title: Response to everolimus is seen in TSC-associated SEGAs and angiomyolipomas independent of mutation type and site in TSC1 and TSC2.
abstract: Tuberous sclerosis complex is an autosomal dominant disorder that occurs owing to inactivating mutations in either TSC1 or TSC2. Tuberous sclerosis complex-related tumors in the brain, such as subependymal giant cell astrocytoma, and in the kidney, such as angiomyolipoma, can cause significant morbidity and mortality. Recently, randomized clinical trials (EXIST-1 and EXIST-2) of everolimus for each of these tuberous sclerosis complex-associated tumors demonstrated the benefit of this drug, which blocks activated mammalian target of rapamycin complex 1. Here we report on the spectrum of mutations seen in patients treated during these trials and the association between mutation and response. TSC2 mutations were predominant among patients in both trials and were present in nearly all subjects with angiomyolipoma in whom a mutation was identified (97%), whereas TSC1 mutations were rare in those subjects (3%). The spectrum of mutations seen in each gene was similar to those previously reported. In both trials, there was no apparent association between mutation type or location within each gene and response to everolimus. Everolimus responses were also seen at a similar frequency for the 16-18% of patients in each trial in whom no mutation in either gene was identified. These observations confirm the strong association between TSC2 mutation and angiomyolipoma burden seen in previous studies, and they indicate that everolimus response occurs regardless of mutation type or location or when no mutation in TSC1 or TSC2 has been identified.
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Novartis Oncology Translational Medicine, Cambridge, MA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Palmer
authors.affiliation: The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jozwiak
authors.affiliation: St Jude Children's Research Hospital, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: John
authors.initials: J
authors.lastname: Bissler
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: David
authors.initials: D
authors.lastname: Franz
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Segal
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
mesh_terms: D000293:Adolescent; D000328:Adult; D018207:Angiomyolipoma / Q000188:drug therapy / Q000235:genetics*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D014402:Tuberous Sclerosis / Q000188:drug therapy / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000068338:Everolimus