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Prolaris (CCP Score) :
Improving 

Prognostic Knowledge in 

Prostate Cancer
Marc Laniado MD FEBU FRCS(Urol)
3rd Techno Ur...
30% Rule
30% “significant”
disease 

on TP mapping
biopsies
30% BCR after
radical
prostatectomy
30% fail
“active surveillan...
All learning to improve diagnosis & therapy to
improve survival and functional outcomes
Selecting men for primary or salvage
therapy without overtreating is difficult
Urgent	
  Need	
  for	
  Precision	
  Medicine
“linkage of molecular data to
health outcomes in order to
allow a more prec...
Biomarkers: measurable entity whose
presence signifies a disease or condition
• Sources
•Nucleic acid (RNA/DNA)
•Protein
•M...
Appearances similar outside
but different inside
Basic
model
Luxury
interior
Sports
engine
PROLARIS:

cell cycle
progression
(CCP) Score
ratio of 31
proliferation
genes to 15
normal genes
Gleason Score 6: same on
histology but different CCP score
Gleason score 6
CCP score -1
Gleason score 6
CCP score 1
Gleaso...
Gleason Score 6: same on
histology but different CCP score
Gleason score 6
CCP score -1
Gleason score 6
CCP score 1
Gleaso...
Levels of Evidence for
Tumour Markers
LOE LOE category Study Design Validation studies required
I A Prospective Preferred,...
Level 1B evidence for CCP
score exists
LOE LOE category Study Design Validation studies required
I A Prospective Preferred...
UK Watchful waiting study: 1 unit change
in CCP score doubles risk of death
• Age < 76 years,
• 337 men (6 Cancer Registri...
Contemporary TRUS biopsy cohort
shows greater prediction by CCP score
Brawer 2014 Focal Therapy
CCP score hazard ratio 

2...
CCP score superior to Ki67
Cuzick Lancet Oncol 2011
Cuzick B J Cancer 2012
16% died if ≤ 5% of cells stained V 48% > 5% of...
More information on death rate from CCP
alone than CAPRA alone
Cuzick 

2014 AUA
Red area (CCR) > Blue area (CAPRA)
CAPRA
...
CCR increases or decreases the predicted
death rates within CAPRA risk categories
Brawer 2014 Focal Therapy
CCR increases or decreases the predicted
death rates within CAPRA risk categories
Brawer 2014 Focal Therapy
CCR increases or decreases the predicted
death rates within CAPRA risk categories
Brawer 2014 Focal Therapy
Most
useful
ra...
CCP Score stratifies risk in
transrectal biopsy cohort
• 442 men in 6 UK cancer registries
• Transrectal prostate 

biopsie...
Combined Risk Score (PSA, GS &
CCP) predicts 10 year death rate
CCP HR 1.65 for 1 unit change at 10 years, 2.56 for 5 year...
CAncer of the Prostate Risk Assessment
(CAPRA) score can predict outcomes
10 year predicted mortality rate on TRUS biopsy
in contemporary cohort = earlier TURP cohort
Red line
contemporary cohort
...
Index & secondary lesions show
similar CCP score - Field Effect
Carvalho 2014 AUA
Combined Clinical Risk (CCR) <0.8 in
“typical” AS cohort - no deaths at 10 years
Stone 2014 SUO
GS ≤ 3+4
< 25% core +ve
PS...
Radical Prostatectomy & CCP
• Radical prostatectomy (n=366)
• 1985 to 1995
• Scott & White Clinic in Texas
• Median age 68...
CCP & Log PSA only significant
variables on multivariate analysis
Cuzick 2011 Lancet Oncology
TRUS Biopsy CCP score
predicts risk after prostatectomy
• Bishoff 2014
• 582 men in 3 Cohorts
• Martini Clinic (simulated ...
Risk of progression after RP
proportional to TRUS biopsy CCP score
Bishoff 2014 J Urol
Risk of metastasis after RP significant
if TRUS biopsy CCP score ≥ 2
Bishoff 2014 J Urol
Progression free survival proportional to
CCP score in contemporary cohort of RP
Cooperberg
2013

