Biomarkers for

Prostate Cancer

Eric Wallen, MD

Department of Urology

Disclosure

• MDxHealth Scientific Advisor

55-year-old man: Poor Guy

• Risk of prostate cancer? 1 in 6

• Risk of prostate cancer death? 1 in 40

• Risk of biopsy related complications 1 in 25

• If PSA elevated and biopsy (-), risk of repeat biopsy 1 in 2.5

• If biopsy negative, risk of missed cancer 1 in 4

• If diagnosed with NCCN low risk CaP,

risk of upgrading/staging at surgery? 1 in 4

• If surgery shows T3 disease, need for radiation? 1 in ?

• Wouldn’t it be great if there were some biomarkers that helped with

these questions?

• What is personalized medicine? • Customization of healthcare based on rational use of an

individual patient’s unique disease features

• What is a biomarker? • A measurable characteristic of the biology of a particular

disease state

– Tissue, blood, serum, urine, EPS, MRI (?)

Is there a need for biomarkers in

mgmt of prostate cancer?

• AUA guidelines 2007 and 2013 discuss in Research

and Future Directions section

– 2007—development of biomarkers of aggressiveness is

desirable

– 2013—many biomarkers, poor evidence

– Yes! We need more decision aids to

provide actionable guidance

• Still in evolution

Bench to bedside DNA, RNA, epigenetic

K. Chiam et al., Cancer Lett. (2012)

Where can biomarkers help?

1. When to biopsy

2. When to re-biopsy

3. When to treat

4. When to treat adjuvant

5. Assess therapeutic response

Where can biomarkers help?

1. When to biopsy

2. When to re-biopsy

3. When to treat

4. When to treat adjuvant

5. Assess therapeutic response

Date of download: 4/20/2014 Copyright © 2014 American Medical

Association. All rights reserved.

From: Operating Characteristics of Prostate-Specific Antigen in Men With

an Initial PSA Level of 3.0 ng/mL or Lower

JAMA. 2005;294(1):66-70. doi:10.1001/jama.294.1.66

AUC indicates area under the receiver operating characteristic curve.

Figure Legend:

Odds Ratios, While Attractive, Must Be Considered

When Evaluating These Tests

OR of 3 reclassifies 25% of results

When to Biopsy

(“screen smarter”)

• Goals: Decrease unnecessary biopsies

Decrease detection of low risk disease

• Currently: PSA, fPSA, PSAd, risk calculators

• Molecular Tests:

– Phi: Prostate Health Index (serum): PSA 2-10, nl DRE

– f/tPSA and proPSA formula generates a score (Clin Chem 2013)

– Multiparametric MRI with MRI fusion biopsies (Rastinehad, JU, 2014)

– OPKO 4K test (serum) incl PSA and hk2 to generate risk score for GS≥7

– eNose (urine) emission testing!

PHI

• Precursor forms of PSA elevated in PCa and measurable in

serum

• Formula includes tPSA and fPSA, as well as (-2)proPSA

• Screening pts with PSA 2.5-10 and nl DRE gives incr sens/spec

(64/63)

– Using cutoff of 35, 26% of biopsies could be avoided

– FDA approved for PSA 4-10

Le, JU, 2010

Lazzeri, BJU, 2013

Sokoll, Cancer Epi Bio Prev 2010

PHI ROC

MPMRI: Pre-biopsy

• Possibly selective detection of high grade lesions and

lower detection of low grade lesions in patients • Possibly a quantum leap

• However…

– Not standardized yet. 3T or 1.5T?

– Endorectal or not? Biopsy in bore, fusion, or cognitive?

– ***radiologist dependent***

– Costly

– Still has false negatives so is standard biopsy still warranted?

