The prostate health index is superior to PSA and %fPSA, and can be integrated with MRI in predicting who needs prostate biopsies, and sparing men from unnecessary biopsies.

1. Role of Prostate Health Index
in the changing landscape of
prostate cancer diagnostics
Dr Lincoln Tan
MBBS,MRCS(Edin),FRCS(Glasg),FAMS
Director of Urologic Oncology
Dept of Urology, NUH
Surgical Oncology, National Cancer Institute Singapore

4. Case study
• 65 yr old man
• Fit, no medical issues
• Referred for LUTS – not any medication
• No family history of prostate CA
• DRE 3fb smooth benign feeling prostate
• PSA 6.2ng/ml
• Repeat PSA 6.0ng/ml

5. What next?
1. 12 core TRUS biopsy
2. Check PSA velocity à Repeat PSA in few months time
3. Free: Total PSA
4. Risk calculator
5. MRI prostate
6. Offer PHI

6. Scope
• Deficiencies in current diagnostic pathway for prostate cancer
• Current tools for deciding if a man needs a prostate biopsy
• Introducing p2PSA and PHI
• Superiority of PHI over PSA, %fPSA
• PHI in combination with MRI
• How to use the PHI - Risk classification vs risk tolerance

8. • 1-3% of prostate cancer detected on
abnormal DRE only
• Of the cancers detected by DRE
alone, 20% non-organ-confined and
20% Gleason score of ≧7
• Dedifferentiated / advanced i.e
“killer” prostate cancer stops
producing PSA!
à DRE necessary even if PSA normal
DRE unreliable, but still important
PSA level Risk of PCa (%) Risk of GS > 7 PCa (%)
0.0-0.5 6.6 0.8
0.6-1.0 10.1 1.0
1.1-2.0 17.0 2.0
2.1-3.0 23.9 4.6
3.1-4.0 26.9 6.7
N Engl J Med, 2004. 350: 2239
J Urol. 2017 Feb;197(2S):S200-S207
Urology. 2007 Dec;70(6):1117-20

9. Benign disease
Cut-off
zone
PSA [ng/mL]
PSA Testing: The Reality
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 100.0
Indolent PCa
Aggressive PCa

10. PSA – Implications of 2 different standards
• Hybritech and WHO standards
do not produce equivalent
results
• Studies show that WHO tests
yield PSA levels approximately
20-23% lower than the
Hybritech ones
• Affects PSAV, PSA density
• Can cause delay in biopsy

12. • ”There is little evidence that calculation of PSA velocity or doubling time in
untreated patients provides predictive information beyond that provided by
absolute PSA level alone”
• PSA and PSAV are highly correlated, and this may explain why PSAV does not
add predictive value

14. Conclusions. Percent free PSA can be a useful adjunct to PSA for primary prostate cancer screening only
under certain defined situations. In the “gray zone,” or reflex range, of PSA testing, %fPSA improves clinical
information only when levels reach extreme values

15. • PSA velocity and PSA-DT may have a prognostic role in treating PCa, but limited
diagnostic use because of background noise (total prostate volume, and BPH),
different intervals between PSA determinations, and acceleration/deceleration of
PSAV and PSA-DT over time. These measurements do not provide additional
information compared with PSA alone
• Free/total (f/t) PSA must be used cautiously because it may be adversely affected
by several pre-analytical and clinical factors (e.g., instability of free PSA at 4°C and
room temperature, variable assay characteristics, and concomitant BPH in large
prostates). However, it continues to have value in stratifying the risk of PCa in men
with 4-10 ng/mL total PSA and negative DRE. Prostate cancer was detected by
biopsy in 56% of men with f/t PSA < 0.10, but in only 8% with f/t PSA > 0.25 ng
/mL. Free/total PSA is of no clinical use if total serum PSA is > 10 ng/mL or during
follow up of known PCa
EAU guidelines

16. EAU guidelines

17. PCPT calculator -http://riskcalc.org:3838/PCPTRC/

18. ESRCP based risk calculators http://www.prostatecancer-
riskcalculator.com/seven-prostate-cancer-risk-calculators
1. the general health calculator is a starting point, looking at family history, age and
any medical problems with urination
2. the PSA risk calculator looks at the levels of prostate specific antigen (PSA) in
patient’s blood to help predict whether further investigation is required.
3. Risk Calculator 3 and 4 with TRUS or DRE: Nowadays these risk calculators are
combined into one decision tree and thus can be used for men that have not been
previously biopsied but also for men that have been screened previously and had a
prostate biopsy with a benign result
4. Risk calculator 3 and 4 with TRUS or DRE and the result of the Phi test: Using these
risk calculators gives you the possibility to include the outcome of the so-called
Prostate Health Index (Phi) blood test which will slightly increase predictive
capability.
5. Risk calculator 5 calculates the chance of having indolent prostate cancer which
may not require immediate treatment.
6. Risk Calculator 6 is the latest in the series — it calculates a man’s future risk over
the next four years, taking into account age, prostate-specific antigen, digital rectal
examination, family history, prostate volume, and previous biopsy status.

24. • AUC of ROC for prostate cancer using PSA alone and the nomogram
were 0.688 and 0.804, respectively
• PSA cutoff 6.7 maybe more appropriate for Filippino population
Asian Journal of Urology (2015) 2, 114e122

25. Can we do better than TRUS biopsy?

28. • Retrospective review of 101 RRP with neg mpMRI
Pathological outcomes Final pathology General reading (%) Expert reading(%)
Extraprostatic extension 16.9 22.3 3.4
GS≥ 4 + 3 and above 13.8 18 3.4
Main tumour volume of ≥ 0.5 55.9 38.2 58.3
Main tumour volume of ≥2.0 20.6 25.5 8.3

29. A negative MRI does not mean the absence
of significant prostate cancer

30. • 1255 neg MRI
• 163 dx with PCA
• 60 of these csPCa

31. • 60yr, PSA 6.9à 7.8, PIRADS 2
• TRUS bx 1 core 4+4; RRP pT3bN1 GS 5+4, predom cribriform pattern

32. Learning curve of fusion biopsies
Calio et al Prostate Cancer and Prostatic Diseases (2017) 00, 1–6

33. MRI is not perfect, and trial results ≠ your centre
MRI guided bx is a team sport
• Tumours are missed on MRI
• Very dependent on radiologists and urologist skill/experience – results from
literature may not translate to your centre
• PROMIS – 5 possible centres excluded because unable to provide sufficient
quality DESPITE expert training and support
• Must evaluate your own centres’ data, determine own NPV and strive to
improve through constant dialogue between Urology and Radiology
Hashim Ahmed personal communication
2017 –EAU)

34. Saturation biopsies reduce sampling/MRI error
• While MRI guided biopsy has better accuracy
than systematic biopsy, still has miss rate
• Deferral of concurrent systematic biopsy should
not be considered until performing quality
assurance and demonstrating the results of MRI-
targeted biopsy within the local practice

35. mpMRI – 2 strategies
• Strategy 1 consists in using mpMRI as a triage test before biopsy. In
this diagnostic pathway, only MRI-TBx would be performed in case of
a positive mpMRI. Patients with a negative mpMRI would not
undergo prostate biopsy at all
• Strategy 2 uses mpMRI to improve the detection of clinically
significant PCa (csPCa). In this diagnostic pathway, magnetic
resonance imaging-targeted biopsies (MRI-TBx) would be added to
systematic biopsies in case of a positive mpMRI, and systematic
biopsies would be performed in all patients with a negative mpMRI.

36. p2PSA and PHI

37. p2PSA is a prostate cancer specific PSA Isoform
[-2]proPSA:
A new biomarker
that is more specific
for prostate cancer

38. Prostate health index (PHI)
PHI = p2PSA x √PSA
freePSA
3x more accurate than PSA

39. PHI is superior to PSA in prediction of positive
prostate biopsy
• Multiple studies in US, European and Asian cohorts show consistently
marked superior AUC on ROC curves compared to PSA
• AUC of PHI in order of 0.70-0.76 vs PSA 0.50-0.55
• Consistently shown to be best predictor for PCa compared to other
PSA markers – PSAD/PSAV/ %fPSA

41. PSA as a predictor for positive prostate biopsy is no
better than a flip of a coin!

42. Higher PHI related to more aggressive PCa
• AUC to detect aggressive prostate cancer was 0.815
• At 95% sensitivity PHI specificity was 36.0% vs 17.2% and 19.4% for tPSA and %fPSA, respectively
• At 95% sensitivity for detecting aggressive prostate cancer the optimal PHI cutoff was 24, which would help avoid 41%
of unnecessary biopsies. A cutoff of 24 led to 36% biopsies avoided with few aggressive cancers missed.
• These results were confirmed in the validation cohort

44. • The phi AUC was 0.703 vs 0.704 for
Hybritech vs WHO calibrations.
• Difference between calibrations 3-5
at higher sensitivities
• PHI can be calculated using
Hybritech or WHO standardized
assays, and significantly improved
the prediction of biopsy outcome
over %fPSA or PSA alone
Loeb et al. J Urol. 2013 May ; 189(5): 1702–1706.

