Prognostic Utility of the Cell Cycle Progression
(CCP) Score Generated from Needle Biopsy in Men
Treated with Prostatectomy
Jay T. Bishoff, MD, FACS
Director, Intermountain Urological Institute, Intermountain Healthcare;
Salt Lake City, Utah
Objectives:
• Describe different criteria for active surveillance
• Discuss genetic testing in prostate cancer
• Discuss variations in behavior of different prostate cancers with
the same Gleason score
Multi‐InstitutionalEvaluationofthe
PrognosticUtilityoftheCCPScore
GeneratedfromBiopsyinMenTreated
withProstatectomy
JayTBishoff,MD
Director,IntermountainUrologicalInstitute
ClinicalProfessorofSurgery
UniversityofUtahCollegeofMedicine
SaltLakeCity,Utah
Introduction
• 30%ofmenafterRPeventuallyexperienceBCR
1)Pound,C.R.,Partin,A.W.,Epstein,J.I.etal.:Prostate‐specificantigenafteranatomicradicalretropubicprostatectomy. Patternsof
recurrenceandcancercontrol.UrolClinNorthAm,24: 395,1997
2)Zincke,H.,Oesterling,J.E.,Blute,M.L.etal.:Long‐term(15years)resultsafterradicalprostatectomyforclinicallylocalized(stageT2cor
lower)prostatecancer.JUrol,152: 1850,1994
3)Catalona,W.J.,Smith,D.S.:5‐yeartumorrecurrenceratesafteranatomicalradicalretropubicprostatectomyforprostatecancer.JUrol,
152: 1837,1994
4)Ohori,M.,Goad,J.R.,Wheeler,T.M.etal.:Canradicalprostatectomyaltertheprogressionofpoorlydifferentiatedprostatecancer?JUrol,
152: 1843,1994
1‐4
Introduction
• 30%ofmenafterRPeventuallyexperienceBCR1‐4
• BCRleadstoadditionaltherapy
• Weuseclinicalandpathologytopredictrecurrence
ClinicalStage
PSA
Gleason'sScore
AmountofCancerpresent(%ofacore,#cores)
Introduction
Currentpredictionmodelspartiallyhelpful
• Canbiomarkers:
•
Individualizedecisionmaking
Improvepredictivepower
Reduceuncertaintyofprognosis
Improveclinicaldecisionmaking
Aidinactivesurveillancedecisions
Decreasecostoftreatment
GenesPeriodicallyExpressedduringCellCycle
STK6/STK15
Whitfield ML et al, Mol. Biol. Cell, v.13, p.1977, 2002.
CellCycleProgressionGenes
CCPgeneencodeproductsthatarerequiredduring
cellcycle progression(mostlyMphase).
Theyareregulated,atleastinpart,atthelevelofRNA
expression(Whitfieldetal.Mol.Biol.Cell2002).
Expressionlevelsmeasurefractionofcellswithin
sampledtissuethatareactivelydividing.
SinceCCPgenesmeasureasinglebiologicalprocess,
theirexpressionlevelsshouldbecorrelated.
7
Introduction
• AnRNAexpressionsignature
• Measurescellcycleprogression(CCP)genes‐ Cell
•
cyclegenesmeasurethecorebiologicalprocess
underlyingcancer
Prolarisscore=Averageexpressionof31cellcycle
genesnormalizedbyaverageexpressionof15
housekeepinggenes
• Assessmentoftheaggressivenessofaprostatecancer
•
•
tumor
Prognosticofdiseaseprogression
WorkswellevenonoldFFPEDxbiopsysamples
PROLARIS 46 GENE PANEL
31 Cell Cycle Progression Genes
15 House Keeper Genes
FOXM1, CDC20, CDKN3, CDC2, KIF11, RPL38, UBA52, PSMC1, RPL4, RPL37, KIAA0101, NUSAP1, CENPF, ASPM, RPS29, SLC25A3, CLTC, TXNL1, PSMA1, BUB1B, RRM2, DLGAP5, BIRC5, RPL8, MMADHC
KIF20QA, PLK1, TOP2A, TK1, PBK, ASF1B, C18orf24, RAD54L, PTTG1, CDCA3, MCM10, PRC1, DTL, CEP55, RAD51, CENPM, CDCA8, ORC6L
These genes are highly correlated and These genes are used to normalize the provide a reproducible measure of cell expression of the cell proliferation proliferation
genes
Estimates of prostate cancer survival
Prolaris Scores
Cuzick, et al. BJC 2012; 106(6): 1095-1099
MULTIVARIATEANALYSISOFNEEDLE
BIOPSYCOHORT
Cuzick, et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively
managed needle biopsy cohort. British Journal of Cancer 2012; 106(6): 1095-1099
ProlarisandAUARisk
AUA RISK
Data on file Myriad Genetic Laboratories, Inc
Kaplan‐meierestimateofprogression‐
freesurvival
Cuzick J, et al. Lancet Oncology 2011; 12: 245-55.
