gsp Mutation Is Not a Molecular Biomarker of Long-Term Response to First-Generation Somatostatin Receptor Ligands in Acromegaly

SIMPLE SUMMARY: Acromegaly treatment consists of surgical, medical, and radiation therapy. First-generation somatostatin receptor ligands are the mainstay of medical therapy, with approximately 40% disease control rate. Several parameters have been evaluated as predictors of response to these drugs, including mutations in the stimulatory G-protein α subunit (gsp mutation), which is still controversial. In this study, we aimed to evaluate in a large series of patients whether gsp mutation predicts long-term response to medical treatment and to characterize the gsp mutated population. The ability to predict response to medical therapy would help to choose a therapy that presents higher odds of controlling the disease, which ultimately would reduce treatment costs and disease morbi-mortality. ABSTRACT: Background: It is still controversial if activating mutations in the stimulatory G-protein α subunit (gsp mutation) are a biomarker of response to first generation somatostatin receptor ligands (fg-SRL) treatment in acromegaly. Thus, we aimed to evaluate whether gsp mutation predicts long-term response to fg-SRL treatment and to characterize the phenotype of patients harboring gsp mutations. Methods: GNAS1 sequencing was performed by Sanger. SST2 and SST5 were analyzed by immunohistochemistry (IHC) and real-time RT-PCR. The cytokeratin granulation pattern was evaluated by IHC. Biochemical control was defined as GH < 1.0 ng/mL and normal age-adjusted IGF-I levels. Results: gsp mutation was found in 54 out of 136 patients evaluated. Biochemical control with fg-SRL treatment was similar in gsp+ and gsp- patients (37% vs. 25%, p = 0.219). Tumors harboring gsp mutation were smaller (p = 0.035) and had a lower chance of invading cavernous sinuses (p = 0.001). SST5 protein (p = 0.047) and mRNA (p = 0.013) expression levels were higher in wild-type tumors. Conclusions: In this largest series available in the literature, we concluded that gsp is not a molecular biomarker of response to fg-SRL treatment in acromegaly. However, the importance of its negative association with cavernous sinus invasion and SST5 expression needs to be further investigated.