507 RELATION OF PLASMA IGF-1 AND IGFBP-3 TO THE RISK OF PROSTATE CANCER

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Indication of bone metastases in prostate cancer patients and their survival outcome in correlation to plasma osteopontin and other bone markers Kramer J., Ramankulov A., Jung K., Loening S.A., Lein M.



506

Can Serum Osteoprotegerin Levels Predict Biochemical Failure in Prostate Cancer? Phillips J., Eaton C., Proctor L., Sokhi D., Hannon R., Cross N., Hamdy F.C. Royal Hallamshire Hospital, Academic Urology Unit, Sheffield, United Kingdom

Charité University Medicine, Urology Campus Charité Mitte, Berlin, Germany Introduction & Objectives: Aim of the Study: to evaluate the diagnostic and prognostic value of plasma osteopontin (OPN) in comparison to bone markers in prostate cancer (PCa)patients and to examine the relationship between the markers and clinico-pathological factors of the disease. Material & Methods: OPN and the bone markers carboxyterminal-telopeptide of type I collagen, bone-specific alkaline phosphatase (bALP), and aminoterminalpropeptide of type I procollagen (PINP) were measured in 90 PCa patients with and without bone metastases, 35 patients with benign prostatic hyperplasia, and 29 healthy men. Results: Compared to the other groups, OPN and bone markers were significantly elevated in patients with bone metastases. We were able to demonstrate a significant correlation for all four bone markers (rs=0.43-0.79, all P <0.01). OPN correlated with tumor grade (rs=0.23, P <0.05). In receiveroperating characteristics (ROC) analyses, OPN and bone markers were effective in distinguishing PCa patients with and without bone metastases showing areas under the curve (AUC) between 0.80 to 0.88 (all P <0.001). OPN had an AUC of 0.85 that increased in combination with bALP up to 0.93 providing at the point with the highest diagnostic accuracy both a sensitivity and specificity of about 90%. A decreased survival of patients with high OPN and bone marker levels was shown in the Kaplan-Meier analyses and Cox proportional hazards regression models, while only high OPN and PINP were independent negative prognostic factors for PCa-related death.

Introduction & Objectives: Recent studies have found elevated serum levels of osteoprotegerin (OPG) in patients with advanced prostate cancer, suggesting its role as an indicator of early disease progression. We have analyzed the behavior of serum OPG levels in 389 patients with histologically confirmed prostate cancer over a 3 year follow-up period. Material & Methods: Serum samples from 389 men with histologically confirmed prostate cancer were analysed. 140 men had organ confined disease and 249 had locally advanced disease. 79 men had bone metastases. 185 men were untreated at the time of initial sampling whilst 204 had already commenced some form of systemic or local treatment. Of these, 117 remained biochemically controlled at the time of recruitment whilst 87 already had PSA relapse. Samples from 45 age-matched men with biopsy proven BPH and 24 young healthy controls (14 male and 10 female) were also analysed. 208 patients underwent further serum sampling over the 3-year follow-up period. Results: During the course of the study, 52 patients developed biochemical relapse and 6 patients developed new bone metastases. Young healthy males and females had significantly lower serum OPG levels than BPH or prostate cancer cases. No significant difference was found between BPH and malignant cases. Patients with locally advanced disease exhibited higher serum OPG levels than those with clinically organ confined disease, with the highest levels in patients with bone metastasis. Higher Gleason Grade was also associated with elevated OPG levels. There was no significant drop in OPG levels after commencement of androgen ablation therapy. Biochemical relapse cases were associated with higher serum OPG levels than patients currently controlled with hormone manipulation therapy. Of the patients with locally advanced disease that had biochemical control on hormone manipulation therapy at the time of recruitment, the group that subsequently developed biochemical relapse exhibited significantly higher baseline serum OPG levels than those that remained controlled despite no difference in baseline PSA levels. The effect was most pronounced in the group with no evidence of bone metastases at baseline. A similar effect was observed in the untreated patients at recruitment that then gained a biochemical response after commencement of treatment followed by subsequent PSA relapse.

Conclusions: For the detection of bone metastases in prostate carcinoma patients, either OPN alone or the combination with bone markers is a useful diagnostic tool. Furthermore, OPN can serve as a prognosticator in the survival prediction of these patients.

Conclusions: Elevated serum OPG levels before or during treatment are associated with propensity to develop biochemical relapse. Serum OPG levels appear to forecast biochemical failure earlier than PSA.





