epca: a silver lining for early diagnosis of prostate cancer gholamreza pourmand, md professor of...
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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
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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
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England64
Brazil50.3
USA83.8
AUS105
China4.3
Russia26.1
SA7.7
Sweden95.4
Iran11.55
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Estimated age-standardised rates (World) per 100,000
Prostate Cancer Incidence & Mortality Worldwide in 2008
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Cancer Incidence & Mortality (Iran)
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Iran Incidence & Mortality (ASR)
GLOBOCAN 2008 (IARC)(3.5.2012)
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Common cancers in Iranian men
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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
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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
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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.
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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.
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PSA Evolution
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Molecular forms of PSA and the Prostate Health Index phi including the respective times of detection.
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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.
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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
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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
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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.
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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.
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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.
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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
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Early Prostate Cancer Antigen (EPCA)
• EPCA staining was demonstrated in primary and metastatic PCa, high grade intraepithelial neoplasia and benign atrophic glands.
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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
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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.)
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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.)
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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.
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Methods and materials
• Serum levels of PSA, Free PSA and EPCA were measured before biopsies.
• pathology reports :
• 107 patients: BPH• 69 patients: Cancer
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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.
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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)
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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.
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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
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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
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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
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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
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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
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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.
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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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Thank you for your attention