Validation of a panel of cell-cycle progression genes for improved risk-stratification in a contemporary radical prostatectomy
cohort. Cooperberg MR, et al. Submitted to the 2012 American Society of Clinical Oncology (ASCO) Genitourinary Cancers
Symposium, February 2-4, 2012, San Francisco, California.
StudyDesign
• Retrospectivecasecontrolledblinded
• ClinicallyLocalizedT1andT2DxBiopsy
• TreatedwithRPatIntermountainMedicalCenter
•
•
•
from1997‐2004
PrimaryendpointwastimetoBCR‐ BCRdefinedas
PSAgreaterthan0.2ng/mlafternadirofzero
Secondaryendpointmetastaticdisease– Confirmed
bywholebodyscan
Controlsrandomlysampledcasetocontrolratioof
1:2
Methods
• 165Patientbiopsysamples
•
•
•
‐ 3patientsexcluded:2neoadjuvant HD,1initial
PSA 121.9ng/ml
‐ 11PatientsBiopsyTissuenotsufficientto
generateCCPscore
151patientseligibleforentryintothestudy
123patientsamplesgeneratedqualitymoleculardata
36patientsdevelopedBCR aftertreatment
Recurrence−freesurvival
Kaplan‐Meierplotsfor10‐yearrecurrence‐
freesurvival
Time(Years)
stratifiedbyone‐unitCCPscoreintervals
Conclusions
• InthisstudytheunivariateanalysisoftheCCPscore
•
•
•
wasstronglyassociatedwith10yearriskofBCR
(HR=1.86,p=0.0028)
InthemultivariateanalysistheCCPscorewas
significantlypredictiveofBCR (HR=1.55,p=0.041)
CCPscorepredictedmetastaticcancerwithoddsratio
of3.32foroneunitincreaseinCCPscore(p=0.035)
Thefutureofaccuratedecisionmakingliesinthe
individualDNAandRNAofapatient’scancer
CCP
• Associatedwithprostatecanceroutcomes
• PreviousstudiesusedCCPfromRPspecimens
• IHCstudyusedbiopsymaterialinmenlatertreated
•
withRP
MultiInstitutionalStudy
• MartiniClinic
• DurhamVA
• IntermountainHealthCare
Methods
• Selectedregionsfrombiopsyspecimen
• Microdissection
• TotalRNAextraction
• CCPScoreCalculated
• SurvivalanalysisCoxproportionalhazardsmethods
•
Endpoint:BCRormetastaticprogrssion
Methods
• MultiInstitutionalStudy
• RPPatients
• BCRPSA>0.2ng/ml
Institution
N
Year RP
Median F/U
Intermountain Health
Care UT
151
19972004
120 months
Martini Clinic Germany
283
20052006
61 months
Durham VA NC
176
19942005
88 months
Clinical characteristics
Variable
CCP score from RP
Age at surgery (yrs)
PSA (ng/ml)
Gleason score
<7
7
>7
Clinical stage
T1
T2
T3
Percent positive cores
Adjuvant therapy
no
yes
Time from surgery to last
follow-up (months)
Biochemical recurrence
events (10-year censoring)
Statistic
Median (IQR)
Median (IQR)
Median (IQR)
Counts
Counts
Median (IQR)
Counts
Median (IQR)
Events / Total
MC
DVA
IHC
-0.4
