Unión Civil no matrimonial, sobre el Proyecto de Ley N° 2647/2013-

evidence for routine population-based PSA screening (51, 52). This was again underlined in the Melbourne Consensus Statement on the early detection of prostate cancer, formed by a multidisciplinary panel of the world’s leading experts on this subject (53). However, population-based estimates of overdiagnosis, causing a negative benefit-harms ratio of population-based screening, are difficult to translate to the individual (54). Unlike the US Preventive Services Task Force, that strongly recommends against any form of prostate cancer screening (55), almost all associations recommend to individualize opportunistic screening with the process of shared decision making (52, 53, 56-60). During this process, men are well informed on the currently existing pros and cons before they make a defi- nite decision on ‘to screen or not to screen’. The recommended age group and screening interval differ between the various guidelines. There is level 1 evidence on prostate cancer mortality reduction by screening provided by the ERSPC in the core age group of 55-69 years (24, 27, 29). Therefore, this is the recommended age group for men at average risk (i.e. without a first-degree relative with PCa and not of African descent) in the American Urological Association (AUA) guideline on prostate cancer screening (56). The American Cancer Society (ACS) guideline on the other hand, recommends screening motivated men from the age of 50 years on (59). This guideline also recommends screening men above 70 years with a life expectancy of more than 10 years, since these men may benefit from screening as well. The European Association of Urology (EAU) and the National Compre- hensive Cancer Network (NCCN) recommend a baseline PSA at 40 years (52, 60), same as the Melbourne Consensus Statement (53). Several guidelines recommend to screen motivated men under the age of 50 years if there is an increased risk of prostate cancer (56, 59, 61). Recommendations on the screening interval vary from annual screening in men with a PSA of 2.5 ng/ml or above (59), to an interval of 8 years in men with a baseline PSA of less than 1.0 ng/ml (52).

new prostate cancer markers

To date, PSA has remains the single most predictive tumor marker for identifying men at increased risk of prostate cancer. However, as stated earlier, the suboptimal performance characteristics of PSA in prostate cancer detection leads to unnecessary testing, overdiag- nosis and overtreatment. Numerous studies have been conducted to identify next gen- eration prostate cancer biomarkers (-omics) in serum and urine (62), like prostate cancer antigen 3 (PCA3) and TMPRSS2-ERG.The genetic marker hypermethylated Glutathione S-transferase P1 (GSTP1) shows promise in reducing the number of unnecessary biopsies (63) and stratifying men with aggressive prostate cancer (64, 65). So far, no biomarker has the potential to replace PSA, although some can have a complementary role, modestly improving the performance of prostate cancer detection. The success of the PSA test led to studies on the performance of other kallikrein markers in prostate cancer detection.

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The percentage free PSA turned out to be lower in men with prostate cancer compared with those without (66). A correlation of lower percentage free PSA with higher prob- ability of a positive biopsy result was shown (67-70). However, the percentage free PSA was not widely implemented as a screening tool due to inconsistent performance in later studies (71, 72). The [-2] isoform of Proenzyme PSA (proPSA) is a promising biomarker in prostate cancer screening due to its correlation with prostate cancer rather than BPH and its accuracy in the detection of cancer (73, 74). The percentage [-2] proPSA particularly is a good predictor of cancer in men with a PSA of 2-10 ng/ml (75). In a small retrospective study, the AUC of percentage [-2] proPSA (0.73) was significantly greater than of total PSA (0.52) and percentage free PSA (0.53) (75). In a larger prospective study, percentage [-2] proPSA had an improved specificity of 44.9% compared with total PSA and percentage free PSA (30.8% and 34.6%, respectively) at an 80% sensitivity (76). In addition, this study showed that the percentage [-2] proPSA increases with increasing Gleason score, and is higher in aggressive cancers (76). The Beckman Coulter Prostate Health Index (PHI®) can be considered a ‘marker’ as well. This index is calculated by the following formula: PHI = ([-2] proPSA/freePSA) × √PSA. Both [-2] proPSA (AUC = 0.76) and PHI (AUC = 0.77) outperform total PSA and percentage free PSA in the PSA range of 2.5-10.0 ng/ml (77). More recent studies underline the superior predictive ability of PHI and percentage [-2] proPSA (78, 79), with a significant improvement of the accuracy compared with standard PSA-based screening (+11% and +10%, respectively)(78). The performance characteristics of PSA can also be improved by combining the test in a panel of four kallikrein markers (i.e. total PSA, free PSA, intact PSA, and hK2). This kallikrein panel improves the AUC of standard PSA- based screening from 0.63 to 0.78 in men with a PSA ≥ 3.0 ng/ml (80).The kallikrein panel could potentially reduce the unnecessary biopsy rates by nearly 50% (81, 82). It seems as if we are far from done with the PSA test. Part of the future of prostate cancer screening lies in improving the performance of PSA, either by using percentage [-2] proPSA/PHI or a kallikrein marker panel with hK2.

Prediction tools to improve PSA-based screening

In addition to combining PSA with other kallikrein markers, the predictive capability can be improved by combining the PSA test with other pre-biopsy variables like the DRE, TRUS and prostate volume (83). Multivariate risk stratification in prostate cancer screen- ing can be done by using various nomograms and prediction tools (84). Two of the most frequently used prediction tools in PSA-based screening are the risk calculators based on data from the Prostate Cancer Prevention Trial (PCPT) and the Rotterdam section of the ERSPC (85, 86). Both risk calculators are specifically of aid in reducing the number of un- necessary prostate biopsies and the rate of overdiagnosis. The Rotterdam Prostate Cancer Risk Calculator (RPCRC, www.prostatecancer-riskcalculator.com) outperforms the PCPT risk calculator in external populations (accuracy of 0.71-0.80 vs. 0.57-0.74) (84). Unfortu-

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