Integrative clinical, hormonal, and molecular data associate with invasiveness in acromegaly: REMAH study
Authors: Sampedro-Nuñez Miguel , Herrera-Martínez Aura Dulcinea , Ibáñez-Costa Alejandro , Rivero-Cortés Esther , Venegas Eva , Robledo Mercedes , Martínez-Hernández Rebeca , García-Martínez Araceli , Gil Joan , Jordà Mireia , López-Fernández Judith , Gavilán Inmaculada , Maraver Silvia , Marqués-Pamies Montserrat , Cámara Rosa , Fajardo-Montañana Carmen , Valassi Elena , Dios Elena , Aulinas Anna , Biagetti Betina , Álvarez Escola Cristina , Araujo-Castro Marta , Blanco Concepción , Paz de Miguel , Villar-Taibo Rocío , Álvarez Clara V , Gaztambide Sonia , Webb Susan M , Castaño Luis , Bernabéu Ignacio , Picó Antonio , Gálvez María-Ángeles , Soto-Moreno Alfonso , Puig-Domingo Manel , Castaño Justo P , Marazuela Mónica , Luque Raúl M ,   REMAH investigators, Adrados Magdalena , Flores Pedro Martínez , Leví Ana María Ramos , Serrano-Somavilla Ana , Díez Juan José , Villanueva Mercedes García , Iglesias Pedro , Berrocal Víctor Rodríguez , Gutiérrez Esperanza Aguillo , Bances Luciano , Calvo Gracia Fernando L , Comunas Fernando , López Iván Quiroga , Hernando Carmen Alameda , Luis Jesús Miguel Pérez , Centeno Rogelio García , Iza Begoña , López Carlos Pérez , Zamarrón Álvaro Pérez , Alén José F , Gutiérrez María Calatayud , Sansinenea Igor Paredes , Otero Álvaro , Córdova José María Recio , Sousa Pablo , Belinchón José , Herguido María José , de Lope Ángel Rodríguez , Delgado Almudena Vicente , Muñoz Fernando , Santos Alicia , Asla Queralt , Servat Andreu Simó , Torres Alberto , Vidal Noemí , Villabona Carles , Sesmilo Gemma , Cambra Guillem Cuatrecasas , Obiols Gabriel , Carrato Cristina , Salinas Isabel , Hostalot Cristina , Blanco Alberto , Zabala Roxana , Simón Inmaculada , Ibáñez Javier , Fernández Honorato García , Serra Guillermo , Riesgo Pedro , Simal-Julian Juan Antonio , Lamas Cristina , Sandoval Hernán , Abarca Javier , Mendoza Nieves Arias , Ortiga Ruth Sánchez , Monjas Irene , Font Teresa Pedro , Troncoso Isabel Alonso , Catalina Pablo Fernández , San Martín Rosa María Álvarez , Ballesteros Pomar María D , Romero Sihara Pérez , Rodríguez Eva Fernández , García-Allut Alfredo , Serramito Ramón , Prieto Alma , Bellas Laura Cotovad , Pardo Jose Ignacio Vidal , Expósito María Rosa Alhambra , Moreno-Moreno Paloma , Padillo-Cuenca José Carlos , Vázquez-Borrego María Carmen , Fuentes-Fayos Antonio Carlos , Leal-Cerro Alfonso , Japón Miguel Ángel , Rivera Natividad González , Arnés Juan Antonio García , González-Molero Inmaculada , Maraver-Selfa Silvia , Vela Elena Torres , Avilés-Pérez María Dolores , Tenorio-Jiménez Carmen , Carazo Alberto Moreno , García José Gregorio Oliva 
Published: May 2024

Abstract

Introduction
Growth hormone (GH)-secreting pituitary tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarker assessment associated with tumor growth and invasion is important to optimize their management.

Objectives
The study aims to identify clinical/hormonal/molecular biomarkers associated with tumor size and invasiveness in GHomas and to analyze the influence of pre-treatment with somatostatin analogs (SSAs) or dopamine agonists (DAs) in key molecular biomarker expression.

Methods
Clinical/analytical/radiological variables were evaluated in 192 patients from the REMAH study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). The expression of somatostatin/ghrelin/dopamine system components and key pituitary/proliferation markers was evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables.

Results
Eighty percent of patients harbor macroadenomas (63.8% with extrasellar growth). Associations between larger and more invasive GHomas with younger age, visual abnormalities, higher IGF1 levels, extrasellar/suprasellar growth, and/or cavernous sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (P &lt; .05) were associated with tumor invasiveness. Least Absolute Shrinkage and Selection Operator’s penalized regression identified combinations of clinical and molecular features with areas under the curve between 0.67 and 0.82. Pre-operative therapy with DA or SSAs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with DA) and FSHB/CRHR1 (down-regulated with SSAs).

Conclusions
A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.