Progress in Understanding the Pathology of Prostate Cancer

M. Scott Lucia, MD Professor and Vice Chair of Anatomic Pathology Chief of Genitourinary and Renal Pathology Director, Prostate Diagnostic Laboratory Dept. of Pathology University of Colorado SOM

Disclosure: Genomic Health - consultant

Metastatic Potential = p X T

p = phenotype (biologic aggressiveness) - Assessed by Gleason grade, biomarkers

T = time - Reflected by volume, stage - Currently difficult to assess

Death from prostate cancer

Metastatic disease develops

Cancer spreads to lymph nodes

Cancer spreads beyond prostate

Cancer detectable—PSA>4 ng/mL Prostate cancer develops

Zone of detection when cure is possible

TIME Death

Role of Pathology

•   Establish a diagnosis –   Cancer –   BPH, inflammation

•   Determine “aggressiveness” –   Grade –   Perineural invasion –   Biomarkers

•   Predict extent –   Percent cores positive –   Linear extent

•   Confirm diagnosis

•   Determine “aggressiveness” –   Grade –   Perineural invasion

–   Vascular invasion

–   Biomarkers

•   Determine extent –   Stage

–   Volume

–   Margin status

Prostate Biopsy Prostatectomy

Assessing the Aggressiveness of Prostate Cancer on Biopsy

•   Histologic grade

•   Perineural invasion

•   Extraprostatic disease

•   Biomarkers/molecular determinants

Assessing the Aggressiveness of Prostate Cancer on Biopsy

•   Histologic grade

•   Perineural invasion

•   Extraprostatic disease

•   Biomarkers/molecular determinants

Prostatic Adenocarcinoma Gleason Grading1

•   Morphologic resemblance to normal prostate

•   Degree of invasiveness

•   Score = most + 2nd most

•   2005 ISUP2: Grading biopsies: ─  Most + highest remaining grade

present ─  Grades 1&2 should not be used

(most upgraded or found to be benign on RP)

1. Gleason DF. Urologic Pathology: The Prostate, 1977. 2. ISUP: Amer J Surg Pathol, 2005.

Prog

ress

ion-

Free

Pro

babi

lity

Months to Progression0 40 80 120 160 200 240

0.00

0.25

0.50

0.75

1.00

GS 7

GS 5-6with tertiary 4/5

GS 5-6162128 99 64 64 77 82 60 58 47 4432

16

7 1

16

2984122

2926 12

33

3552

6972

771

3

Months to Progression0 40 80 120 160 200 240

0.00

0.25

0.50

0.75

1.00

GS 8

GS 7with tertiary 5

9 2

1

8412229

7277

GS 7

11

1

12

813

44

6

7

2

1

1

14

6952

3526

Prog

ress

ion-

Free

Pro

babi

lity

Prog

ress

ion-

Free

Pro

babi

lity

Months to Progression0 40 80 120 160 200 240

0.00

0.25

0.50

0.75

1.00

GS 7

GS 5-6with tertiary 4/5

GS 5-6162128 99 64 64 77 82 60 58 47 4432

16

7 1

16

2984122

2926 12

33

3552

6972

771

3

Months to Progression0 40 80 120 160 200 240

0.00

0.25

0.50

0.75

1.00

GS 8

GS 7with tertiary 5

9 2

1

8412229

7277

GS 7

11

1

12

813

44

6

7

2

1

1

14

6952

3526

Prog

ress

ion-

Free

Pro

babi

lity

HG = high-grade *Tertiary pattern is defined as a third Gleason pattern in a tumor that occupies less than 5% of the tumor.

Pan CC, et al. Am J Surg Pathol. 2000;24:563-9.

Significance of Tertiary (<5%) HG Gleason Pattern*

-100

0

100

0

Gleason Grade 4/5 (%)

Cumulative No-Evidenceof-Disease Rate (%)

Fail Rate (%)

1–10

11–20

21–30

31–40

41–50

51–60

61–70

71–80

81–90

91–100

-100

0

100

0

Gleason Grade 4/5 (%)

Cumulative No-Evidenceof-Disease Rate (%)

Fail Rate (%)

1–10

11–20

21–30

31–40

41–50

51–60

61–70

71–80

81–90

91–100

Stamey TA, et al. JAMA. 1999;281:1395-400. © 1999, American Medical Association.

