prolaris to help make treatment decisions in localised prostate cancer
TRANSCRIPT
Prolaris -
a gene expression assay for
assessing long-term risk of
prostate cancer progression
Marc Laniado MD FEBU FRCS(Urol)
Hertzelia/Israel
26 May 2017
Difficult decisions in many scenarios
because prognostication poor
Risk on prostate
biopsies uncertain
30% BCR after
radical
prostatectomy
30% fail
“active surveillance”
Can a genomic test help us
make better decision
Very Low
Low
Intermediate
Individual Risk
Add independent predictive information
beyond standard clinical & pathological measures
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
Allow more accurate risk assessment
Influences physician treatment decisions
Individualised treatment decisions
PROLARIS:
cell cycle progression (CCP)
Score
- Score = ratio of 31
proliferation genes
to 15 normal genes
- RNA expression
assay RT PCR
Genes correlated with CCP
score include DNA repair genes
DNA Repair Genes
Some CCP genes are target of
chemotherapy & radiotherapy
Anthracycline
Gemcitabine
premetrexed
Taxanes
Fluorouracil
Radiotherapy
Oncotype: 1
proliferation gene only
TPX2
CCP score in published
studies use DIFFERENT
scale
THE CURRENT PROLARIS SCORE
IS
THE OLD CCP SCORE +4
CCP score has a normal
distribution in men prostate cancer
Porpiglia 2015 EAUMedian -0.4
Num
er
of m
en
Level 1B evidence for biomarkers
score exists for Prolaris
LOE LOE category Study Design Validation studies required
I A Prospective Preferred, but not required
BProspective using
archived samples≥ 1 with consistent results
II BProspective using
archived samplesNone or inconsistent results
CProspective/Obser
vational≥ 2 with consistent results
III CProspective/Obser
vational
None or 1 with consistent results
or inconsistent results
IV-V DRetrospective/Obs
ervationaln/a
Simon 2009 JNCI
CCP score evaluated in biopsy/TURP/ RP
tissue & after conservative/radical treatment
Study Sample typeNo of patients
(events)Endpoint Ref
TURP WW TURP chips 337 (76) Death (PCa) Cuzick 2011
TRUS biopsy WW Biopsy 349 (90) Death (PCa) Cuzick 2012
TRUS biopsy WW Biopsy 585 (100) Death (PCa) Cuzick 2015
RP Biopsy 582 (166, 12)BCR,
metastasisBishoff 2014
EBRT Biopsy 141 (19) BCR Freedland 2013
RP (low risk) Biopsy 188 (56) BCR Tosian 2017
RP Surgical specimen 353 (132) BCR Cuzick 2011
RP Surgical specimen 413 (82) BCR Cooperberg 2013
EBRT after RP Surgical specimen 47 (36)BCR/metasta
sisKoch 2016
RP or RT men (AA 36%) Biopsy 767 (281) Metastasis Bardot 2017
CCP score evaluated in cohorts
similar to today’s patients
StudySample
type
No of
patients
(events)
EndpointCharacteristc: age, PSA,
ISUP grade group
CCP
scoreRef
TURP WWTURP
chips337 (76)
Death
(PCa)age 70, PSA 8, GG 1 0.67 Cuzick 2011
TRUS biopsy
WWBiopsy 349 (90)
Death
(PCa)age 70, PSA 19, GG 2 1.03 Cuzick 2012
TRUS biopsy
WWBiopsy 585 (100)
Death
(PCa)Age 71, PSA 15, GG 2 0.40 Cuzick 2015
RP (low risk) Biopsy 188 (56) BCR Age 61, PSA 6, GG 1 -0.15 Tosian 2017
RP Biopsy582 (166,
12)
BCR,
metastasisAge 62, PSA 6, GG 1
-0.4 to
0.3Bishoff 2014
RPSurgical
specimen353 (132) BCR age 68, PSA 7, GG 1 0.16 Cuzick 2011