(-0.9, 0.2)
63
(58, 66)
6.4
(4.6, 9.2)
0.0
(-0.4, 0.6)
62
(58, 67)
7.2
(5.1, 11.0)
0.3
(-0.3, 0.9)
62
(57, 67)
5.5
(4.4, 7.6)
159 (56%)
107 (38%)
17 (6%)
102 (58%)
59 (34%)
15 (9%)
77 (63%)
38 (31%)
8 (6%)
216 (77%)
63 (21%)
4 (1%)
33
(20, 50)
88 (62%)
53 (38%)
0 (0%)
33
(20, 50)
52 (42%)
71 (58%)
0 (0%)
36
(25, 50)
275 (97%)
8 (3%)
61
(60, 73)
142 (81%)
34 (19%)
88
(69, 119)
48/283 (17%)
83/176 (47%)
110 (89%)
13 (11%)
132
(123, 143)
35/123
(28%)
Biochemical Recurrence
Metastasis-free Survival
Multivariable Cox PH model of time
from surgery to BCR for all cohorts
Variable
CCP score
Ln (1+PSA ng/ml)
Gleason score
<7
7
>7
CCP score
Ln (1+PSA ng/ml)
Gleason score
<7
7
>7
Adjuvant treatment
no
yes
CCP score
Ln (1+PSA ng/ml)
Biopsy Gleason score
<7
7
>7
Hazard ratio
95% CI
MC Cohort (N = 283 with 48 events)
1.66
1.19, 2.32
2.13
1.32, 3.45
ref
ref
1.50
0.78, 2.86
3.59
1.46, 8.85
DVA Cohort (N = 176 with 83 events)
1.34
1.03, 1.74
1.49
1.05, 2.12
ref
1.24
1.22
ref
0.78, 1.97
0.57, 2.64
ref
ref
1.69
1.04, 2.74
IHC Cohort (N = 123 with 35 events)
1.55
1.02, 2.37
3.03
1.77, 5.21
ref
2.14
2.27
ref
0.98, 4.69
0.71, 7.21
p-value
0.0033
0.0029
0.038
0.031
0.029
0.65
0.043
0.041
<10-3
0.14
Univariable Cox PH models of time to
BCR for all cohorts
Variable
CCP score
Ln (1+PSA ng/ml)
Gleason score
Clinical stage
% Positive cores
Adjuvant treatment
Age at diagnosis (yrs)
CCP score
Ln (1+PSA ng/ml)
Gleason score
Clinical stage
% Positive cores
Adjuvant treatment
Age at diagnosis (yrs)
CCP score
Ln (1+PSA ng/ml)
Gleason score
Clinical stage
% Positive cores
Adjuvant treatment
Age at diagnosis (yrs)
Number of patients
Hazard ratio
95% CI
p-value
Pearson correlation with CCP
score (ρ)
283
283
MC Cohort
2.05
2.84
1.49, 2.82
1.76, 4.57
<10-4
<10-4
1
0.13
<7
7
>7
159
107
17
ref
2.17
5.59
ref
1.17, 4.02
2.33, 13.4
<10-3
0.27
I
II or III
216
67
162
ref
1.57
1.01
ref
0.85, 2.88
1.00, 1.02
0.16
0.17
0.15
0.10
no
yes
275
8
283
0.15
0.12
0.75
0.04
1.04, 1.70
1.12, 2.23
0.027
0.012
1
0.09
176
176
ref
2.71
1.01
DVA Cohort
1.33
1.58
ref
0.84, 8.76
0.96, 1.05
<7
7
>7
102
59
15
ref
1.33
1.54
ref
0.84, 2.11
0.72, 3.26
0.34
0.18
I
II or III
88
53
152
ref
1.14
1.00
ref
0.70, 1.86
0.99, 1.01
0.60
0.08
0.70
0.19
no
yes
142
34
176
ref
1.08, 2.84
0.96, 1.04
0.029
-0.01
1.00
0.02
1.25, 2.78
2.42, 6.75
0.0028
<10-5
1
0.13
123
123
ref
1.75
1.00
IHC Cohort
1.86
4.04
<7
7
>7
77
38
8
ref
3.37
5.62
ref
1.63, 6.94
1.98, 15.9
<10-3
0.30
I
II or III
52
71
123
ref
0.65
1.01
ref
