title: CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer.
abstract: Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).
authors.affiliation: From the Herbert Irving Comprehensive Cancer Center and the Departments of Pathology and Cell Biology and Medicine, Columbia University, New York (P.D.); Institute for Stem Cell Biology and Regenerative Medicine (P.D., D.S., P.S.R., S.P.M., S.H., J.H., D.Q., M.F.C.) and the Departments of Pathology (X.G., E.F., M.R.), and Medicine, Division of Oncology (N.W.-F., G.A.F., M.F.C.), Stanford University, Stanford, and the Departments of Pediatrics and Computer Science and Engineering, University of California San Diego, San Diego (D.S.) - both in California; Faculty of Engineering, Bar-Ilan University, Ramat Gan, Israel (T.K.); the National Surgical Adjuvant Breast and Bowel Project, NRG Oncology (S.P., G.Y., N.S., N.W.) and the Allegheny Cancer Center at Allegheny General Hospital (N.W.) - both in Pittsburgh; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea (S.P.); and the Department of Biochemistry and Molecular Biology, Medical School of Henan University, Kaifeng, China (X.G.).
authors.forename: Piero
authors.initials: P
authors.lastname: Dalerba
authors.forename: Debashis
authors.initials: D
authors.lastname: Sahoo
authors.forename: Soonmyung
authors.initials: S
authors.lastname: Paik
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Guo
authors.forename: Greg
authors.initials: G
authors.lastname: Yothers
authors.forename: Nan
authors.initials: N
authors.lastname: Song
authors.forename: Nate
authors.initials: N
authors.lastname: Wilcox-Fogel
authors.forename: Erna
authors.initials: E
authors.lastname: Forgó
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Rajendran
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Miranda
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hisamori
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hutchison
authors.forename: Tomer
authors.initials: T
authors.lastname: Kalisky
authors.forename: Dalong
authors.initials: D
authors.lastname: Qian
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
authors.forename: George A
authors.initials: GA
authors.lastname: Fisher
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Michael F
authors.initials: MF
authors.lastname: Clarke
mesh_terms: D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D000071616:CDX2 Transcription Factor; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D030541:Databases, Genetic; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D012333:RNA, Messenger