45. • 8 studies involving 2969 patients with a tPSA range of 2–10
ng/mL undergoing first biopsy included in this meta-analysis
• Biopsy confirmed PCa detected in 1287 (43.3%) men
• Areas under curve (AUCs) of PHI and %fPSA were 0.74 (95%
CI 0.70–0.77) and 0.63 (95% CI, 0.58– 0.67), respectively
• Meta-regression analysis confirmed the superiority of PHI
which showed, compared with %fPSA, a relative diagnostic
odds ratio of 2.81 (95% CI, 2.19–3.6; P , 0.0001).
Transl Res. 2014 Dec;164(6):444-51.

46. Asian data shows PHI outperforms PSA and F/T PSA
Authors Country n PSA Positive
biopsies %
Biopsy
cutoff
Specificity of PHI
at 90% sensitivity
(%)
Specificity of PSA
at 90%
sensitivity(%)
% avoidable
biopsies
AUC
ROC of
PHI
AUC of
ROC of
F:T PSA
AUC of
ROC of
PSA
L Tan et
al1
Singapore 157 4-10 19.1 26.75 58.27 17.3 49% 0.79 0.42 0.48
CF Ng
et al2
Hong
Kong
230 4-10 9.1 26.54 49.76 17.2 49.8 0.78 0.57 0.55
Na et
al3
Shanghai 660 2-10 20.6 28 50.6 93.4 7.4 98.7 41.5 0.87 0.68 0.60
Hsieh
PF et
al4
Taiwan 154 4-10 23.4 29.6 57.1 0.76 0.33 0.57
Park H
et al5
South
Korea
155 3.5-10 39.4 68.3 21.2 21.3 0.76 0.69 0.56
1Asian Journal of Andrology (2016) 18, 1–5 2 Int Urol Nephrol (2014) 46:711–717
3The Prostate. 2017;77:1221–1229. 4Kaohsiung Journal of Medical Sciences (2018) 34, 461-
466 5Korean Med Sci. 2018 Mar 12;33(11):e94

47. • 503 European (Munster, Hamburg, Paris, Rennes) and 1150 Asian (Hong Kong,
Shanghai, Singapore, Taipei, Taichung)
• PCa and HGPCa were 4 times more common in European

48. • Net clinical benefit of PHI over PSA in both groups
• A higher proportion of biopsies could be avoided in Asian men using PHI
• Reference range specific to each ethnic group are advised

49. PHI cutoff depends on study population and
level of risk you can tolerate
• EAU guideline – no phi cut off recommended
• NCCN guidelines recommend phi>35
• Cutoff is a balance between reducing unnecessary biopsies vs
reducing missed significant Pca

50. Are Filipinos at lower risk of PCa like other
Asians?
Matias PJM, Raymundo EM (2014) Prostate Cancer and the Filipino:
An Updated Review of Publications. J Urol Res 1(3): 1016.

52. Risk of csPCa based on PIRADS in PRECISION

53. Combining MRI and PHI reduces missed clinical
significant PCa in men with negative mpMRI
• Cambridge – In repeat biopsy cohort - Negative mpMRI (Likert score
<3) + PHI ≥ 35 detected 95% of clinically significant tumours, sparing
42% of cohort from negative biopsy
• Hopkins – No men with PHI < 27 and PI-RADS⩽ 3 had GG ⩾2 cancer; as
compared with 29% men with PI-RADS⩽ 3 and PHI ⩾ 27.
• Singapore – Men with PI-RADS 3 lesions, PHI <27, no missed csPCa and
spared 34% from negative biopsy
Sci. Rep. 6, 35364
Prostate Cancer and Prostatic Diseases (2017) 20, 228–233
J Endourol. 2017 Nov;31(11):1111-1116.

