A gene-expression signature assay called ColDx (Almac Diagnostics) successfully identified high-risk patients with stage II colon cancer who would benefit from chemotherapy, according to results of a new, prospective analysis of the previously published phase 3 Alliance C9581 clinical trial. For patients with stage I colon cancer, surgery is the treatment of choice, whereas for stage III disease, patients receive adjuvant chemotherapy. For patients with stage II disease, however, the best approach to the therapy has not been well-defined.
This new study, recently published in the Journal of Clinical Oncology (Niedzwiecki D, et al. 2016 Jul 18. Epub ahead of print), shows that the ColDx assay could be incorporated into risk stratification for patients with stage II colon cancer and could identify patients who are at risk for recurrence and would benefit from chemotherapy instead of observation alone.
Previously, ColDx was found to be an independent prognostic tool for recurrence-free interval and overall survival in patients with colon cancer.
“The ColDx assay has now been prospectively validated for a second time as a prognostic marker for patients with stage II colon cancer and in this patient subset superior to current prognostic markers such as T stage, nodal sampling, and MMR [mismatch repair] status. This study is then an external validation of the prognostic value of the ColDX assay,” wrote lead investigator Donna Niedzwiecki, PhD, of the Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC, and colleagues.
“Thus, ColDx assay results could be incorporated with the traditional clinical markers of risk to refine prognosis,” they added.
As background, the optimal management of stage II colon cancer is not clearly established. Approximately 25% of all patients with colon cancer are diagnosed at stage II disease, which relapses in 15% to 20% of patients.
Historical prognostic factors have limited utility and do not accurately classify low-risk versus high-risk patients, nor do they predict the benefit of adjuvant chemotherapy. ColDx has the potential to fill this need.
The Alliance C9581 trial was a randomized phase 3 clinical trial of 1738 patients with stage II colon cancer and no high-risk features. The study compared edrecolomab, a monoclonal antibody directed against the 17-1A antigen found on the surface of cancer cells, with observation, and failed to show a survival benefit for edrecolomab.
The study reported by Dr Niedzwiecki and colleagues validated the ColDx assay by testing 634 probeset genes using formalin-fixed, paraffin-embedded tumor specimens from a subset of trial participants. Tumor specimens were available for 360 trial participants with 58 relapses, as well as from an additional 33 patients whose disease relapsed.
The risk status for each patient was determined with the use of the ColDx assay.
Of the 393 patients with available tumor specimens, 216 (55%) were found to have high-risk disease based on the assay. In a multivariate analysis adjusted for mismatch repair deficiency and other conventional prognostic factors, the patients who were identified with high-risk using ColDx had a significantly (P <.01) shorter recurrence-free interval compared with patients classified with low-risk disease using the assay.
The risk of disease recurrence at 5 years was 82% (18% probability) in the high-risk group compared with 91% (9% probability) in the low-risk group. Age and mismatch repair status were of marginal significance in the multivariate analysis.
“A direction for future research would be to show that prognostic gene expression signatures are also predictive for treatment efficacy,” the investigators suggested.