinical progression, TTP Sulphoraphane Broccoli soup (3 versions) Gene expression AS exercise /wk home walking Genetic signature changes Exercise training 2015 Active or completed lifestyle studies in AS Low fat diet, fish oil Supervised/independent aerobic exercise x 12 months Feasibility, adherence 100 Fish oil caps x 1 yr, low fat diet Ki-67 in Pca tissue Diet/exercise Diet, 16 1 hr exercise over 24 wk IGF, adiponectin, etc Cholecalciferol Cholecal. X 9 mo PSA kinetics Capsaicin Capsaicin 1 tab bid Gene expression Dutasteride, diet consultations, Omega 3, 5ARI Lipids, genes, PCA3

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

36 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

37 Conclusions: Gleason pattern 3 is a non-metastasizing lesion lacking most hallmarks of cancer High volume Gleason 3 mainly significant as a risk factor for co-existent higher grade cancer Race, high PSA density Presence of any Gleason 4 at baseline confers significant increased risk of metastasis at 15 years MRI and biomarkers will play a significant role in early identification of occult aggressive disease Further risk stratification (not perfect) Risk nomograms incorporating these an unmet need