Does neoendocrine (neuroendocrine) prostate cancer express Prostate-Specific Membrane Antigen (PSMA)?

PSMA Expression in Neuroendocrine Prostate Cancer

Neuroendocrine prostate cancer typically does not express PSMA, which has significant implications for imaging and treatment selection. 1, 2

PSMA Expression Patterns in Prostate Cancer Subtypes

Conventional Adenocarcinoma vs. Neuroendocrine Prostate Cancer

• Conventional prostate adenocarcinoma: Typically shows high PSMA expression

  • PSMA-based imaging agents like 68Ga-PSMA PET/CT show promising results with high sensitivity and specificity (86% for both) 3
  • PSMA expression generally increases with higher Gleason scores in conventional adenocarcinoma

• Neuroendocrine prostate cancer (NEPC):

  • Characterized by significant suppression of FOLH1 (the gene encoding PSMA) 2
  • Loss of PSMA expression occurs during neuroendocrine differentiation 2, 4
  • This suppression is observed in both de novo NEPC and treatment-induced neuroendocrine differentiation 1

Molecular Mechanisms of PSMA Suppression in NEPC

• NEPC development is associated with:

  • Loss of androgen receptor (AR) signaling
  • Acquisition of neuroendocrine markers
  • Suppression of PSMA expression 2
  • Upregulation of alternative markers such as somatostatin receptor type 2 (SSTR2) 2

• In 18 NEPC patient-derived xenograft models, significant suppression of FOLH1 (PSMA) and amplification of SSTR2 expression was observed 2

Clinical Implications

Imaging Considerations

• PSMA-targeted imaging may be ineffective for NEPC lesions due to PSMA suppression 2
• Alternative imaging approaches for NEPC:
  • SSTR2-targeted imaging may be more appropriate for NEPC 2
  • 18F-FDG PET may be more sensitive for NEPC due to altered glucose metabolism 5
  • NEPC shows differential expression of glucose transporters and hexokinases, with GLUT12 suppression and glucokinase upregulation 5

Treatment Implications

• PSMA-targeted radioligand therapy (e.g., 177Lu-PSMA-617) may have limited efficacy in NEPC
• The VISION trial for 177Lu-PSMA-617 specifically required PSMA-positive lesions for inclusion 3
• AUA/ASTRO/SUO guidelines note: "A subset of prostate cancer may not produce PSA or express PSMA, for example poorly differentiated or neuroendocrine prostate cancer" 3
• For PSMA-negative disease, alternative approaches such as 18F-fluciclovine-PET/CT or FDG-PET may be useful 3

Diagnostic Approach for Suspected NEPC

1. Consider NEPC in patients with:

   • Rapidly progressive disease despite AR-targeted therapy
   • Low or rapidly declining PSA relative to disease burden
   • Predominant visceral or lytic bone metastases

2. Imaging strategy:

   • PSMA PET may show negative or low uptake in NEPC lesions
   • Consider alternative imaging modalities:
     • 18F-FDG PET (may show higher uptake in NEPC) 5
     • SSTR2-targeted imaging 2

3. Tissue biopsy with immunohistochemistry for:

   • Neuroendocrine markers (synaptophysin, chromogranin A, CD56)
   • PSMA expression
   • AR expression

Important Caveats

• Not all PSMA-negative prostate cancers are neuroendocrine

  • Some non-neuroendocrine dedifferentiated acinar prostate cancers can also lose PSMA expression 4

• Circulating neuroendocrine biomarkers (progastrin-releasing peptide, neuron-specific enolase, chromogranin-A) may not predict response to PSMA-targeted therapy 6

• The degree of PSMA expression in NEPC can be variable, with some tumors retaining partial expression

  • Intensity of PSMA-ligand uptake in metastases remains a strong predictor of treatment response to PSMA-targeted therapy 6

In summary, the loss of PSMA expression in neuroendocrine prostate cancer has important implications for both diagnostic imaging and therapeutic approaches, necessitating alternative strategies for this aggressive prostate cancer variant.