RPSurgical
specimen413 (82) BCR Age 63, PSA 6, GG 1 -0.37 Cooperberg 2013
EBRT Biopsy 141 (19) BCR Age 66, PSA 8, GG 2 0.12 Freedland 2013
EBRT after RPSurgical
specimen 47 (36)
BCR/metast
asisAge 60, PSA 9, GG 2 0.4 to 0.6 Koch 2016
RP or RT men
(AA 36%)Biopsy 767 (281) Metastasis Age 65, PSA 6, GG 2 - Bardot 2017
CCP score varies within same
ISUP prognostic grade groupCCP score -1 CCP score 1 CCP score > 1
Increasing ratio of proliferation gene activity
Gleason score 6 & 7 tumours
have have low & high CCP score
Porpiglia 2015 EAU
CCP score distribution similar amongst
Caucasian & African American
Freedland 2013
Bardot 2017 AUA
CCP score poorly correlated to
PSA, Gleason Score or stageStudy Sample type
No of patients
(events)
PSA correlation Gleason score
correlationRef
TURP WW TURP chips 337 (76) 0.27 0.57 Cuzick 2011
TRUS biopsy WW Biopsy 349 (90) 0.14 0.37 Cuzick 2012
TRUS biopsy WW Biopsy 585 (100) 0.3 0.4 Cuzick 2015
EBRT Biopsy 141 (19) <0.33 <0.33 Freedland 2013
RP Biopsy 582 (166, 12) 0.09 to 0.13 0.18 to 0.30 Bishoff 2014
RPSurgical
specimen353 (132) 0.21 0.22 Cuzick 2011
RPSurgical
specimen413 (82) 0.11 0.18 Cooperberg 2013
EBRT after RPSurgical
specimen 47 (36) “weak” “weak” Koch 2016
This is a benefit!
Gleason score, PSA and stage poorly
predict who benefits from treatment
There is a need to better stratify the risk for patients
Wilt 2017 AUA PIVOT study
Is the CCP score a useful
biomarker?
Associated with meaningful endpoints
death
Metastases
Provide additional information above nomograms
Allow more accurate risk assessment
Influences physician treatment decisions
Individualised treatment decisions
CCP score independently associated
with metastasis/death in multiple studies
Study
No of
patients
(events)
EndpointCCP
scoreP PSA
Gleason
scoreRef
TURP WW 337 (76) Death (PCa)Univ. 2.9 <10-21 <10-13 <10-18
Cuzick 2011Multiv. 2.6 <10-10 <10-7 <10-4
TRUS biopsy
WW349 (90) Death (PCa)
Univ. 2.0 <10-9 <10-4 <10-7
Cuzick 2012Multiv. 1.7 <10-4 0.017 0.002
RP (bx) 582 (12) MetastasisUniv. 5.4 <10-7 <10-8 <10-3
Bishoff 2014Multiv. 1.5 <10-4 <10-5 0.02
TRUS biopsy
WW585 (100) Death (PCa)
Univ. 2.1 <10-14 <10-8 <10-11
Cuzick 2015Multiv. 1.8 <10-6 - -
Salvage EBRT
after RP (RP)47 (36) Met/progress
Univ. 3.7 0.006 0.83 0.007Koch 2016
Multiv. 10.4 0.003 0.55 0.002
RP or RT treated
men (AA 36%)767 (281) Metastasis
Univ. 2.8 <10-11 - -Bardot 2017
Multiv. 2.0 <10-5 - -
CCP score predicts death in
conservatively managed men
CCP score predicts death in
conservatively managed men after TURP
Cuzick 2011 Lancet Oncology
CCP Score < 0
CCP Score 0 to 1
CCP Score 1 to 2
CCP Score >2
Typical pt: age 70, PSA 8, Gleason score 3+3=6
CCP Score stratifies mortality
risk in transrectal biopsy cohort
• 442 men in 6 UK cancer
registries (90 to 96)
• Transrectal prostate
biopsies 1990 to 1996
• Average 3 cores/pt
• Median age 70, PSA 19,
GS 3+4=7,
CCP score 1.03
• 20% died overall
CCP >3
CCP 2-3
CCP <2
Cuzick 2012 B J Cancer
HR 2.56 (CI 1.9 to 3.5)
CCP score predicts death inTRUS bx cohort
after conservative mx in more recent cohort
Cuzick 2015 BJC
n = 761 men
2002
Average 6 cores
age 71,
