Personalized medicine in prostate cancer care

D.Jacqmin

EAU Board Member

EAPM Treasurer

1

Surveillance is Under-utilized

Adapted from Cooperberg MR, et al. BJU Int;2013

Nu

mb

er

of

pat

ien

ts (

%)

CAPRA score

100

80

60

40

20

0 0 2 3 4 5 6 7 8 9 10 1

AS/WW RP Brachy EBRT Cryo ADT

8.5 2.0 6.5 5.8 4.4 2.9 2.6 3.3

24.7 33.6

44.5 49.9

51.7 56.7

59.7

90.0

16.1 17.8

7.0

11.1

10.3

13.7 14.0

1.0

5.2 2.8 6.0

8.1

3.6

8.9

12.8

4.0

11.5

12.3

5.7

14.0

16.0

5.2

21.1

20.2

5.6

27.0

2.6 2.5 9.0

4.1

15.5

3.7

20.0

5.0

12.6

6.0

19.2

5.3

72.2 67.3

54.3

7.4

20.9

5.7

38.0

2

Clear Need and Opportunity to Improve Prostate Cancer Management

• Significant driver of over treatment is limited accuracy of low

risk classification based on measures available today

• Despite low (3%) risk of disease progression1 and modest treatment benefit2, >90%3 of low risk men will receive immediate treatment

1. Boorjian SA, et al. Urol Oncol 2008; 2. Wilt TJ, et al. N Engl J Med. 2012; 3. Cooperberg MR et al. J Clin Oncol 2010; 4. Otis W. Brawley, MD, American Cancer Society

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“We desperately need the ability to predict which patient has a localized cancer that is going to metastasize and cause suffering

and death, and which patient has a cancer that is destined to stay in the patient's prostate for the remainder of his life.”

-American Cancer Society4

Prostate cancer care

• How to have a more personalized approach ?

• What’s new ?

• Genomic tests

– Oncotype DX prostate cancer test

– Prolaris test

– Decipher test

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ONCOTYPE DX PROSTATE CANCER TEST

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The Oncotype DX® Prostate Cancer Assay

• WHAT is the test? – A tumor gene expression assay which produces a Genomic Prostate Score

(GPS) to help guide initial treatment decisions at the time of biopsy

• WHO is the test for? – Newly diagnosed men with low to low-intermediate risk prostate cancer

(GS 3+3, low volume 3+4)

• WHY do the test? – To improve risk stratification by incorporating individual underlying tumor

biology

– To identify appropriate patients for Active Surveillance (AS) or immediate treatment

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Oncotype DX® GPS Provides More Accurate and Individualized Risk Assessment at Time of Biopsy

• Developed to address tumor heterogeneity and biopsy under-sampling

• Based on multiple biologic pathways predictive of aggressive prostate cancer

• Optimized technology for very small amounts of tumor from needle biopsies

• Independently validated in contemporary low and low-intermediate risk patients

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1. Klein et. al. ASCO GU 2011; 2. Klein et. al. ASCO 2012; 3. Cooperberg et. al. AUA 2013

Validation Study #1 UCSF Clinical Validation Study

Needle biopsy specimens (n=395) GPS Predicts Adverse Pathology

Development Study #1 Prostatectomy Study (Cleveland Clinic)

Two tumor foci per patient (n=441) 1º endpoint: Clinical Recurrence

2º endpoints: PCSS, BCR, Adverse Pathology at RP

Prostate Cancer Technical Feasibility

Assay Finalization & Analytical Validation Oncotype DX GPS

Development Study #2 Biopsy Study (Cleveland Clinic)

Needle biopsy specimens (n=167)

Development Study #1 Radical Prostatectomy Study (Cleveland Clinic)

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Objectives:

• Identify genes associated with clinical recurrence (local recurrence or distant metastases) accounting for tumor heterogeneity

• Additional endpoints included PCSS, biochemical recurrence, and adverse pathology at RP

Development Study #1 Prostatectomy Study (Cleveland Clinic)

Two tumor specimens per patient (n=441)

Development Study #2 Biopsy Study (Cleveland Clinic)

Needle biopsy specimens (n=167)

