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. Cancer 2012. © 2012 American Cancer Society.

Promoter CpG island methylation of RET predicts poor prognosis in stage II colorectal cancer patients

“…In the last decade many studies have been conducted to seek for molecular biomarkers to identify high‐risk stage II CRC patients. Recently developed gene expression profiling (GEP) assays, such as the ColoPrint (Agendia BV, Amsterdam, The Netherlands) (Salazar et al., 2011), Oncotype DX ® Colon Cancer Assay (Genomic Health, Los Angeles, USA) (Clark‐Langone et al., 2010) and OncoDefender™–CRC (Everist Genomics, Ann Arbor, USA) (Lenehan et al., 2012), are commercially available molecular marker assays to predict disease prognosis for high‐risk stage II CRC patients, but up till now they are not conventionally used in clinical practice. So far, the level of evidence for the OncotypeDX Colon Cancer assay and the OncoDefender‐CRC assay is still low, whereas the Coloprint assay has been validated in two independent studies and a prospective trial is ongoing.…”

Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges

“…Both genome classifiers have been proposed to be capable of predicting the development of distant metastasis in stage II CRC patients and to identify patients who may be safely managed without chemotherapy, independently of other clinical risk factors. Other commercial kits, such as OncoDefender [128] and GeneFX [129] (Table 3), are also available, but possess a far lower market share than OncotypeDX. ColoGuideEx [130] and ColoGuidePro [131], first published in 2012, are two prognostic gene expression signatures for stage II and III CRC, respectively.…”

Systematic evaluation of medium-throughput mRNA abundance platforms

“…For example, the limited length of 6 microarray probes (25-100 bp) can result in nonspecific binding of transcripts (Zhang et al 2002), particularly in disease states. Instead, many groups have sought to develop multigene biomarkers (sometimes called ''signatures'') composed of tens to hundreds of genes that could be assayed using technologies with superior performance on FFPE material, reduced cost, and increased performance (Chen et al 2012;Kratz et al 2012;Lenehan et al 2012).…”