EPCA: A silver lining for early diagnosis of prostate cancer GHOLAMREZA POURMAND, MD Professor of Urology Urology Research Center Tehran University of

EPCA: A silver lining for early diagnosis

of prostate cancer

GHOLAMREZA POURMAND, MD

Professor of UrologyUrology Research Center

Tehran University of Medical SciencesTehran, Iran

Oct.,2014

Introduction

• Prostate cancer (PCa) is among the most prevalent cancers of men in the world.

• Like other countries, PCa diagnosis, especially willingness towards its early diagnosis has increased in Iran

England64

Brazil50.3

USA83.8

AUS105

China4.3

Russia26.1

SA7.7

Sweden95.4

Iran11.55

Estimated age-standardised rates (World) per 100,000

Prostate Cancer Incidence & Mortality Worldwide in 2008

Cancer Incidence & Mortality (Iran)

Iran Incidence & Mortality (ASR)

GLOBOCAN 2008 (IARC)(3.5.2012)

Common cancers in Iranian men

Tumor marker vs. Tissue marker

• Tissue markers are expressed evenly by normal ,inflamed or infected tissue as well as cancerous tissue but in different extents

• Tumor markers are expressed only in cancerous tissue

Why to use tumor markers?

• Tumor markers are used to:– Cancer diagnosis– Follow-up for recurrence when definitive therapy

performed– Monitor the response to palliative therapy

How definite are tumor/tissue markers

• Using prostate-specific antigen to diagnose prostate cancer: sailing in uncharted waters

• Ann Intern Med. 1993 Nov 1;119(9):948-9.

Introduction

• The discovery of Prostate Specific Antigen (PSA) was revolutionary in early diagnosis of PCa

• PSA is a tissue marker with restrictions due to its lack of specificity for PCa cells serum levels of which may change following inflammation, infection or manipulation of the prostate.

• Despite variations in different countries, PSA cut-off point is determined at 7.85ng/mL in Iran, according to a recent study.

PSA Evolution

Molecular forms of PSA and the Prostate Health Index phi including the respective times of detection.

Why to seek for other markers?

• However, since PSA is prostate-specific but not cancer-specific, it is an imperfect biomarker.

• For example, PSA can increase in older men with benign prostatic hyperplasia.

Why to seek for other markers?

• Several new biomarkers are being investigated to improve the diagnosis of prostate cancer.

• Many other markers are investigated to replace PSA, like:

• PCA 3• EPCA 1 & 2

Prostate cancer antigen 3

• Is a gene that expresses a non-coding RNA.

• PCA3 is only expressed in human prostate tissue, and the gene is highly overexpressed in prostate cancer.

• Because of its restricted expression profile, the PCA3 RNA is useful as a tumor marker.

• Compared to serum PSA, PCA3 has a lower sensitivity but a higher specificity and a better positive and negative predictive value


• It is independent of prostate volume, whereas PSA is not.

• It should be measured in the first portion of urine after prostate massage with digital rectal examination.


• PCA3 has been shown to be useful to predict the presence of malignancy in men undergoing repeat prostate biopsy

• This means that it could be useful clinically for a patient for whom digital rectal examination and PSA suggest possible prostate cancer, but the first prostate biopsy returns a normal result.

Early Prostate Cancer Antigen (EPCA)

• EPCA is a matrix protein of prostate cells core with the two irrelevant types of EPCA-1 and EPCA-2.

• EPCA can be measured in serum (unlike PCA3) and considering its specificity compared to PSA

• It can probably distinguish PCa patients more precisely to avoid unnecessary biopsies in suspicious cases and function as an appropriate and promising alternative for early diagnosis of PCa.


• Prior studies revealed that intense immunohisto-chemical expression of EPCA in histologically benign prostate, regardless of extent, demonstrated – a high sensitivity (84% to 94%) – and specificity (85% to 100%)– for the presence of associated PCa.

• These studies compared EPCA expression in benign prostate tissue from negative biopsies, organ donors and cystoprostatectomies from men with bladder cancer to those from radical prostatectomies from men with PCa


• EPCA staining was demonstrated in primary and metastatic PCa, high grade intraepithelial neoplasia and benign atrophic glands.


• Leman, Getzenberg and colleagues describe, in the April 2007 issue of Urology, the performance characteristic of EPCA-2, a novel nuclear protein marker for prostate cancer cells.

• A study was initiated which suggested that the EPCA-2 protein serum assay exhibits favorable performance characteristics which are potentially superior to serum PSA.

• However more studies are necessary to see if this test will retain its sensitivity when used in a screening population


• Using a cutoff of 30 ng/mL:

– If EPCA 2<30• 92% specificity for healthy men and men with benign

prostatic hyperplasia

– If EPCA 2>30 • 94% sensitivity for overall prostate cancer.

