Role of Receptor Profiling for Personalized Therapy in a Patient with a Growth Hormone-Secreting Macroadenoma Resistant to First-Generation Somatostatin Analogues

Abstract

Background: Acromegaly is almost always caused by a pituitary adenoma and is associated with high morbidity and mortality when uncontrolled. Trans-sphenoidal removal of the adenoma is the mainstay of therapy, but fails to control the disease in a significant number of patients who require further treatment. Somatostatin analogues (SSAs) as monotherapy or in combination with growth hormone (GH)-receptor antagonists and/or dopamine agonists are used either alone or in combination following surgical failure to achieve disease control. The use of specific biomarkers may help to individualize the therapeutic plan after surgical failure and direct towards a more personalized approach.

Methods: We report a 41-year-old man with acromegaly and residual disease after repeated surgery that was resistant to first-generation SSAs.

Results: Biochemical and tumor control were achieved following the administration of a second-generation SSA, pasireotide, combined with pegvisomant, both at maximal doses and along with cabergoline. Histology specimens showed a sparsely-granulated GH-immunostaining pituitary adenoma with intense positivity for somatostatin receptors 2 and 5 and low levels of E-cadherin.

Conclusion: Personalized medical therapy guided by currently available biomarkers, such as immunohistochemically-characterized receptor profiling or adhesion molecules, resulted in controlled insulin-like growth factor-1 (IGF-1) and GH levels and symptom alleviation following the combination of three drug-classes.

Keywords: acromegaly; e-cadherin; personalized treatment; resistant acromegaly; somatostatin analogue; somatostatin receptor.

Figure 1

Magnetic resonance imaging showing macroadenoma (mass of 3.6 × 3.3 × 2.2 cm) in the sella turcica with right latero- and supra-sellar extension encasing the right internal carotid artery and compressing the optic chiasm: grade 4 according Knosp (A: coronal, B: sagittal plane); more recent MRI showing a decrease in the size of the macrodenoma, still extending towards the floor of the third ventricle and encasing the right cavernous sinus in the coronal plane (C); in the sagittal plane, a rather lobulated suprasella extension is shown but no evidence of stalk involvement (D). Initial laboratory testing confirmed an elevated serum IGF-1 of 988 (94-284) ng/mL, no suppression of GH after a 75 g glucose load (7 ng/mL), mild hyperprolactinemia and hypogonadism.

Figure 2

Pharmacological effects on serum IGF-1 (A), growth hormone (GH) (B), prolactin levels (C), and adenoma size (D) with different therapeutic modalities.

Figure 3

(A) Focally weak cytoplasmic expression of E-cadherin. (B,C) Circumferential membranous expression of SSTR2 and SSTR5, respectively, in more than 50% of the tumor cells, Volante score.

Figure 4

Suggested algorithm of the use of biomarkers in clinical practice. insulin-like growth factor-1 (IGF-1); IHC: immunohistochemistry; SSAs: somatostatin analogues; SSTR: somatostatin receptor.