Pinpointing which colon cancer patients need chemotherapy in addition to surgery can be difficult. Studies have suggested that those with stage-2 disease aren't likely to benefit from chemotherapy, so doctors may chose to bypass the treatment and its toxic side effects.
Now cancer biologist Michael Clarke, MD, working with former postdoctoral scholars Piero Dalerba, MD, and Debashis Sahoo, PhD, have found a way to identify a small but significant minority of stage-2 patients who differ from their peers: They have a poorer overall prognosis, but they are also more likely than other stage-2 patients to benefit from additional chemotherapy. The research was published today in the New England Journal of Medicine.
This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes
From our press release:
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.
Dalerba and Sahoo identified a protein called CDX2 that is expressed during colon tissue maturation. Most colon cancer cells also express CDX2. But about four percent of tumors are made up of cells that don't make this protein. Only about 41 perenct of people with these tumors, the researchers found, lived disease-free for five years after treatment. In contrast, about 74 percent of those whose tumors did make CDX2 achieved the five-year disease-free milestone. But there's more:
...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.
The study analyzed gene expression in cancers and tissues from more than 2,000 people whose treatment courses and outcomes were known. This is called a retrospective study, and it's an important way for researchers to formulate theories about the effect of different types of therapy. But the researchers emphasize that the findings need to be confirmed in a prospective, randomized clinical trial before final conclusions can be made and clinical changes are codified. Nonetheless, the research provides important insight into how best to tailor treatments to individual patients, and may improve the outcome for some colon cancer patients.
"A major question in the cancer field is whether the study of cancer stem cells can lead to increases in survival for cancer patients," said Clark. "This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes."
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.