Biomarker of Early-stage Aggressive Colon Cancer
Lack of the biomarker CDX2 identifies a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. These patients are usually treated with surgery alone.
Piero Dalerba et al identified CDX2 (a transcriptional factor that regulates intestinal development) using a bioinformatics approach to search for markers of colon epithelial differentiation based on gene expression signatures. The authors ranked candidate genes according to the availability of clinical-grade diagnostic assays. Then, in subgroup analyses of independent and retrospective cohorts of patients with stage II or stage III colon cancer, Dalerba et al tested candidate genes for their association with disease-free survival and efficacy of adjuvant chemotherapy.
The authors found that a lower proportion of patients with CDX2-negative CRC survived disease-free for 5 years than patients with CDX2positive tumors. In addition, the analysis showed that odds of 5-year disease-free survival was greater among patients with CDX2-negative stage II disease who received adjuvant chemotherapy, compared with those who did not receive adjuvant chemotherapy.
“CDX2 has identified a group of patients with stage II CRC who will benefit from adjuvant chemotherapy,” principal investigator Michael F. Clarke (Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine) told Medscape Medical News.
In an editorial that accompanies the article, C. Richard Boland and Ajay Goel explain that approximately 20% of patients with stage II colon cancers have a recurrence, and adjuvant chemotherapy provides minimal benefit that is usually considered to be not worth the toxic effects of the drugs.
Boland and Goel state that the new marker could allow oncologists to identify patients with colon cancer who might benefit from adjuvant chemotherapy.
In designing the experiment, Dalerba et al reasoned that tumors containing stem cell–like cells would be more aggressive. They examined a large database of colon cancers and found 16 genes whose expression was inversely related to the stem cell–like state. The CDX2 gene product could be detected by immunohistochemistry, so the authors tested this marker first.
They found that 5-year disease free survival was 48% for patients with CDX-negative vs 71% for patients with CDX2-positive (n = 318) tumors. Overall survival was also lower — 33% vs 59%.
In discovery and validation datasets, the association remained significant regardless of age, sex, tumor stage, and tumor grade.
A significantly smaller proportion of patients with stage II disease and CDX2-negative tumors survived for 5 years in the discovery (49% vs 87% for patients with CDX-positive tumors) and validation sets (51% vs 81% for patients with CDX-positive tumors).
Most important was the observation that a greater proportion of patients with CDX2-negative tumors who received chemotherapy survived for 5 years, compared with those who did not receive chemotherapy.
The benefit of adjuvant chemotherapy was seen regardless of depth of invasion of the primary tumor, number of lymph nodes resected at surgery, or number of metastatic lymph nodes.
“Our 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,” said Dalerba et al.
Boland told Medscape Medical News that although all patients with stage III disease are candidates for adjuvant chemotherapy according to the guidelines, there is an issue of the standard of care for patients with stage II disease.
“The current standard for clinical prognostication relies principally on pathological staging,” said Boland and Goel in their editorial. Although findings of Dalerba et al are not definitive, they provide “an opportunity for oncologists to move beyond what has been an inadequate method of selecting patients with stage II colon cancer for adjuvant chemotherapy.”
“With the availability of CDX2 as a diagnostic test, clinicians are likely to use CDX2 to identify stage II patients who may benefit from adjuvant chemotherapy,” Boland told Medscape Medical News.