Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma

Peter F. Lenehan, Lisa A. Boardman, Douglas Riegert-Johnson, Giovanni De Petris, David W. Fry, Jeanne Ohrnberger, Eugene R. Heyman, Brigitte Gerard, Arpit A. Almal, William P. Worzel

Research output: Contribution to journalArticle

24 Scopus citations

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. Cancer 2012.

Original languageEnglish (US)
Pages (from-to)5234-5244
Number of pages11
JournalCancer
Volume118
Issue number21
DOIs
StatePublished - Nov 1 2012

Keywords

  • colonic polyps
  • colorectal cancer
  • gene expression signatures
  • machine learning
  • prognosis
  • recurrence
  • reverse transcriptase-polymerase chain reaction
  • sensitivity and specificity
  • validation studies

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lenehan, P. F., Boardman, L. A., Riegert-Johnson, D., De Petris, G., Fry, D. W., Ohrnberger, J., Heyman, E. R., Gerard, B., Almal, A. A., & Worzel, W. P. (2012). Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma. Cancer, 118(21), 5234-5244. https://doi.org/10.1002/cncr.27628