8 - CaP - Basics & Dx Flashcards
Draw the different zones of prostate. Which zone is prostate cancer most commonly found?
Prostate cancer most commonly found in peripheral zone (70%) because it contains most glandular tissue
How common is prostate cancer?
Based on HK Cancer Registry:
- 3rd most common cancer in male
- 4th cause of cancer death in male
Worldwide figure:
- 2nd most common cancer in male
- 3rd cause of cancer death in male
Risk factors for CA prostate
1) Age >50yo
2) African Ancestry >40yo
3) Family history of Prostate cancer
- esp closer degree of relatives
- number of diagnosed relatives
- younger age diagnosis <65yo
4) Genetic mutations and syndromes
5) Alcohol
Genetic mutations that increases risk of CaP
Need to update
Classified based on gene function
1) HHR (Homologous Recombination Repair) Genes mutations
1.1) BRCA1 conflicting evidence
1.2) BRCA2
=> 2-6 times more common, earlier age, more aggressive, advanced stage, hight mortality (most common germline mutation for mCaP)
=> potential candidate for PARP inhibitor
- 3) CHEK2 mutation
- I 157 T mutation
- a/w CaP, ccRCC, Breast, colon, thyroid - 4) ATM gene
- 5) PALB2
2) DNA Mismatch Repair Genes
- Lynch Syndrome (HNPCC) which involves:
- MLH1
- MSH2, MSH6
- PMS2
=> 2-6 times more common; but not age of onset or aggressiveness
=> mutation will cause deficient mismatch repair (dMMR) causing microstatellite instability
=> candidate for pembrolizumab
3) Regulatory genes
- HOXB13
3)
=>
TNM Staging of CaP
T1 non-palpable disease
- T1a TURP ≤5%
- T1b TURP >5%
- T1c Identified by biopsy
T2 palpable by DRE
- T2a <50% of one lobe
- T2b >50% of one lobe
- T2c both lobes
T3 outside prostate
- T3a Extracapsular extension
- T3b Seminal vesicle invasion
T4 Invades adjacent structures
N1 Regional LN +
M stage:
- M1a Non-regional LN
- M1b Bone
- M1c Other sites
Regional lymph nodes of CA prostate
Regional lymph nodes are the nodes of the true pelvis, i.e. below the bifurcation of the common iliac arteries:
1) Pelvic LN
2) Hypogastric LN
3) Obturator LN
4) Iliac LN
5) Sacral LN
Other LNs are considered distant mets, including: para-aortic lumbar, common iliac, inguinal LNs (deep or superficial), retroperitoneal, and any more distal LNs
Definition of suspicious LNs on CT or MRI
Detected using CT or MRI, based on LN size and morphology (sensitivity <40%)
Considered malignant if >8mm in the pelvis or >10mm outside the pelvis
How would you classify localised CA prostate?
Based on D’Amico risk groups|
- i.e. risk of biochemical / PSA recurrence after radical treatment at 5 years
- 15% / 40% / 70% respectively
1) Low risk
- PSA <10
- ISUP 1 (GS 3+3)
- T2a or below
2) Intermediate risk
- PSA 10-20
- ISUP 2-3 (GS 3+4 and 4+3)
- T2b
3) High risk
- PSA >20
- ISUP 4 or above
- T2c or above
➔ Locally advanced included in high risk: cT3-T4 or cN1
Would you offer PSA testing for an asymptomatic man? Explain
What are the pros and cons
DRE and PSA taking can be offered to asymptomatic men for opportunistic early detection of prostate cancer, if:
1) Patient is at risk e.g. age >50
2) Patient is well informed
3) and has a life expectancy of at least 15 years
I will counsel the patient adequately to arrive at a shared decision
Benefit based on the ERSPC at 16 year update:
- 21% RRR in CSM
- NNI 570 and NND 18 to prevent 1 CaP death
(Or Gotenborg 1 trial)
Disadvantage is that:
- no OS benefit
- also issue of over-diagnosis of clinically insignificant / low risk cancer, over-treatment, and morbidities and mortalities from invasive procedures
The local HKUA recommendations suggest opportunistic early detection for men 50-77yo
Who are the patients at elevated risk for prostate cancer? (who should have early PSA testing for opportunistic early detection)
According to EAU (2024):
1) Men >50yo
2) Men >45yo with family history
3) Men >45yo of African descent
4) Men >40yo with BRCA2 mutations
HKUA recommends screening for men age 50-77yo
What is screening? How is it different from early detection?
Screening is defined by population / systematic examination or testing in asymptomatic normal population, to identify individuals at risk for an unrecognised disease
Early detection is initiated at individual level
What are some criteria to consider if screening is recommended?
WHO Criteria by Wilson and Junger:
A. Disease related
1) Important health problem
2) Well understood natural history
3) Long latent stage
B. Screening test related
1) Suitable and acceptable screening test
2) Cost effective
3) Continuous case finding
C. Treatment related
1) Acceptable treatment, that is more beneficial if started early
2) Agreed policy on whom to treat
3) Available facilities for Dx and Tx
What are the current evidence of PSA screening for prostate cancer?
