title: Extended RAS analysis for anti-epidermal growth factor therapy in patients with metastatic colorectal cancer.
abstract: RAS family proteins (including KRAS and NRAS) play important roles in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in RAS genes (occurring at loci in exons 2, 3, and 4) often result in constitutive activation of RAS proteins and persistent downstream signaling. Mutations in KRAS exon 2 (codon 12/13) are an established predictor of lack of response to the anti-EGFR monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer (mCRC), and have been used routinely in clinical practice to identify patients unlikely to derive benefit from these therapies. However, a meaningful proportion of patients with mCRC have tumors bearing other mutations in RAS genes. Recent studies have demonstrated that evaluation of an extended panel of RAS mutations—including mutations in KRAS exon 2, 3, and 4 and NRAS exons 2, 3, and 4—can better define the patient population that is unlikely to benefit from anti-EGFR therapy, with concomitant improvements in outcomes in the more highly selected RAS wild-type group. This discovery has changed the practice of oncology and has the potential to spare patients from exposure to ineffective therapy. In the near future, it is important for the oncology community to validate extended RAS analysis assays and make certain that patients who are candidates for anti-EGFR therapy undergo appropriate testing and treatment.
authors.affiliation: Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: JRHecht@mednet.ucla.edu.
authors.forename: J Randolph
authors.initials: JR
authors.lastname: Hecht
authors.affiliation: Integrated Centres of Oncology R. Gauducheau and University of Nantes, Nantes, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.affiliation: University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Schwartzberg
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Grothey
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Rong
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.affiliation: Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Sidhu
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009362:Neoplasm Metastasis; D000077544:Panitumumab; D010597:Pharmacogenetics; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000077544:Panitumumab; D066246:ErbB Receptors; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab
keywords: Biomarker; Cetuximab; EGFR; Metastatic colorectal cancer; Panitumumab; RAS mutation