title: Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy.
abstract: OBJECTIVE
  Rapalogs are allosteric mTOR inhibitors and approved agents for advanced kidney cancer. Reports of clonal heterogeneity in this disease challenge the concept of targeted monotherapy, yet a small subset of patients derives extended benefit. Our aim was to analyze such outliers and explore the genomic background of extreme rapalog sensitivity in the context of intratumor heterogeneity.
  
  
  METHODS
  We analyzed archived tumor tissue of 5 patients with renal cell carcinoma, who previously achieved durable disease control with rapalogs (median duration, 28 months). DNA was extracted from spatially separate areas of primary tumors and metastases. Custom target capture and ultradeep sequencing was used to identify alterations across 230 target genes. Whole-exome sequence analysis was added to investigate genes beyond this original target list.
  
  
  RESULTS
  Five long-term responders contributed 14 specimens to explore clonal heterogeneity. Genomic alterations with activating effect on mTOR signaling were detected in 11 of 14 specimens, offering plausible explanation for exceptional treatment response through alterations in two genes (TSC1 and MTOR). In two subjects, distinct yet functionally convergent alterations activated the mTOR pathway in spatially separate sites. In 1 patient, concurrent genomic events occurred in two separate pathway components across different tumor regions.
  
  
  CONCLUSIONS
  Analysis of outlier cases can facilitate identification of potential biomarkers for targeted agents, and we implicate two genes as candidates for further study in this class of drugs. The previously reported phenomenon of clonal convergence can occur within a targetable pathway which might have implications for biomarker development beyond this disease and this class of agents.
authors.affiliation: Authors' Affiliations: Departments of Medicine, Surgery, Pathology, Radiology, and Computational Biology; Human Oncology and Pathogenesis Program; Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Weill Medical College of Cornell University, New York, New York.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Voss
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.forename: Can G
authors.initials: CG
authors.lastname: Pham
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.forename: Ying-Bei
authors.initials: YB
authors.lastname: Chen
authors.forename: Luis F
authors.initials: LF
authors.lastname: Cunha
authors.forename: Oguz
authors.initials: O
authors.lastname: Akin
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Shugaku
authors.initials: S
authors.lastname: Takeda
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: Paul
authors.initials: P
authors.lastname: Russo
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059472:Exome; D015894:Genome, Human; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage; D015398:Signal Transduction / Q000235:genetics; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib