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Biomarker predicts which stage II colon cancer patients may benefit from chemotherapy

A multicenter research team has identified a biomarker that predicts which stage II colon cancer patients may benefit from chemotherapy after surgery to prevent a recurrence of their disease.

The study was published today in the online edition of the New England Journal of Medicine.

The majority of patients with stage II colon cancer--cancer that has grown into or through the outer layer of the colon but has not spread to lymph nodes or distant organs--are cured by surgery alone.

However, about 15 to 20 percent of these patients eventually relapse and die of metastatic disease.

"The problem is that we don't have an easy way to single out these patients before they relapse and accurately predict who could benefit from postsurgical, or adjuvant, chemotherapy," said Piero Dalerba, MD, assistant professor of medicine, pathology and cell biology at Columbia University Medical Center (CUMC) and the Herbert Irving Comprehensive Cancer Center (HICCC), and first author of the paper.

Previous studies have found biomarkers in tumour cells that identify which stage II colon cancer patients are at higher risk for relapse after surgery.

However, many of those biomarkers do not also predict which of these patients would actually benefit from adjuvant chemotherapy.

The current study took a different approach to the search for potential biomarkers.

Instead of looking at gene-expression patterns obtained from the random sampling of tumour cells, the researchers focused on the gene-expression pattern of cancer stem cells--the source of mature, or differentiated, tumour cells--a field of study pioneered by the paper's senior author Michael F. Clarke, MD, of Stanford University.

"We reasoned that tumours containing high numbers of cancer stem cells might be associated with a more aggressive disease, and wanted to find a way to easily find them," said Dr Dalerba.

To identify these tumours, the authors took advantage of a novel bioinformatics approach designed by Debashis Sahoo, PhD, of the University of California-San Diego, and co-first author of the study.

"In essence, we asked a computer the following question: can you help us find a gene whose lack of expression is always associated with high levels of cancer stem cell markers?" said Dr Sahoo.

By analysing data from more than 2,000 colon cancer patients, the authors identified 16 biomarkers that fulfilled this criterion.

Of these, only one--a gene called CDX2--was found to be clinically actionable, meaning that a standardised diagnostic test for detecting expression of the gene was already available.

CDX2 is known to regulate cell differentiation in the layer of cells that line the colon, where the cancer begins.

In the study, patients whose tumours lacked CDX2 expression had a poorer prognosis compared to those whose tumours scored positive for CDX2 expression.

"We wanted to understand if the small group lacking CDX2 expression--approximately 4 percent of the global colon cancer population--fared poorly because of an intrinsic resistance to chemotherapy," said Dr Dalerba.

"To our surprise, we found that, on the contrary, tumours lacking CDX2 expression, despite being very aggressive from a biological point of view, also appeared to benefit from early treatment with adjuvant chemotherapy."

Further analysis using data from the National Surgical Adjuvant Breast and Bowel Project revealed that this observation also held true for stage II colon cancer patients, again showing that patients with tumours lacking CDX2 expression were more likely to benefit from adjuvant chemotherapy than patients whose tumours did express the gene.

"What's exciting is that an inexpensive, simple test for CDX2 expression is already widely available," said Dr Dalerba.

Additional clinical studies, such as prospective and randomised clinical trials, are needed before using the test as a clinical decision-making tool for colon cancer patients, he added.

Source: Columbia University Medical Center



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