Endocrine Abstracts (2011) 26 P247

A multicenter study on acromegalic patients treated with pegvisomant monotherapy or with pegvisomant plus somatostatin analogues: role of exon 3 deleted GH receptor polymorfism

Marcello Filopanti1, Luca Olgiati1, Andrea Lania2, Paolo Beck-Peccoz1,2, Laura De Marinis3, Silvia Grottoli4, Chiara Martini5, Salvatore Cannavò6, Fausto Bogazzi7, Diego Ferone8, Giorgio Arnaldi9, Alessandro Peri10, Patrizia Tita11, Francesca Pigliaru12, Gabriella Angeletti13, Marie-Lise Jaffrain-Rea14, Marco Losa15 & Anna Spada1,2

1Unit of Endocrinology and Diabetology, Fondazione IRCCS Ca’ Granda, Milan, Italy; 2Endocrinology Unit, Department of Medical Sciences, University of Milan, Milan, Italy; 3Division of Endocrinology, School of Medicine, Catholic University, Rome, Italy; 4Division of Endocrinology, Department of Internal Medicine, University of Turin, Turin, Italy; 5Internal Medicine 3, Department of Medical and Surgical Sciences, University School of Padova, Padua, Italy; 6Section of Endocrinology, Department of Medicine and Pharmacology, University of Messina, Messina, Italy; 7Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy; 8Department of Endocrinology, University of Genoa, Genoa, Italy; 9Division of Endocrinology, Department of Internal Medicine, Polytechnic University of Marche Region, Ancona, Italy; 10Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy; 11Divisione Clinicizzata di Endocrinologia, Ospedale Garibaldi, Catania, Italy; 12Endocrinology and Metabolism, Department of Medical Sciences, University of Cagliari, Cagliari, Italy; 13Section of Internal Medicine and Endocrinological and Metabolic Sciences, Internal Medicine Department, University of Perugia, Perugia, Italy; 14Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy; 15Pituitary Unit, Department of Neurosurgery, Istituto Scientifico San Raffaele, Università Vita-Salute, Milan, Italy.

Introduction: To date, two pharmacogenetic studies investigated the effect of the common exon 3 deletion of GH receptor (d3-GHR) variant in small series of acromegalic patients treated with Pegvisomant (Peg), suggesting an association of d3-GHR allele with better response to Peg.

Aim: To assess the influence of d3-GHR variant in a large cohort of acromegalics with active disease and resistance to somatostatin analogues (SSA) treated with either Peg monotherapy or Peg plus SSA.

Patients and methods: A multicenter cross-sectional pharmacogenetic study was conducted in 16 Italian Endocrinology Centers. Data of 127 Peg treated patients were recorded with online case report form and DNA was genotyped by the coordinating center.

Results: Eighteen patients (13.9%) were d3-GHR homozygotes, 41 (34.3%) heterozygotes, and 68 (51.9%) were homozygotes for full-length GHR (fl-GHR) without any significant differences in allele frequencies in respect of both normal subjects and non-Peg treated acromegalics. However, the distribution of GHR genotypes among Peg patients did not follow the Hardy–Weinberg equilibrium. A similar frequency of d3-GHR allele was observed in 64 patients receiving Peg + SSA therapy. Pegvisomant dosage was similar in patients having or not d3-GHR both in Peg (1.3±0.42 vs 1.5±0.6, P=0.396) and in combined treatment (1.2±0.4 vs 1.3±0.7, P=0.482). Fourteen patients experienced adverse effects (lipohypertropy, increased hepatic enzymes, pain) that were not associated with GHR genotype. Nine patient had tumour residue growth (5 fl-GHR homozygotes, 4 d3-GHR).

Conclusions: This study did not confirm the association of d3-GHR with better response to Peg treatment both in monotherapy and combined with SSA. Further studies are needed to assess whether the unfitted Hardy–Weinberg equilibrium exclusively found in Peg treated patients may be attributed to a random genetic drift or may reflect a role of d3-GHR in the severity of disease activity and outcome.

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