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Molecular determinants of enhanced response to somatostatin receptor ligands after debulking in large GH-producing
Joan Gil1, Montserrat Marques-Pamies2, Mireia Jordà1
1Endocrine Research Unit, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain.
Objective:
Large somatotrophic adenomas depict poor response to somatostatin receptor ligands (SRLs). Debulking has shown to enhance SRLs effect in some but not all cases and tumour volume reduction has been proposed as the main predictor of response. No biological studies have been performed so far in this matter. We aimed to identify molecular markers of response to SRLs after surgical debulking in GH-secreting adenomas.
Design:
We performed a multicenter retrospective study.
Patients:
24 patients bearing large GH-producing tumours.
Measurements:
Clinical data and SRLs response both before and after surgical debulking were collected, and 21 molecular biomarkers of SRLs response were studied in tumour samples by gene expression.
Results:
From the 21 molecular markers studied, only two of them predicted enhanced SRLs response after surgery. Tumours with improved response to SRLs after surgical debulking showed lower levels of Ki-67 (MKI67, FC = 0.17 and P = .008) and higher levels of RAR-related orphan receptor C (RORC) (FC = 3.1 and P ˂ .001). When a cut-off of no detectable expression was used for Ki-67, the model provided a sensitivity of 100% and a specificity of 52.6% with an area under the curve of 65.8%. Using a cut-off of 2 units of relative expression of RORC, the prediction model showed 100% of sensitivity and specificity.
Conclusions:
High levels of RORC and low levels of Ki-67 identify improved SRLs response after surgical debulking in large somatotropic adenomas. To determine their expression would facilitate medical treatment decision-making after surgery.
Insights
Low Ki-67 and high RAR-related orphan receptor C (RORC) levels predict better response to somatostatin receptor ligands (SRLs) after surgery for large GH-secreting adenomas. These molecular markers can guide treatment decisions post-operatively.
Area of Science:
- Endocrinology and Oncology
- Molecular Biology
- Surgical Oncology
Background:
- Large somatotrophic adenomas often show limited response to somatostatin receptor ligands (SRLs).
- Surgical debulking can improve SRL efficacy, but response prediction remains challenging.
- Molecular predictors of treatment response in these tumors are largely unexplored.
Purpose of the Study:
- To identify molecular markers that predict response to SRLs following surgical debulking in patients with large GH-secreting adenomas.
- To investigate the role of gene expression in determining treatment outcomes after combined surgical and medical therapy.
Main Methods:
- A multicenter retrospective study involving 24 patients with large GH-producing adenomas.
- Collection of clinical data and SRL response before and after surgical debulking.
- Analysis of 21 molecular biomarkers using gene expression in tumor samples.
Main Results:
- Two molecular markers, Ki-67 (MKI67) and RAR-related orphan receptor C (RORC), significantly predicted SRL response.
- Lower Ki-67 expression (FC=0.17, P=0.008) and higher RORC expression (FC=3.1, P<0.001) were associated with improved SRL response post-surgery.
- Predictive models using Ki-67 and RORC achieved high sensitivity and specificity.
Conclusions:
- Elevated RORC and reduced Ki-67 levels are key indicators of enhanced SRL response after surgical debulking in large somatotrophic adenomas.
- These biomarkers can aid clinicians in making informed treatment decisions for patients post-surgery.
- Further validation of these molecular markers may refine therapeutic strategies for pituitary adenomas.
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