Identification of Predictive Biomarkers
Condition: Prostate Cancer Recurrent
MeSH terms: Prostatic Neoplasms
Study type: Interventional

Summary: 
      Molecular nuclear imaging in prostate cancer has made significant progress in the last few
      years. The introduction of tracers that target the prostate-specific membrane antigen (PSMA)
      has profoundly influenced imaging diagnostics in prostate cancer. In case of relapse after
      curative treatment (especially after radical prostatectomy), PSMA positron emission
      tomography (PET) has the ability to detect lesions already at very low prostate-specific
      antigen (PSA) levels. The improved detection of relapses increases the interest of
      individualized targeted therapies in patients with prostate cancer recurrence. Thus, this
      development led to the acceptance of PSMA PET for diagnostics in prostate cancer patients
      with biochemical relapses in national and international guidelines.
    

Detailed description: 
      As mentioned before, current data on salvage lymphadenectomy in prostate cancer is very
      limited and stems mainly from retrospective series. Prospective studies are not available.
      Furthermore, most of these analyses are based on choline-based positron emission tomography,
      which by now has been progressively replaced with the significantly more sensitive and
      specific PSMA-based PET. Diagnostic advantages are especially obvious in early biochemical
      recurrence with low PSA levels . The high specificity of a PSMA Tracer in diagnosing prostate
      cancer tissue is further demonstrated by the introduction of PSMA-radioguided surgery. Here,
      patients are injected intravenously before surgery with 111In- or 99mTc-labeled PSMA ligands
      in order to enhance intraoperative detection of affected lymph nodes that show radiotracer
      accumulation.

      Regarding biomarkers used in prostate cancer, besides PSA and PSA-associated variations,
      there also exists a multiple number of different biomarkers. However, most of these
      biomarkers are used in the primary diagnostic setting or in advanced metastatic tumor stages
      with a castration-resistant stage. However, especially in early biochemical recurrences there
      is a need for biomarkers to help determine whether or not local salvage treatment can or
      should be considered. Circulating tumor cells (CTCs) are promising candidates as a biomarker,
      that could support the decision-making process. While the prognostic relevance of CTCs for
      patients with a metastatic castration-resistant stage prostate cancer has been shown in many
      studies, far less data exists for patients with hormone-sensitive metastatic prostate cancer.
      Regardless of the fact, survival is associated with the number of CTCs measured in peripheral
      blood. Recently, we were able to show that CTCs in patients with limited metastatic prostate
      cancer exhibited higher prognostic relevance, before and after cytoreductive radical
      prostatectomy, than conventional biomarkers (PSA, LDH =lactate Dehydrogenase and BAP). Even
      when the conventional biomarkers were combined with routine markers and CTCs, the prognostic
      relevance did not increase. Although the case numbers were very small, in the future, CTCs
      could still help identify patients that would most profit from a cytoreductive radical
      prostatectomy.

      Therefore, this project will investigate whether or not CTCs can preoperatively provide
      prognostic information on the postoperative oncological response, as described in the study
      protocol. The plan is to withdraw blood (7,5 ml) before surgery from 150 limited metastatic
      prostate cancer patients. These patients have to qualify for salvage surgery according to the
      PSMA-PET. The blood will be examined with the Cell-Search-Systems for CTCs and their PSMA
      Expression.

      Plasma samples and peripheral blood mononuclear cells (PBMCs) from peripheral blood will also
      be stored. These samples will be used later for a further project on prostate cancer-specific
      exosomes where PSMA positivity and cell-free circulating nucleic acids will be examined. The
      expertise for such analyses, standard operating procedures (SOPs) and necessary equipment are
      available.

      Furthermore, the Institute for Tumor Biology has recently established a new blood test for
      detecting breast cancer. This test will also be used on prostate cancer patients within the
      scope of this project. This test measures the serum concentration of Cyr61-Proteins. The
      Institute has established an Enzyme-Linked Immunosorbent Assay (ELISA), which has already
      been successfully implemented for the analysis of blood plasma in 527 breast cancer patients.
      Consequently, this newly developed blood test presents an important improvement in the
      diagnosis of breast cancer (International patent System 2018/054052). It would also like to
      test this method for its adequacy and improvement in the diagnosis of prostate cancer within
      the context of this project.

      Furthermore, in a subset of patients additionally tissue from metastatic lymph nodes will be
      collected for molecularpathologic analysis if tissue sampling does not affect routine
      pathological examination.
    

Intervention name(s): Blood sample
Intervention type(s): Other
Intervention description(s): Additional blood sample of about 30 ml that will be drawn for biomarker analyses (2 EDTA = ethylenediaminetetraacetic acid and 1 Cell-search-tubes).The drawn blood for CTC-Analysis and biomarker identification will be promptly processed ac-cording to the established standards at the Institute for Tumor Biology (see below).
The histological analysis of the resected tissue during salvage surgery is carried out according to clinical routine (conventional haematoxylin and eosin stained and PSMA-Immunohistochemistry). Additionally, tissue samples will undergo molecularpathological analysis if this does not affect routine pathological examination.
Intervention model: Single Group Assignment
Intervention model description: In this single-arm prospective clinical study, various blood- and serum-based biomarkers, from patients with early PSMA PET positive limited metastatic prostate cancer relapse after radical prostatectomy, will be examined according to their potential predictive significance for a successful salvage surgery. Results from the various biomarker values, after salvage surgery, with following clinical endpoints will be assessed:
postoperative complete biochemical response (cBR: PSA <0,2ng/ml)
biochemical relapse-free without further prostate cancer specific treatment (time from salvage surgery to first PSA level >0,2ng/ml)
prostate cancer specific treatment-free interval (time from salvage surgery to initiation of a prostate cancer specific treatment)
Masking: None (Open Label)
Primary purpose: Prevention