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 HardyWeinberg 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 HardyWeinberg 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.
30 Apr - 04 May 2011
European Society of Endocrinology