Population screening remains controversial, the evidence as follows:
Cochrane Review of 5 RCTs (2018):
- increased CaP Dx
- higher detection of localised disease, and less advanced disease
- No CSM or OS benefit
However individual RCTs suggest there is CSM benefit, including:
1) ERSPC Study (European Randomised Study on Screening of Prostate Cancer):
- at 16 years
- 21% RRR in CSM; no OS benefit
- NNI 570 and NND 18 to prevent 1 CaP death
2) Gotenbog-1 Trial
- at 18 years
- 42% RRR in CSM; no OS benefit
- NNI 139 and NND 13
Have you heard of the PLCO trial? What is it and what are its problems?
PLCO = prostate, lung, colorectal, ovarian cancer screening trial
Annual PSA for 6 years
Bx if PSA >4 or abnormal DRE
➔ Did not show CSM or OS benefit
However it has multiple problems including:
1) Underpowered
2) Pre-screening ~45%
3) Contamination up to 50%
4) Non-compliance to Bx up to 50%
➔ Better evidence with ERSPC and Gotenbog-1 study
How frequent should we monitor PSA if overall low risk and not indicated for MRI or Bx
The optimal FU interval is still unknown. Different screening trials have different FU interval:
- PLCO: annual PSA
- ERSPC: every 4 years
- Gotenbog: every 2 years
(EAU 2024): We should adopt a risk-adapted strategy based on initial PSA level.
If initially at risk, i.e.
- PSA >1 at 40yo
- PSA >2 at 60yo
Then 2 yearly PSA checking
If not at risk, then postpone FU up to 8 years
A patient presents with elevated PSA to your clinic, how would you assess him?
I will obtain a comprehensive history first:
1) Actual age
2) Reason for PSA checking
3) Aysmptomatic vs symptomatic
4) Any urinary symptoms / LUTS or red flags e.g. haematuria / bone pain / incontinence
5) Any confounders e.g. UTI / ROU / instrumentation / ejaculation
6) Medication use esp 5ARI
7) Family history of CaP and other cancers
8) Past medical history
- assess co-morbidities and medication e.g. antiplatelet or anticoagulant
- previous prostate surgery / pelvic surgery / RT
Physical examination:
- Abdominal exam for ballotable kidneys, palpable bladder
- DRE: size, contour, hard nodule, anal tone
Investigations
- Baseline blood tests including CBC Clotting LRFT
- Urine culture
Discuss options:
- if asymptomatic with normal DRE, PSA 3-10 ➔ EAU suggests to repeat the PSA first prior to further investigation
- additional serum or urine biomarkers
- MRI
- Prostate biopsy
What’s the performance of DRE for CA prostate detection?
Tumour may be detected if size ≥2mm, but it is operator dependent
- if suspicious DRE but PSA <2, PPV = 5-30%
- in ESRPC trial, abnormal DRE in high PSA doubles the risk of positive biopsy
- also associated with high ISUP, csCAP
- needed for clinical T-staging and D’amico risk stratification
(other evidence):
PLCO – Suspicious DRE
- HR 2.1 for clinically significant CaP
PCPT – Abnormal DRE
- Increased CaP detection 2.5-fold
- High-grade disease 2.7-fold
What is PSA
(composition, gene, origin, function)
PSA is Prostate Specific Antigen, a serum marker that is organ-specific but not disease-specific
It is composed of a:
- 34kD serine protease (glycoprotein)
- 261 amino acids
- aka Human Kallikrein 3 (HK3)
Gene: encoded on KLK3 gene on Chromosome 19
Origin: Secreted by ductal epithelial cells
Function: liquefy semen coagulum within the ejaculate
Half life of PSA
Total PSA = half life of 2.5 days
➔ therefore recheck after 2-3 weeks if in doubt (7x half life)
Free PSA = half life of 2 hours
PSA synthesis pathway
Pre-ProPSA
➔ [-7]Pro-PSA / Pro-PSA
➔ PSA
How is PSA measured
Automatically using monocloncal antibody assay
2 major commercial kits with different calibrations:
- WHO
- HydriTech
WHO assay yield ~20% lower value than Hybritech
Different forms of PSA
1) Free / unbounded PSA (25%)
- e.g. proPSA, intact PSA, benign PSA
- half life = 2 hours
- eliminated by kidneys
2) Bounded PSA (75%)
- eliminated by liver
a) ACT bound
- alpha-1 anti-chymo-trypsin
- detected in assays
- half life 4-5 days
b) AMG bound
- alpha-2 macroglobulin
- not detected in assays
- ~10%
c) API
- alpha-1 protease inhibitor
- ~1%
What is the detection rate of PSA for prostate cancer?
