SAN DIEGO—Using a novel biometrics approach, researchers at the University of California, San Diego (UCSD), along with colleagues at Columbia University and Stanford University, have discovered a distinctive molecular feature—a new protein biomarker—that identified colon cancer patients who were most likely to remain disease-free up to five years after surgery.
The lynchpin of the discovery is CDX2, a biomarker which also helped the researchers identify Stage II colon cancer patients who are most likely to benefit from chemotherapy. Colon cancer patients lacking the protein CDX2 have a poorer prognosis than patients with CDX2, but in some cases are still more likely to benefit from chemotherapy. The retrospective study was published Jan. 21 by the New England Journal of Medicine (NEJM).
Debasish Sahoo, UCSD assistant professor of pediatrics, computer science and engineering, led the study along with Piero Dalerba of Columbia University and senior author Michael Clarke from Stanford University.
Sahoo had hoped to develop a computerized model of cancer and use it to discover biomarkers to benefit medical research since they succeeded in finding that the protein CDX2 can help identify a smaller group of Stage II colon cancer patients who would benefit from chemotherapy.
Sahoo’s use of a “bioinformatics approach” allowed the team to differentiate gene expression patterns, and this found specific genes that take part in stem cell differentiation which allowed the team to find the biomarker CDX2, he said.
“Our new discovery will most likely help us identify an aggressive form of colon cancer,” Sahoo told the UCSD Guardian. “It gives us strong evidence that the early-stage patients with this aggressive colon cancer may benefit from traditional chemotherapy.”
The majority of the “patients with stage II colon cancer are cured by surgery alone,” Sahoo tells DDNews. “However, 15 to 20 percent of them relapse and die from the disease. Therefore, it is extremely useful to identify who among these patients may benefit from treatment with adjuvant chemotherapy to prevent disease recurrence.”
According to the American Cancer Society “there will be estimated 134,490 new cases and 49,190 deaths from colorectal cancer in 2016,” Sahoo says. “The number of Stage II colorectal cancer is around 36 percent (48,416). We estimate around 4 percent (1,936) are CDX2-negative who may benefit from chemotherapy.”
Columbia University’s Dalerba told the UCSD Guardian that Stage II colon cancer can be cured through surgery. However, about 4 percent of patients require more specialized treatment.
Dalerba explained that the research started off as a computer-assisted search for genes that were associated with a molecular marker known as activated leukocyte cell adhesion molecule.
“We found a list of candidate genes that fulfilled this condition, and then ranked them based on the availability of diagnostic assays that could be used to test for their expression in primary tumors,” Dalerba said. “Only one of the candidate genes, the gene encoding for the transcription factor CDX2, fulfilled this requirement and was selected for further investigation.”
There were two steps to completing this study.
“First, the researchers identified candidate genes and then tested the association between the CDX2 expression, patient survival and benefits from adjuvant chemotherapy,” Dalerba said. “The second part involved collecting and analyzing over 1,800 samples from multiple databases which is why the task took over five years to complete.”
Sahoo said, “Because previous studies did not take into account differences between colon cancers with and without CDX2, doctors have long struggled to identify which Stage II colon cancer patients might benefit from adjuvant chemotherapy. We now have a biomarker to tell the difference, potentially saving many lives and reducing toxicity from unnecessary treatment.”
Dalerba and Sahoo also discovered that when the gene CDX2 is “off,” another molecular marker of stem-like cells in colon tumors, called ALCAM, is always “on.”
“We reasoned that colon tumors lacking CDX2 would likely contain a higher number of stem-like cells, and would therefore be more aggressive than CDX2-positive tumors,” said Dalerba.
Next, the team analyzed a database of cancer gene expression from more than 2,000 patients with known treatment courses and outcomes. The team found that 4 percent of colon cancers lack CDX2. They then used the database to determine if there is an association between CDX2 status and patient outcomes.
By examining data on 466 patients with any stage of colon cancer, the team discovered that CDX2-negative tumors were associated with poorer prognosis. Forty-one percent of colon cancer patients with CDX2-negative tumors survived five years disease-free, as compared to 74 percent of patients with CDX2-positive colon tumors.
Ninety-one percent of CDX2-negative Stage II colon cancer patients survived five years disease-free when they were treated with chemotherapy. In contrast, significantly fewer (56 percent) CDX2-negative stage II colon cancer patients who did not receive chemotherapy survived five years disease-free.
The original article, entitled “CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer,” notes that “Currently, tumor stage, tumor grade and microsatellite instability remain the most important among a handful of prognostic variables that are considered in the development of algorithms for the treatment of patients with early-stage colon cancer … 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. Given the exploratory and retrospective design of our study, these results will need to be further validated. We advocate for these findings to be confirmed within the framework of randomized, clinical trials, in conjunction with genomic DNA sequencing studies.”