title: Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma.
abstract: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).
  
  
  
  We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.
  
  
  
  Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.
  
  
  
  In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445-52. ©2016 AACRSee related commentary by Voss and Hsieh, p. 2320.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.|Harvard Medical School, Boston, MA, US.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.|Harvard Medical School, Boston, MA, US.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|PUCRS School of Medicine, Porto Alegre, Brazil.
authors.forename: André P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Department of Medical Oncology, Cleveland Clinic, Cleveland, US.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, US.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.
authors.forename: Guillermo
authors.initials: G
authors.lastname: de Velasco
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.
authors.forename: Magdalena E
authors.initials: ME
authors.lastname: Tyburczy
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.
authors.forename: Lana
authors.initials: L
authors.lastname: Hamieh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|Institut Gustave Roussy, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Department of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Arizona, Scottsdale, AZ, US.
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, US.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Song
authors.affiliation: Harvard Medical School, Boston, MA, US.|Department of Pathology, Brigham and Women's Hospital, Boston, MA, US.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Pignon
authors.affiliation: PUCRS School of Medicine, Porto Alegre, Brazil.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Barrios
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA.
authors.forename: M Dror
authors.initials: MD
authors.lastname: Michaelson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.|Harvard Medical School, Boston, MA, US.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Van Allen
authors.affiliation: Department of Radiology, Dana Farber Cancer Institute, Boston, MA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Krajewski
authors.affiliation: San Matteo University Hospital Foundation, Pavia, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.affiliation: Department of Medical Oncology & Therapeutics Research, City of Hope, US.
authors.forename: Sumanta
authors.initials: S
authors.lastname: Pal
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.|Harvard Medical School, Boston, MA, US.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Harvard Medical School, Boston, MA, US.|Deparment of Medical Oncology, Beth-Israel Deaconess Medical Center, Boston, MA, US.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Tom Baker Cancer Center and University of Calgary, Calgary, Canada.
authors.forename: Daniel Y C
authors.initials: DYC
authors.lastname: Heng
authors.affiliation: Biostatistics & Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, US.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Gray
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.|Harvard Medical School, Boston, MA, US.|Department of Pathology, Brigham and Women's Hospital, Boston, MA, US.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
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