title: Novel Approach for Clinical Validation of the cobas KRAS Mutation Test in Advanced Colorectal Cancer.
abstract: Our objective was to assess the performance of the cobas test versus comparators for KRAS mutation status and predicting clinical response to anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC).
  
  
  
  mCRC samples from 398 patients from Roche study NO16968 (XELOXA) and 82 supplemental samples were tested with the cobas(®) KRAS mutation test (cobas test), the therascreen(®) KRAS RGQ PCR kit test (therascreen test), and Sanger sequencing as the reference method for detecting mutations in codons 12/13.
  
  
  
  For 461 eligible samples, the cobas test, therascreen test, and sequencing had invalid results for 5.2, 10.8, and 2.6 % of specimens, respectively. Valid cobas and therascreen test results had similar KRAS mutation-positive rates (37.3 vs. 36.3 %, respectively); sequencing was 28.5 %. Positive and negative percent agreement (PPA/NPA) between the cobas test and sequencing was 96.9 % (95 % confidence interval [CI] 92.2-98.8), and 88.7 % (95 % CI 84.7-91.8), respectively. PPA/NPA between the cobas and therascreen tests was 93.3 % (95 % CI 88.1-96.3) and 96.5 % (95 % CI 93.5-98.1), respectively. Bridging analysis from NCIC-CO.17 and NCT00113763 using the cobas test yielded modeled hazard ratios for overall survival and progression-free survival (PFS) of 0.558 (95 % CI 0.422-0.752) and 0.413 (95 % CI 0.304-0.550), respectively, for cetuximab and 0.989 (95 % CI 0.778-1.299) and 0.471 (95 % CI 0.360-0.626), respectively, for panitumumab, demonstrating significant efficacy in the KRAS-negative population for PFS.
  
  
  
  The cobas test showed similar accuracy to the therascreen test for detecting KRAS mutations and could appropriately identify mCRC patients ineligible for anti-EGFR therapy as demonstrated by bridging analysis results.
authors.affiliation: Medical Affairs Department, Roche Molecular Systems, 4300 Hacienda Drive, Pleasanton, CA, 94588, USA.
authors.forename: Abha
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Medical Affairs Department, Roche Molecular Systems, 4300 Hacienda Drive, Pleasanton, CA, 94588, USA.
authors.forename: Guili
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Medical Affairs Department, Roche Molecular Systems, 4300 Hacienda Drive, Pleasanton, CA, 94588, USA.
authors.forename: Shagufta
authors.initials: S
authors.lastname: Aslam
authors.affiliation: Medical Affairs Department, Roche Molecular Systems, 4300 Hacienda Drive, Pleasanton, CA, 94588, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Yu
authors.affiliation: Medical Affairs Department, Roche Molecular Systems, 4300 Hacienda Drive, Pleasanton, CA, 94588, USA.
authors.forename: Melody
authors.initials: M
authors.lastname: Chee
authors.affiliation: Medical Affairs Department, Roche Molecular Systems, 4300 Hacienda Drive, Pleasanton, CA, 94588, USA. john.palma@roche.com.
authors.forename: John F
authors.initials: JF
authors.lastname: Palma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011933:Reagent Kits, Diagnostic; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011933:Reagent Kits, Diagnostic; D018631:ras Proteins