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

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 firstgeneration SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (PZ0.04). 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 (PZ0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; PZ0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; PZ0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; PZ0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; PZ0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; PZ0.04). 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.

T2-weighted MRI signal predicts hormone and tumor responses to somatostatin analogs in acromegaly

“…Also, tumors with low levels of somatostatin receptor subtype 2 (SSTR2) tend to have a lower responsiveness to treatment with SSTR2-specific SSA like octreotide (Ferone et al 2008, Taboada et al 2008. Responses to pasireotide, a multi-somatostatin receptor specific ligand, also appear to be related to somatostatin receptor subtype 5 (SSTR5) expression (Iacovazzo et al 2016). However, for predicting responses to primary pre-operative SSA therapy, noninvasive characteristics are required, which has driven the recent interest in MRI characteristics at diagnosis, particularly the T2 image intensity.…”

MANAGEMENT OF ENDOCRINE DISEASE: Personalized medicine in the treatment of acromegaly

“…This was also shown in a small in vivo study that found that sst5 expression was a biomarker of response to pasireotide in patients whose disease was not controlled with fg-SRL 97 . Somatostatin receptor type 2 expression was also a biomarker of response to pasireotide.…”

“…Somatostatin receptor type 2 expression was also a biomarker of response to pasireotide. In addition, the same study demonstrated that although AIP expression is a biomarker of response to fg-SRL, it did not seem to be a biomarker of the response to pasireotide 97 .…”

“…This is especially the case for the fg-SRL, which are still considered the first-choice medical treatment for the vast majority of acromegaly patients despite the knowledge that approximately 20-25% of patients will present resistance to the treatment 3,7 . The change to a personalized medicine approach to treating the disease will allow an optimization of therapy, reduce the GH burden (as disease control can be with low sst2 expression, high sst5 expression and low AIP expression 96,97 .…”

Pituitary acromegaly: not one disease

“…Tumors that are dependent on cAMP signaling would logically be responsive to the inhibition of this pathway that is mediated by somatostatin analogs, especially those that target the somatostatin receptor type 2 (SSTR2). Those receptors are highly expressed in most somatotroph tumors, but recent studies have suggested that SSTR2 may be downregulated in the sparsely granulated tumors (Kato et al 2012, Brzana et al 2013, Casar-Borota et al 2013, Mayr et al 2013, Kiseljak-Vassiliades et al 2015b, Iacovazzo et al 2016.…”