AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients

Abstract

Acromegaly is a rare disease due to chronic excess growth hormone (GH) and IGF-1. Aryl hydrocarbon receptor interacting protein (AIP) mutations are associated with an aggressive, inheritable form of acromegaly that responds poorly to SST2-specific somatostatin analogs (SSA). The role of pasireotide, an SSA with affinity for multiple SSTs, in patients with AIP mutations has not been reported. We studied two AIP mutation positive acromegaly patients with early-onset, invasive macroadenomas and inoperable residues after neurosurgery. Patient 1 came from a FIPA kindred and had uncontrolled GH/IGF-1 throughout 10 years of octreotide/lanreotide treatment. When switched to pasireotide LAR, he rapidly experienced hormonal control which was associated with marked regression of his tumor residue. Pasireotide LAR was stopped after >10 years due to low IGF-1 and he maintained hormonal control without tumor regrowth for >18 months off pasireotide LAR. Patient 2 had a pituitary adenoma diagnosed when aged 17 that was not cured by surgery. Chronic pasireotide LAR therapy produced hormonal control and marked tumor shrinkage but control was lost when switched to octreotide. Tumor immunohistochemistry showed absent AIP and SST2 staining and positive SST5. Her AIP mutation positive sister developed a 2.5 cm follicular thyroid carcinoma aged 21 with tumoral loss of heterozygosity at the AIP locus and absent AIP staining. Patients 1 and 2 required multi-modal therapy to control diabetes. On stopping pasireotide LAR after >10 years of treatment, Patient 1’s glucose metabolism returned to baseline levels. Long-term pasireotide LAR therapy can be beneficial in some AIP mutation positive acromegaly patients that are resistant to first-generation SSA.

The role of AIP variants in pituitary adenomas and concomitant thyroid carcinomas in the Netherlands: a nationwide pathology registry (PALGA) study

“…This patient came from an AIPmutated FIPA kindred, however, her pituitary gland was unaffected. This supports that the finding of DTCs and pituitary adenomas are not totally fortuitous coexistence in an AIP mutation-positive FIPA kindred, thereby echoing a recent finding of FTC in an AIP mutation carrier by Daly et al [28]. In a second patient with a somatotropinoma with two benign AIP-variants (p.Q288K and p.Q307R), a somatic BRAF (p.V600E) mutation was detected in PTC specimen in combination with a partial chromosome 11 LOH deletion.…”

“…In addition, in the two previously reported cases of acromegaly and concomitant PTC, and harboring a germline AIP variant, both patients were female and diagnosed with acromegaly at age 67 and 74, respectively. This is in contrast to the clinical characteristics of patients bearing germline AIP mutations; the disease usually manifests in the second decade of life, almost all cases are diagnosed before the age of 30 years [28,[41][42][43][44] and they are predominantly males [45]. With this in mind, it should be stressed that after progress is made in the treatment of pituitary adenomas and its complications, these patients may live long enough to reach the age of increased cancer risk.…”

“…Coexistence of PTCs with somatotropinomas in AIPmutated patients is very rare and has been described in three cases [25,26]. Although only one case of LOH at the AIP locus (11q13) in FTCs is previously described [27], Daly et al recently described an FTC in a teenaged AIP mutationpositive carrier in which decreased AIP staining was seen in the FTC tumor that was accompanied by LOH at the AIP locus in the tumor DNA [28]. Thus, the finding of DTCs and pituitary adenomas in the same individuals or kindreds could represent a rare association of germline AIP mutations.…”

Somatic and germline mutations in the pathogenesis of pituitary adenomas

“…Similarly, in a second patient hormonal and tumoral control was observed, but this hormonal control was lost after switching to octreotide. AIP protein and SST2 expression was lost, while SST5 staining was positive on immunohistochemistry in that case (116).…”

“…Such adenomas may also be good candidates for pasireotide treatment. Recently, clinical evidence for long-term pasireotide efficacy in first generation SSA-resistant AIP mutated adenomas has been reported (116). Ten-year treatment with pasireotide LAR in one patient led to hormonal control and significant tumor remnant reduction, which allowed discontinuation of the medication with continuous hormonal control (off therapy) for more than two years currently.…”