July 1, 2008—(BRONX, NY)—By measuring the activity of four genes in cancer cells, scientists at the Albert Einstein College of Medicine of Yeshiva University accurately predicted whether colorectal tumors are sensitive or resistant to 5-Fluorouracil (5-FU), an important chemotherapy drug. The diagnostic advance, described in the July 1 issue of Cancer Research, could help doctors make the crucial decision as to whether a colorectal patient should receive 5-FU or instead be treated surgically or with other chemotherapy agents.
Several years ago, Dr. Robert Singer and colleagues at Einstein developed a novel microscopy technique known as fluorescence in situ hybridization (FISH) that allows researchers to see whether a gene of interest in a single cell is activated (transcribed). In this study, Dr. Singer wanted to see whether FISH could help in treating patients with colorectal cancer, the second-leading cause of cancer death among men and women in the U.S.
"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," says Dr. Singer, professor and co-chair of anatomy and structural biology at Einstein. "The drug 5-Fluorouracil is a mainstay of chemotherapy for colorectal cancer, but only 30 percent of patients respond to it—and there's no way to know in advance which patients will benefit and which won't. We showed in this study that applying our FISH technique to colorectal tumors could accurately predict the patients' responses to 5-FU chemotherapy."
The researchers started with 12 "candidate genes" that earlier were found to correlate with response to 5-FU. They then tested each gene in four different colorectal cancer cell lines (two extremely sensitive to 5-FU and two extremely resistant), using the FISH technique to look for active transcription sites in individual cells. 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 found a pattern of four genes that correctly classified each of the four cell lines as either sensitive or resistant to 5-FU.
To see whether their four-gene "signature" would work under clinical conditions, the researchers obtained biopsy specimens from seven patients who had undergone treatment for colorectal cancer at the Kimmel Cancer Center in Philadelphia. Then, to predict 5-FU sensitivity or resistance, they measured the activity of the four genes in several hundred cells from each specimen. (The treatment results for all patients were known, but the Einstein researchers were "blinded" to the outcomes until later.) For all seven patients, the gene-expression pattern correctly predicted whether their tumors were sensitive or resistant to 5-FU chemotherapy.
"Taking a chemotherapy drug that won't help you means not only risking serious side effects but losing valuable time that would better be spent on a different and more effective treatment option," says Dr. Singer. "We hope that this four-gene test may ultimately help steer colorectal cancer patients to a treatment strategy with the best chance for a successful outcome." The next step, he says, is a clinical trial in which the four-gene pattern will be tested on a larger number of patients.
Other Einstein researchers involved in the study were lead author Rossanna C. Pezo, Saumil J. Gandhi and Leonard H. Augenlicht. Collaborators also included L. Andrew Shirley and Richard G. Pestell of Thomas Jefferson University in Philadelphia.