[Aggressive variant prostate cancer and transdifferentiated neuroendocrine prostate cancer: from diagnosis to...

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.