CDX2 Loss Predicts High-Risk Stage II/III Colon Cancer

Biomarker may indicate consideration of adjuvant chemotherapy in patients with stage II or III colon cancer

medwireNews: Loss of caudal-type homeobox transcription factor 2 (CDX2) is a prognostic biomarker for stage II and III colon cancer, say researchers who believe that it might help identify patients at high risk of recurrent disease.

“[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”, the team reports in The New England Journal of Medicine.

Piero Dalerba, from Columbia University in New York, USA, and co-authors examined gene expression arrays for biomarkers linked to colon epithelial differentiation that were negatively associated with activated leukocyte cell adhesion molecule, found in immature cells.

The top gene identified, CDX2, has previously been linked to aggressive characteristics in colon cancer, such as poor differentiation and BRAFmutation, they explain.

When the team examined CDX2 expression in a discovery set of 466 colon cancer patients, the rate of 5-year disease-free survival (DFS) was significantly lower among the 6.9% of patients with CDX2-negative tumours than the 93.1% whose cancers expressed the marker, with a hazard ratio (HR) of recurrence of 3.44 after adjusting for age, gender and tumour stage and grade.

This finding was replicated in a validation group of 314 patients, with an adjusted HR of 2.42 for recurrence among the CDX2-negative patients.

And separate analysis of patients with stage II colon cancer showed that those with CDX2-negative tumours were significantly less likely to achieve 5 years of DFS than those with the CDX2-positive disease, an association that was true for both the discovery (49 vs 87%) and validation (51 vs 80%) cohorts.

This pattern was confirmed when patient records for 669 stage II and 1228 stage III patients were pooled from four databases.

Five-year DFS in the minority of these patients with stage II, CDX2-negative colon cancer was significantly more common in those who had received adjuvant chemotherapy than patients who had been treated only with surgery, at 91% versus 56%. This was also true among the stage III, CDX2-negative colon cancer patients who had received adjuvant chemotherapy compared with those who had not, with 74% achieving 5-year DFS compared with 37%.

Moreover, the relationship between CDX2 status and the benefit of adjuvant chemotherapy was not altered by known survival confounding factors for stage II/III colon cancer patients, such as depth of tumour invasion and the number of positive lymph nodes.

“Given the exploratory and retrospective design of our study, these results will need to be further validated”,Piero Dalerba et al say.

“Weadvocate for these findings to be confirmed within the framework of randomized, clinical trials, in conjunction with genomic DNA sequencing studies.”

C Richard Boland, from the Baylor Research Institute, and Ajay Goel, from the Baylor University Medical Center, both based in Dallas, Texas, USA, note in an accompanying comment the small number of patients and question whether the rapid throughput immunohistochemical technique employed in the study may have underestimated the heterogeneity of CDX2 expression within tumours.

But they comment that “these findings raise the important question of what mechanism might be at work in silencing CDX2; the answer to this question could lead to the discovery of new approaches to treating the fundamental problem.”

The commentators conclude: “This study provides an opportunity for oncologists to move beyond what has been an inadequate method of selecting patients with stage II colon cancer for adjuvant chemotherapy.”

References

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 2016; 374: 211–222.DOI: 10.1056/NEJMoa1506597

Boland CR, Goel A. Prognostic subgroups among patients with stage II colon cancer. N Engl J Med 2016; 374: 277–278.DOI: 10.1056/NEJMe1514353

medwireNews (www.medwireNews.com ) is an independent medical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2016