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CDX2 may serve as prognostic biomarker for stage II colon cancer
The lack of caudal-type homeobox transcription factor 2 expression identified patients with high-risk stage II colon cancer who benefited from adjuvant chemotherapy, according to research published in The New England Journal of Medicine.
“During the past decade, DFS among patients with stage III colon cancer has increased significantly owing to the introduction of new adjuvant chemotherapy regimens,” Piero Dalerba, MD, assistant professor of pathology and cell biology at Columbia University Medical Center, and colleagues wrote. “This therapeutic success, however, has not translated into longer DFS among patients with earlier-stage (stage I or II) cancer. The lack of simple, reliable criteria for the identification of patients with early-stage disease who are at high risk for relapse has made it difficult to identify patients in whom the hazards of multiagent chemotherapy may be offset by benefits with respect to DFS.”
Thus, Dalerba and colleagues sought to identify biomarkers to aid in the identification of patients with early-stage colon cancer who may benefit from adjuvant chemotherapy.
The researchers used bioinformatics to search for biomarkers of colon epithelial differentiation across gene-expression assays. They identified 16 candidate genes, however only caudal-type homeobox transcription factor 2 (CDX2) encoded a protein that could be studied via immunohistochemical analysis with the use of a clinical-grade diagnostic test.
The lack of CDX2 has been associated with aggressive colorectal cancer features, such as advanced stage, poor differentiation and BRAF mutations, according to the researchers.
Of 2,115 available tumor samples derived from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) repository, 4.1% (n = 87) lacked CDX2 expression. This cohort also had high levels of ALCAM expression and little overlap with tumors defined by microsatellite instability or TP53 mutations.
Researchers then evaluated the association between CDX2 mRNA expression and DFS from an NCBI-GEO discovery data set of 466 patients. Thirty-two of these patients (6.9%) lacked CDX2 expression.
Overall, fewer patients who lacked CDX2 expression achieved 5-year DFS than patients with CDX2-positive tumors (41% vs. 74%; P ˂ .001).
Results of a multivariate analysis restricted to 216 patients with data on pathological grade showed patients with CDX2-negative tumors had a higher risk for recurrence (HR = 3.44; 95% CI, 1.6-7.38). Researchers noted this HR for recurrence associated with CDX2 expression appeared higher than that of pathological grade (HR 0.99; 95% CI, 0.56-1.74).
To confirm these findings, researchers evaluated CDX2 protein expression from a validation data set of 366 patients from the NCI’s Cancer Diagnosis Program, 48 (13%) of whom had CDX2 protein-negative disease.
Overall, patients who lacked CDX2 protein expression had lower rates of 5-year DFS (48% vs. 71%), OS (33% vs. 59%) and disease-specific survival (45% vs. 72%; P ˂ .001 for all).
Multivariate analyses showed CDX2 protein expression increased risk for recurrence (HR = 2.42; 95% CI, 1.36-4.29), mortality (HR = 1.79; 95% CI, 1.18-2.71) and disease-specific death (HR = 2.09; 95% CI, 1.22-3.58).
When researchers evaluated data only from patients with stage II colon cancer, the association between poorer rates of 5-year DFS and lack of CDX2 expression persisted in the discovery set (49% vs. 87%; P = .003) and validation set (51% vs. 80%; P = .004).
The researchers then conducted a pooled analysis of 669 patients with stage II colon cancer and 1,228 patients with stage III colon cancer from four independent patient cohorts to evaluate whether patients with CDX2-negative tumors might benefit from adjuvant chemotherapy.
Results showed that chemotherapy improved the rate of DFS among those with CDX2-negative tumors who had stage II (91% vs. 56%; P = .006) and stage III (74% vs. 34%; P ˂ .001) disease.
“Our results indicate that patients with stage II or stage III CDX2-negative colon cancer might benefit from adjuvant chemotherapy and that adjuvant chemotherapy may be a treatment option for patients with stage II CDX2-negative disease, who are commonly treated with surgery alone,” Dalerba and colleagues wrote. “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.” – by Cameron Kelsall
Disclosure: Dalerba reports nonfinancial support from BD Biosciences during the conduct of the study, as well as other support from Quanticel Pharmaceuticals Inc. outside the submitted work and royalties from patents licensed to OncoMed Pharmaceuticals and Quanticel Pharmaceuticals. Please see the full study for a list of all other researchers’ relevant financial disclosures.