In a study reported in The New England Journal of Medicine, Piero Dalerba, MD, of Columbia University, and colleagues found that absence of the transcription factor CDX2 was prognostic for poor outcome in patients with stage II and III colon cancer vs cancers with CDX2 expression.¹ However, adjuvant chemotherapy significantly improved disease-free survival among patients with CDX2-negative stage II disease.

Study Details

The study involved use of a novel bioinformatics approach to identify biomarkers of colon epithelial differentiation across gene-expression arrays, with candidate genes ranked according to availability of clinical-grade diagnostic assays. The top candidate gene was assessed for association with disease-free survival and benefit from adjuvant chemotherapy using subgroup analysis in independent and retrospective cohorts of patients with stage II or III disease.

CDX2-Negative vs CDX2-Positive Disease

Screening tests ranked the transcription factor CDX2 as the top candidate gene. CDX2 expression was absent in 87 (4.1%) of 2,115 tumor samples. In a discovery data set of 466 patients, 5-year disease-free survival among 32 patients (6.9%) with CDX2-negative colon cancers vs 434 (93.1%) with CDX2-positive colon cancers was 41% vs 74% (P < .001). In multivariate analysis excluding age, sex, and tumor stage as confounding variables, the hazard ratio for disease recurrence for CDX2-negative vs CDX2-positive tumors was 2.73 (P < .001). In multivariate analysis restricted to 216 patients with information on pathologic grade, the hazard ratio was 3.44 (P = .002).

Piero Dalerba, MD

In a validation data set of 314 patients, 5-year disease-free survival for 38 patients (12.1%) with CDX2 protein–negative colon cancer vs 276 (87.9%) with CDX2 protein–positive colon cancer was 48% vs 71% (P < .001). In multivariate analysis excluding age, sex, tumor stage, and tumor grade as confounding variables, the hazard ratio was 2.42 (P = .003). In this set, 5-year overall survival was 33% vs 59% (P < .001), and 5-year disease-specific survival was 45% vs 72% (P < .001). In the multivariate analysis, the hazard ratios were 1.79 (P = .006) for overall survival and 2.09 (P = .007) for disease-specific death.

Stage II Disease

Among patients with stage II cancer, 5-year disease-free survival was 49% among 15 patients with CDX2-negative tumors vs 87% among 191 patients with CDX2-positive tumors (P = .003) in the discovery set and 51% among 15 patients with CDX2-negative tumors vs 80% among 106 patients with CDX2-positive tumors (P = .004) in the validation set. Similar outcomes in the validation set were found for overall survival (40% vs 70%, P < .001) and disease-specific survival (66% vs 89%, P = .005), with the associations not being confounded by such factors as depth of invasion of the primary tumor or number of lymph nodes resected.

Effect of Adjuvant Chemotherapy

In analysis of a pooled database of all patient cohorts, 5-year disease-free survival was 91% among 23 patients with stage II CDX2-negative tumors who received adjuvant chemotherapy vs 56% among 25 who did not receive adjuvant chemotherapy (P = .006). Benefit of adjuvant chemotherapy was also observed in the stage III subgroup of patients with CDX2-negative disease, with 5-year disease-free survival of 74% with vs 37% without chemotherapy (P < .001).

The investigators concluded: “Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy…. [O]ur results indicate that patients with stage II or stage III CDX2-negative colon cancer might benefit from adjuvant chemotherapy and that adjuvant chemotherapy might be a treatment option for patients with stage II CDX2-negative disease, who are commonly treated with surgery alone. Given the exploratory and retrospective design of our study, these results will need to be further validated. We advocate for these findings to be confirmed within the framework of randomized, clinical trials, in conjunction with genomic DNA sequencing studies.” ■

Disclosure: The study was funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Dalerba P, Sahoo D, Paik S, et al: CDX2 as a prognostic biomarker in stage II and stage III colon cancer. N Engl J Med 374:211-222, 2016.