Failure Rates as a Function of Percent Gleason Pattern 4/5 Cancer

Predicting 15-year prostate cancer specific mortality after radical prostatectomy1

PCSM (black areas) and mortality from competing causes (gray areas) by pathological Gleason score and patient age at diagnosis.

1. Eggener SE, et al. J Urol 2011;185:869-75. http://dx.doi.org/10.1016/j.juro.2010.10.057

N=23,910 across 5 institutions

Impact of grade stratification on biochemical recurrence

Pierorazio PM et al. BJU Int 2013;111:753-60. ©2013 BJU International doi:10.1111/j.1464-410X.2012.11611.x

Multivariate regression

HR (95% CI) P

Preoperative variables

Family history 0.77 (0.54-1.08) 0.132

PSA 1.06 (1.04-1.07) <0.001

cT2b 2.70(1.79-4.06) <0.001

cT2c-cT3 3.36(1.55-7.31) 0.002

Biopsy Gleason score

3 + 4 2.19 (1.35-3.56) 0.002

4 + 3 5.38 (3.33-8.68) <0.001

8 6.92 (3.99-11.98) <0.001

9-10 10.27 (5.29-19.92) <0.001

>3 cores 0.96 (0.65-1.42) 0.834

>50% positive 1.99 (1.31-3.00) 0.001

Prostate Cancer in the Contemporary Era: Does it make sense to continue to use a

2-10 scaled grading system?

•   Gleason score 6 has favorable outcomes

•   Gleason score 6 (low grade) is halfway between Gleason score 2 and 10 –   Contributes to reluctance to choose active

surveillance

•   Gleason scores 2-5 rarely used and not prognostically different from GS6

•   Amount of pattern 4/5 most important for prognosis

Classification of Prostate Cancer Using 5-teired Prognostic Grade Groupings

•   2014 ISUP (Nov. 2014, Chicago) –   85 GU pathologists from 17 countries with input from

urologists

–   Voted to adopt 5-teired system (90% consensus)

–   Recommended that percent high grade patterns be specified for groups II and III

–   Manuscript pending – stay tuned!

The overall Gleason score is based on the core with the highest Gleason score. Gleason scores can be grouped and range from Prognostic Grade Group I (most favorable) to Prognostic Grade Group V (least favorable).

Gleason score ≤ 6: Prognostic Grade Group IGleason score 3 + 4 = 7: Prognostic Grade Group IIGleason score 4 + 3 = 7: Prognostic Grade Group IIIGleason score 8: Prognostic Grade Group IVGleason score 9-10: Prognostic Grade Group V

Gleason Grading on Needle Biopsy: Limitations

•   Cancer sampling is a function of tumor volume: prostate volume

–   Similarly, sampling of high-grade tumor is a function of high-grade component: prostate volume

•   Biopsy may not sample highest grade

3-Dimensional Reconstruction of Prostatectomy: Tumor Multifocality and Heterogeneity

Gleason Grading on Needle Biopsy: Limitations

•   Cancer sampling is a function of tumor volume: prostate volume

–   Similarly, sampling of high-grade tumor is a function of high-grade component: prostate volume

•   Biopsy may not sample highest grade

Have consequences for choice and potential effectiveness of expectant management

Can we improve our prognostic ability through the addition of molecular biomarkers?

Prognostic Biomarkers for Prostate Cancer

•   Identifying molecular markers associated with potentially aggressive cancer to aid in therapeutic decision making –   Risk of progression

–   Monitoring for expectant management or targeted focal therapy

•   Independent of Gleason grade and biopsy sampling

•   Readily available

Prognostic value of a cell cycle progression signature* for prostate cancer death in a

conservatively managed needle biopsy cohort1

1. Cuzick J et al. Br J Cancer 2012; 106(6):1095-1099. © 2012 Cancer Research UK.

*Prolaris®, Myriad Genetics, Inc.