0.33, 1.25
1.00, 1.03
0.20
0.07
0.12
0.22
no
yes
110
13
123
ref
1.73
1.01
ref
0.72, 4.18
0.25
0.10
0.78
0.00
0.96, 1.06
Cox PH models of time to BCR
stratified by cohort
(N = 582 with 166 events)
Variable
Number
of
patients
Hazard
ratio
95% CI
p-value
Univariable Analysis
CCP score
Ln (1+PSA
ng/ml)
Gleason score
<7
7
>7
Clinical stage
I
II or III
% Positive cores
Adjuvant
treatment
no
yes
Age at diagnosis
(yrs)
Variable
Hazard
ratio
95% CI
p-value
Multivariable Analysis
582
1.60
1.35, 1.90
<10-6
582
2.21
1.73, 2.84
<10-8
338
204
40
ref
1.85
2.87
ref
1.33, 2.56
1.75, 4.70
<10-4
356
191
437
ref
1.08
1.00
ref
0.77, 1.52
1.00, 1.01
527
55
ref
1.83
ref
1.22, 2.73
0.0052
546
1.01
0.98, 1.03
0.75
0.66
0.22
CCP score
Ln (1+PSA
ng/ml)
Gleason score
<7
7
>7
Adjuvant treatment
no
yes
1.47
1.89
1.23, 1.76
1.47, 2.42
<10-4
<10-5
ref
1.48
1.85
ref
1.06, 2.07
1.10, 3.10
0.021
ref
1.32
ref
0.88, 1.98
0.19
Cox PH models of time from surgery to
metastatic disease stratified by cohort
(N = 582 with 12 events)
Variable
Number
of
patients
Hazard
ratio
95% CI
p-value
Univariable Analysis
CCP score
Ln (1+PSA
ng/ml)
Gleason score
<7
7
>7
Clinical stage
I
II or III
% Positive cores
Adjuvant
treatment
no
yes
Age at diagnosis
(yrs)
Hazard
ratio
Variable
95% CI
p-value
Multivariable Analysis
582
5.35
2.89, 9.92
<10-7
582
1.57
0.64, 3.86
0.35
338
204
40
ref
4.82
23.4
ref
0.93, 24.9
4.49, 122
<10-3
356
191
437
ref
2.77
1.02
ref
0.76, 10.1
1.00, 1.05
527
55
ref
1.54
ref
0.32, 7.42
0.61
582
1.01
0.92, 1.11
0.88
0.11
0.089
CCP score
Ln (1+PSA
ng/ml)
Gleason score
<7
7
>7
4.19
1.23
2.08, 8.45
0.57, 2.68
<10-5
0.60
ref
3.09
5.12
ref
0.57, 16.7
0.84, 31.2
0.15
Conclusion:
•
•
•
•
CCPcanbegeneratedfromparaffinbiopsysamples
andwasassociatedwithadverseoutcomesafter
surgery
InunivariableanalysisCCPscorewaspredictiveof
BCRHR1.60,P<10‐6
TheHR/unitincreaseCCPwas1.86p=0.0028
Therewerefewmetastaticevents,buttheCCPscore
waspredictiveofMetastaticdisease
PredictedRISKofBiochemicalRecurrence
GleasonAlonevs.withProlaris
IntroductionQuestions
•
Canbiomarkers:
Individualizedecisionmaking
Improvepredictivepower
Reduceuncertaintyofprognosis
Improveclinicaldecisionmaking
Aidinactivesurveillancedecisions
Decreasecostoftreatment
IntroductionQuestions
•
Studytoincorporatewithactive
surveillancedecision:
IntermountainCriteria
•
•
•
•
•
•
•
PSA≤8ng/ml
Gleasonscore≤6(allow1corewith<20%
Gleason7)
<20%maxpositivepercore
Ageatdiagnosis>55years
≤3positivecores:unilateral
DREstageT1orT2a
Prolaris Test