title: Feasibility of proposed single-nucleotide polymorphisms as predictive markers for targeted regimens in metastatic colorectal cancer.
abstract: BACKGROUND
  Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy.
  
  
  METHODS
  A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway.
  
  
  RESULTS
  For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively.
  
  
  CONCLUSIONS
  LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.
authors.affiliation: Department of Surgery, University of Ulsan College of Medicine, Seoul, Korea. jckim@amc.seoul.kr
authors.forename: J C
authors.initials: JC
authors.lastname: Kim
authors.forename: Y J
authors.initials: YJ
authors.lastname: Ha
authors.forename: S A
authors.initials: SA
authors.lastname: Roh
authors.forename: E Y
authors.initials: EY
authors.lastname: Choi
authors.forename: Y S
authors.initials: YS
authors.lastname: Yoon
authors.forename: K P
authors.initials: KP
authors.lastname: Kim
authors.forename: Y S
authors.initials: YS
authors.lastname: Hong
authors.forename: T W
authors.initials: TW
authors.lastname: Kim
authors.forename: D H
authors.initials: DH
authors.lastname: Cho
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D017302:Annexins / Q000235:genetics*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000235:genetics; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000235:genetics*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D017302:Annexins; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; C507840:LIFR protein, human; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D011518:Proto-Oncogene Proteins; D000068258:Bevacizumab; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab