# Treatment-emergent neuroendocrine transformation (recognising it)

Source: https://onco.cc/biomarkers/nepc-transformation/  
OnCo record `nepc-transformation` (Biomarker). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The test result that shows a prostate cancer has changed into a different, faster kind of cancer under hormone treatment. It is made on a biopsy, usually prompted by disease that is growing while the PSA stays flat.

## Summary

This readout is about recognition rather than about the entity itself, which is a WHO tumour type with its own record. Morphology comes first: a Prostate Cancer Foundation working committee set out named categories, separating usual adenocarcinoma with neuroendocrine differentiation from small cell carcinoma, large cell neuroendocrine carcinoma and mixed neuroendocrine carcinoma with acinar adenocarcinoma, and naming the situation in which castration-resistant disease presents clinically like small cell cancer (Epstein 2014). Supporting molecular features are loss of both RB1 and TP53, which is what permits the lineage change (Ku 2017, Mu 2017), and AURKA with MYCN co-amplification, present in 40% of neuroendocrine tumours against 5% of adenocarcinomas (Beltran 2011). In 59 samples from 40 men meeting clinical aggressive variant criteria, RB1 stained in under 10% of cells in 61% and androgen receptor in 36%, and RB1 copy loss was the strongest single discriminator from unselected castration-resistant disease (Aparicio 2016). The transition is epigenetic before it is genetic, since methylation separates the two states far more sharply than mutation does (Beltran 2016), and cell-free DNA methylation discriminated the two with an area under the curve of 0.96 and 1.0 in two small cohorts (Berchuck 2022).

## Fields

- Kind: Biomarker
- Last checked: 2026-09-25
- Also known as: neuroendocrine transformation; NEPC; t-NEPC; CRPC-NE; small cell transformation prostate; neuroendocrine differentiation prostate; aggressive variant prostate cancer
- Tags: biomarker; resistance

## Sources

- Epstein et al., Am J Surg Pathol 2014: proposed morphologic classification of prostate cancer with neuroendocrine differentiation (Prostate Cancer Foundation working committee): https://doi.org/10.1097/PAS.0000000000000208
- Beltran et al., Nat Med 2016: divergent clonal evolution of castration-resistant neuroendocrine prostate cancer (114 samples): https://doi.org/10.1038/nm.4045
- Aparicio et al., Clin Cancer Res 2016: combined RB1, TP53 and PTEN defects characterise clinically defined aggressive variant prostate cancer (59 samples from 40 trial participants): https://doi.org/10.1158/1078-0432.CCR-15-1259

## Connected records

- biomarkers: [AR amplification (gene and upstream enhancer)](https://onco.cc/biomarkers/ar-amplification/), [AR-V7 splice variant](https://onco.cc/biomarkers/ar-v7-splice-variant/)
- cancers: [Metastatic castration-resistant prostate cancer](https://onco.cc/cancers/prostate-mcrpc/), [Neuroendocrine and small-cell prostate cancer](https://onco.cc/cancers/prostate-nepc/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/)
- targets: [Androgen receptor](https://onco.cc/targets/androgen-receptor/), [AURKA](https://onco.cc/targets/aurka/), [MYCN (N-myc)](https://onco.cc/targets/mycn/), [RB1](https://onco.cc/targets/rb1/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [Androgen receptor signalling](https://onco.cc/pathways/ar-signaling/), [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/)
- terms: [Biopsy](https://onco.cc/terms/biopsy/), [Castration-resistant prostate cancer (CRPC)](https://onco.cc/terms/castration-resistance/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Immunohistochemistry (IHC)](https://onco.cc/terms/ihc/), [PSA (prostate-specific antigen)](https://onco.cc/terms/psa/)
- key papers: [Combined tumour suppressor defects characterise clinically defined aggressive variant prostate cancers](https://onco.cc/key-papers/paper-aparicio-aggressive-variant-prostate-tumour-suppressors-ccr-2016/), [Detecting neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis](https://onco.cc/key-papers/paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022/), [Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/), [Molecular characterisation of neuroendocrine prostate cancer and identification of new drug targets](https://onco.cc/key-papers/paper-beltran-nepc-aurka-mycn-cancer-discov-2011/), [Proposed morphologic classification of prostate cancer with neuroendocrine differentiation](https://onco.cc/key-papers/paper-epstein-neuroendocrine-prostate-morphologic-classification-ajsp-2014/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/)

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