• Multi-institutional trials to come

Bjurlin, UCNA, 2014

Siddiiqui, Eur Urol, 2013

Marks, Curr Op Urol 2013

Wysock, Eur Urol, 2013

Albertsen, Jurol, 2013

OPKO 4K Test

• 4 kallikreins: tPSA, fPSA, iPSA, hk2 measured in serum and

used in nomogram with DRE and age to get probability score for

prostate cancer

• When used in serum from ERSCP prostatectomies, good

predictor of aggressive disease

• Prospective multi-institutional trial results presented by Daniel

Lin at AUA2014. AUC .82 for prediction of GS≥7

• Cost: $400, currently available Carlsson, EurUrol, 2013

Voigt, The Prostate, 2013

TMPRSS2-ERG

• ERG oncogene fusion with TMPRSS2 is an early change in

prostate cancer

• TMPRSS2-ERG fusion can be measured in urine post DRE

– High specificity, low sensitivity

• U Mich group reported at AUA2014 a large study of

T2ERG+PCA3+PSA that had AUC score of .73 in predicting

GS≥7

• Prob will seek FDA approval in combination with PCA3 for

screening

Leyten, Eur Urol, 2014

PCA3

(not approved for screening, but…)

• Post prostatic massage urine test for RNA that is elevated in PCa, score

generated

• Extensively studied, FDA approved for repeat bx only

– Most studies done are on patients already selected for biopsy (not

screening)

• Strength appears to be specificity (75%) not sensitivity (50%)

• Score correlates with increasing grade

• Better than PSA for all grades of PCa, equivalent for GS≥7

– Prob won’t be approved for screening (not selective for higher grade

prostate cancer) but more studies pending, incl combinations with other

biomarkers

Chevli, Jurol, 2014

PCA3 for Screening: No

Chevli, Jurol, 2014

Summary: Screening Smarter

• Use PCPT and/or ERSPC risk calculator

• Use online life expectancy calculator

• Consider molecular tests (PHI, 4K) but watch out for cost

• Consider MRI but you must have an experienced, trained

radiologist (cost too)

• Minimize infection risk of biopsy

Where can biomarkers help?

1. When to biopsy

2. When to re-biopsy

3. When to treat

4. When to treat adjuvant

5. Assess therapeutic response

Repeat Biopsy: The Numbers

• ≈1.3M biopsies/yr

• ≈1M are negative

• 43% repeat biopsy within 3 yr

• Biopsies carry risk – Infection

– Hospitalization

Pinsky, BJUI, 2007

Loeb, Jurol, 2011, 2014

Tests To Help Decision to Re-Biopsy

• PCA3 (urine after prostate massage)

• RNA overexpressed in Pca

• ConfirmMDx: Epigenetic Test on negative biopsy tissue

• MATLOC, DOCUMENT (JU, 2013, JU 2014)

• NPV 90%

• Assesses epigenetic changes for 3 genes

• Mitomics (mitochondrial DNA testing on negative biopsy tissue)

PCA3 for Rebiopsy

• FDA approved for cutoff= 25

• Sens/spec up to 90/50

• Can help guide decision to

rebiopsy

• May help avoid up to half of

repeat biopsies

Luo, Asian J Androl, 2014

Test detects an epigenetic field effect

with the “cancerization” process at the

DNA level

The field effect around the cancer

focus can be present despite the

normal micro appearance of cells

Detection of field effects extends the

coverage of the biopsy helping to rule

in, or rule out, occult cancers

Biopsy

Cancer

Field

Effect

ConfirmMDx: Epigenetic Changes Influence Gene

Expression Without Changing the Genome

ConfirmMDx clinical validation studies

• MATLOC and DOCUMENT

– Approx 500 patients who had 2 biopsies each

– All with negative first biopsy, biopsy tissue tested

– Approx 100 cancers seen on re-biopsy, NPV 90%

– Test identified 2/3 of these as positive, sensitivity/specificity 66%

– 1/3 of cancers Gleason >6

– Could also decrease repeat biopsies significantly

Stewart, JU, 2013

MPMRI for Rebiopsy

• Provides anatomic information

• Can help guide re-biopsy and detects PCa in up to 50% of pts

• MPMRI outperformed PCA3 and PHI in pts undergoing rebiopsy

• If MPMRI negative, repeat biopsy for ongoing concern yielded

very few significant cancers

• NICE (English cost-effectiveness guidelines group): Consider

pre-re-biopsy

• Intergroup study pending

– Needs to be done as techniques vary widely

Bjurlin, J Urol., 2014, UCNA 2014

Porpiglia, J Urol, 2014

Hong, Diag Interv Rad, 2014

Where can biomarkers help?

