title: A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer.
abstract: BACKGROUND
  The mutation in KRAS exon 2 is a validated biomarker of resistance to anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). Several reports have confirmed associations of other RAS mutations with resistance to anti-EGFR therapy. However, the impact of BRAF and PIK3CA mutations on the efficacy of anti-EGFR therapy remains controversial. Little is known about the frequencies and clinicopathological features of these mutations, as well as the therapeutic effects of anti-EGFR therapy in mCRC patients with these mutations, especially in the Asian population.
  
  
  METHODS
  In this retrospective observational study, frequencies and clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations were evaluated in patients with mCRC. Among patients treated with anti-EGFR therapy, objective response, progression-free survival (PFS), and overall survival (OS) were evaluated according to gene status.
  
  
  RESULTS
  Among 264 patients, mutations in KRAS exon 2, KRAS exons 3 or 4, NRAS, BRAF and PIK3CA were detected in 34.1%, 3.8%, 4.2%, 5.4% and 6.4%, respectively. Thus, a total of 12.1% of patients without KRAS exon 2 mutations had other RAS mutations. Primary rectal tumors tended to be more frequently observed in RAS mutant tumors. BRAF mutations were more frequently observed with right-sided colon, poorly differentiated or mucinous adenocarcinoma, and peritoneal metastasis. Among the 66 patients with KRAS exon 2 wild-type tumors treated with anti-EGFR agents, PFS (5.8 vs. 2.2 months) and OS (17.7 vs. 5.2 months) were significantly better in patients with all wild-type tumors (n = 56) than in those with any of the mutations (n = 10). The response rate also tended to be better with all wild-type tumors (26.8 vs. 0%).
  
  
  CONCLUSIONS
  Other RAS and BRAF mutations were observed in KRAS exon 2 wild-type tumors, which were associated with some clinicopathological features and resistance to anti-EGFR therapy in our patient cohort.
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. akawazoeakihito@gmail.com.
authors.forename: Akihito
authors.initials: A
authors.lastname: Kawazoe
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. kshitara@east.ncc.go.jp.|Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan. kshitara@east.ncc.go.jp.
authors.forename: Kohei
authors.initials: K
authors.lastname: Shitara
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. shfukuok@east.ncc.go.jp.
authors.forename: Shota
authors.initials: S
authors.lastname: Fukuoka
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. ykuboki@east.ncc.go.jp.
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Kuboki
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. hbando@east.ncc.go.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Bando
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. wokamoto@east.ncc.go.jp.|Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan. wokamoto@east.ncc.go.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Okamoto
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. takojima@east.ncc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. nofuse@east.ncc.go.jp.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Fuse
authors.affiliation: Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan. yamanaka@yokohama-cu.ac.jp.|Department of Biostatistics, Yokohama City University, Kanagawa, Japan. yamanaka@yokohama-cu.ac.jp.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp.|Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan. tdoi@east.ncc.go.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. aohtsu@east.ncc.go.jp.|Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan. aohtsu@east.ncc.go.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.affiliation: Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tyoshino@east.ncc.go.jp.|Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan. tyoshino@east.ncc.go.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D015398:Signal Transduction; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins