The objective of the studies included in this thesis is to deepen the understanding and applicability of useful biomarkers for implementing personalized medicine in pituitary neuroendocrine tumors (PitNETs), specifically in somatotropic tumors and non-functioning tumors. A prospective study (the ACROFAST study) was conducted in patients with acromegaly on the efficacy of a personalized treatment algorithm based on predictive factors of response to first-generation somatostatin receptor ligands (fgSRLs), compared to a group of patients treated according to the standard therapeutic decision-making algorithm. Additionally, the accuracy of the short version of the Acute Octreotide Test (sAOT) as a predictive factor of response to these compounds was reevaluated. Furthermore, the research also investigates prognostic biomarkers in non-functioning PitNETs, specifically the expression of genes involved in the epithelial-mesenchymal transition process (TEM) and genes identified as predictive factors of response to fgSRLs and dopamine agonists. The results obtained show that the individualized algorithm allows a more efficient and effective control of acromegaly, achieving disease control in 78% vs 53% of patients in the personalized protocol compared to the standard protocol at the end of the study (p = 0,04). Moreover, the time to disease control, considering a maximum period of 365 days in uncontrolled patients, was shorter in the personalized group [182 (92 - 365) days vs 305 (137 - 365) days; p = 0,06]. The GH level at 2 hours after the acute administration of 100 μg of octreotide proved to be a precise and effective biomarker, with an Area Under Curve (AUC) of 83,2% for identifying non-responders. Two clinically useful cutoff points were identified: GH2h ≤ 1,4 ng/dL identified esponding patients (VPP = 96%, VPN = 67%), while GH2h ≥ 4,3 ng/dL identified non-responding patients (VPP = 86%, VPN = 72%). These results had greater predictive power than other evaluated clinical parameters and were associated with E-cadherin immuno staining [GH2h = 0,9 (0,3-2,1) ng/mL vs 3,3 (1,5-12,1) ng/mL; p < 0,01 in patients with positive vs negative E-cadherin expression]. The same association could not be demonstrated with SSTR2 [GH2h = 0,9 (0,2 - 1,9) ng/mL vs 2,2 (0,6 - 7,8) ng/mL; p = 0,16 using an IRS-Score for SSTR2 greater or less than 5], although patients with positive E-cadherin did exhibit higher expression of SSTR2 (7,5 ± 4,2 vs. 3,3 ± 2,0; p = 0,01). The study of non-functioning tumors revealed that the markers of the TEM process SNAI1 (p = 0,049) and VIM (p = 0,039) were associated with tumor invasion, while E-cadherin was associated with intrasellar localization (p = 0,047). Among the studied markers, the higher expression of PEBP1 in tumors with recurrence after surgery was notable (p = 0,04), with an AUC of 69,9% for predicting recurrence. This work demonstrates that individualized treatment in acromegaly is superior to conventional treatment and that there are biomarkers in non-functioning PitNETs with potential benefit in predicting their behaviour. It is our duty as physicians and a right for patients to advocate for the application of individualized medicine in clinical practice.
| Date of Award | 20 May 2025 |
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| Original language | Spanish |
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| Supervisor | Manuel Luis Puig Domingo (Director) & Joan Gil Ortega (Director) |
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