1.
Prostate specific antigen (PSA)
​Dr Mayank Mohan Agarwal
MBBS, MS, MRCS(Ed), ​DNB, MCh (PGIMER, Chandigarh)
VMMF and IAUA Fellowships Uro-Oncology, Pelvic Floor Reconstruction
(MSKCC, NY; UCLA, LA; WFUBMC, NC)​
Formerly Associate Professor of Urology, PGIMER, Chandigarh
Formerly Consultant & Head of Urology, NMC specialty Hospital, Abu Dhabi
Consultant and Head of Urology
(Aster) Dr. Ramesh Cardiac and Multispecialty Hospitals Pvt. Ltd.
Guntur (AP), India

2.
Introduction
• PSA physiology
• PSA parameters
• for diagnosis of CAP
• for prognosis of CAP
• Summary and conclusion

3.
Population based PSA screening
• Population based RCT n = 182000
0
0.2
0.4
0.6
0.8
1
1.2
50-54 55-59 60-64 65-69 70-74
CAP specific deaths per 1000 person-year
screening control
Schroder FH et al. N Engl J Med 2009;360:1320-8.

4.
PSA (human Kallikrein peptidase 3)
• Serine protease, member of a family of 15 hkp’s
• preproPSA  proPSA  PSA  _mg/ml into semen
A millionth (_ng/ml)
unprocessed
Processed
in prostate
(70-80%)
(90-95%)
(5-10%)
(1-2%)
(20-30%)

5.
PSA (human Kallikrein peptidase 3)
• Serine protease, member of a family of 15 hkp’s
• preproPSA  proPSA  PSA  _mg/ml into semen
A millionth (_ng/ml)
unprocessed
Processed
in prostate
(70-80%)
(90-95%)
(5-10%)
(1-2%)IN
CANCER
(<20-30%)

6.
PSA (human Kallikrein peptidase 3)
• Organ specific (almost)
– breast tissue, breast milk, breast/kidney/adrenal cancer, parotid
• Disease non-specific
– prostatic hyperplasia, prostatitis, prostate manipulation, prostate cancer

7.
Risk of CAP based on PSA
• PSA is a continuous variable
• There is actually no “normal” value
• “probability” of having CAP proportional to PSA
0
20
40
60
80
100
0.0-0.5 0.6-1.0 1.1-2.0 2.1-3.0 3.1-4.0 4.1-10.0 10.1-20.0 >20.1
% risk of CAP
Thompson, I.M., et al. N Engl J Med 2004; 350: 2239.

8.
Attempts to improve sens-spec of PSA
• Age-specific PSA
• PSA density
• Total
• TZ
• % free PSA
• PSA kinetics
• PHI
• others

9.
AGE REFERENCED PSA
Age PSA
40-49 0.0 – 2.5
50-59 0.0 – 3.5
60-69 0.0 – 4.5
70-79 0.0 – 6.5
Oesterling JE et al. JAMA 1993; 270: 860-864
0
20
40
60
80
100
40-49 50-59 60-69 70-79
PSA sensitivity age-sp PSA sensitivity
PSA specificity age-sp PSA specificity

10.
PSA density
• PSA per unit volume (PSAD) 0.10 – 0.15
• PSA per unit TZ volume (PSAD-TZ) ?? 0.20 – 0.30
0
20
40
60
80
100
0.1 0.15 0.2 0.3
sensitivity specificity
PSAD-TZ
0
20
40
60
80
100
0.075 0.1 0.15 0.2 0.25
sensitivity specificity
PSAD

11.
Percent free PSA
• “more the merrier”
0
20
40
60
80
100
8 10 11 12 13 14 15 17
perc free PSA
sensitivity specificity
unprocessed
Processed
in prostate
(70-80%)
(90-95%)
(5-10%)
(1-2%)IN
CANCER
(<20-30%)

12.
PSA kinetics
• Change of PSA over time
PSA VELOCITY
(ng/ml/YEAR)
PSA DOUBLING TIME
(MONTHS)
V1
V2
V3
Vav = (V1+V2+V3)/3
Before
diagnosis
After
diagnosis

13.
PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 2-4 cutoffs as low as 0.1ng/ml/yr predict cancer probability over
10 year period

