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

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. © 2012 American Cancer Society. The first tumor gene‐based prognostic assay (OncoDefender‐CRC) for both stage I colorectal cancer and stage II colon cancer has been generated and externally validated. It outperforms standard clinicopathol