F/U 10 y
Diagnoses 2002
GS 3+4=7
PSA 15
Analysis of most significant lesion may be
important: CCP score drops slightly as
move away from tumour in RP specimens
n=35 overall, but bigger drop
0.8 unit in CCP for Gleason
score 8-10 tumours (n=5)
Berman 2013 EAU
PSA failure & metastases
proportional to CCP score in
needle bx & RP specimens
CCP score independently associated
with PSA recurrence after treatment
Study
No of
patients
(events)
EndpointCCP
scoreP PSA
Gleason
scoreRef
RP (RP
specimen)353 (132) BCR
Univ. 2.0 <10-8 <10—17 <10-9
Cuzick 2011
Multiv. 1.7 <10-5 <10-8 0.028
RP (RP
specimen)413 (82) BCR
Univ. 2.1 <10-5 0.003 <10-5
Cooperberg
2013Multiv. 2.0 <10-4 0.12 0.17
EBRT
(TRUS bx)141 (19) BCR
Univ. 2.6 0.002 <10-3 0.051
Freedland 2013
Multiv. 2.1 0.035 0.054 0.20
RP (TRUS
bx)582 (166, 12) BCR
Univ. 1.6 <10-6 <10-8 <10-4
Bishoff 2014
Multiv. 1.5 <10-4 <10-5 0.02
RP (GS6 low
risk) -TRUS
Bx
188 (56) BCR
Univ. 1.8 0.002 0.001 -
Tosian 2017
Multiv. 1.8 0.003 - -
Risk of progression after RP proportional to
TRUS biopsy CCP score - margin -ve only
Bishoff 2014 J Urol
Oncotype: only 1 proliferation
gene test - not significant
CCP score > 2 on biopsies predicted
25% with metastases after RP at 5
years
HR 5 (univariate)
HR 4 (multivariate)
n=582 Bishoff 2014 J Urol
CCP score > 2 on biopsies predicted 25%
with metastases after RP/RT at 5 years
independent of race, treatment type
Bardot 2017 AUAYears after diagnosis
Me
tasta
tic d
isease
n=767CCP 2 to 5
CCP 1 to1.99
CCP < 1
New Prolaris reporting forms show metastasis
risk at 10 years with definitive treatment
BCR after radiotherapy
predicted by CCP score
Freedland 2013 Int J Rad Oncol
CCP Score < 0
CCP Score < -1
CCP Score < 1
CCP Score >1
CCP Score predicts BCR,
metastasis & death
✔️Associated with meaningful endpoints ✔️
death ✔️
Metastases ✔️
Provide additional information above nomograms
Allow more accurate risk assessment
Influences physician treatment decisions
Individualised treatment decisions
Does biomarker provide additional
information above nomograms?
✔️Associated with meaningful endpoints ✔️
death ✔️
Metastases ✔️
Provide additional information above
nomograms e.g. CAPRA score
Allow more accurate risk assessment
Influences physician treatment decisions
Individualised treatment decisions
Clinical Risk Tools: (CAPRA)
CAncer of the Prostate Risk Assessment
Cooperberg JNCI 2009
Predicts:
• PSA failure
• Metastases
• Death
CAPRA score combined with CCP score
“clinical cell-cycle risk [CCR]score” -
predict 10 year chance of death
CCR = (0.39 x CAPRA + 0.57 x CCP)
CCR (CCP score combined with CAPRA)
improves risk classification on CAPRA alone
Cuzick 2105
Provides additional information
compared to nomograms
✔️Associated with meaningful endpoints ✔️
death ✔️
Metastases ✔️
Provide additional information above
nomograms ✔️
Allow more accurate risk assessment
Influences physician treatment decisions
Individualised treatment decisions
✔️Associated with meaningful endpoints ✔️
death ✔️
Metastases ✔️
Provide additional information above nomograms ✔️
Allow more accurate risk assessment
Active surveillance Y/N?