J Clin Oncol
Meta-analysis of 16 studies: each unit
increase in CCP doubles risk of death
Sommariva 2014 Eur Urol (online Dec 14)
Prolaris needs to be better
than multivariable prediction
• Sloane Kettering Nomogam
• CAPRA-s score
CAncer of the Prostate Risk
Assessment Post-Surgical CAPRA-S
Variable Level Points
Pre-op PSA 0.00 to 6.00 0
6.01 to 10.00...
72 years, PSA 8, pT2, Gleason pattern 4
cancer at the apex - adjuvant radiotherapy?
CAncer of the Prostate Risk
Assessment Post-Surgical CAPRA-S
Variable Level Points
Pre-op PSA 0.00 to 6.00 0
6.01 to 10.00...
CCP score & CAPRA-s
reclassifies low risk to greater risk
Cooperberg
2013

J Clin Oncol
Low risk patients 

(CAPRA-s 0 to 2)
CCP score & CAPRA-s reclassifies
higher risk to lower risk
Cooperberg
2013

J Clin Oncol
Higher risk patients 

(CAPRA-s ≥ ...
10 year progression free probability
predictable from CCP score & CAPRA-S
Combina5on	
  of	
  CCP-­‐score	
  &	
  CAPRA-­‐S	
  has	
  greater	
  
net	
  benefit	
  than	
  CAPRA-­‐S	
  alone	
  to	...
CCP score changed treatment decisions
by patients & urologist ➔ to less treatment
Gonzalgo 2014 SUO
Crawford 2014 CMRO
Biomarkers: measurable entity whose
presence signifies a disease or condition
•Associated with meaningful endpoint✔️
•Provi...
CCP Score Advantages
• CCP score is a strong independent predictor of
death
• CCP is best used in combination with other
p...
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Prolaris improving the prognosis of prostate cancer

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The use of a cell cycle progression score can improve the discrimination of men with low to medium risk prostate cancer before and after treatments

