title: Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer.
abstract: OBJECTIVE
  To investigate whether EGF receptor (EGFR) pathway mutations predicted response to monotherapy with panitumumab, an anti-EGFR monoclonal antibody, in a randomized phase III study of metastatic colorectal cancer.
  
  
  METHODS
  Using massively parallel multigene sequencing, we analyzed 320 samples for 9 genes, with multigene sequence data from 288 (90%) samples.
  
  
  RESULTS
  Mutation rates were: KRAS (45%), NRAS (5%), BRAF (7%), PIK3CA (9%), PTEN (6%), TP53 (60%), EGFR (1%), AKT1 (<1%), and CTNNB1 (2%). In the randomized study and open-label extension, 22 of 138 (16%) wild-type KRAS (codons 12/13/61) patients versus 0 of 103 mutant KRAS (codons 12/13) patients had objective responses. Of 6 mutant KRAS (codon 61) patients, 1 with a Q61H mutation achieved partial response during the extension. Among wild-type KRAS (codons 12/13/61) patients, 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab. No patients responded to best supportive care alone. Panitumumab treatment was associated with longer progression-free survival (PFS) among wild-type KRAS (codons 12/13/61) patients [HR, 0.39; 95% confidence interval (CI), 0.28-0.56]. Among wild-type KRAS patients, a treatment effect for PFS favoring panitumumab occurred in patients with wild-type NRAS (HR, 0.39; 95% CI, 0.27-0.56) and wild-type BRAF (HR, 0.37; 95% CI, 0.24-0.55) but not mutant NRAS (HR, 1.94; 95% CI, 0.44-8.44).
  
  
  CONCLUSIONS
  These results show the feasibility and potential clinical use of next-generation sequencing for evaluating predictive biomarkers.
authors: Department of Oncology, Antwerp University Hospital, Edegem, Belgium. Marc.Peeters@uza.be
authors: Marc
authors: M
authors: Peeters
authors: Kelly S
authors: KS
authors: Oliner
authors: Alex
authors: A
authors: Parker
authors: Salvatore
authors: S
authors: Siena
authors: Eric
authors: E
authors: Van Cutsem
authors: Jing
authors: J
authors: Huang
authors: Yves
authors: Y
authors: Humblet
authors: Jean-Luc
authors: JL
authors: Van Laethem
authors: Thierry
authors: T
authors: André
authors: Jeffrey
authors: J
authors: Wiezorek
authors: David
authors: D
authors: Reese
authors: Scott D
authors: SD
authors: Patterson
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D011905:Genes, ras; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058885:Multilocus Sequence Typing; D009154:Mutation; D059645:Mutation Rate; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077544:Panitumumab; D066246:ErbB Receptors