A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN

LESSONS LEARNED. This is the first human interventional study in patients with Cowden syndrome that is driven by inactivation of germline PTEN gene. Single‐agent sirolimus, a mTOR inhibitor, suppressed mTOR signaling in surrogate human tissues without significant toxicity. BACKGROUND. Cowden syndrome is characterized by inactivating germline PTEN mutations, which can lead to activation of the PI3K‐Akt‐mTOR pathway. METHODS. Adult subjects with germline PTEN mutation who met international diagnostic criteria for Cowden syndrome and who had Eastern Cooperative Oncology Group (ECOG) performance status 0–2 and adequate organ function were enrolled. Subjects were treated with a 56‐day course of daily oral sirolimus. In addition to symptom assessment and physical examination, dermatologic, endoscopic, neurologic (cerebellar), and radiographic assessments were conducted. Inhibition of the mTOR pathway in benign skin and gastrointestinal (GI) lesion was assessed by immunohistochemistry. RESULTS. A total of 18 patients and 16 families were enrolled. PTEN mutations were located at exons 1–8. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Neurological evaluation showed improvement in cerebellar function score at 1 month. Immunohistochemistry (IHC) analysis in skin and GI benign lesions showed a decrease in the ratio of phosphorylated (p)S6 to total S6 in response to sirolimus. Ratios of pS6K to total S6 at days 14 and 56 were significantly lower than at baseline (p = .0026, p = .00391, respectively). A 56‐day course of sirolimus was well tolerated. CONCLUSION. A 56‐day course of sirolimus was well tolerated in subjects with Cowden syndrome and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling.