Growth hormone receptor variants and response to pegvisomant in monotherapy or in combination with somatostatin analogs in acromegalic patients: A multicenter study

M. Filopanti, L. Olgiati, G. Mantovani, S. Corbetta, M. Arosio, V. Gasco, Laura De Marinis Grasso, C. Martini, Cecilia Martini, F. Bogazzi, S. Cannavò, A. Colao, D. Ferone, G. Arnaldi, F. Pigliaru, A. Peri, G. Angeletti, M. L. Jaffrain-Rea, A. G. Lania, Anna Spada

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Abstract

Context: The influence of full-length GH receptor (GHR) and exon 3-deleted GHR (d3GHR) on responsiveness to pegvisomant (PEG-V) in acromegalic patients is uncertain. Objective: The aim of the study was to assess the distribution of GHR genotypes in a large series of patients on PEG-V therapy and their influence on treatment efficacy and adverse effects. Design and Setting: A cross-sectional multicenter pharmacogenetic study was conducted in 16 Italian endocrinology centers of major universities and tertiary care hospitals. Patients: The study included 127 acromegalic patients enrolled from 2009 to 2010 not cured by previous surgery, radiotherapy, and long-acting somatostatin (SST) analogs, treated with PEG-V. Intervention and Main Outcome Measure: Sixty-three of 127 patients received combined PEG-V + SST analog therapy. Clinical and hormonal data at diagnosis and before and during PEG-V therapy were inserted in a database. GHR exon 3 deletion and other polymorphisms were genotyped by the coordinator center. Differences in PEG-V dosage required for IGF-I normalization and occurrence of adverse effects between carriers and noncarriers of GHR variants were evaluated. Results: d3GHR variants were not in Hardy-Weinberg equilibrium (P = 0.008). No association of these variants with PEG-V dose required for IGF-I normalization, adverse effects occurrence, and tumor regrowth was found in patients on PEG-V and on PEG-V + SST analog treatment. Similar data were obtained considering the GHR variant rs6180. Conclusions: This study did not confirm a better response of d3GHR to PEG-V treatment in acromegaly. Other studies are needed to determine whether deviation from Hardy-Weinberg equilibrium may indicate an association of d3GHR genotype with poor response to usual treatments. Copyright © 2012 by The Endocrine Society.
Lingua originaleEnglish
pagine (da-a)E165-E172
RivistaTHE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
Volume97
DOI
Stato di pubblicazionePubblicato - 2012

Keywords

  • DNA sequence
  • adult
  • article
  • combination chemotherapy
  • controlled study
  • drug efficacy
  • drug response
  • drug safety
  • drug tolerability
  • drug withdrawal
  • exon
  • female
  • gene deletion
  • gene frequency
  • gene location
  • genetic variability
  • genotype
  • growth hormone receptor
  • human
  • intermethod comparison
  • lipohypertrophy
  • major clinical study
  • male
  • marker gene
  • molecular pathology
  • monotherapy
  • multicenter study
  • multiplex polymerase chain reaction
  • nucleotide sequence
  • outcome assessment
  • patient compliance
  • pegvisomant
  • prediction
  • priority journal
  • side effect
  • single nucleotide polymorphism
  • somatostatin derivative, acromegaly
  • tumor volume

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