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Relation of plasma IGF-1 and IGFBP-3 to the risk of prostate cancer

Tyrosin-phosphatase SHP-1 present in prostate cancer can be a novel marker of prognosis

Woongeol Y.1, Kwanjin P.2, Seong Jin J.1, Eunsik L.1

Angulo J.1, Ferruelo A.2, Lopez J.I.3, Rodriguez-Barbero J.4, Santana A.5, FernandezSegoviano P.4, Lujan M.1, Garcia-Mediero J.1, Pascual-Mateo C.1, Lopez-Ruiz P.6, Colás B.6, Berenguer A.1

Seoul National University, Urology, Seoul, South Korea, 2Korea Cancer Center Hospital, Urology, Seoul, South Korea 1

Introduction & Objectives: The incidence and mortality of prostate cancer in Korean, compared to Western population are relatively low, for reasons that are not clear. Experimental evidences suggests that insulin-like growth factor I (IGF-I) and its major binding protein (IGFBP-3) have been implicated in the development of prostate cancer, however previous epidemiologic studies, mainly conducted in Western population, have inconsistently associated IGF-I and IGFBP-3 with prostate cancer. To try and further clarify these potential associations in low risk Korean population, we undertook a matched case–control study.

Hospital Getafe, Urology, Getafe, Spain, 2Hospital Getafe, Investigation, Getafe, Spain, 3Hospital Basurto, Pathology, Bilbao, Spain, 4Hospital Getafe, Pathology, Getafe, Spain, 5Hospital Principe Asturias, Pathology, Alcalá Henares, Spain, 6Universidad Alcalá, Biochemistry, Alcalá Henares, Spain 1

Introduction & Objectives: Tyrosin-phosphatase SHP-1 has been recently described in human and murine prostate and also in established prostate cancer cells. We have described loss of expression of SHP-1 in poorly differentiated prostate cancers and hormone resistant PC-3 cells (J Clin Endocr Metab, 87: 915-926, 2002). Following the hypothesis that tyrosin-phosphatase may act as a suppressor gene we have evaluated immunohistochemical and RT-PCR expression of SHP-1 in a clinical series of prostate cancers with adequate long-term follow-up and performed a multivariate analysis of prognostic factors.

Material & Methods: Serum IGF-I and IGFBP-3 were determined for 330 men (165 cases treated by radical prostatectomy and 165 healthy age-matched controls). Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the serum IGF levels and prostate cancer. We also investigated the potential influence of the associations by disease aggressiveness at diagnosis, where aggressive disease was defined as having a Gleason score≥8, or PSA≥20, or tumor stage≥ T3.

Material & Methods: A series of 114 patients with prostate cancer of variable clinical stage (22 T1, 34 T2, 46 T3, 12 T4) were retrospectively analyzed. Specimens were collected from radical prostatectomy and TUR tumour samples. Clinico-pathologic data were homogeneously evaluated. Immunohistochemistry (IHQ) was performed using SHP-1 commercial antibody. Total RNA was extracted after deparaffination of tumour tissue. Real time RT-PCR was performed using specific primers for SHP-1 and ribosomal 18S. The quatification value of SHP-1 mRNA was described as each value relative to 18S mRNA (DDCt method). Ki-67 index and the expression of neuroendocrine markers (chromogranin and synaptophisin) were also evaluated. Multivariate analysis regarding disease-specific mortality was performed for prediction of prognosis.

Results: The risks of prostate cancer were unrelated to IGF-1 and IGF-I: IGFBP3 molar ratio. In contrast, strong inverse association was observed between IGFBP-3 levels and prostate cancer risk. Men in the highest quartile of IGFBP3 had 88% reduced risk of prostate cancer compared with men in the lowest quartile (OR= 0.12; CI, 0.05-0.64; p trend <0.01). When we restrict our analysis to individual risk strata, we also found 48% and 76% reduced risk of aggressive disease in 3rd and 4th quartiles compared to 1st quartile.

Results: 48% of the patients revealed immunohistochemical expression of SHP-1, and that was not associated to T category, metastatic status or Gleason score. All patients were followed with emphasis on disease specific mortality (28% die of cancer during follow-up). Patients dying of other cause were censored. Mean follow-up was 68.06 (60.58-75.55) months, range 10-166. Multivariate analysis revealed metastatic disease at the time of diagnosis (p<0.0001), Ki-67 index (p<0.0001), absence of SHP-1 expression on IHQ (p=0.003) and elevated Gleason score (p=0.05) were independent predictors. Expression of SHP-1 on RT-PCR was 2.07 times higher in tumours staining positive for SHP-1 on IHQ and 4.7 times lower in hormone-resistant disease.

Conclusions: Our findings in a low-risk population provide evidence that IGFBP-3 is the protective factor in prostate cancer, and may have implications for risk reduction and treatment.

Conclusions: Loss of tyrosin-phosphatase SHP-1 expression appears an unfavourable independent variable for the prediction of prognosis in patients with prostate cancer, nonassociated to standard clinico-pathologic predictors. It is likely that this enzyme may act as the product of a suppressor gene, the role of which in prostate cancer needs further investigation.

Eur Urol Suppl 2007;6(2):149