Assay Finalization & Analytical Validation Oncotype DX GPS

Development Study #2 Biopsy Study (Cleveland Clinic) Commercial Assay Finalization

and Analytical Validation

Objectives:

• To confirm that genes robust to heterogeneity are predictive when assessed in biopsy specimens

• Likelihood of adverse pathology (high grade or non-organ confined disease) at prostatectomy

Objective:

• Finalize standardized analytical platform for reliable measurement of gene expression in small volume tumor tissue from needle biopsies

GPS Development and Validation: A Proven and Rigorous Approach

GPS Incorporates Multiple Biologic Pathways Predictive of Prostate Cancer Aggressiveness

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Stromal Response BGN

COL1A1 SFRP4

Proliferation TPX2

Androgen Signaling FAM13C

KLK2 AZGP1

SRD5A2

Cellular Organization

FLNC GSN

TPM2 GSTM2

The combination of multiple pathways

is more predictive than

any single pathway

Genes Associated with Better Outcome

Genes Associated with Worse Outcome

ARF1 ATP5E CLTC

GPS1 PGK1

Reference Genes

Development Study #2 Biopsy Study (Cleveland Clinic)

Needle biopsy specimens (n=167)

Objectives:

• To validate GPS as a predictor of adverse pathology in a contemporary early-stage patient cohort

• To determine whether GPS adds independent predictive information beyond standard clinical and pathologic data

Independent Clinical Validation Study of the 17-Gene Oncotype DX® GPS

Validation Study #1 UCSF Clinical Validation Study

Needle biopsy specimens (n=395)

Development Study #1 Prostatectomy Study (Cleveland Clinic)

Two tumor specimens per patient (n=441)

Prostate Cancer Technical Feasibility

Assay Finalization & Analytical Validation Oncotype DX GPS

1. Klein et. al. ASCO GU 2011; 2. Klein et. al. ASCO 2012; 3. Cooperberg et. al. AUA 2013 10

Validation Study Focused on Men Who Were Potential Candidates for Active Surveillance

UCSF Database 1997-2011 Consented RP patients meeting

active surveillance criteria at diagnosis Low/Intermediate risk biopsy

GS 3+3 and low volume 3+4 (fewer than 4 positive cores) Eligible Population

n = 412

17 (4%) Excluded for insufficient RNA quality

Final Evaluable Population n = 395

11 Cooperberg et al, AUA 2013

Combining Biologic & Clinical Information Refines Risk Stratification for Individual Patients

VERY LOW RISK LOW RISK INTERMEDIATE RISK

More Individualized Biologic and Clinical Risk Assessment

Likelihood of Favorable Pathology 100% 30%

Population-Based Clinical Risk Assessment

VERY LOW RISK

LOW RISK INTERMEDIATE RISK

GPS=8 84%

GPS=51 57%

10% (N=37) 49% (N=191) 41% (N=160)

44% (N=169) 31% (N=119)

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GPS=25 75%

UCSF Validation Study NCCN Risk Classification

• 10% Very Low-risk • 49% Low-risk • 41% Intermediate Risk

GPS Provides Biologic Risk Information

GPS

• Adds more accurate risk assessment by combining biological and clinical risk factors

• Predicted which patients have risk consistent with their NCCN clinical risk group

26% (N=100)

• 35% of men in the NCCN Low-risk group had more indolent biology and likelihood of favorable pathology consistent with Very Low-risk

• 10% of men in the NCCN Low-risk group had more aggressive biology and likelihood of favorable pathology consistent with Intermediate risk

• Identified patients in the NCCN Very Low-risk group who had more aggressive biology, with likelihood of favorable pathology consistent with Low and Intermediate risk disease

• Identified patients with Intermediate risk who had more indolent biology, predicted to be consistent with Low-risk disease

• Enables more accurate identification of a larger population of patients who can more confidently choose active surveillance

• Precisely identifies a patient’s tumor biology and refines the population-based clinical risk assessment with a more personalized risk assessment

Cooperberg et al, AUA 2013

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Actionable

Information

Biologic

Criteria

Clinical

Criteria VERY LOW INTERMEDIATE

VERY LOW INTERMEDIATE

ACTIVE

SURVEILLANCE

IMMEDIATE

TREATMENT

GPS

More favorable Consistent with

clinical criteria Less favorable

More favorable than clinical criteria alone: The biology of the tumor is predicted to be less aggressive, and the risk profile is predicted to be more

favorable than NCCN low-risk disease. These patients may be appropriate for Active Surveillance.

