title: Retrospective study of RAS/PIK3CA/BRAF tumor mutations as predictors of response to first-line chemotherapy with bevacizumab in metastatic colorectal cancer patients.
abstract: After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer.
  
  
  
  Of the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status.
  
  
  
  The ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab.
  
  
  
  Patient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors.
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Izuma
authors.initials: I
authors.lastname: Nakayama
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. eiji.shinozaki@jfcr.or.jp.
authors.forename: Eiji
authors.initials: E
authors.lastname: Shinozaki
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsushima
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Wakatsuki
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Ozaka
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Takahari
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Suenaga
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Keisho
authors.initials: K
authors.lastname: Chin
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Mizunuma
authors.affiliation: Department of Gastroenterology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
authors.forename: Kensei
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics*
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D000068258:Bevacizumab; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins
keywords: BRAF mutation; Colorectal cancer; PIK3CA mutation; RAS mutation; bevacizumab