Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta‐analysis

Abstract

Background: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. We performed a systematic review and meta-analysis to evaluate the prevalence of genomic alterations in NEPC and better understand its molecular features to potentially inform precision medicine.Methods: EMBASE, PubMed, and Cochrane Central Register of Controlled Trials databases were searched for eligible studies until March 2022. Study qualities were assessed using the Q-genie tool. The prevalence of gene mutations and copy number alterations (CNAs) were extracted, and meta-analysis was performed using R Studio with meta package.Results: A total of 14 studies with 449 NEPC patients were included in this metaanalysis. The most frequently mutated gene in NEPC was TP53 (49.8%), and the prevalence of deleterious mutations in ATM/BRCA was 16.8%. Common CNAs in NEPC included RB1 loss (58.3%), TP53 loss (42.8%), PTEN loss (37.0%), AURKA amplification (28.2%), and MYCN amplification (22.9%). RB1/TP53 alterations and concurrent RB1 and TP53 alterations were remarkably common in NEPC, with a prevalence of 83.8% and 43.9%, respectively. Comparative analyses indicated that the prevalence of (concurrent) RB1/TP53 alterations was significantly higher in de novo NEPC than in treatment-emergent NEPC (t-NEPC).Conclusions: This study presents the comprehensive prevalence of common genomic alterations and potentially actionable targets in NEPC and reveals the genomic differences between de novo NEPC and t-NEPC. Our findings highlight the importance of genomic testing in patients for precision medicine and provide insights into future studies exploring different NEPC subtypes.

Treatment‐related neuroendocrine prostate cancer with BRCA2 germline mutation treated with olaparib

“…Loss of function in TP53 or RB1 is not observed in a few t‐NEPC cases 10 . These genomic features may be deeply involved in the development of t‐NEPC; 3 however, we did not observe these gene mutations in our patient, indicating there might be other genomic or epigenetic alterations that trigger t‐NEPC arising from initial adenocarcinoma 11 . t‐NEPCs often present poorer prognosis than common prostate adenocarcinoma 4 .…”

“… 10 These genomic features may be deeply involved in the development of t‐NEPC; 3 however, we did not observe these gene mutations in our patient, indicating there might be other genomic or epigenetic alterations that trigger t‐NEPC arising from initial adenocarcinoma. 11 t‐NEPCs often present poorer prognosis than common prostate adenocarcinoma. 4 Following the National Comprehensive Cancer Network guidelines version 1.2023, the standard treatment for NEPC is chemotherapy with ETP and platinum‐based drugs such as CDDP.…”

Lactate as Key Metabolite in Prostate Cancer Progression: What Are the Clinical Implications?

“…However, it can assess the uptake and accumulation of the non-metabolizable glucose analogue 18 F-FDG, which often correlates with glycolytic flux and lactate synthesis in cancer. 18 F-FDG PET shows a limited usefulness in the detection and staging of primary PCa, whose oxidative/lipogenic phenotype is better captured using precursor radionucleotides such 11 C/ 18 F-choline and 11 C-acetate [17,114]. During castration resistance, PCa undergoes the glycolytic switch and enhances glucose uptake, which can be captured with 18 F-FDG PET.…”

“…On this basis, 18 F-FDG PET can be exploited to monitor disease progression and predict the response to ADT before clinical effects are evident. Oyama et al have indeed shown that 18 F-FDG outperforms 11 C-acetate in monitoring ADT efficacy in CWR22 xenograft tumors from mice that were exposed to ADT (diethylstilbestrol) or a vehicle for a week. While 11 C-acetate uptake did not show a significant difference after ADT treatment, 18 F-FDG uptake was already markedly reduced, suggesting that 18 F-FDG PET may predict the ADT response [17].…”

“…The situation is further aggravated by the emergence of very aggressive neuroendocrine variants that often occur after hormonal treatments. These variants display a loss of AR expression, gain of neuroendocrine or pro-neural markers (i.e., neuron-specific enolase and synaptophysin), and combined alterations in the tumor suppressors phosphatase and tensin homolog (PTEN), TP53, and RB transcriptional corepressor 1 (RB1) [ 11 ]. Neuroendocrine CRPC shows epithelial lineage plasticity and a poor response to available therapies [ 12 ].…”