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Einstein Researchers ID Gene Pattern Linked to 5-FU Response in Colon Cancer

Scientists at the Albert Einstein College of Medicine of Yeshiva University have accurately predicted whether colorectal cancer tumors are sensitive or resistant to treatment with 5-fluorouracil by measuring the activity of four genes in cancer cells, they reported in a recent study.
The study, published in the July 1 issue of Cancer Research, “could help doctors make the crucial decision as to whether a colorectal [cancer] patient should receive 5-FU or instead be treated surgically or with other chemotherapy agents,” university researchers said in a statement. 
Study leader Robert Singer wanted to test whether a fluorescence in situ hybridization assay could help personalize treatments for colorectal cancer patients.
"Since genes play such a significant role in causing cancer, you'd assume that you might find a different transcriptional profile in cancers that are sensitive to chemotherapy from those that are resistant," Singer, professor and co-chair of anatomy and structural biology at Albert Einstein, said in a statement.
Although 5-FU is a widely used chemotherapeutic agent in colorectal cancer, the treatment has only a 30-percent average response rate. “There's no way to know in advance which patients will benefit and which won't,” Singer said. “We showed in this study that applying our FISH technique to colorectal tumors could accurately predict the patients' responses to 5-FU chemotherapy.”
Study researcher Saumil Gandhi told Pharmacogenomics Reporter this week that following this preliminary research, a wide-scale clinical trial would further demonstrate the benefits of using the genetic pattern identified by researchers to determine response to 5-FU.
“Although we have no plan of commercializing this technology yet, we would be open to collaborating with an industry partner to bring this test to the clinic,” Gandhi said.
The Study
Initially, researchers focused on 12 candidate genes that have been identified in the scientific literature to be associated with 5-FU response. The 12 candidate genes included: MRGX (MORF-related protein X); TYMS (thymidylate synthase); BAK (BCL2-antagonist/killer 1); ATP7B (ATPase, Cu2+ transporting, β polypeptide); PPP4R1 (protein phosphatase 4, regulatory subunit 1); FLJ22474; ATUB2 (tubulin, α2); KIDDNS; PB1 (polybromo1); PRSS (protease, serine 15); NUCB2 (nucleobindin 2); TSSC3 (tumor suppressing, subtransferable candidate 3).

“Although we have no plan of commercializing this technology yet, we would be open to collaborating with an industry partner to bring this test to the clinic.”

Using FISH, researchers then looked for active transcription sites for each gene in individual cells in four colorectal cancer cell lines, two very sensitive to 5-FU and two resistant to the treatment. Tissue samples came from 15 anonymous colon cancer patients with unknown clinical outcomes.
“Various combinations of these genes were then examined in search of a gene-expression pattern that was associated with either resistance or sensitivity to 5-FU,” the researchers (said in a statement. “The researchers found a pattern of four genes that correctly classified each of the four cell lines as either sensitive or resistant to 5-FU.”
The four genes predictive of 5-FU response were TYMS, MRGX, BAK, and ATP7B.
The predictive model developed by the researchers classified 11 of the 15 samples as sensitive and two samples as resistant. The remaining two samples showed mixed characteristics, according to the study abstract.
After identifying the four genes, researchers tested the accuracy of their predictive model in tumor samples from seven colorectal cancer patient treated with 5-FU, for whom treatment results were known. Researchers were blinded to patient outcomes until the conclusion of this phase of the study.
The gene expression pattern was able to correctly predict in six out of seven patients if they were sensitive or resistant to 5-FU.
“The seventh patient was classified as resistant by the predictive model, although [the patient] has had no tumor recurrence following a second surgery (the tumor recurred after the first surgery),” Gandhi told Pharmacogenomics Reporter via e-mail.
Following this preliminary study, the Albert Einstein researchers plan to launch a larger clinical trial to test their predictive model.
Although there are no commercialization plans for a diagnostic test for this indication, a predictive assay could potentially save healthcare dollars. 
“While the monetary cost of 5-FU is negligible, the cost in terms of risking serious side effects and losing valuable time for treatment are quite significant,” Gandhi said. “Furthermore, ineffective chemotherapy often allows the resistant subpopulation of cells to grow more rapidly, which results in a more aggressive tumor.”
The severity of the side effects associated with 5-FU treatment depends on the amount and schedule of the administration. Common reactions include mouth soreness, difficulty swallowing, diarrhea, stomach pain, low white blood count, low platelet count, anemia, sensitivity to sun exposure, and excessive tearing.
Patients who have DPD deficiency, an enzyme crucial for the metabolism and deactivation of 5-FU, experience serious side effects with very small doses of the drug.
5-FU is the standard of care in colorectal cancer treatment and is commonly used as part of a combination regimen in the advanced stages of the disease. 

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