Chemotherapy may benefit subgroup of stage-2 colon cancer patients

A small subset of colon cancers lacks the CDX2 protein — a hallmark of colon tissue maturation. Patients with these cancers may benefit more than others from chemotherapy.

Michael Clarke and his colleagues found that stage-2 colon cancer patients with a particular gene-expression pattern may benefit from chemotherapy after surgery.
Norbert von der Groeben

Stage-2 colon cancer patients whose tumors lack a particular protein may benefit from the use of chemotherapy after surgery, according to a retrospective study by researchers at the Stanford University School of Medicine. Previous studies have suggested that chemotherapy given to stage-2 patients had limited benefit.

The study was published Jan. 21 in The New England Journal of Medicine along with two editorials describing its significance.

The researchers categorized colon cancer patients based on the presence or absence of a protein called CDX2, which is found in mature colon cells. In these cells, CDX2 helps to control the expression of other genes that drive colon cell specialization. The researchers found that about 4 percent of people with colon cancer have tumors that don’t express CDX2. In an initial study of 466 patients with any stage of colon cancer, only about 41 percent of those with cells lacking CDX2 lived disease-free for five years after treatment, compared to 74 percent of those with CDX2 in their cancer cells.  

CDX2-negative cancers respond well to chemo

But the researchers identified another important distinction between the two groups, particularly in those with stage-2 disease: Patients whose tumor cells didn’t express CDX2 were much more likely to benefit from chemotherapy in addition to surgery than were people with CDX2-positive tumors. About 91 percent of patients with CDX2-negative cancers treated with chemotherapy in addition to surgery lived disease-free for five years versus about 56 percent of those who did not receive chemotherapy. Previous studies that did not distinguish between CDX2-positive and CDX2-negative cancers suggested that chemotherapy provided little additional benefit to stage-2 colon cancer patients.

“We’ve learned that a patient group that formerly was not known to need adjuvant chemotherapy may, in fact, benefit from this treatment. Conversely, it may be possible to identify those patients who could avoid the toxic side effects of chemotherapy,” said Michael Clarke, MD, professor of medicine and the Karel H. and Avice Beekhuis Professor in Cancer Biology. 

This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes.

The retrospective study looked at gene expression in cancer cells and tissues from over 2,000 patients whose treatment courses and outcomes were known. The researchers emphasize that a randomized, prospective clinical trial is necessary to further confirm the results before clinical changes are codified.

Clarke, who is also a member of the Stanford Cancer Institute and the associate director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, is the senior author of the study. Former instructors and Siebel fellows Piero Dalerba, MD, and Debashis Sahoo, PhD, share lead authorship of the study. Dalerba is now an assistant professor of pathology and cell biology and of medicine (Division of Digestive and Liver Diseases) at Columbia University, and Sahoo is an assistant professor of pediatrics and of computer science at the University of California-San Diego.

Stem cell, cancer connection

Clarke and his colleagues have been studying the connection between stem cells and cancer for several years. For this study, Dalerba and Sahoo sought to devise a way to identify colon cancers that were more stem-cell-like, and thus likely to be more aggressive. They looked for a gene that was expressed in more mature cells but not in stem or progenitor cells. They did this by using a novel bioinformatics approach that drew on their knowledge of stem cell biology to identify developmentally regulated genes important in colon tissue maturation.

Because they knew from previous research by Dalerba in the Clarke laboratory that stem and immature colon cells express a protein called ALCAM, Dalerba and Sahoo looked for genes whose protein product was negatively correlated with ALCAM expression. “We reasoned that those proteins would likely be involved in the maturation of colon tissue and might not be found in more aggressive, immature cancers,” Sahoo said.

Finally, to ensure their results would be useful to doctors, the researchers added another criterion: The gene had to make a protein that was easily detectable by an existing, clinical-grade test.

The screening technique identified a promising candidate: the CDX2 protein. “We chose CDX2 because it was the only candidate that was already used as a diagnostic biomarker in the clinic,” Dalerba said. “However, we were also intrigued by the fact that CDX2 is a master transcription factor controlling the expression of many differentiation genes in colon epithelial cells.”

When they separated colon cancer cases into those with cells that either did or did not express CDX2, they found a marked difference in both five-year, disease-free survival rates and in response to chemotherapy.

Data sharing and collaboration

“The CDX2 protein plays a role in the differentiation of the intestinal epithelium,” said Clarke, who is also deputy director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. “The novel bioinformatics analyses used in this paper links its expression to more differentiated cells in colon cancers. We found that patients whose cancers lacked CDX2 expression, which suggests that their tumors have a high proportion of cancer stem and progenitor cells, had a much worse prognosis. However, their outcomes improved significantly if they had received chemotherapy as part of their treatment.”

The study is hailed in an accompanying editorial in the journal as an endorsement of data sharing and collaboration among many different research groups. The Stanford researchers used information stored in the National Center for Biotechnology Information’s Gene Expression Omnibus database to identify CDX2. Tissue samples were provided by the Cancer Diagnosis Program of the National Cancer Institute, the National Surgical Adjuvant Breast and Bowel Project and the Stanford Tissue Microarray Database.

“A major question in the cancer field is whether the study of cancer stem cells can lead to increases in survival for cancer patients. This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes,” Clarke said. 

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat it in the ill.

Stanford co-authors of the study are former research assistant Pradeep Rajendran; former graduate student Stephen Miranda; former postdoctoral scholars Shigeo Hisamori, MD, Tomer Kalisky, PhD, and Erna Forgo, MD; project coordinator Jacqueline Hutchison; lab manager Dalong Qian, MD; medical student Nate Wilcox-Fogel; postdoctoral scholar Xiangqian Guo, PhD; pathology professor Matt van de Rijn, MD, PhD; and professor of medicine George Fisher, MD, PhD.

The research was supported by the National Comprehensive Cancer Network, the National Institutes of Health (grants U54CA126524, P01CA139490, R00CA151673, U24CA114732, U10CA37377, U10CA180868, U10CA180822, UG1CA189867 and U24CA196067), the Siebel Stem Cell Institute, the Thomas and Stacey Siebel Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the California Institute for Regenerative Medicine, the Department of Defense, the Bladder Cancer Advocacy Network and BD Biosciences.

Stanford’s Department of Medicine also supported the work.

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