1. Gian Maria Busetto Sapienza Rome University Prostate cancer gene 3 (PCA3) and multiparametric magnetic resonance (mMRI) can reduce unnecessary biopsies: decision curve analysis to evaluate predictive models.

2. - Widespread use of prostate-specific antigen (PSA). - Detection of some carcinomas that would otherwise remained undetected during life. - Well know serum PSA deficiencies as PCa-specific diagnostic test. BACKGROUND

3. On one hand Missing PCa in patients with PSA increase On the other Large number of unecessary prostate biopsy BACKGROUND PSA increase

4. Prostate Cancer diagnosis TRUS guided PROSTATE BIOPSY GOLD STANDARD Novel biomarkers development remains and exciting challenge CHALLANGE

5. TRUS-guided biopsy TRUS-GUIDED BIOPSY Made on a random scheme due to inability of TRUS to detect prostatic nodules. More than 30% of neoplastic foci are misdiagnosed (23% are high grade).

6. PCA3 (prostate cancer antigen 3): prostate-specific noncoding mRNA OVEREXPRESSION (60-100 times) in 95% of PCa tissue in comparison with non-neoplastic prostatic cells. Urine-based biomarker (Bussemakers Cancer Res 1999)

7. Urine-based biomarker - PCA3 value does not change with prostate volume and with flogist process. - Importance of the SCORE as a predictor of biopsy outcome. (de Kok Cancer Res 1999)

8. - High diagnostic accuracy of combined proton 1 H- magnetic resonance spectroscopic imaging (MRSI) and dynamic contrast-enhanced imaging magnetic resonance (DCEMR) in the management of PCa. - The substances analyzed by MRSI are citrate, creatine and choline and then their ratio is calculated. Imaging

9. Study - PURPOSE Our aim is to evaluate the ability of MRI combined with MRS and DCEMR versus PCA3 urinary test to improve PCa biopsy detection in cases of PSA increase and previous negative prostate biopsy. vs

10. Study - MATERIALS and METHODS 171 patients (48 to 69 y.o.) PATIENT POPULATION and STUDY DESIGN INCLUSION - previous negative biopsy for PCa or PIN - persistent elevated PSA (≥4 and <10 ng/ml) - negative DRE (digital rectal exam) EXCLUSION - previous hormonal therapy, surgery, radiation - urine not collected after DRE and prior biopsy - biopsy with less than 10 cores - MR with MRS and DCEMR not possible - men who declined consent to the study

11. Study - MATERIALS and METHODS EACH PATIENT MRI + MRS + DCEMR Urine collection after DRE for PCA3 test (3 comp. per lobe) TRUS-guided prostate biopsy (10 core laterally directed random speciments) If positive RRP (Radical Retropubic Prostatectomy)

12. Study - IMAGING 3T Magnet, Magnetom Vario (Siemens Medical Solutions), equipped by surface phased array (Body Matrix, Siemens) and endorectal coil (Medrad, PA, USA Siemens interface) filled with 50 – 60 ml of air. MORPHOLOGIC IMAGING made by acquiring turbo spin echo (TSE) T2-weighted sequances in the axial, sagittal and coronal planes with the use of optimized parameters. 1H-MRSI made by a point-resolved spectroscopic sequence obtained with the use of three-dimensional (3D) chemical shift imaging sequence with spectral/spatial pulses optimized for quantitative detection of choline and citrate. DCEMR made using a Gradient-Echo (GRE) T1-weighted sequence during i.v. contrast agent administration (injection of 1.0 mmol/mL of Gadobutrol). IMAGE acquisition MR equipment

13. Study – CASE 1 A: Signal-intensity time curve, malignant pattern curve 1. B: Bilateral mild hypointense area in the peripheral zone at level of apex. C: Dynamic subtracted image representing region enhancement and ROI. D-F: MRSI analysis with reference images on the right side, high choline level detected in 3 consecutive voxels. Prostate cancer, Gleason score 6 (3+3).

14. Study – CASE 2 A: Signal-intensity time curve, note the malignant pattern in curve 1 (high peak enhancement and wash-out). B: Focal hypointense area in the left portion of the peripheral zone at middle gland. C: dynamic subtracted image representing region enhancement and ROI. D-F: MRSI analysis with reference images on the left side, high choline level. Prostate cancer, GS 7 (4+3).

15. Study – RESULTS PCA3 169/171 patients analyzed Sensitivity: 68% Specificity: 49% PPV: 49% NPV: 68%MRI 169/171 patients analyzed Sensitivity: 90% Specificity: 62% PPV: 63% NPV: 89% 68 biopsies were positive for prostate adenocarcinoma, 95 were negative (25 BPH/inflammation). Of the 68 positive patients 34 had GS 7 or higher.

16. Study – AUC Table 4 PredictorAUC95% CI p-value (vs base) Base clinical model0,5510,461to0,640- Base clinical model + PCA30,7420,664to0,8210,0002 Base clinical model + MRSI0,7810,710to0,851<.0001 Full clinical model0,8080,742to0,874<.0001

17. Study – DECISION CURVE

18. - Choosing a predicted probability threshold of 20% and applying the full clinical model, it would have performed 66% fewer biopsies in patients with persistent high PSA serum levels, missing only 9% of PC patients among the real number of PC patients. - Similar results were obtained applying the base clinical model + MRSI, while no evaluable clinical gain were obtained by applying the other two analyzed models.

19. Study – CONSIDERATION - According to our experience the use of mMRI to drive TRUS-guided prostate biopsy can increase both the accuracy of this procedure and the sensitivity of the PCA3 test. - The use of the full model, including base clinical variables together with mMRI and PCA3 can significantly improve the cost benefit ratio. - mMRI is advisable because of its high performances instead od PCA3 that could be recommended only in association with other tests.

20. Study – CONSIDERATION II MR, with morpho and functional valuation, has the capability to detect neoplastic foci. Allow assessment of local extent and thus can help in local staging. Capability to guide the sites where to perform biopsy with reduction in negative one’s. Metabolic study of the prostate using the spectroscopy. High costs for the equipment and high experience needed.