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

England 64 Brazil 50.3 USA 83.8 AUS 105 China 4.3 Russia 26.1 SA 7.7 Sweden 95.4 Iran 11.55

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)( )

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 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

Prostate cancer antigen 3 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.

Prostate cancer antigen 3 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.

Early Prostate Cancer Antigen (EPCA) 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

Early Prostate Cancer Antigen (EPCA) EPCA staining was demonstrated in primary and metastatic PCa, high grade intraepithelial neoplasia and benign atrophic glands.

Early Prostate Cancer Antigen (EPCA) 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

Early Prostate Cancer Antigen (EPCA) 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.)

Early Prostate Cancer Antigen (EPCA) 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.

Methods and materials Serum levels of PSA, Free PSA and EPCA were measured before biopsies. pathology reports : 107 patients: BPH 69 patients: Cancer

Methods and materials 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 GroupNMean(SD) p_value Age BPH (9.47) <0.00 Cancer (9.02) EPCA-2 BPH (48.60) <0.00 Cancer (124.05) PSA BPH (13.99) <0.00 Cancer (33.14) Hb BPH (1.54) 0.03 Cancer (1.95) Plt*10 4 BPH (5.81) <0.00 Cancer (4.32) Cr BPH (0.35).82 Cancer (0.40)

Multivariable analysis of association between various independent variables with the outcome: logistic regression, Enter method 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 Different cut off of PSA for cancer diagnosis

Frequency of cancer according to PSA strata

Relationship between EPCA and Cancer according to PSA groups: groupNMean Std. Deviation Std. Error Mean P_value EPCA BPH Cancer PSA<10 groupNMean Std. Deviation Std. Error Mean P_value EPCA BPH < Cancer PSA>10

Diagnostic indices of EPCA when PSA is more than 10 Cut-Offsensitivity(%)specificity(%)PPV(%)

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.

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