– (Eddy S. Leman, Grant W. Cannon, Bruce J. et, al , Prostate. Jul 1, 2012; 72(10): 1157.)


• Additionally, EPCA-2 was highly accurate in differentiating between localized and extracapsular disease

• (Eddy S. Leman, Grant W. Cannon, Bruce J. et, al ,Prostate. Jul 1, 2012; 72(10): 1157.)

Methods and materials

• In a study conducted at Urology Research Center of Sina University Hospital, PCa suspicious cases and candidates of prostate biopsy were determined :

• PSA measurement • Digital Rectal Exam.


• Serum levels of PSA, Free PSA and EPCA were measured before biopsies.

• pathology reports :

• 107 patients: BPH• 69 patients: Cancer


• Para clinical and physical examination results as well as demographic information of the patients were gathered and entered into the data bank for performing statistical analysis.

Results: association between quantitative variables and the outcome

Group N Mean(SD) p_value

AgeBPH 107 63.34( 9.47)

<0.00Cancer 69 70.33(9.02)

EPCA-2BPH 107 43.54(48.60)

<0.00Cancer 68 111.72(124.05)

PSABPH 94 13.41( 13.99)

<0.00Cancer 62 26.81(33.14 )

HbBPH 51 14.99(1.54)

0.03Cancer 41 14.20(1.95)

Plt*104BPH 107 23.46( 5.81)

<0.00Cancer 69 21.32(4.32)

CrBPH 51 1.20(0.35)

.82Cancer 39 1.19(0.40)

Multivariable analysis of association between various independent variables with the outcome: logistic regression,

Enter method

B S.E. OR(exp b) P_value

Age .077 .024 1.080 .00

Using medication -.061 .39 .941 .87

Prostate in family -.145 .396 .865 .713

EPCA-2 .009 .004 1.009 .021

PSA -.007 .015 0.993 .62

Considering control of other independent variables, Age, UTO

and EPCA-2 have significant

association with the outcome.

Different cut off of EPCA-2 for cancer diagnosis

Cut-Off Sen. Spe.PPV%()

3.93 100 1 40.2412.15 87.9 20.6 42.4619.52 79.3 34.0 44.4728.55 74.1 50 49.6959.62 50 75.3 57.4399.69 36.2 91.8 74.63

148.61 22.4 96.9 82.80375.38 6.9 100 100

Different cut off of PSA for cancer diagnosis

Cut-Off Sen. Spe. PPV%()

1.95 100 2.1 40.51

3.97 94.9 5.2 40.02

7.02 79.7 29.9 43.1168.42 74.6 50 49.86

13.35 50 73.2 55.4320.25 39 85.6 64.3530.2 23.7 90.7 62.9498 8.5 100 100

Frequency of cancer according to PSA strata

PSA groups Frequency Percent Valid Percent

missing

BPH 10 50.0 50.0

Cancer 10 50.0 50.0

Total 20 100.0 100.0

<10BPH 59 72.8 72.8

Cancer 22 27.2 27.2

Total 81 100.0 100.0

10-20BPH 23 62.2 62.2

Cancer 14 37.8 37.8

Total 37 100.0 100.0

20<BPH 15 39.5 39.5

Cancer 23 60.5 60.5

Total 38 100.0 100.0

Relationship between EPCA and Cancer according to PSA groups:

group N Mean Std. Deviation

Std. Error Mean P_value

EPCA BPH 59 30.59 40.76 5.30 0.85Cancer 21 32.36 27.32 5.96

PSA<10

group N Mean Std. Deviation

Std. Error Mean P_value

EPCABPH 38 66.55 56.77 9.21

<0.0001Cancer 37 156.26 140.16 23.04

PSA>10

Diagnostic indices of EPCA when PSA is more than 10

Cut-Off sensitivity)%( specificity)%( PPV)%(

3.23 100 0 49.33

30.1 89.2 23.7 53.23

43.79 75.7 39.5 54.92

55.62 70.3 50 57.78

119.41 51.4 86.8 79.12

133.98 40.5 94.7 88.15

164.54 35.1 97.4 92.93

375.38 10.8 100 100

Discussion

• It is more than 30 years from clinical application of PSA for prostate cancer screening and detection.

• It is demonstrated that PSA is not as specific as needed and its local and racial variations are too high

Discussion

• Many patients with elevated PSA suffer repeated negative biopsies as well as concern of undiagnosed cancer

• EPCA seems to be a good predictor of cancer presence in combination with PSA to avoid unnecessary biopsies.

Conclusion

• EPCA changes in BPH and Cancer groups, independent of PSA and age, were statistically significant (P-value<0.001).

• EPCA 2 can play a prominent role in diagnosing PCa.

Thank you for your attention

Documents

EPCA: A silver lining for early diagnosis of prostate cancer GHOLAMREZA POURMAND, MD Professor of Urology Urology Research Center Tehran University of