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Generation and external validation of a tumor-derived 5-gene prognostic signature for recurrence of lymph node-negative, invasive colorectal carcinoma †
Article first published online: 17 MAY 2012
Copyright © 2012 American Cancer Society
Volume 118, Issue 21, pages 5234–5244, 1 November 2012
How to Cite
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. and 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: 5234–5244. doi: 10.1002/cncr.27628
Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms
- Issue published online: 19 OCT 2012
- Article first published online: 17 MAY 2012
- Manuscript Accepted: 2 APR 2012
- Manuscript Revised: 13 MAR 2012
- Manuscript Received: 17 OCT 2011
- Unknown funding agency
- colorectal cancer;
- gene expression signatures;
- machine learning;
- reverse transcriptase-polymerase chain reaction;
- validation studies;
- sensitivity and specificity;
- colonic polyps
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.
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.
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).
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. © 2012 American Cancer Society.