Joan Gil1, Montserrat Marques-Pamies2, Mireia Jordà1, Carmen Fajardo-Montañana3, Araceli García-Martínez4,5, Miguel Sampedro5,6, Guillermo Serra7, Isabel Salinas2, Alberto Blanco8, Elena Valassi9, Gemma Sesmilo10, Cristina Carrato11, Rosa Cámara12, Cristina Lamas13, Paula Casano-Sancho5,14, Clara V Alvarez15, Ignacio Bernabéu16, Susan M Webb9, Antonio Picó5,17, Mónica Marazuela5,6, Manel Puig-Domingo1,2,5,17. 1. Endocrine Research Unit, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain. 2. Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital, Badalona, Spain. 3. Department of Endocrinology, Hospital Universitario de La Ribera, Alzira, Spain. 4. Hospital General Universitario de Alicante-Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain. 5. Biomedical Research Networking Center in Rare Diseases (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain. 6. Department of Endocrinology and Nutrition, Hospital de la Princesa, Universidad Autónoma de Madrid, Instituto Princesa, Madrid, Spain. 7. Department of Endocrinology and Nutrition, Son Espases University Hospital, Palma de Mallorca, Spain. 8. Department of Neurosurgery, Germans Trias i Pujol University Hospital, Badalona, Spain. 9. Department of Endocrinology/Medicine, CIBERER U747, ISCIII, Research Center for Pituitary Diseases, Hospital Sant Pau, IIB-SPau, Universitat Autònoma de Barcelona, Barcelona, Spain. 10. Department of Endocrinology and Nutrition, Hospital Universitari Dexeus, Barcelona, Spain. 11. Department of Pathology, Germans Trias i Pujol University Hospital, Badalona, Spain. 12. Department of Endocrinology and Nutrition, Hospital Universitario y Politécnico La Fe, Valencia, Spain. 13. Department of Endocrinology and Nutrition, Hospital General Universitario de Albacete, Albacete, Spain. 14. Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain. 15. Neoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), Instituto de Investigación Sanitaria (IDIS), Santiago de Compostela, Spain. 16. Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS)-SERGAS, Santiago de Compostela, Spain. 17. Department of Medicine, Autonomous University of Barcelona (UAB), Barcelona, Spain.
Abstract
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.
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.