Consistent with clinical criteria: The biology of the tumor is predicted to be consistent with the risk profile of men with NCCN low-risk

disease. These patients may be appropriate for either Active Surveillance or immediate treatment.

Less favorable than clinical criteria alone: The biology of the tumor is predicted to be more aggressive, and the risk profile is predicted to be less

favorable than NCCN low-risk disease. These patients may be appropriate for immediate treatment.

0 100

LOW

LOW

More Accurate Risk Discrimination Delivers Confident Decision Making

NCCN Low Risk Refined by GPS

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PROLARIS TEST

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Prolaris test

• Studied on biopsies or RP specimens

• 31 cell cycle progression genes (cell proliferation)

• 15 housekeeper genes

• CCP score

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Prolaris test

• Cell progression genes :

– FOXM1, CDC20, CDKN3, CDC2, KIF11, KIA0101, NUSAP1, CENPF, ASPM, BUB1B, RRM2, DLGAP5, BIRC5, KIF20A, PLK1, T0-P2A, TK1, PBK, ASF1B, C18orf24, RAD54L, PTTG1, CDCA3, MCM10, PRC1, DTL, CEP55, RAD51, CENPM, CDCA8, ORC6L

• Housekeeping genes (reference) :

– RPL38, UBA52, PSMC1, RPL4, RPL37, RPS29, SLC25A3, CLTC, TXNL1, PSMA1, RPL8, MMADHC, RPL13A, LOC723658, PPP2CA, MRFAP1

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CCP score 10 years CSS

• 0 = risk of NCCN classification

• + 1 means risk x 2

• - 1 means lower risk than NCCN classification

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Cuzick et al.Lancet Oncol.:2011;12;245-255.

Cooperberg et al.:J.C.Oncol.2013;31;1428-1434.

Positive prostate biopsy

Low Risk

Low Prolaris Score

Active Surveillance

High Prolaris Score

Single Modality Treatment

Intermediate Risk

Low Prolaris Score

Active Surveillance

High Prolaris Score

Multimodality Treatment

High Risk

Low Prolaris Score

Single Modality Treatment

High Prolaris Score

Multimodality Treatment

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DECIPHER TEST

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Decipher Prostate Cancer Test

• Predicts probability of metastasis after surgery

• Performed on Radical Prostatectomy specimen

• Validated retrospectively in US on 2000 patients

• Based on 22 RNA biomarkers associated with aggressive prostate cancer

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Decipher Prostate Cancer test

• Validation study :

– 545 patients operated between 87-01 with high Gleason score, extra-prostatic extension, seminal vesicle invasion or N+

– 192 progressive disease, 353 controls

– Confirmed by 3 other studies from Mayo and CC

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Erho et al:PLoSone2013;8;e66855.

Klein et al.:Eur.Urol.2015;67;778-786.

Karnes et al.:J.Urol.2013;190;2047-2053.

Den et al.:Int.J.Radiat.Oncol.Biol.Phys.2014;89;1038-1046

Decipher Prostate Cancer Test

• RNA biomarkers :

– LASP1, IQGAP3, NFIB, S1PR4, THBS2, ANO7, PCDH7, MYBPC1, EPPK1, TSBP, PBX1, NUSAP1, ZWILCH, UBE2C, CAMK2N1, RABGAP1, PCAT-32, GLYATL1P4/PCAT-80, TNFRSF19

• Select patients who may benefit from adjuvant treatment after surgery

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Conclusion

• Genomic tests will help to tailored treatment for Prostate Cancer Patients

• Oncotype DX Prostate Cancer Test : Will help to select Patients candidates for Active Surveillance

• Prolaris test : Will impact the follow-up of patients at risk

• Decipher test : Will detect candidates for early adjuvant treatment in high risk group

• Clinical criteria combined with genomic tests will improve the personalization of treatment in Prostate Cancer Patients

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