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Biomarker Guided Prostate Cancer Management

Periodic Reporting for period 1 - BioGuidePCa (Biomarker Guided Prostate Cancer Management)

Reporting period: 2014-11-01 to 2015-04-30

Prostate Cancer (PCa) is the second most frequently diagnosed cancer and the sixth leading cause of cancer related deaths in males worldwide. Application of the serum PSA test led to a significant increase in the number of diagnosed cases but failed to show a statistically significant benefit on PCa mortality benefit. Ninety-five percent of men with PSA-detected cancer who are followed for 12 years do not die from PCa, even in the absence of definite treatment such as radical prostatectomy, radiation therapy or hormonal therapy. This has significantly exaggerated our current inability to make evidence-based recommendations on treatment choices according to tumour behaviour, namely clinically insignificant and clinically significant. disease. Hence new screening assays are urgently needed to improve the discriminatory accuracy between tumours with a favourable clinical prognosis even withouttherapy and disease that merits immediate treatment by radical prostatectomy. This would improve onover-diagnosis and over-treatment and guide early initiation of the appropriate intervention. On the other hand, advanced metastasized prostate cancer is still a lethal disease. Therapy of advanced castration resistant prostate cancer (CRPC) relies on hormone therapy and cytotoxic chemotherapy. Recent developments have resulted in a variety of novel approved substances for the treatment of CRPC, although an optimal therapeutic scheme, and the optimal timing for initiation of the therapy has not been yet defined. Thus the development of a diagnostic test for early detection of tumor recurrence and progression to metastatic disease would be beneficial. During Phase 1 of the BioGuidePCa project we aimed to conduct a preliminary study regarding the development of two diagnostics test aiming to address the above-mentioned clinical needs, that were identified in cooperation with Prof. Dr. Merseburger from the Hannover Medical School. In addition we wanted to perform a market analysis and develop a business plan to investigate the profitability of the diagnostics.
During Phase 1 of the BioGuidePCa project a team at the mosaiques diagnostics GmbH has investigated the clinical potential of diagnostic biomarker tests, namely the PCa Status Test and the mCRPC Progression test, for the application in the clinical needs that were summarised above. The PCa Status Test should be developed as a non-invasive seminal fluid based biomarker assay, that is able to differentiate between clinical significant from clinical insignificant disease, hence should guide radical prostatectomy and therefore reduce the associated overtreatment in at least 45% of the patients. The mCRPC Progression Test should be developed for the use in therapy for castra-tion resistant prostate cancer. Here it should detect early disease progression and predict therapy outcome. The market potential of both diagnostics was investigated in a feasibility study, including a business plan, a market analysis and a marketing concept. Based on the analyses, it was shown that both tests can upgrade prostate cancer management since no alternative diagnostics are currently available in the market. Based on this fact, the market potential of both tests is predicted to be high, with a total of 60,000 potential customers per year in Germany.

In the context of the feasibility analysis we also performed a preliminary study, investigating the producibility of the mCRPC Progression Test as well as the PCa Status Test. For the evaluation of the concept of the mCRPC Pro-gression Test, a total of 10 mCRPC patients and 16 non-mCRPC diseased controls were obtained from the Urology Department of the Hannover Medical School. Primary classification of the samples with a previously reported General Cancer biomarker classifier resulted in poor differentiation between cases and controls (AUC = 0.744). Hence the available samples were divided in a training- and test-set in order to perform further statistical analysis targeting the development of a new more specific biomarker classifier. Classification with the newly established specific mCRPC biomarker pattern resulted in an AUC of 1.0. We therefore suggest that the biomarker should be further developed in a subsequent study, best funded in the framework of Phase 2. For the preliminary study of the PCa Status Test, seminal fluid samples were analysed. A total of three biomarker classifiers were developed to allow accurate classification of the tumour according to its Gleason Score and TNM Stage. For all classifiers AUC values > 0.84 were obtained, verifying the functionality of the test according to the defined clinical need. Since the results of the preliminary study are excellent, both diagnostics test should be developed to marketability in the framework of the PHC 12-2105-2 call of the Horizon 2020 program.
In the last two decades an increase in the detection of insignificant prostate cancers was observed. There is a growing consensus that this increase is a result of the establishment of PSA screening test in men’s health care that ultimately leads to over-diagnosis and over-treatment. Consequently, for selected patients with low-risk disease, active surveillance has been endorsed in recent clinical guidelines as an alternative to immediate therapy. Currently no reliable diagnostics for discriminating between aggressive and non-aggressive prostate cancer prior to operation or radiotherapy is available. Active surveillance depends on insignificant means like the PSA doubling time or on invasive repeated biopsies. The PCa Status Test will be precisely developed for the use during active surveillance and for correct assignment of Gleason Score < 8 prostate cancer cases. This test has the potential to revolutionize the management of early stage prostate cancer by reducing the current observed prostate cancer related over-treatment, clearly enhancing the patient's quality of life.

PCa mortality is typically attributed to the metastatic castration-resistant prostate cancer (mCRPC). Thus mCRPC represents the end stage of the disease. Historically the median survival for men with mCRPC has been less than two years. Although the disease is not curable, the quality of life can nowadays be improved by palliative therapy. Unfortunately successful therapy cannot be predictable as it depends on the molecular behaviour of the tumour. Hence incorrect drugs with not life prolonging effect are regularly applied. The mCRPC Progression test will be developed for patients that are either diagnosed biochemically or radiologically with CRPC at the beginning of treatment. The mCRPC Progression test will be able to detect early metastatic growth and predict disease progression, hence enabling advanced treatment decision-making. By using the mCRPC Progression test early treatment failure could be detected, guiding thus the doctor and the patient for treatment adjustment. The mCRPC progression test is non-invasive. Urine is easily accessible and has no physical side effects for the patient. The aforementioned biomarker panel will permit an individual as well as a small-meshed monitoring during treatment.
Implementation of the mCRPC Progression Test in Clinical Practise
Implementation of the PCa Status Test in Clinical Practise