title: Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma.
abstract: BACKGROUND
  One in 4 patients with lymph node-negative, invasive colorectal carcinoma (CRC) develops recurrent disease after undergoing curative surgery, and most die of advanced disease. Predicting which patients will develop a recurrence is a significantly growing, unmet medical need.
  
  
  METHODS
  Archival formalin-fixed, paraffin-embedded (FFPE) primary adenocarcinoma tissues obtained at surgery were retrieved from 74 patients with CRC (15 with stage I disease and 59 with stage II disease) for Training/Test Sets. In addition, FFPE tissues were retrieved from 49 patients with stage I CRC and 215 patients with stage II colon cancer for an External Validation (EV) Set (n = 264) from 18 hospitals in 4 countries. No patients had received neoadjuvant/adjuvant therapy. Proprietary genetic programming analysis of expression profiles for 225 prespecified tumor genes was used to create a 36-month recurrence risk signature.
  
  
  RESULTS
  Using reverse transcriptase-polymerase chain reaction, a 5-gene rule correctly classified 62 of 92 recurrent patients and 87 of 172 nonrecurrent patients in the EV Set (sensitivity, 0.67; specificity, 0.51). "High-risk" patients had a greater probability of 36-month recurrence (42%) than "low-risk" patients (26%; hazard ratio, 1.80; 95% confidence interval, 1.19-2.71; P = .007; Cox regression) independent of T-classification, the number of lymph nodes examined, histologic grade/subtype, anatomic location, age, sex, or race. The rule outperformed (P = .021) current National Comprehensive Cancer Network Guidelines (hazard ratio, 0.897). The same rule also differentiated the risk of recurrence (hazard ratio, 1.63; P = .031) in a subset of patients from the EV Set who had stage I/II colon cancer only (n = 251).
  
  
  CONCLUSIONS
  To the authors' knowledge, the 5-gene rule (OncoDefender-CRC) is the first molecular prognostic that has been validated in both stage I CRC and stage II colon cancer. It outperforms standard clinicopathologic prognostic criteria and obviates the need to retrieve ≥12 lymph nodes for accurate prognostication. It identifies those patients most likely to develop recurrent disease within 3 years after curative surgery and, thus, those most likely to benefit from adjuvant treatment.
authors.affiliation: Everist Genomics, Inc., Ann Arbor, MI 48108, USA. pl@everistgenomics.com
authors.forename: Peter F
authors.initials: PF
authors.lastname: Lenehan
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Boardman
authors.forename: Douglas
authors.initials: D
authors.lastname: Riegert-Johnson
authors.forename: Giovanni
authors.initials: G
authors.lastname: De Petris
authors.forename: David W
authors.initials: DW
authors.lastname: Fry
authors.forename: Jeanne
authors.initials: J
authors.lastname: Ohrnberger
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Heyman
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gerard
authors.forename: Arpit A
authors.initials: AA
authors.lastname: Almal
authors.forename: William P
authors.initials: WP
authors.lastname: Worzel
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012008:Recurrence; D012680:Sensitivity and Specificity; D059467:Transcriptome