Influences physician treatment decisions
Individualised treatment decisions
Does the CCP score allow more
accurate risk assessment?
Conservative management fails because
risk poorly predicted at diagnosisKlotz 2015 JCO
Hamdy 2016 NEJM PROTECTWilt 2017 AUA
Moore 2017
Combined score (CCR) improves risks prediction
in candidates for conservative management
Cuzick 2015
CCR upgraded 14%
to >4% DSM
CCR downgraded 5%
to PCM < 4%
Most
useful
Capra
2 to 3?
Which CAPRA threshold?
Depends on life expectancy & man’s values
Life Expectancy
Typical patient for AS?
Cooperberg JNCI 2009
CAPRA 2
If CCR <0.8 no deaths at 10 y - good
candidate for conservative management
Stone 2014 SUOGS ≤ 3+4, < 25% core +ve, PSA < 10, Clin stage ≤ T2a
(AUA/ASTRO/SUO favourable intermediate risk or below)Cuzick 2015 AUA
CCR ≧ 0.8
CCR < 0.8
n = 505
New Prolaris reporting form shows the man
has very low chance of dying at 10 years
Young healthy men need to know
AS will “miss a window of
opportunity”
Currently, no reliable tools or markers that can predict
outcome for 20 years or more
Life expectancy
Age
Missing the window of opportunity would mean a
rising PSA after treatment
CCP > 0 predicts rising PSA after
RP in grade group 1 tumours Only low risk NCCNLow & Intermediate risk
Implication: CCP < 0 not to miss window of opportunity in young men
Which test to use or not?
Depends on life expectancy & man’s values
Life Expectancy
Age
groupComorbidity
Life
ExpectancyVery low Low
Favourable
intermediate
Unfavourable
IntermediateHigh risk
80 Healthy 12 WW WW WW CCR > 0.8 Treat
Normal 8 WW WW WW CCP > 2 Treat
Unhealthy 4 WW WW WW CCP > 2 WW
70 Healthy 20 CCP > 0 CCP > 0 CCP > 0 Treat Treat
Normal 14 CCP > 0 CCP > 0 CCP > 0 Treat Treat
Unhealthy 7 WW WW WW CCP > 2 Treat
60 Health 31 CCP > 0 CCP > 0 CCP > 0 Treat Treat
Normal 21 CCP > 0 CCP > 0 CCP > 0 Treat Treat
Unhealthy 11 WW WW WW Treat Treat
50 Healthy 44 CCP > 0 CCP > 0 CCP > 0 Treat Treat
Normal 29 CCP > 0 CCP > 0 CCP > 0 Treat Treat
Unhealthy 15 CCR > 0.8 CCR > 0.8 CCP > 0 Treat Treat
This is my speculation!
Treatment algorithm in 50 - 60 y.o. man with
localised, single lesion on mpMRI fusion biopsy
GG 2, 3(CR- & IDC-)
ProlarisCCP < 0
GG 2, 3
FT
GG 4/5
RP/RT
CCP 0 to 1
CCP > 1
AS:
PSA
mpMRI
Rebiopsy & redo CCP score < 3-5 y
GG 1
<3 mm ≧3 mm
CR+ or IDC+CR+
CCP threshold are MY arbitrary values
✔️Associated with meaningful endpoints ✔️
death ✔️
Metastases ✔️
Provide additional information above nomograms ✔️
Allow more accurate risk assessment
Active surveillance/Watchful waiting ✔️
Influences physician treatment decision and
individualised treatment decisions
The CCR score allow more
accurate risk assessment
✔️Associated with meaningful endpoints ✔️
death ✔️
Metastases ✔️
Provide additional information above nomograms ✔️
Allow more accurate risk assessment
Active surveillance/Watchful waiting ✔️
Influences physician treatment decision &
Individualise treatment decisions
Does the CCR score
influence decision making?
