Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Donato Iacovazzo; Eivind Carlsen; Francesca Lugli; Sabrina Chiloiro; Serena Piacentini; Antonio Bianchi; Antonella Giampietro; Marilda Mormando; Andrew J Clear; Francesco Doglietto; Carmelo Anile; Giulio Maira; Libero Lauriola; Guido Rindi; Federico Roncaroli; Alfredo Pontecorvi; Márta Korbonits; Laura De Marinis

doi:10.1530/EJE-15-0832

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Eur J Endocrinol. 2016 Feb;174(2):241-50. doi: 10.1530/EJE-15-0832. Epub 2015 Nov 19.

Authors

Donato Iacovazzo¹, Eivind Carlsen², Francesca Lugli², Sabrina Chiloiro², Serena Piacentini², Antonio Bianchi², Antonella Giampietro², Marilda Mormando², Andrew J Clear², Francesco Doglietto², Carmelo Anile², Giulio Maira², Libero Lauriola², Guido Rindi², Federico Roncaroli², Alfredo Pontecorvi², Márta Korbonits³, Laura De Marinis²

Affiliations

¹ EndocrinologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKPathologySTHF, N-3710 Skien, NorwayEndocrinologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyHaemato-OncologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKNeurosurgeryUniversità di Brescia, 25121 Brescia, ItalyNeurosurgeryUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyNeurosurgeryHumanitas, 20089 Milan, ItalyPathologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyBrainBehaviour and Mental Health, University of Manchester, M13 9PT Manchester, UK EndocrinologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKPathologySTHF, N-3710 Skien, NorwayEndocrinologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyHaemato-OncologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKNeurosurgeryUniversità di Brescia, 25121 Brescia, ItalyNeurosurgeryUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyNeurosurgeryHumanitas, 20089 Milan, ItalyPathologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyBrainBehaviour and Mental Health, University of Manchester, M13 9PT Manchester, UK.
² EndocrinologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKPathologySTHF, N-3710 Skien, NorwayEndocrinologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyHaemato-OncologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKNeurosurgeryUniversità di Brescia, 25121 Brescia, ItalyNeurosurgeryUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyNeurosurgeryHumanitas, 20089 Milan, ItalyPathologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyBrainBehaviour and Mental Health, University of Manchester, M13 9PT Manchester, UK.
³ EndocrinologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKPathologySTHF, N-3710 Skien, NorwayEndocrinologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyHaemato-OncologyBarts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, UKNeurosurgeryUniversità di Brescia, 25121 Brescia, ItalyNeurosurgeryUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyNeurosurgeryHumanitas, 20089 Milan, ItalyPathologyUniversità Cattolica del Sacro Cuore, 00168 Rome, ItalyBrainBehaviour and Mental Health, University of Manchester, M13 9PT Manchester, UK m.korbonits@qmul.ac.uk.

PMID: 26586796
DOI: 10.1530/EJE-15-0832

Abstract

Aim: To gather data regarding factors predicting responsiveness to pasireotide in acromegaly.

Patients and methods: SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR.

Results: None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to first-generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04).

Conclusion: The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

MeSH terms

Acromegaly / drug therapy*
Adenoma / drug therapy*
Adult
Drug Resistance
Female
Growth Hormone-Secreting Pituitary Adenoma / drug therapy*
Humans
Intracellular Signaling Peptides and Proteins
Ki-67 Antigen
Male
Middle Aged
Receptors, Somatostatin / metabolism*
Somatostatin / administration & dosage
Somatostatin / analogs & derivatives*
Somatostatin / pharmacology
Treatment Outcome

Substances

Intracellular Signaling Peptides and Proteins
Ki-67 Antigen
Receptors, Somatostatin
SSTR2 protein, human
aryl hydrocarbon receptor-interacting protein
somatostatin receptor 3
Somatostatin
somatostatin receptor 5
pasireotide