title: Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer.
abstract: The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse-free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery-alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Surgery, Imperial Household Agency Hospital, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Akasu
authors.affiliation: Division of Colorectal Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Saito
authors.affiliation: Division of Gastrointestinal Surgery, Prefectural Aichi Hospital, Okazaki, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Nakamori
authors.affiliation: Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Komori
authors.affiliation: Division of Gastroenterology and Gastrointestinal Oncology, Ibaraki Prefectural Central Hospital and Cancer Center, Kasama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Amagai
authors.affiliation: Department of Surgery, Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ohue
authors.affiliation: Department of Global Clinical Research, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
mesh_terms: D000328:Adult; D000368:Aged; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000601:surgery; D053843:DNA Mismatch Repair / Q000235:genetics*; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D005641:Tegafur / Q000627:therapeutic use*; D016896:Treatment Outcome; D014498:Uracil / Q000627:therapeutic use*
chemical_list: D005641:Tegafur; D014498:Uracil
keywords: Adjuvant chemotherapy; RAS; colorectal cancer; mismatch repair; tegafur-uracil