11 / 26 / 65
Based on Catalona’s landmark paper:
- PSA<4 ➔ 11% detection
- PSA 4-10 ➔ 26% detection
- PSA >10 ➔ 65% detection
- PSA >100 ➔ 100% metastatic disease
What is normal PSA value
What is its sensitivity and specificity?
What is Age-specific PSA level
No normal PSA cut-off can be defined
- in prostate cancer prevention trial (PCPT), in PSA <0.5 there is still 6% of CaP detected
- in Catalona, PSA <4 there is still 11% of CaP detected
In clinical practice
- Absolute value of 4ng/mL proposed by Catalona (1994) with ROC analysis
- Sensitivity 80%
- Specificity 70%
Age-specific cut-offs
- proposed by Oesterling (JAMA 1993)
- 40-49yo: 2.5
- 50-59yo: 3.5
- 60-69yo: 4.5
- > 70yo: 6.5
What are some ways to improve PSA performance?
By calculating with dynamics or volume, or different PSA forms, including:
1) PSA velocity, PSA doubling time
2) PSA density, PSA density of TZ
3) Free to total PSA ratio
4) PHI
Cut-off value for
1) PSA velocity
2) PSA doubling time
3) PSA density
4) PSA density of transitional zone
5) Free to total PSA
1) PSA velocity
- (Carter JAMA 1992): Normal = <0.75 ng/mL/year
- At least 3 results, with at least 6 months apart (needed due to variability of the test)
2) PSA doubling time
- Normal = >3 years
- At least 3 results, with at least 4 weeks apart, with minimum increase of 0.2-0.4ng/mL
3) PSA density
- Normal = <0.15 ng/mL/mL
4) PSA density of transitional zone
- Normal = <0.35 ng/mL/mL
5) Free-to-total PSA
- Normal = >20%
Principle of free to total PSA ratio
What is its indication?
PSA produced by malignant cells appears to be more frequently escape proteolytic processing
i.e. less free PSA, and more bounded PSA to ACT (alpha 1 anti-chylotryptin)
Normal value = >20%
Indication: PSA 4-10, with normal DRE
What isoforms of PSA does total PSA include
Total PSA = free PSA + ACT bound PSA
(alpha-1 anti-chymo-trypsin)
What is the EAU recommended next step for:
1) Asymptomatic men with PSA 3-10, normal DRE
2) Asymptomatic men with PSA 3-20, normal DRE
1) To repeat PSA test once more first prior to further investigation
2) Use additional tool for biopsy indication:
i) mpMRI
ii) risk calculator (provided it is correctly calibrated to population prevalence)
±iii) additional serum or urine biomarker
What prosate cancer risk calculator do you know of? What is their limitation?
Many risk calculators has been developed:
1) ERSPC risk calculators
2) PCPT calculator
However they are all limited by issue of mis-calibration, and would not be accurate if not calibrated to the local disease prevalence (difficult as hard to determine, also change with time)
Louie meta-analysis showed:
- PCPT calculator AUC 0.66, similar to PSA testing
- ERSPC risk calculator 3 has highest AUC of 0.79
What biomarkers have been proposed to improve detection and risk stratification of CaP?
Further study is needed to validate their efficacy, but include blood and urine based biomarkers:
BLOOD:
1) PHI
2) 4K score
3) IsoPSA
4) Stockholm3
5) Pro-Clarix
URINE:
1) PCA3
2) SelectMDX
3) Michigan Prostate Score (MiPS)
4) ExoDx
5) Urine spermine
What is PHI?
What is its indication
Prostate Health Index:
= (p2PSA/fPSA) x ⎷tPSA
i. e. a composite score proposed by Catalona, consisting of:
1) p2PSA = [-2]proPSA
2) fPSA = free PSA
3) tPSA = total PSA
Principle: CaP tissue secrets more p2PSA, which is a precursor of PSA; and has a low free to total PSA ratio
It is FDA approved (2012) for detection of CA prostate in:
1) Age >50yo
2) PSA 2-10
3) Normal DRE
Benefits of PHI
1) Correlated with GS in biopsy
2) Reduces unnecessary biopsy by 33% (Loeb 2015)
3) 10% delay in diagnosis of GS ≥ 7
4) ROC analysis shows AUC 0.7
➔ higher than f:tPSA ratio (0.65) and PSA (0.53)
Components and indication of 4K score
“4 Kallikrein” score is developed based on data from ERSPC and ProTECT Trial
A composite based on 4 kallikrein:
1) PSA
2) free PSA
3) intact PSA
4) HK2 (human Kallikrein 2)
And clinical factors:
5) Age
6) DRE
7) Prior prostate biopsy
Indication:
- elevated PSA, or
- abnormal DRE
ISUP Groups
ISUP 1 = GS 3+3
ISUP 2 = GS 3+4
ISUP 3 = GS 4+3
ISUP 4 = GS 4+4
ISUP 5 = GS 9-10