14.
PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 2-4 cutoffs as low as 0.1ng/ml/yr predict cancer probability over
10 year period – better still in men <50 years of age
• Proposed cutoff for men <50
• PSA 2.0 - 2.5
• PSAV 0.2 - 0.6
Sun L et al. BJUI 2007; 99: 753-757

15.
PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 2-4 cutoffs as low as 0.1ng/ml/yr short term predictability very
poor
Djavan B. UROLOGY 1999; 54: 517–522

16.
PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 4-10 cutoffs 0.35-0.75 ng/ml/yr have been used with relatively
high specificity but low sensitivity
Mettlin C. Cancer 1994; 74:1615-20; Lee SC. Korean J Urol 2004;45:747-752

17.
VERDICT
Schroder FH et al. Eur Urol 2008; 53: 468-477

18.
PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
Ali et al. Int J cancer 2006; 120: 170-4

19.
PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Active surveillance
Ali et al. Int J cancer 2006; 120: 170-4

20.
PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post-radical prostatectomy biochemical recurrence
Pound CR et al. JAMA 1999; 281: 1591-7
METSfreesurvivalprobability

21.
PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post-radical prostatectomy cancer-specific mortality
Freedland SJ et al. JAMA 2005; 294: 433-9. Freedland SJ et al. J Clin Oncol 2007; 25: 1765-1771

22.
PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post-radical radiotherapy
Pollack A et al. Cancer 1994; 74:670-8.
PSADT
<5m
5-12m
>12m
Local control Metastasis-free Any relapse

23.
PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post CRPC status – prognostication and possible aggression of treatment
Smith MR et al. J Clin Oncol 2013; 31:3800-3806

24.
PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post CRPC status – prognostication and possible aggression of treatment
Armstrong AJ, et al. Clin Cancer Res 2007;13(21). 6396-6403
PSADT
PSA

25.
VERDICT
Maffezzini M et al. Eur Urol 2007; 51: 605-613. Pound CR et al. JAMA 1999; 281: 1591-7

26.
PROSTATE HEALTH INDEX (PHI)
• PHI = p2PSA x √PSA / fPSA
• PSA 2-10
• Probability of having prostate cancer based on score
10
20
30
40
50
60
0-24.9 25-34.9 35-54.9 ≥55
%cancer risk % ≥7 gleason
Loeb & Catalona. Ther Adv Urol 2014; 6: 74–77

27.
PROSTATE HEALTH INDEX (PHI)
• PHI = p2PSA x √PSA / fPSA
• PSA 2-10
• Sensitivity for cancer detection
Loeb & Catalona. Ther Adv Urol 2014; 6: 74–77

28.
PROSTATE HEALTH INDEX (PHI)
• PHI = p2PSA x √PSA / fPSA
• PSA 2-10
• Prediction of adverse histology after RP
Guazzoni G et al. Eur Urol 2012; 61: 455-466

29.
Other parameters
• 4 kallikrein score (PSA, fPSA, p2PSA, hK2, DRE, age, previous Bx)
• ConfirmDx
• PCA3 (EPS urine)
• ExoDx (PCA3, ERG RNA)
• Mi-prostate score (PSA, PCA3, ERG)
• Select MDx (EPS urine DLX1, HOXC6, KLK3)

30.
SUMMARY AND CONCLUSION
• PSA –
• First alert for biopsy
• Risk stratification after diagnosis (<10, 10-20, >20)
• Monitor recurrence after radical treatment
• Alert for salvage treatment
• Prognostication after recurrence
• PSADT -
• Alert for radical treatment in surveillance patients
• Alert for salvage treatment
• Prognostication after recurrence
<3-6m vs
6-12m vs
>12-24m

31.
SUMMARY AND CONCLUSION
• PSA parameters –
• %fPSA
• PSAD
• PSAD-TZ
• PSAV
• For aiding timely biopsy
• Possibility for prognostication
once diagnosis made 0
20
40
60
80
100
%fPSA (<15) PSAV
(>0.75)
PSAD
(>0.15)
combined CPC
PSA >4
sensitivity specificity
Murray NP et al. BioMed Res Int; 2014
• PHI
• 4k score

32.
SUMMARY AND CONCLUSION
• In absence of conclusive evidences, logic must prevail