Neuroendocrine prostate cancer

Neuroenocrine prostate cancer (NEPC) is aggressive histologic except type of prostate cancer. 

It is formed de novo at the time of diagnosis.

NEPC accounts for less than 1% of all prostate cancers. 

Patients with NEPC are likely to have metastatic disease at the time of diagnosis. 

Up to 15% of metastatic castration resistant prostate cancers transition into NEPC: prostate cancer that started out as an adenocarcinoma at the time of diagnosis may morph into treatment emergent NEPC.

It most commonly arises in later stages of prostate cancer as a mechanism of treatment resistance. 

One of the pathways for resistance of androgen deprivation therapy is lineage plasticity, in which the cells transition from one type of cancer to another through epigenetic modification.

NEPC lesions frequently have deletion or an activation of multiple tumor suppressor genes, especially RB1 and TP 53. 

 NEPC histologically appears similar to small cell lung cancer with small, round, dark cells, and a high proliferation rate. minimal cytoplasm, nuclear molding, fine chromatin pattern, and extensive tumor necrosis/apoptosis, without glandular structure.

NEPC is not dependent on androgen signaling, so it is unresponsive to hormone therapy. 

The poor prognosis of NEPC is attributed in part to late diagnosis and a lack of effective therapeutic agents. 

Dependence on androgen receptor (AR) signaling is lost as tumors progress from a prostate adenocarcinoma to a NEPC.

Changes typically manifest by downregulation of androgen receptor, PSA, and PSMA expression in tumors. 

Genomic analyses has pointed to loss of tumor suppressors RB1 and TP53 as key facilitators of lineage plasticity. 

The activation of oncogenic drivers combined with significant epigenetic changes (EZH2 overexpression, DNA methylation) further drive tumor proliferation and expression of downstream neuronal and neuroendocrine lineage pathways.

Further study of the dynamic process that leads to NEPC is required for the development of effective strategies to identify and treat patients developing lineage plasticity as a mechanism of treatment resistance.

Most castration resistant prostate cancers (CRPC) are still dependent on AR signaling through acquired AR gene mutation, amplification, or other means to re-activate the AR.

This has led to alternative strategies to further target AR signaling.

Approximately 15–20% of CRPC tumors will lose dependence on AR signaling at some point during their disease course.

One apparent clinical manifestation of CRPC is histologic transformation from an AR-expressing prostate adenocarcinoma to an AR-negative, poorly differentiated small cell neuroendocrine carcinoma histology.

Neuroendocrine prostate cancer (NEPC) to broadly encompasses both pure small cell carcinomas as well as mixed adenocarcinoma- neuroendocrine tumor morphologies. 

AR expression is typically low but even when AR is expressed, NEPC tumors tend to be less dependent, or indifferent to AR signaling. 

The diagnosis of NEPC is based on metastatic tumor biopsy confirming tumor morphology. 

NEPC, is considered in patients with particularly aggressive disease, atypical spread, and/or progression with low or non-rising PSA levels. 

Prostate cancer patients that develop small cell carcinoma could be considered for platinum-based chemotherapy regimens, similar to small cell lung cancer.

The incidence of AR-independent prostate cancer seems to be increasing, which may be related in part to the introduction of more potent and effective drugs that target the AR. 

In an autopsy study, 13.3% of patients harbored metastatic lesions that were AR-negative with neuroendocrine (NE) features and an additional 23.3% harbored AR-negative lesions without NE features. 

The median time from initial diagnosis of prostate cancer to NEPC development is 20 months, and high Gleason score (≥ 8) at diagnosis was an independent risk factor for early NEPC development.

The median survival after NEPC diagnosis was 7 months and involvement of more than three metastatic organs was associated with shorter survival.

In another analysis of 87 patients with histologically confirmed de novo or treatment-related NEPC, the median overall survival from time of prostate cancer diagnosis in de novo NEPC was 16.8 months which was shorter than those with treatment related-NEPC.

Median time from diagnosis of prostate adenocarcinoma to treatment related-NEPC was 39.7 months. 

At the time of NEPC, median PSA level was less than 4 ng/ml while serum chromogranin A and LDH levels were elevated in 48.3% and 62.5%, respectively. 

NEPC patients have more frequent visceral metastases compared to patients with castration resistant adenocarcinoma (62% vs 24%.

Tumors with mixed adenocarcinoma-NEPC harbored better prognosis than those with pure small cell NEPC (26.1 vs 8.9 months in median survival from the time of NEPC diagnosis.

