Successful mTOR inhibitor therapy for a metastastic neuroendocrine tumour in a patient with a germline TSC2 mutation
Authors: J. Schrader, F.O. Henes, D. Perez, S. Burdak-Rothkamm, A. Stein, J.R. Izbicki, A.W. Lohse
Journal: Annals of Oncology (2017)

We here report a 41-year-old patient with tuberous sclerosis and a known germline mutation in the TSC2 gene. During ultrasound tumour screening done for unexplained varicella reactivation a tumour of the left kidney and a lesion in the pancreatic tail were discovered. Pathologic examination of the surgical removed tumours revealed an angiomyolipma of the left kidney and a well-differentiated neuroendocrine tumour of the pancreas (pT2N0cM0,V0L0) with a proliferative index of 5% (G2). According to guidelines no adjuvant therapy was given and the patient was entered into our 6-monthly follow-up scheme. 12 months after the successful removal of the primary tumour the patient developed four new small lesions in the liver with a MRI-morphology coherent with neuroendocrine tumour metastasis. The development of pancreatic neuroendocrine tumours in patients with tuberous sclerosis is a rare event with <20 reports in the literature [1.Larson A.M. Hedgire S.S. Deshpande V. et al.Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex.Clin Genet. 2012; 82: 558-563Crossref PubMed Scopus (66) Google Scholar]. Therefore, no experience with regard to treatment is available. It is well known, that TSC2 is a negative upstream regulator of the mTOR pathway resulting in an uncontrolled mTOR activation in patients carrying loss of function mutations in TSC1 or TSC2 genes. Indeed, immunohistochemistry of the primary tumour confirmed strong activation of the Akt/mTOR pathway in our patient (Figure 1). Given the positive data on the use of everolimus for benign tumours in patients with tuberous sclerosis we considered starting everolimus as a first line therapy in our patient [2.Sasongko T.H. Ismail N.F. Zabidi-Hussin Z. Rapamycin and rapalogs for tuberous sclerosis complex.Cochrane Database Syst Rev. 2016; 7: CD011272PubMed Google Scholar]. On the first treatment control scan done after 3 months we already observed a partial remission of liver metastasis and continued treatment. Six months after the initiation of therapy we achieved a 46% reduction of liver tumour burden with two lesions even no longer visible. Treatment was well tolerated except for grade 2 hypophosphatemia requiring long-term phosphate supplementation. Apart from using PARP inhibitors for tumour therapy in BRCA mutation carriers to enhance DNA-damage response, this is one of the rare cases of a successful signalling pathway targeting therapy of a malignant tumour in a patient harbouring a germline mutation in the targeted pathway. Data from a large randomized trial of everolimus in pancreatic neuroendocrine tumours (pNETs) describe halt of tumour growth in the majority of patients, whereas partial tumour regression was only observed in 5% of patients [3.Yao J.C. Shah M.H. Ito T. et al.Everolimus for advanced pancreatic neuroendocrine tumors.N Engl J Med. 2011; 364: 514-523Crossref PubMed Scopus (2250) Google Scholar]. The strong response towards treatment in our patient was unexpected, but points to a driver function of TSC2 mutations in pNETs directly activating the mTOR pathway. It is open to speculation, whether similar mutations might be found in the subgroup of patients responding well to everolimus treatment. Loss of TSC2 expression is correlated with a poor prognosis in pNET patients, but has not been evaluated as a stratifying factor for therapeutic options [4.Missiaglia E. Dalai I. Barbi S. et al.Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway.J Clin Oncol. 2010; 28: 245-255Crossref PubMed Scopus (430) Google Scholar]. Interestingly, increased activation of the mTOR pathway itself has not been shown to be a good prognostic marker regarding response towards everolimus treatment [5.Benslama N. Bollard J. Vercherat C. et al.Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors.Invest New Drugs. 2016; 34: 654-662Crossref PubMed Scopus (16) Google Scholar]. Therefore, we propose, that defining TSC2 status in pNET patients could be of more prognostic value than activation of the mTOR pathwayper se with regard to everolimus response. Nevertheless, proving the same profound effect for sporadic TSC2 mutations on everolimus response in pNETs as observed in our patient has yet to be shown in appropriate designed clinical trials. None declared.