title: Effect of low-frequency KRAS mutations on the response to anti-EGFR therapy in metastatic colorectal cancer.
abstract: BACKGROUND
  Only patients with wild-type (WT) KRAS tumors benefit from anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (Mabs) in metastatic colorectal cancer (mCRC). Pyrosequencing is now widely used for the determination of KRAS mutation burden and a conservative cut-off point of 10% has been defined. Up until now, the impact of low-frequency KRAS mutations (<10%) on the response to anti-EGFR Mabs has yet to be evaluated.
  
  
  METHODS
  Tumors from patients receiving anti-EGFR Mabs based on a WT genotype for KRAS, as determined using direct sequencing, have been retrospectively analyzed by pyrosequencing. Patients were categorized as WT (no KRAS mutation) or low-frequency mutation when KRAS mutation was <10% (KRAS low MT).
  
  
  RESULTS
  A total of 168 patients treated by anti-EGFR Mabs for mCRC were analyzed. According to pyrosequencing, 138 tumors remained KRAS WT, while 30 tumors were KRAS low MT. In the KRAS low MT and KRAS WT groups, the response rates were 6.7% and 37.0%, respectively, while stabilization amounted to 23.3% versus 32.6% and progression to 70% versus 29% (P < 0.01). Progression-free survival (PFS) was 2.7 ± 0.5 months for KRAS low MT and was 6.0 ± 0.3 months for KRAS WT (P < 0.01).
  
  
  CONCLUSIONS
  These results appear to validate consideration of low-frequency KRAS mutation tumors as positive, and justify a large-scale prospective study.
authors.affiliation: Department of Gastroenterology, Poitiers University Hospital, 2 rue de la Milétrie, 86000 Poitiers Cedex, France. davidtougeron@hotmail.fr
authors.forename: D
authors.initials: D
authors.lastname: Tougeron
authors.forename: T
authors.initials: T
authors.lastname: Lecomte
authors.forename: J C
authors.initials: JC
authors.lastname: Pagès
authors.forename: C
authors.initials: C
authors.lastname: Villalva
authors.forename: C
authors.initials: C
authors.lastname: Collin
authors.forename: A
authors.initials: A
authors.lastname: Ferru
authors.forename: J M
authors.initials: JM
authors.lastname: Tourani
authors.forename: C
authors.initials: C
authors.lastname: Silvain
authors.forename: P
authors.initials: P
authors.lastname: Levillain
authors.forename: L
authors.initials: L
authors.lastname: Karayan-Tapon
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000188:drug therapy; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins