How to detect and investigate Prostate Cancer before TRT Frans M.J. Debruyne Professor of Urology Andros Men s Health Institutes, The Netherlands Bruges, 25-26 September 2014 PRISM
Recommendations for monitoring prostate health before and Normal digital rectal examination (DRE) PSA <4.0 ng/ml Evaluate individual risk of prostate cancer During therapy Measure PSA At 3 6 months Annually or semiannually as long as treatment continues Perform DRE Annually or semiannually as long as treatment continues Refer for urological evaluation and possible prostate biopsy if - Prostate is abnormal on DRE or PSA >4 ng/ml or - PSA increase >1 ng/ml after 3 4 months on testosterone treatment - Or PSA velocity >1.5 ng/ml/y or >0.75 ng/ml/y over 2 years - Or PSA velocity >0.4 ng/ml/y over an observation period of <3 years (with PSA after 6 months on testosterone therapy used as a reference point)
Digital Rectal Examination (DRE)
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PSA The Diagnostic Triad in Prostate Cancer
Digital Rectal Examination For patients with a PSA over 4 ng/ml (n=9,776) Normal DRE, Normal TRUS: PPV 17% Normal DRE, Abnormal TRUS: PPV 33% Abnormal DRE, Normal TRUS: PPV 32% Abnormal DRE, Abnormal TRUS: PPV 75% Rietbergen et al, J Urol, 1999 For patients with a PSA less than 4ng/ml DRE is of no value Schroeder et al, JNCI 1999
Prostate Specific Antigen (PSA)
Age specific PSA levels AGE PSA LEVEL 40-50 Years 0-2.5ng/ml 50-60 Years 0-3.5ng/ml 60-70 Years 0-4.5ng/ml 70-80 Years 0-6.5ng/ml Oesterling et al 1993 Kalish et al 1994
Transrectal Ultrasound (TRUS)
TRUS Cheap, but operator dependent Examines the prostate in different planes, but only on the basis of one section at any time. uses a spatially flexible and variable twodimensional imaging technique, to visualise a three-dimensional (3-D) anatomy and disease process The capsule, strictly speaking is not visible, and the diagnosis of extracapsular involvement relies on disruption of the periprostatic fat
Diagnostic triad for early detection of prostate cancer
Trans-Rectal-Ultra-Sound Biopsy
T1: non palpable not visible laesion T1a: < 5% T1b: > 5% T1c: tumor identified by biopsy (elevated PSA)
T2: limited to the prostate T2a: halve a lobe or less T2b: more than halve a lobe but only unilaterally T2c: both lobes
Staging Prostate Cancer 21
Problems: TRUS Bx Important cancers are missed Clinically insignificant cancers are identified by chance 36-46% undergrading of Gleason score
Imaging with Multi-parametric Learning Objectives MRI 1. High resolution T2-w: anatomy 2. Diffusion Weighted Imaging: function 3. Dynamic Contrast Enhanced: function 4. Hydrogen MR-Spectroscopy: function
MP-MRI: Learning anatomy Objectives 1 mm
MR-anatomy of PCa Low SI: PCa
MR-anatomy of PCa B B H H Low SI: PCa + hematoma + prostatitis + BPH
Multi-modality MRI: DWI Organised galandular tissue Tightly packed cellular tissue DWI: PCa restricted H 2 O movement Specificity, aggression!
Multi-modality MRI: DCE DCE MRI: PCa increased vascular permeability Sensitivity!
MR Spectroscopy Metabolite ratios Cho + Cr Cit Cho Cr Citrate 0.37 / 0.64
Multiparametric magnetic resonance images of the prostate at 3 T van Leeuwen, Eur Urol 5 9 ( 2 0 1 1 )
Prostate Cancer Biomarkers 32
CRITERIA IDEAL BIOMARKER FOR PCa PSA Produced only by tumor tissue Non-invasive easy to manage As inexpensive as possible to encourage widespread use Ability to detect PCa at an early stage Ability to differentiate aggressive tumors leading to death High specificity High sensitivity 33
PROMISING PCa BIOMARKERS IN THE FIELD PCA3 (Prostate CAncer gene 3) TMPRSS2-ERG (Transmembrane Protease, Serine) CTCs (Circulating Tumor Cells) 34
Is the PCA3 test the future? Cells in prostatic urethra Digital Rectal Exam (DRE)
PCA3 Non coding messenger RNA Prostate cancer specific urine test Median 66x more PCA3 mrna in prostate tumour cells PCA3 score = [PCA3 mrna]/[psa mrna] x 1000 Cutoff score 35 Sensitivity 47-69% Specificity 72-79% PSA 4,0-10,0: Specificity 25-40% 36
Aubin, J Urol 10 Conclusions: PCA3 clinical performance was validated in the largest repeat biopsy study to date. Use of PCA3 in combination with serum prostate specific antigen and other risk factors significantly increased diagnostic accuracy.
PCA3 UPDATE PCA3 to aid in the decision to take initial biopsies. 1 PCA3 correlated with tumour volume and insignificant PCa. 2,3 PCA3 does not correlate with ECE or SVI. 3 PCA3 no independent risk factor for aggressive disease. 1. De la Taille et al. Clinical evaluation of the PCA3 assay in guiding initial biopsy decisions. J Urol 2011. 2. Ploussard et al. Prostate cancer antigen 3 score accurately predicts tumour volume and might help in selecting prostate cancer patients for active surveillance. Eur Urol 2011. 3. Auprich et al. Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging. Eur Urol 2011. 38
TMPRSS2-ERG Gene-rearrangement (fusion of TMPRSS2 and ETS) Non-invasive urine-test In ± 50% of PCa patients Sensitivity 32-51% Specificity 91-94% Association with cancer aggressiveness?? Demichelis F, Fall K, Perner S, et al. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 2007;26:4596-9. Attard G, Clark J, Ambroisine L, et al. Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 2008;27:253-63. FitzGerald LM, Agalliu I, Johnson K, et al. Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer 2008;8:230. Hessels D, Smit FP, Verhaegh GW et al. Detection of TMPRSS2-ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer. Clin Can Res. 2007; 13: 5103-8. 39
CIRCULATING TUMOR CELLS (CTCs) Cancer cell that has detached from a solid tumor lesion and entered the peripheral blood circulation Tumor metastatic spread of cancer cells Death.. 40
A needle in a haystack But what kind of needle?