Urologie最新文献

Aggressive variants of prostate cancer (AVPC) comprise a heterogeneous group of prostate carcinomas characterized by androgen-independent, aggressive tumor growth. Clinically, they are characterized by prostate-specific antigen (PSA)-negative progression and an atypical metastatic pattern with increased visceral and osteolytic metastasis. Based on immunohistochemistry and transcriptome profiling, AVPC are divided into four subgroups: neuroendocrine prostate cancer (NEPC), amphicrine prostate cancer, androgen receptor-low expressing prostate cancer and double-negative prostate cancer. However, differentiating between the subgroups can be challenging. For the transformation process of an adenocarcinoma into an AVPC, so-called transdifferentiation, the inactivation of the tumor suppressor genes RB1, PTEN and TP53 plays a crucial role. Epigenetic changes contribute to the development of stem cell-like properties. AVPC is mostly treated with platinum-based chemotherapy, depending on the subtype in combination with etoposide or a taxane. New therapeutic approaches are investigating the use of chemotherapy combinations with PARP inhibitors, checkpoint inhibitors or immunomodulators. In addition, T‑cell engagers have achieved initial promising results, particularly in NEPC. Treatment of AVPC patients in trials is desirable to improve evidence for this aggressive form of prostate cancer.

Depending on the risk status, the treatment options for non-muscle-invasive bladder cancer (NMIBC) can include a bladder-preserving strategy with intravesical instillation treatment or early radical cystectomy. Established intravesical treatment options such as mitomycin C (MMC) or Bacillus Calmette-Guérin (BCG) are available to reduce the probability of progression and recurrence. This article classifies the intravesical treatment options in the therapeutic landscape of NMIBC and provides an overview of the indications and application regimens.

Introduction: Prostate cancer guidelines recommend molecular analysis of biomaterial following resistance to first-line systemic therapy in order to identify druggable mutations. We report on our results of molecular analysis of tissue specimens via next generation sequencing (NGS) in men with metastatic castration resistant prostate cancer (mCRPC).

Patients and methods: In all, 311 mCRPC patients underwent NGS analysis from biopsy samples of progressive metastatic lesions or archival radical prostatectomy specimens. NGS analysis was either performed using a panel of 18 prostate cancer-specific amplicons or via the TS0500 panel.

Results: Of the 311 biopsies, 299 (96%) revealed sufficient DNA content for NGS analysis independent on the specimen origin. Biopsies were taken from prostate (31%), lymph nodes (26%), visceral (17%) or osseous (18%) metastases. In 223 (75%) and 76 (25%) patients activating/inhibiting and no mutations were identified, respectively. Most frequently, mutations of HRD genes including a positive HRD score and p53 were identified in 22% of patients each. About 50% of HRD gene mutations were pathogenic and treatment with PARP inhibitors was initiated. Although the majority of p53 alterations were inactivating mutations, 3 patients demonstrated gain-of-function mutations resulting in an inactivation of ATM. Activating androgen receptor mutations and inactivating PTEN mutations were identified in 42 (14%) and 24 (8%) patients, respectively. Specific AR mutations resulted in a switch of hormonal therapy. Mutations of mismatch repair deficiency genes/MSI high were identified in 5 patients resulting in the administration of pembrolizumab. Addition of the TSO 500 panel identified additional mutations in 4.5% of patients and only 2% of the total cohort would have benefitted from this large panel with the identification of druggable mutations.

Conclusion: Druggable mutations were identified in one third of mCRPC patients using an 18 amplicon-panel analyzed via NGS. Based on our data, molecular analysis of AR mutations or mutations of the HRD genes should be performed following progression after first-line hormonal therapy. A more extensive molecular analysis seems to be useful following progression to the standard sequential hormonal, cytotoxicand radioligand therapies. Use of the expensive TSO 500 panel seems to be of additional therapeutic value in only a minority of patients.