Tuesday, 6 November 2007 - The 1st European Multidisciplinary Meeting on Urological Cancers held in Barcelona from 1 to 4 November tackled the current developments on biomarkers and molecular pathology of prostate cancer (PCa). The first-day plenary session featured molecular diagnostics, molecular mechanisms and targets, clinical implications of TMPRSS2-ETS fusion PCa, and the latest developments in molecular pathology.

Carlos Cordon-Cardo, professor and vice chair at the Department of Pathology and associate director of the Herbert Irving Comprehensive Cancer Center at Columbia University, USA,  chaired the session. Jack Schalken, professor and research director of Experimental Urology at the Radboud University Nijmegen Medical Centre, the Netherlands, spoke on molecular diagnostics and Mark Rubin, professor at the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, USA, discussed the clinical and biologic implications of TMPRSS2-ETS fusion PCa. Cordon-Cardo closed the session with a lecture on new developments in molecular pathology, underscoring the role of image analysis.

Highlights and summaries from the session on molecular pathology of PCa:
In introducing his topic, Schalken said: “We truly believe that the way forward is the use of new biomarkers. (But) to identify a candidate biomarker and to bring that into clinical practice is not a simple procedure.” He showed a slide with 10 biomarkers and picked out two,  methylation specific PCR and TMPRSS2-erg fusion, as among the most promising markers currently under investigation.

Concluding his lecture, Schalken said that molecular diagnosis of prostate cancer such as the PCA3 biomarker, is available for clinicians. With this biomarker, the higher the PCA3 score, the greater the likelihood of a positive biopsy and the greater the risk of significant PCa. He, however, added that since only 90% of PCa have the PCA3 biomarker, there is a need for complementary biomarkers, which should have a significant impact on the diagnosis and staging of PCa, such as TMPRSS2-erg, AMACR and PCGEM. Regarding molecular diagnostics, Schalken said that with PCA3 and TMPRSS2-erg as combination markers the sensitivity is 73% with a specificity of 69%.

Rubin continued the discussion on biomarkers with his lecture on TMPRSS2 providing an overview on translocation tumours and the biologic impact of gene fusion on cancer. The fundamental biology of TMPRSS2-ERG fusion prostate cancer is inadequately understood. But data show that TMPRSS2-ERG fusion is a frequent and early event in prostate cancer pathogenesis, with distinct biology and a more aggressive phenotype. With the query what is the evidence for gene fusion’s role in initiating cancer, Rubin said fusion is associated with tumour phenotype, there is a distinct molecular signature, and that the treatment of chimera eradicates the tumour. “Looking forward we’re hoping that by understanding the biology (of TMPRSS2-ERG) that it might help identify which men have more aggressive disease and perhaps identify treatment strategies related to targeting the fusion,” said Rubin.

In his lecture on “New developments in molecular and systems pathology,” Cordon-Cardo underscored the need to use a new approach in pathology to overcome the limitations imposed by histology. “One of the most interesting microchips has already been created, and the (human) tissue itself is the ultimate chip,” Cordon-Cardo explained the use of systems pathology that integrates clinical variables, histological features and molecular profiles. He explained that this is achieved through the application of novel techniques in areas such as machine vision, pattern recognition and quantitative biomarker multiplexing. Furthermore, this approach relies on complex datasets which are analysed by supervised mathematical approaches, including machine learning algorithms and neural networks.

A study by Cordon-Cardo demonstrated the potential of a systems pathology approach with a resulting incremental trend of improved PSA recurrence prediction by combining clinicopathological, immunohistochemistry and imaging information using domain expertise and supervised analytical techniques. The study provided supportive evidence that the approach of systems pathology has the potential to be the basis of a new generation of predictive clinical tools. “We can identify patients that have a more insignificant versus patients that have significant disease in the context of tumour recurrence. But more importantly we have a predictive accuracy of around 85% to 95%,” said Cordon-Cardo.

He concluded his lecture by showing slides that present new imaging technologies such as proteomics and image guided prostate biopsy. He also  noted that advances in imaging are moving from anatomy, chemistry, metabolism to functionality.

Cordon-Cardo: “We think that the management of PCa is going to change. We are going to look at disease management as a continuum. It’s probably going to start with body fluids, exfoliated cells… and we are going to move into tissues from which we can extract more information. Then there are the new technologies that will allow us to follow the patient more rationally, and there will be integration of all these markers in the context of patient management…there will be a paradigm shift (in patient diagnosis) and I believe that functional imaging is going to be part of this.”