CDX2 a promising prognostic biomarker in Stage II/III colon cancer

1. The expression status of biomarker CDX2 was identified as an independent prognosticator in stage II and III colon cancer (CC).

2. CDX2-negative CC had a lower 5-year disease free survival rate compared to CDX5-positive CC, while a higher 5-year disease free survival rate was observed in CDX2 negative stage II CC treated with adjuvant chemotherapy compared to those without adjuvant chemotherapy.

Evidence Rating Level: 2 (Good)           

Study Rundown: While 5-year disease free survival has improved in stage III CCs owing to improved adjuvant chemotherapy regimens, the same success had not been seen in earlier stage (I and II) CC. This is due to the lack simple and reliable criteria identifying these early stage patients at high risk of relapse, where the benefits of adjuvant chemotherapy would outweigh the risks. Using bioinformatics analysis of gene-expression array databases, genes fulfilling the “x-negative implies activated leukocyte-cell adhesion molecule (ALCAM)-positive” Boolean relationship identified and ranked candidate genes. Subgroup analysis with independent and retrospective cohorts of stage II and III CC patients then isolated a top candidate gene: CDX2 ranked first from this screening process, and was further analyzed in discovery and validation data sets. In each of these data sets, the rate of 5-year disease free survival was lower in patients with CDX2-negative CCs compared to CDX2-negative CCs. Furthermore, in pooled database analysis of all patient cohorts, the rate of 5-year disease free survival was higher among stage II CC patients having adjuvant chemotherapy compared to those without adjuvant chemotherapy. The main weakness of this study is its retrospective design. However, the large numbers in the patient datasets give strength to the analyses and in turn, strengthen the conclusions. Overall, the statistical significant results provide clinically significant implications in that identifying the presence or absence of CDX2 can aid in prognostication, and can potentially guide management decisions in those with early stage CC.

Click to read the study, published today in NEJM

Relevant Reading: Adjuvant chemotherapy for stage II colon cancer with poor prognostic features

In-Depth [retrospective cohort]: This retrospective review used a bioinformatics approach to search and examine biomarkers of colon epithelial differentiation across gene-expression arrays, with subsequent ranking of candidate genes. A subgroup analysis of independent and retrospective cohorts of stage II and III CC patients isolated the top candidate gene: CDX2.

There were a total of 2115 tumour samples, of which all had the CDX2 clinically actionable biomarker. Of those samples, the discovery data set included 466 patients, with a 5-year disease free survival rate lower among 32 patients (6.9%) with CDX2 negative status compared to the 434 (93.1%) with CDX2 positive status (HR for disease recurrent, 3.44: 95% [CI], 1.6 to 7.38; p=0.002).  In the multivariate analysis excluding age, sex, and tumour stage, the HR associated with disease recurrence for patients with CDX2-negative versus CDX2-positive tumours was 2.73 (95% [CI], 1.58 to 4.72; P<0.001). In stage II CC patients., the 5-year disease free survival was significant in both the validation (51% among 15 patients with CDX2-negatve status vs. 80% among 106 with CDX2-positive status, p=0.0004) and discovery data sets (49% among 15 patients with CDX2-negatve status vs. 87% among 191 patients with CDX2-positive status, p=0.0004).  Treatment with adjuvant chemotherapy was associated with a rate of higher disease-free survival in the stage III subgroup (74% with chemotherapy vs. 37% with no chemotherapy, p<0.001). In stage II CC patients, the 5-year disease free survival rate was higher among 23 patients with CDX2-negative stats and adjuvant chemotherapy, compared to the 25 patients who did not have adjuvant chemotherapy (91% vs 56%, p=0.006)

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