Published in: Health & Medicine

Prolaris improving the prognosis of prostate cancer

  1. 1. Prolaris (CCP Score) : Improving 
 Prognostic Knowledge in 
 Prostate Cancer Marc Laniado MD FEBU FRCS(Urol) 3rd Techno Urology Meeting 21 January 2015
  2. 2. 30% Rule 30% “significant” disease 
 on TP mapping biopsies 30% BCR after radical prostatectomy 30% fail “active surveillance”
  3. 3. All learning to improve diagnosis & therapy to improve survival and functional outcomes
  4. 4. Selecting men for primary or salvage therapy without overtreating is difficult
  5. 5. Urgent  Need  for  Precision  Medicine “linkage of molecular data to health outcomes in order to allow a more precise clinical decision making that is tailored to individual patients” Institute of Medicine, 2011
  6. 6. Biomarkers: measurable entity whose presence signifies a disease or condition • Sources •Nucleic acid (RNA/DNA) •Protein •Metabolite Associated with meaningful endpoints Provide additional information above nomograms Influences physician treatment decisions Allow more accurate risk assessment
  7. 7. Appearances similar outside but different inside Basic model Luxury interior Sports engine
  8. 8. PROLARIS:
 cell cycle progression (CCP) Score ratio of 31 proliferation genes to 15 normal genes
  9. 9. Gleason Score 6: same on histology but different CCP score Gleason score 6 CCP score -1 Gleason score 6 CCP score 1 Gleason score 6 CCP score 2 Increasing ratio of proliferation gene activity
  10. 10. Gleason Score 6: same on histology but different CCP score Gleason score 6 CCP score -1 Gleason score 6 CCP score 1 Gleason score 6 CCP score 2 Increasing ratio of proliferation gene activity
  11. 11. Levels of Evidence for Tumour Markers LOE LOE category Study Design Validation studies required I A Prospective Preferred, but not required B Prospective using archived samples ≥ 1 with consistent results II B Prospective using archived samples None or inconsistent results C Prospective/ Observational ≥ 2 with consistent results III C Prospective/ Observational None or 1 with consistent results or inconsistent results IV-V D Retrospective/ Observational n/a Simon 2009 JNCI
  12. 12. Level 1B evidence for CCP score exists LOE LOE category Study Design Validation studies required I A Prospective Preferred, but not required B Prospective using archived samples ≥ 1 with consistent results II B Prospective using archived samples None or inconsistent results C Prospective/ Observational ≥ 2 with consistent results III C Prospective/ Observational None or 1 with consistent results or inconsistent results IV-V D Retrospective/ Observational n/a Simon 2009 JNCI
  13. 13. UK Watchful waiting study: 1 unit change in CCP score doubles risk of death • Age < 76 years, • 337 men (6 Cancer Registries in UK) • Clinically localised cancer • Diagnosed by TURP (1990 to 1996) • histology central review (median Gleason score 6) • PSA at baseline (median < 10) • 51% died within 10 years: 20% prostate cancer; 31% other cause Cuzick 2011 Lancet Oncology < 0 0 to 1 1 to 2 CCP Score > 2
  14. 14. Contemporary TRUS biopsy cohort shows greater prediction by CCP score Brawer 2014 Focal Therapy CCP score hazard ratio 
 2.1 (CI 1.8 to 2.5)
  15. 15. CCP score superior to Ki67 Cuzick Lancet Oncol 2011 Cuzick B J Cancer 2012 16% died if ≤ 5% of cells stained V 48% > 5% of cells Ki67 Univariate analysis: hazard ratio = 1.77, P= 1.4 x 10-8 Multivariate analysis: hazard ratio = 0.98, P= 0.86
  16. 16. More information on death rate from CCP alone than CAPRA alone Cuzick 
 2014 AUA Red area (CCR) > Blue area (CAPRA) CAPRA CCRCAPRA CCR CCR = clinical cell cycle (CCR) score i.e. CCP score & standard clinical variables
  17. 17. CCR increases or decreases the predicted death rates within CAPRA risk categories Brawer 2014 Focal Therapy
  18. 18. CCR increases or decreases the predicted death rates within CAPRA risk categories Brawer 2014 Focal Therapy
  19. 19. CCR increases or decreases the predicted death rates within CAPRA risk categories Brawer 2014 Focal Therapy Most useful range?
  20. 20. CCP Score stratifies risk in transrectal biopsy cohort • 442 men in 6 UK cancer registries • Transrectal prostate 
 biopsies 1990-1996 • Age < 76 years • Central pathology 
 review • Median follow up 11.8 years CCP >3 CCP 2-3 CCP <2 Cuzick 2012 B J Cancer HR 2.56 (CI 1.9 to 3.5)
