Treatment-induced neuroendocrine prostate cancer and de novo neuroendocrine prostate cancer: Identification, prognosis and survival, genetic and epigenetic factors

Abstract

Neuroendocrine prostate cancer (NEPC) shows an aggressive behavior compared to prostate cancer (PCa), also known as prostate adenocarcinoma. Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer. NEPC may arise de novo or develop following androgen deprivation therapy (ADT). NEPC that arise following ADT has the nomenclature “treatment-emerging/induced NEPC (t-NEPC)”. t-NEPC would be anticipated in castration resistant prostate cancer (CRPC) and metastatic PCa. t-NEPC is characterized by low or absent androgen receptor (AR) expression, independence of AR signaling, and gain of neuroendocrine phenotype. t-NEPC is an aggressive metastatic tumor, develops from PCa in response to drug induced ADT, and shows very short response to conventional therapy. t-NEPC occurs in 10%-17% of patients with CRPC. De novo NEPC is rare and is accounting for less than 2% of all PCa. The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated. Sphingosine kinase 1 plays a significant role in t-NEPC development. Although neuroendocrine markers: Synaptophysin, chromogranin A, and insulinoma associated protein 1 (INSM1) are expressed in t-NEPC, they are non-specific for diagnosis, prognosis, and follow-up of therapy. t-NEPC shows enriched genomic alteration in tumor protein P53 (TP53) and retinoblastoma 1 (RB1). There are evidences suggest that t-NEPC might develop through epigenetic evolution. There are genomic, epigenetic, and transcriptional alterations that are reported to be involved in development of t-NEPC. Knock-outs of TP53 and RB1 were found to contribute in development of t-NEPC. PCa is resistant to immunotherapy, and at present there are running trials to approach immunotherapy for PCa, CRPC, and t-NEPC.

Keywords: Prostate cancer; Neuroendocrine carcinoma; Treatment induced neuroendocrine prostate cancer; Androgen deprivation therapy; Genetic and epigenetic factors; Castration resistant prostate cancer; De novo neuroendocrine prostate cancer

Core Tip: Neuroendocrine prostate cancer (NEPC) are aggressive metastatic tumors, and there are two distinct types. De novo NEPC, which is less than 2% of all prostate cancer, is categorized as an entity of the endocrine tumors. The other type is the treatment induced NEPC (t-NEPC) that develops in castration resistant prostate cancer (CRPC) following androgen deprivation therapy, and it is an aggressive metastatic tumor occurs in 10%-17% of patients with CRPC and metastatic cancer, with median survival of 7 months after diagnosis. Genomic, epigenetic, and transcriptional alternation has been reported to be involved in its development. Future expectations for treatment would be tumor-directed immunotherapy.