title: CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer.
abstract: BACKGROUND
  The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer (CRC) cases. CIMP status, which is closely associated with specific clinicopathological and molecular characteristics, is considered a potential predictive biomarker for efficacy of cancer treatment. However, the relationship between the effect of standard chemotherapy, including cytotoxic drugs and anti-epidermal growth factor receptor (EGFR) antibodies, and CIMP status has not been elucidated.
  
  
  METHODS
  In 125 metastatic colorectal cancer (mCRC) patients, we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR (MSP) and to genetic status in five EGFR-related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) as detected by direct sequencing.
  
  
  RESULTS
  CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis (all P values <0.05). The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first-line treatment followed by irinotecan-based therapy as the second-line treatment (median = 6.6 months) was inferior to that of such patients receiving the reverse sequence (median = 15.2 months; P = 0.043). Furthermore, CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes (74.1 %) than the CIMP-negative tumors did (50.0 %). Among the KRAS wild-type tumors, CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy.
  
  
  CONCLUSIONS
  Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors. High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors.
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.|Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimodaira
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.|Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Soeda
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.|Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Komine
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Ouchi
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.|Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.|Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan.|Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aobaku, Sendai, 980-8575, Japan. chikashi@idac.tohoku.ac.jp.|Department of Clinical Oncology, Tohoku University Hospital, Sendai, Japan. chikashi@idac.tohoku.ac.jp.
authors.forename: Chikashi
authors.initials: C
authors.lastname: Ishioka
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018899:CpG Islands / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D018773:Genes, erbB-1 / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D000071185:Pharmacogenomic Testing; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013223:Statistics as Topic; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D002166:Camptothecin
keywords: Anti-EGFR antibody; BRAF; CpG island methylator phenotype; Irinotecan- and oxaliplatin-based chemotherapy; Metastatic colorectal cancer; RAS