  21. 21. Combined Risk Score (PSA, GS & CCP) predicts 10 year death rate CCP HR 1.65 for 1 unit change at 10 years, 2.56 for 5 years Cuzick 2012 BJC
  22. 22. CAncer of the Prostate Risk Assessment (CAPRA) score can predict outcomes
  23. 23. 10 year predicted mortality rate on TRUS biopsy in contemporary cohort = earlier TURP cohort Red line contemporary cohort Green line earlier cohort Cuzick 2014 AUA; Cuzick 2012 BJC
  24. 24. Index & secondary lesions show similar CCP score - Field Effect Carvalho 2014 AUA
  25. 25. Combined Clinical Risk (CCR) <0.8 in “typical” AS cohort - no deaths at 10 years Stone 2014 SUO GS ≤ 3+4 < 25% core +ve PSA < 10 Clin stage ≤ T2a
  26. 26. Radical Prostatectomy & CCP • Radical prostatectomy (n=366) • 1985 to 1995 • Scott & White Clinic in Texas • Median age 68 years • Clinical T2 67% • Median preop 6.9 ng/ml • BCR criteria > 0.3 • Median Gleason score 6 • SM+ 23% • T3 34% • Median follow up 9.8 years • 36% recurrence rate at 10 years Normal distribution of CCP score Cuzick 2011 Lancet Oncology
  27. 27. CCP & Log PSA only significant variables on multivariate analysis Cuzick 2011 Lancet Oncology
  28. 28. TRUS Biopsy CCP score predicts risk after prostatectomy • Bishoff 2014 • 582 men in 3 Cohorts • Martini Clinic (simulated biopsy; n= 283, 2005-2006, median f/u 61 month) • Durham Veteran Affairs Center (TRUS bx, n=176, 1994-2005, median f/u 88 months) • Intermountain Healthcare (TRUS bx n=123, 1997-2004, 132 months) Bishoff 2014 J Urol
  29. 29. Risk of progression after RP proportional to TRUS biopsy CCP score Bishoff 2014 J Urol
  30. 30. Risk of metastasis after RP significant if TRUS biopsy CCP score ≥ 2 Bishoff 2014 J Urol
  31. 31. Progression free survival proportional to CCP score in contemporary cohort of RP Cooperberg 2013
 J Clin Oncol
  32. 32. Meta-analysis of 16 studies: each unit increase in CCP doubles risk of death Sommariva 2014 Eur Urol (online Dec 14)
  33. 33. Prolaris needs to be better than multivariable prediction • Sloane Kettering Nomogam • CAPRA-s score
  34. 34. CAncer of the Prostate Risk Assessment Post-Surgical CAPRA-S Variable Level Points Pre-op PSA 0.00 to 6.00 0 6.01 to 10.00 1 10.01 to 20.00 2 > 20.00 3 Path. Gleason < 3 + 3 = 6 0 3 + 4 = 7 1 4 + 3 = 7 2 > 4 + 4 = 8 3 Margins Negative 0 Positive 2 ECE No 0 Yes 2 SVI No 0 Yes 2 LNI No 0 Yes 1 • CAPRA-S 0-2 
 low risk • CAPRA-S 3-5 
 Intermediate risk
 • CAPRA-S >5 
 High risk Cooperberg 2011 Cancer
  35. 35. 72 years, PSA 8, pT2, Gleason pattern 4 cancer at the apex - adjuvant radiotherapy?
  36. 36. CAncer of the Prostate Risk Assessment Post-Surgical CAPRA-S Variable Level Points Pre-op PSA 0.00 to 6.00 0 6.01 to 10.00 1 10.01 to 20.00 2 > 20.00 3 Path. Gleason < 3 + 3 = 6 0 3 + 4 = 7 1 4 + 3 = 7 2 > 4 + 4 = 8 3 Margins Negative 0 Positive 2 ECE No 0 Yes 2 SVI No 0 Yes 2 LNI No 0 Yes 1 • CAPRA-S 0-2 
 low risk
 • CAPRA-S 3-5 
 Intermediate risk
 • CAPRA-S >5 
 High risk
  37. 37. CCP score & CAPRA-s reclassifies low risk to greater risk Cooperberg 2013
 J Clin Oncol Low risk patients 
 (CAPRA-s 0 to 2)
  38. 38. CCP score & CAPRA-s reclassifies higher risk to lower risk Cooperberg 2013
 J Clin Oncol Higher risk patients 
 (CAPRA-s ≥ 3) Consider no adjuvant treatment if CCP < -1
  39. 39. 10 year progression free probability predictable from CCP score & CAPRA-S
  40. 40. Combina5on  of  CCP-­‐score  &  CAPRA-­‐S  has  greater   net  benefit  than  CAPRA-­‐S  alone  to  predict  PFS 37 Cooperberg J Clin Oncol 2013 Decision Curve Analysis
  41. 41. CCP score changed treatment decisions by patients & urologist ➔ to less treatment Gonzalgo 2014 SUO Crawford 2014 CMRO
  42. 42. Biomarkers: measurable entity whose presence signifies a disease or condition •Associated with meaningful endpoint✔️ •Provide additional information above nomograms ✔️ •Influences physician treatment decisions ✔️ •Allow more accurate risk assessment ✔️ •Individualised treatment decisions ✔️
  43. 43. CCP Score Advantages • CCP score is a strong independent predictor of death • CCP is best used in combination with other predictors e.g. CAPRA, CAPRA-s • Low CCP scores and BCR after treatment possibly indicate local recurrence • High CCP scores indicate higher chance of metastatic disease & need for adjuvant Rx

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