CCR score reclassifies low and intermediate
risk into lower or higher risk categories
Original Category
Reclassification with CCR score
Stone 2017 ASCON=16,442
If low risk initially, and CCR reclassifies
risk to intermediate, suggest treatment
AUA,
ASTRO,
SUO
2017
guideline
If intermediate risk, & CCR reclassifies
to low risk, consider active surveillance
AUA,
ASTRO,
SUO
2017
guideline
The reclassification makes clinicians
more or less likely to advise on treatment
Absolute change in visual analogue score after CCR scoreGonzalgo 2014 SUO
The reclassification by CCR score changed
treatment chosen by patients & urologist in 44%
Gonzalgo 2014 SUO. Crawford 2014 CMRO
44% changed choice 32% chose less treatment
CCP/CCR score: meets the
criteria for a useful Biomarker
•Predicts men at risk of metastases/death who are
conservatively managed or treated✔️
• CCR score (CCP & CAPRA) better than
conventional variables alone✔️
•Predicts men suitable for conservative management
or in need of adjuvant treatment after surgery✔️
• Influences clinicians and patients choices so more
choose conservative management ✔️
• Individualised treatment decisions ✔️
Case Examples
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Would what
would you do
with this man?
Age 55 years
PSA 6.5
14% free PSA,
clinical stage Stage T2
No Family history
No comorbidity
55 year old, PSA 6.5,
prostate vol 45 cc
mpMRI
T2
T2
DCE
ADC
55 year old, PSA 6.5,
Gleason Score 3+3=6, prostate vol 45 cc
mpMRI
T2
T2
DCE
ADC
CCP score poorly correlated with
mpMRI ADC value
CCP score:
< 0(blue)
> 0 (red)
CCP score & ADC value correlation coefficient 0.36, P=0.0003
ADC
Max T
um
our
length
Renard-Penna 2015 J Urol
Years after diagnosis
Dead from
prostate
cancer
Dead
from
other
causes
4% chance of dying after 10 y for low risk
disease in PSA era in 65 year old
Contains Gleason pattern 3 only
1 2 3 4 5
Prolaris 10 year prostate cancer specific
mortality rate was reduced to 1%
Continued with active surveillance
2 3 4 5 6 7 8 Prolaris score
72 years, PSA 8, pT2, Gleason pattern 3+4=7,
apical positive margin - adjuvant radiotherapy?
CAncer of the Prostate Risk
Assessment Post-Surgical CAPRA-
S
• CAPRA-S 0-2
low risk
• CAPRA-S 3-5
Intermediate risk
• CAPRA-S >5
High risk
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 ≥ 3)
Consider no adjuvant
treatment if CCP < -1
Prolaris post robotic prostatectomy -
15% chance of PSA failure at 10 years
Chose no adjuvant radiotherapy
&
Very Happy!
91
Prolaris Advantages
• independent predictor of death or metastases
• CCP score best used in combination with other
predictors e.g. CAPRA, CAPRA-s
• High biomarker scores at diagnosis indicate higher
chance of metastatic disease & need for adjuvant
Rx after primary treatment
Tumour adjacent ‘normal’ prostate
mutations may not affect survival
Weischenfeldt J, Cancer Cell 2013;23:159–70
Schlomm Eur Urol 2015
TMPRSS2:ERG fusion:
• commonest genomic alteration in PCa
• Seen in normal ‘prostate’ tissue’
CCP score & mpMRI