title: Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma.
abstract: Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial.
  
  
  
  To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients.
  
  
  
  Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC).
  
  
  
  Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests.
  
  
  
  Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics.
  
  
  
  PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients.
  
  
  
  Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: hsiehj@mskcc.org.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
authors.affiliation: Novartis Oncology, East Hanover, NJ, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Wang
authors.affiliation: Novartis Oncology, East Hanover, NJ, USA.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Marker
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Almedina
authors.initials: A
authors.lastname: Redzematovic
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Ying-Bei
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: S Duygu
authors.initials: SD
authors.lastname: Selcuklu
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nils
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bouvier
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Kety H
authors.initials: KH
authors.lastname: Huberman
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Umesh
authors.initials: U
authors.lastname: Bhanot
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA; Barnes Jewish Hospital, St. Louis, MO, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Chevinsky
authors.affiliation: Novartis Oncology, East Hanover, NJ, USA.
authors.forename: Parul
authors.initials: P
authors.lastname: Patel
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA; Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pinciroli
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Won
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Daoqi
authors.initials: D
authors.lastname: You
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.affiliation: Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Knox
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Voss
authors.affiliation: Novartis Oncology, East Hanover, NJ, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Voi
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D000068338:Everolimus / Q000627:therapeutic use; D005260:Female; D056466:Histone Demethylases / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D011758:Pyrroles / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D000077210:Sunitinib; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C400134:BAP1 protein, human; D004268:DNA-Binding Proteins; D007211:Indoles; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D011758:Pyrroles; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000068338:Everolimus; D056466:Histone Demethylases; C086877:KDM5C protein, human; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D043222:Ubiquitin Thiolesterase; C497446:VHL protein, human; D000077210:Sunitinib
keywords: BAP1; Everolimus; Genomic biomarker; KDM5C; Kidney cancer; PBRM1; SETD2; Sunitinib; Targeted therapy; Tumor suppressor gene