Pathologic subtypes of neuroendocrine prostate cancer

(i)usual prostate adenocarcinoma with NE differentiation

(ii) adenocarcinoma with Paneth call NE differentiation

(iii) carcinoid tumor Well-differentiated NE tumor in the prostate gland that is either not closely associated with usual prostate carcinoma or originates in the urethra.

(iv)small cell carcinoma

(v)large cell NE carcinoma

(vi)mixed (small or large cell) NE carcinoma-acinar adenocarcinoma

PSMA PET is generally negative in NEPC.

FDG-PET-CT, standardly used in SCLC, may be useful in identifying NEPC tumors as they tend to be metabolically active.

The role and application of somatostatin receptor targeting peptides (e.g., 68Ga-DOTATATE, 177Lu-DOTATATE) used in well-differentiated NE tumors are also being investigated in NEPC

Genomic studies have supported NEPC tumors evolving from a prostate adenocarcinoma precursor, with shared genomic alterations between adenocarcinoma and metastatic NEPC tumors and between different histologies within mixed tumors.

Alterations such as TP53 and RB1 loss, enriched in NEPC tumors, are often acquired during the course of therapy resistance. 

The loss of RB1 and TP53 is also frequent in other small cell carcinomas and universally lost in SCLC,

Multiple studies now have support  combined TP53 and RB1 deficiency as key facilitators of the NE-like phenotype.

RB1 loss in particular is associated with poor prognosis in CRPC-Adeno, and future studies are warranted to address whether single or combined loss of these tumor suppressors predicates NEPC transformation and identifies patients at higher risk for developing lineage plasticity. 

Although less common, de novo small-cell prostate carcinoma can also occur. 

Similar genomic alterations were observed in de novo cases as seen in treatment-related NEPC including frequent biallelic deletion and /or mutation of TP53, RB1 and PTEN. 

Epigenetic alterations also play a key role in lineage plasticity leading to acquisition of stem-like cell properties and changes in differentiation.

These epigenetic features, including changes in DNA methylation, histone modifications, and chromatin integrity and accessibility, are responsible for transcriptional regulation.

DNA methylation patterns can distinguish NEPC.

NEPC associated DNA methylation changes are detectable in the circulation using cell free DNA (cfDNA).

EZH2 is highly expressed in many types of cancers including NEPC, and may be a targetable modulator of lineage plasticity

NEPC is characterized by the expression of genes involved in neuronal and neuroendocrine differentiation, epithelial-mesenchymal transition, stem-like/developmental pathways, and cell cycle markers.

During the transition from adenocarcinoma to NEPC, markers of prostate lineage are typically downregulated and androgen receptor activity is suppressed.

Critical dysregulation of key oncogenic drivers as well as transcription factors SOX2, ASCL1, BRN2, MYCN, ONECUT2 and others, drive plasticity and maintain the NE state.

N-myc is a transcription factor upregulated in NEPC and also implicated as a key oncogenic driver in other neuroendocrine tumors.

N-myc functions as a suppressor of AR-signaling and driver of lineage plasticity.

N-myc is not normally expressed in normal prostate cells.

Tumor overexpression of N-myc has been associated with shorter OS in patients with CRPC-Adeno and NEPC.

Platinum-based chemotherapy is commonly administered to patients with pure small cell carcinoma based on SCLC data and the accumulating data for aggressive variant prostate cancer

The evaluated treatment response of carboplatin and etoposide every 3 weeks in 60 patients with CRPC who were considered to have NE differentiation based on elevated serum CgA and NSE levels and/or visceral metastases had an objective with measurable disease (8.9%) and PSA response rate was 8%. 

The median progression-free survival (PFS) and OS were 2.9 months and 9.6 months, respectively. 

NEPC frequently has combined tumor suppressor loss (RB1, TP53, and/or PTEN) which are also frequent gene alterations.

Beyond platinum, therapy for NEPC is not well established.

AURKA inhibitor alisertib was evaluated in a phase Ⅱ trial  in the context of RB1 loss 6 months radiographic PFS was 13.4% and median survival was 9.5 months.: four patients showed outstanding response to alisertib with disappearance of liver metastases and durable stable disease, suggesting that patient selection, potentially by MYCN or RB1 biomarker status may be important 

Delta-like protein 3 (DLL3) is a protein expressed on the cell surface of various neuroendocrine tumors including SCLC and NEPC: observed in the majority of NEPC tumors (76.6%) and also a subset of CRPC-Adeno (12.5%), with minimal or absent expression in localized prostate cancer and benign tissues 

The epigenetic regulator EZH2 expression is higher in NEPC tissues compared to CRPC, localized prostate cancer and benign prostate tissues.

In preclinical studies, EZH2 inhibitors have shown activity in NEPC.

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