Pasireotide Diaspartate

MAX is a tumor suppressor gene, with germline pathogenic variants predisposing primarily to pheochromocytomas and, uncertainly to pituitary neuroendocrine tumor (PitNET). We report the first molecularly confirmed case of a MAX-related growth hormone (GH)-PitNET. A 20-year-old woman presented with acute hemiparesis, hemianopsia, and recent acromegaloid changes. MRI showed a giant invasive PitNET with brainstem compression. Biochemical testing confirmed acromegaly. Despite multimodal therapy (lanreotide, cabergoline, two debulking surgeries), disease control was achieved only after pasireotide and adjuvant proton therapy. Histology confirmed a sparsely granulated somatotroph adenoma. Germline analysis identified a heterozygous MAX pathogenic variant c.97C>T, introducing a premature stop codon (p.Arg33Ter). Tumor analysis found loss of heterozygosity and absence of MAX protein expression. The same variant was found in her father, who had a smaller intrasellar macroadenoma causing acromegaly. This familial observation provides the functional evidence that MAX is a driver in GH-PitNET and a candidate gene for PitNET predisposition.

The majority of prolactinomas are treated with dopamine agonists (DA) with excellent response, however DA-resistance occurs in 10% of prolactinomas. Somatostatin (SST) receptors have been increasingly studied in prolactinomas. There are five SST receptor subtypes and a significant number of prolactinomas show expression of SST 5 and SST 1 mRNA. The somatostatin analog (SSA) pasireotide, which has 40-fold greater binding affinity to SST 5 compared to first-generation SSAs, shows promising results in case reports of DA-resistant prolactinomas. This two-center retrospective cohort study investigated the expression patterns of dopamine 2 (D2R), SST 2 and SST 5 receptors in surgical specimen of 34 patients with prolactinomas, 22 of which were DA-resistant. In vitro effects of cabergoline, octreotide and pasireotide on prolactin production was also examined in cultured prolactinoma cells. Receptor expression was scored using the immunoreactivity score (IRS). 31/34(91%) patients used DA preoperatively; 22/34(64.7%) were DA-resistant. Receptor expression in the cases was 97.1% for D2R, 70.6% for SST 5 and 41.2% for SST 2 . In the majority of SST 2 positive cases SST 2 expression was very low. In in vitro studies comparing the effects of octreotide, pasireotide, and cabergoline on prolactin secretion, octreotide was the least potent drug and cabergoline was the most potent. SST 5 and D2R expression was highest in prolactinomas showing the highest response to pasireotide and cabergoline in vitro (median D2R IRS 1.0 vs 8.0 for < 50% vs. > 50% inhibition by cabergoline and median SST 5 IRS 3.5 avs. 12.0 for < 50% vs. > 50% inhibition by pasireotide). In a subgroup, pasireotide inhibited prolactin secretion with comparable potency to cabergoline. Targeting SST 5 with pasireotide may be a potential treatment modality for further clinical investigation in the treatment of a subset of DA resistant or intolerant prolactinomas.