54. Extended use of PHI?
•5ARIs
•PSA>10
•Prev negative biopsies
OFF LABEL

55. Urologic Oncology:Seminars and Original Investigations34(2016)415.e13–415.e19

57. • Chinese men with PSA 10–20 ng/mL and normal DRE, the overall prostate cancer detection rate was 17.2%,
which is comparable to that of the Western population at PSA level of 4–10 ng/mL.
• 57.1% biopsies could be avoided with the cost of missing 6.7% any grade prostate cancer and 2.2% high
grade prostate cancer in men with PHI<35.
• Another recent Chinese cohort (Na et al) showed a higher positive biopsy rate of 36.5% for men with 10–20
ng/ mL (about 30% abnormal DRE), which was was still similar to that in Caucasian with PSA 4–10 ng/mL
• Although PHI indicated in men with PSA 4–10 ng/mL and normal DRE, PHI may play an important role at
PSA 10–20 ng/mL in the Chinese population

59. • At a PHI cutoff of 28.8, 116 (52.25%)
biopsies could have been avoided,
missing prostate cancer in 6 patients,
but none with a GS ≥ 7
• %p2PSA and phi were significantly
higher in men with PCa at repeat biopsy,
and are the most accurate predictors of
outcome compared with reference
standard tests

60. When is PHI useful?
• Many men are not keen for biopsies, yet remain anxious ++
• Better risk classification can “nudge” those who need biopsies to go for it
• Very high PHI is very persuasive
• Multiple parameters that indicate low risk can reassure men who are PSA-
terrified
• Sometimes urologists are not keen to biopsy, but patients are risk
adverse
• Elderly men with <10yr LE with grey zone PSA
• Large prostates with low PSAD, or clinical prostatitis
• Young men with abnormal PSA

61. Risk classification vs risk tolerance
• No test or combination of test (as well as biopsy) can exclude all risk
of prostate cancer
• 5% risk in 50 year old fit man vs 75 yr old man has different value
• Understanding your own and your patient risk tolerance will
determine the level of investigation/risk classification needed
• Avoiding unnecessary biopsies is good risk mitigation strategy for your
practice
• Pt more accepting of complications if they can see that you have
taken all effort to avoid unnecessary biopsy

62. Utility of PHI depends on patient’s and your risk tolerance
PHI Risk of positive biopsy Good
Age/comorbidity
profile + Low risk
tolerance
Good
Age/comorbidity
profile + High risk
tolerance
Poor
Age/comorbidity
profile + low risk
tolerance
Poor Age/
comorbidity
profile + high risk
tolerance
PHI <23 Lower than expected
(2-17)
Observe +/- MRI Observe Observe/discharge PHI not useful
PHI 23-45 17.1-24.1%
As expected
Biopsy +/-MRI MRI +/-Observe Observe/discharge
+/- MRI
PHI not useful
PHI >45
(>35)
35.8-52.5%
Higher than expected
Biopsy +/- MRI Biopsy – +/- MRI MRI PHI not useful
PHI <27 Minimal risk of missing
csPCa based on Asian
data
Observe +/-MRI Observe Observe/discharge PHI not useful
• PSA 4-10 – risk of positive bx 20-25% (intermediate risk)
• Further risk classification often useful
• Cut offs vs ranges

63. How I use PHI in new diagnostic landscape
Grey zone PSA
PHI
MRI
PHI ≧27
PIRADS 4-5
Observe or discharge
Observe or dischargePIRADS 1-2
PHI<27
PHI ≧27

64. How I use PHI in new diagnostic landscape
Grey zone PSA
PHI
MRI
PIRADS 1-3
10-15% PCa
PIRADS 4-5:
60-80% csPCa
Observe or discharge
PHI<27
PHI ≧27

65. Conclusions
• Traditional diagnostic pathway of PSA followed by TRUS biopsy is deeply
flawed
• PSA to diagnose prostate is a coin flip
• Important to be aware of PSA calibration
• PSA dynamics, %fPSA not useful
• MRI good diagnostic tool, but must evaluate your own centres’ data and NPV
• Do targeted biopsies together with systematic biopsies (until mount learning
curve for radiologist and urologist)

66. Take home message
• Global and Asian studies consistently show PHI outperforms PSA and
F/T PSA ratio as predictor of clinically significant PCa on biopsy
• Higher PHI points to more aggressive disease
• Ideal cutoff point depends on population tested – local studies
needed to validate
• No test is perfect – combination of tests help in developing best risk
assessment for individual patient – decision to biopsy depends on
pt/clinician risk appetite

67. Salamat!
Lincoln Tan
about.me/lincoln.tandrlincolntan@gmail.com