"Tamoxifen for residual NF-PitNETs: A Proof-of-Concept study integrating receptor profiling, pilot trial, and target pathway analysis".

BACKGROUND: Non-functioning neuroendocrine pituitary neuroendocrine tumors (NF-PitNETs) pose a therapeutic challenge due to their hormonal inactivity, mass effects and limited medical treatment options for residual or recurrent disease. There is increasing evidence that the oestrogen receptor (ER) is involved in the pathogenesis of these tumours. In this study, the potential therapeutic role of tamoxifen, a selective ER modulator, was investigated. METHODS: Fifty NF-PitNET samples were analysed for ERα and ERβ expression by immunohistochemistry. A randomised, open-label clinical trial was conducted in 20 patients with postoperative residual tumours comparing tamoxifen treatment (n = 10) with observation (n = 10), with MRI volume analysis performed at baseline and after six months. In parallel, tamoxifen targets were predicted with SwissTargetPrediction and analysed with enrichment tools (DAVID, STRING, Cytoscape). RESULTS: ERβ expression was present in 68% of tumours, while ERα was detected in 18%. In the tamoxifen group, the tumour shrank in 40% of patients and the disease remained stable in 60%. In contrast, tumour progression occurred in 20% of patients in the observation group (p = 0.043). The computational analysis revealed 109 predicted tamoxifen targets that were significantly enriched in neuroactive ligand–receptor interactions, calcium signalling and cAMP pathways. Gene ontology terms indicated involvement in G protein-coupled receptor activities and synaptic signalling pathways, with key nodes being AKT1, MAPK14, ESR1, DRD2, EGFR and CDKN1B. CONCLUSION: These preliminary results suggest that tamoxifen may provide clinical benefit in residual NF-PitNETs, particularly those expressing ERβ. Further validation studies are required to confirm efficacy and identify predictive molecular markers.