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Content archived on 2024-05-29

Validation of recently developed diagnostic and prognostic markers and identification of novel markers for prostate cancer using European databases

Final Report Summary - P-MARK (Validation of recently developed diagnostic and prognostic markers and identification of novel markers for prostate cancer using European databases)

Prostate cancer is nowadays the most frequent cancer in European men and one of the major causes of cancer-related death. The incidence of this malignancy is increasing as a result of screening for prostate cancer via a test that measures the level of Prostate specific antigen (PSA) in blood. While screening for prostate cancer has become a common phenomenon for men above the age of 50, its value has not been established yet and is currently subject of investigation in the European Randomised Study of Screening for Prostate Cancer ( ERSPC, please see http://www.erspc.org online). If the amount of the blood marker PSA is elevated, a prostate biopsy is performed to determine the presence of tumour cells.

Because PSA is not only increased in prostate cancer but also in other physical conditions such as inflammation and benign prostate enlargement, unnecessary biopsies are being performed in a significant number of men who are screened for prostate cancer. In addition, PSA is a poor predictor of the aggressiveness of a prostate tumour. It is known that more than half of the prostate cancers detected by screening are harmless and not life-threatening, and can therefore best be treated by active surveillance. Since PSA cannot discriminate well between these indolent tumours and relevant tumours that need invasive therapy, a large proportion of men diagnosed with prostate cancer is unnecessarily treated by complete surgical removal of the prostate or by radiotherapy.

These treatments are associated with side effects that severely affect quality of life, including impotence and incontinence. It is clear that there is a strong clinical need for novel markers that can improve the diagnosis and prognosis of prostate cancer and that can stratify between patients who need active curative therapy and patients who are better off with active surveillance. For a period of four years (1 November 2004 - 31 October 2008), the members of the P-MARK project have searched for improved diagnostic and prognostic prostate cancer markers by the identification and evaluation of novel markers as well as the evaluation and validation of recently developed promising markers.

The availability of well-characterised clinical specimens is often a barrier in biomarker development. Therefore, the clinical centres in P-MARK (Erasmus MC, Lund University, Radboud University Nijmegen Medical Centre and University of Sheffield) have joined efforts to establish a European prostate cancer biorepository with blood and urine specimens from controls and patients with various stages of prostate cancer. The P-MARK biobank contains a collection of over 2 000 historical serum samples. This collection has been extensively used for the discovery of novel markers in serum within P-MARK. In addition, a prospective multicentre collection has been initiated that is composed of longitudinal blood (serum, plasma, DNA and RNA) and urine (urinary fluid and sediment) samples from men who are biopsied because of suspicion of having prostate cancer. The unique aspect of this prospective collection is that samples are being collected, processed and stored according to standardised protocols. This biobank therefore allows for the composition of large multicentre sample cohorts with a significant reduced risk of sampling bias. Furthermore, on the longer term this biobank of longitudinal specimens will be of high value to test biomarkers for their prognostic value or for their value in the assessment of response to treatment.

It can be concluded that the P-MARK project has successfully met four of the five main project objectives within the time-frame of the project:
1) Establishment of a serum biorepository and a urine biorepository: The P-MARK biobank has been established, consisting of an extensive retrospective serum collection and a unique multicentre prospective blood and urine collection.
2) Discovery of novel prostate cancer biomarkers in serum and urine by innovative mass spectrometry tools: A list of novel potential candidate biomarkers has been delivered for further research beyond P-MARK.
3) Establishment of the clinical utility of recently developed promising prostate cancer markers: The clinical utility was demonstrated for osteoprotegerin, multi-kallikreins and PCA3, warranting further validation studies on these biomarkers.
4) Validation of prostate cancer markers and identification of risk groups in the general population in Europe: Osteoprotegerin, multi-kallikreins and PCA3 were extensively validation. PCA3 was introduced into the clinic. The research on the identification of risk groups in the general European population has resulted in the development of the prostate risk indicator.
5) The last objective relates to the development of guidelines for cost-efficient strategies for prostate cancer detection and therapy. In the nearby future, studies initiated within P-MARK may eventually result in new guidelines for prostate cancer. For instance, the ERSPC study on the applicability of PCA3 as a first line screening test might lead to novel recommendations for PCA3.

Furthermore, commercial interest in the multi-kallikreins may result in the development of commercial assays and subsequently to the implementation of these biomarkers in the clinic through updates of current guidelines and recommendations, including the prostate risk indicator developed by Erasmus MC.
4-p-mark-final-activity-report-v01.pdf