Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR® responsiveness in acromegaly

Abstract

We present two acromegalic patients in which clinical and molecular data are discussed in regard to their ability to predict long term octreotide LAR ® therapy response. Case reports: Patient 1: female, 36 years old at diagnosis. Basal GH and IGF-I at diagnosis were 133 ng/mL and 181% above the upper limit of reference values (ULRV), respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 133 to 13 ng/mL. Patient started on primary octreotide LAR ® therapy (20mg q28 days) and achieved biochemical parameters of disease control after 6 months. Molecular analysis of tumor fragments: gsp +; quantitative analysis of SSTR (somatostatin receptor) and DR (dopamine receptor) mRNA -SSTR2 23954; SSTR5 2407; DR2 total 17016 copies. Patient 2: male, 38 years old at diagnosis. Basal GH and IGF-I at diagnosis were 120 ng/mL and 114% ULRV, respectively. Patient underwent noncurative trans-sphenoidal surgery. Post-operative GH and IGF-I were 112 ng/ mL and 137% ULRV, respectively. Growth hormone during acute test with subcutaneous octreotide decreased from 112 to 7 ng/mL. Octreotide LAR ® therapy (20 mg q28 days) was then initiated. After 6 months of treatment, patient did not attain biochemical control of disease and displayed increased tumor volume. Molecular analysis of tumor fragments: gsp not done; quantitative analysis of SSTR and DR mRNA -SSTR2 416; SSTR5 3767; DR2 total 3439 copies. In conclusion, these two cases illustrate how laboratory data can be confl icting as predictors of octreotide LAR ® responsiveness and how molecular analysis of tumor fragments can help explain different behaviors in clinically similar patients. RESUMO Expressão dos Receptores da Somatostatina Subtipos 2 e 5 e do Receptor da Dopamina tipo 2 e gsp Status como Preditores de Resposta ao Octreotide LAR® na Acromegalia.Apresentamos dois pacientes acromegálicos nos quais dados clínicos e moleculares são discutidos quanto à sua capacidade de predizer a resposta a longo prazo ao tratamento com octreotide LAR ® . Relato dos casos: Paciente 1: Feminina, 36 anos de idade ao diagnóstico. GH e IGF-I ao diagnóstico 133 ng/mL e 181% acima do limite superior do valor de referência (LSVR), respectivamente. GH durante o teste agudo com octreotide subcutâneo diminuiu de 133 para 13 ng/mL. Foi iniciado tratamento primário com octreotide LAR ® (20 mg q28 dias) e a paciente alcançou os parâmetros bioquímicos de controle de doença depois de seis meses. Análise molecular do tumor: gsp +; análise quantitativa do mRNA de SSTR (receptores de somatostatina) e DR (receptor de dopamina) -SSTR2 23.954; SSTR5 2.407; DR2 total 17.016 có-pias. Paciente 2: Masculino, 38 anos de idade ao diagnóstico. GH e IGF-I ao diagnóstico 120 ng/mL e 114% LSVR, respectivamente. Paciente foi sub-

Magnetic Resonance Imaging as a Predictor of Response to Somatostatin Analogs in Acromegaly after Surgical Failure

“…Moreover, other biological determinants play a crucial role in the response to SSA, namely the distribution of SSR2 and SSR5, as well as the other SSR subclasses and the dopamine receptor 2 and the rest of dopamine receptors subclasses. Their coexistence and interrelationship in a given tumor in terms of heterodimerization and internalization process, as well as the interaction with Gs␣, a pathway highly related to hypersecretory somatotropinomas, are nowadays the better characterized factors involved in SSA response (13,14,25,26). Unfortunately, neither SSR nor dopamine receptor studies were done in our patients.…”

Resistance to octreotide LAR in acromegalic patients with high SSTR2 expression: analysis of AIP expression

“…Considering their affinity to the five SSTRs, it is expected that the expression of SSTR2 is mandatory for good response to these drugs (3). Indeed, it has been demonstrated by our group and others, that disease activity is not controlled in the presence of low SSTR2 expression (4,5,17,18). However, the presence of a high SSTR2 expression is not invariably associated with good response to SSAs therapy (5).…”

A review on the diagnosis and treatment of patients with clinically nonfunctioning pituitary adenoma by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism

“…SA exerts its pharmacological properties through SSTR, with five subtypes having been identified in humans (SSTR1, 2, 3, 4 and 5) and present in normal pituitary and pituitary adenoma (96,(109)(110)(111).…”