Colon cancer test points to most effective treatments

November 29, 2001

Cancer researchers have added a valuable tool to oncologists' tumor-fighting toolbox: a way to find more effective medicines to give advanced colon cancer patients after their first round of chemotherapy failed.

Just by analyzing tissue from a patient's tumor, research oncologists at the USC/Norris Comprehensive Cancer Center can predict whether a patient is likely to respond to treatment that combines one of the world's most-prescribed anti-cancer drugs and a powerful platinum-based chemotherapy.

Oncologist Heinz-Josef Lenz, M.D., associate professor of medicine at the Keck School of Medicine of the University of Southern California, reported the findings in the Dec. 1 issue of the Journal of Clinical Oncology. The results mean physicians can better customize treatment for metastatic colon cancer patients and steer them toward medicines that hold the greatest potential for extending patients' lives.

"For the first time, we are finding markers that identify the success of second-line therapy," says Lenz, scientific director of cancer genetics at USC/Norris. "We can predict who will respond to this therapy, while sparing others the discomfort of a therapy that probably would not help them."

Lenz and his team studied tumor response and patient survival using chemotherapy combining oxaliplatin and 5-FU, or fluorouracil. Oxaliplatin is an investigational platinum compound and 5-FU is a longstanding drug used to battle many cancers. The team is the first to look at such tumor testing and patient outcome with oxaliplatin.

The study included 50 patients with advanced colorectal cancer. Patients had already failed at least one prior chemotherapy regimen before oncologists placed them on 5-FU and oxaliplatin.

Researchers analyzed tissue from participants' surgically removed tumors to see how much of two key enzymes the tumors expressed. Those amounts can vary from patient to patient, depending on genes.

In this case, Lenz and colleagues looked at two key genetic players: the excision repair cross-complementing gene 1, known as ERCC1 for short, and the thymidylate synthase, or TS, gene.

In a healthy person, ERCC1 helps repair routinely damaged genetic material in cells, and TS helps reproduce this genetic material. Unfortunately, though, cancerous tumor cells use the enzymes, too. They can feed off the TS to reproduce their own DNA, and use ERCC1 to fix the DNA that chemotherapy is meant to damage.

This is important for cancer patients, Lenz explains, because it appears the more their tumors' genes can make the enzymes, the more their tumors can resist certain chemotherapy drugs.

By testing tumor tissue samples through a unique technology, the USC/Norris researchers determined exactly how much of the enzymes each patient's tumor produced.

They found that patients with low TS and low ERCC1 expression survived a median of 336 days after starting the 5-FU and oxaliplatin chemotherapy--more than three times longer than the median 95 days survived by patient with tumors that expressed high levels of TS or ERCC1.

So oxaliplatin and 5-FU therapy is indeed more effective for patients with low TS and ERCC1 expression, Lenz concludes. If patients can be tested for these characteristics before starting treatment, doctors can make sure they give oxaliplatin and 5-FU to patients most likely to benefit--and spare others uncomfortable chemotherapy that would not be of much help.

It also could point physicians to try other drugs for these patients.

"We now need to test whether these patients who would not do well with oxaliplatin should be treated with alternative therapies," Lenz says. USC/Norris is now a site for a clinical trial of an investigational drug called TLK 286, which appears to work well against tumors that are resistant to oxaliplatin. And another new drug, known as NB 1011, actually focuses on tumor cells that express high levels of TS.

In the future, the USC/Norris team will conduct similar tests with other genes responsible for repairing DNA and other markers that may predict whether tumors will respond to standard and investigational chemotherapies. They also will examine such markers in different types of cancer.

Finding out more about these markers may also help researchers develop more targeted anti-cancer drugs.

The need for more customized, effective therapy is clear: Colorectal cancer is the third most common cancer in the United States, and experts expect 130,000 new cases to be diagnosed this year. Unfortunately, the five-year survival rate for patients with advanced or metastatic disease is less than 10 percent.
Yoshinori Shirota, Jan Stoehlmacher, Jan Brabender, Yi-Ping Xiong, Kathleen D. Danenberg, Susan Groshen, Denise D. Tsao-Wei, Peter V. Danenberg, Heinz-Josef Lenz. "ERCC1 mRNA Levels and Thymidylate Synthase (TS) mRNA Levels Predict Survival for Colorectal Cancer Patients Receiving Combination Oxaliplatin and Fluorouracil Chemotherapy" Journal of Clinical Oncology, Dec. 1, 2001, Vol. 19, No. 23.

University of Southern California

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