N=349

Endpoint PCA specific death

Events 90 (26%)

Med years follow-up 11.8 (10.8, 12.7)

Median age 71 (66, 73)

Gleason <7 7 >7

106 (30%) 152 (44%) 91 (26%)

Median PSA 21.4 (11.9, 42)

Variable Hazard Ratio (95% CI)

p-value

Prolaris Score

1.65 (1.31, 2.09) <0.0001

Gleason <7 7 >7

0.61 (0.32, 1.16)

1 (ref) 1.90 (1.18, 3.07)

<0.0001

--- ---

PSA 1.37 (1.05, 1.79) 0.017

Multivariate analysis

Prognostic utility of the cell cycle progression score generated from needle biopsy in men

treated with prostatectomy1

1. Bishoff et al. J. Urology 2014; 192 (2).

A. Biochemical recurrence: Multivariate analysis: HR=4.83 (CI 95%); p<10-5

B. Metastasis-free survival: Multivariate analysis: HR=1.53 (CI 95%); p<10-4

N=582

Copyright © 2014 AUA Education and Research, Inc.

Genomic Prostate Score (GPS)*

Stromal Response BGN

COL1A1 SFRP4

Proliferation TPX2

Androgen Signaling FAM13C

KLK2 AZGP1

SRD5A2

Cellular Organization

FLNC GSN TPM2

GSTM2

Genes Associated with Better Outcome

Genes Associated with Worse Outcome

ARF1 ATP5E CLTC

GPS1 PGK1

Reference Genes

•   PCR-based expression assay

•   17 gene panel •   5 reference genes •   12 genes covering

multiple pathways predictive of:

1.  Metastasis & Death

when measured in RP specimens

2.  Dominant grade pattern

4 & EPE/SV/LN+ when measured in biopsy specimens

* Oncotype DX®, Genomic Health, Inc

UCSF Validation Study of GPS

0 70 10 20 30 40 50 60

GPS

Very Low Low

Intermediate

10

90 80 70 60 50 40 30 20

100

0

Like

lihoo

d of

Fav

orab

le

Path

olog

y (%

)

0 70 10 20 30 40 50 60

Very Low Low

Intermediate

NCCN Intermediate = 56%

NCCN Very Low = 84%

NCCN Low = 75%

Klein EA et al, Eur Urol 2014. http://eorder.sheridan.com/30/app/orders/3732/article.php

Multivariate Analysis NCCN p-value = 0.002 GPS p-value = 0.001

Improved Risk Discrimination with Addition of GPS to NCCN in 395 Men with Very Low-Intermediate Risk Prostate Cancer on Biopsy

Fav

orab

le P

ath=

GS≤3

+4

+ p

T2

Genomic prostate score predicts adverse pathology1 at radical prostatectomy with adjustment for the clinical/

pathology covariates (n=382)

Model Variable OR 95% CI p value

1 GPS/20 units 3.23 2.14–4.97 <0.001

Biopsy Gleason score 3 + 4 vs ≤3 + 3 1.89 1.12–3.18 0.016

2* GPS/20 units 3.25 2.12–5.10 <0.001

NCCN risk group: low vs very low 3.17 1.33–8.81 0.008

Intermediate vs very low 4.52 1.81–13.03 <0.001

3** GPS/20 units 2.74 1.77–4.36 <0.001

Age at diagnosis, yr 1.06 1.02–1.09 <0.001

NCCN risk group: low vs very low 3.44 1.43–9.65 0.005

Intermediate vs very low 5.20 2.05–15.18 <0.001

CI = confidence interval; GPS = Genomic Prostate Score; OR = odds ratio; *n = 372 (NCCN risk category could not be assigned for 10 patients).

1. Adverse pathology=GS≥4+3, any pattern 5; or ≥pT3

Cullen J, et al. Eur Urol 2014. http://dx.doi.org/10.1016/j.eururo.2014.11.030

Univariable odds ratios for GPS in predicting adverse pathology at radical prostatectomy within different

clinical subgroups

Cullen J, et al. A Biopsy-based 17-gene Genomic Prostate Score Predicts Recurrence After Radical Prostatectomy and Adverse Surgical Pathology in a Racially Diverse Population of Men with Clinically Low- and Intermediate-risk Prostate Cancer . Eur Urol 2014. http://dx.doi.org/10.1016/j.eururo.2014.11.030

Risk of Progression Choice of Management

Clinical Factors: PSA

Stage

Molecular Profiling

Pathologic Factors: Grade Extent

(# pos cores, etc)

Mutational Analysis

Primary Data

Secondary Data

Other?

Current

Future?