1. When to biopsy

2. When to re-biopsy

3. When to treat

4. When to treat adjuvant

5. Assess therapeutic response

Active Surveillance is Underutilized

31

Cooperberg MR et al. J Clin Oncol. 2010 Mar 1;28(7):1117-23.

No

. o

f p

ati

en

ts (

%)

CAPRA score: Increased score, increased risk

100

80

60

40

20

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

WW RP Brachy EBRT Cryo PADT

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

Aids in AS vs Treatment

• Prolaris: Cell cycle gene panel

• Oncotype DX: Mixed gene panel

• MPMPRI

Cuzick, Lancet Oncol 2011

Prolaris

• Application: Predict BCR, metastasis, and risk of death

– Measures panel of cell cycle genes, which are increased in more

aggressive disease

– Evaluated in prostatectomy specimens from pts with extended f/u, then

extended to prostate biopsy specimens

• AUA2014: 3 clinical validation studies

– Improves upon age, GS, stage

– Predicts metastasis

• Improved dataset, not clear if this information would predict

actual outcome in a modern cohort

– Prospective studies may be necessary to support adoption

Oncotype DX

• Application: Active surveillance candidates

– Seeks to predict adverse pathology: T3, GS>7 or primary 4

– Tests cancer foci in biopsy for 17 genes found to be indicators of

aggressiveness

– May reclassify pts in NCCN category

• Goal: Increase the number of patients and urologists who can

feel reassured on AS, identifies a few who have aggressive

features

• Predicts pathology, not clinical outcomes

Klein, Eur Urol, 2014

Population-Based Clinical Risk Assessment

VERY LOW

RISK LOW RISK LOW-INTERMEDIATE

RISK

GPS=8

84%

GPS=51

57%

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

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

GPS=25

75%

GPS Provides Biologic Risk Information

26% (N=100)

Where can biomarkers help?

1. When to biopsy

2. When to re-biopsy

3. When to treat

4. When to treat adjuvant

5. Assess therapeutic response

Tests for Prostatectomy Specimens

• Prolaris

– Increased score could help tip decision toward adjuvant therapy

• Decipher

• PTEN: FISH assessment of a common gene alteration in

aggressive disease

CTC: Circulating Tumor Cells

• Measurement of CTC in CRPC trials

– Decrease during treatment highly predictive of treatment response and

survival (Scher, Lancet Oncol, 2009)

Figure 1 Cumulative survival ROC curves comparing GC score and individual clinicopathological factors for predicting clinical

metastasis 5 years after RP. GC showed noticeably higher discrimination than individual clinicopathological factors. Path , patho...

R. Jeffrey Karnes , Eric J. Bergstralh , Elai Davicioni , Mercedeh Ghadessi , Christine Buerki , Anirban P. Mitra ...

Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient

Population

The Journal of Urology, Volume 190, Issue 6, 2013, 2047 - 2053

http://dx.doi.org/10.1016/j.juro.2013.06.017

Considerations

• Prostate cancer is genetically complex

• Molecular tests are evolving rapidly

• Characteristics of a good test – Answers a clinical question (utility)

– Is based on good evidence

– Is actionable—changes a treatment

• Tests cannot be applied to all populations if not tested in them

• Rigorous validation with consistent methodology needed – How costly will that be?

– Cost may limit development and evaluation of innovative tests

• Test must be applied to the specific and appropriate clinical context

Conclusions

• PSA screening identifies many non-aggressive cancers

• Uncertainty and fear cause patients and doctors to treat aggressively

• Before placing QOL at risk we need to better identify which patients

need treatment, and the recent biomarker explosion seeks to do this

• Are the tests good enough yet? They are getting there

• If good enough, who pays for them?

• If used, are we and are patients going to abide by the result? – If not, why order the test?

– If so, treatment will decrease significantly as we will flip the script on AS vs intervention