May 2001

From University of Southern California

Genes can determine chemotherapy program for colorectal cancer patients

Certain genes in tumors of patients with metastatic colorectal cancer can predict whether further chemotherapy will help prolong their lives

SAN FRANCISCO, May 14, 2001—Testing the tumors of advanced colorectal cancer patients can determine whether patients who have already failed a round or more of chemotherapy would benefit from further chemotherapy, according to a study by USC/Norris Comprehensive Cancer Center oncologists presented this weekend at the American Society of Clinical Oncology annual meeting.

The researchers showed that when given a combination of two chemotherapy drugs—5-FU (fluorouracil) and oxaliplatin—patients whose tumor cells expressed low levels of two key enzymes survived five times longer than patients whose tumor cells expressed high levels of the enzymes.

According to research oncologist Heinz-Josef Lenz, M.D., associate professor of medicine at the Keck School of Medicine of the University of Southern California, the study is the first to look at the use of such tumor testing and clinical outcome with the drug oxaliplatin.

The research is part of USC/Norris oncologists’ ongoing efforts to customize the most effective and tolerable treatments for each colorectal cancer patient based on the patient’s genes and the unique characteristics of the cancer.

Lenz and colleagues conducted the clinical study of 50 patients with advanced colorectal cancer. Patients had already failed at least one prior chemotherapy regimen before the oncologists placed them on 5-FU and oxaliplatin.

Meanwhile, researchers tested patients’ tumor biopsies to see how much of two key enzymes they expressed—an amount that varies from patient to patient.

Two important genes give orders to express these enzymes: the excision repair cross-complementing gene 1 (ERCC1) and thymidylate synthase (TS) gene.

In a healthy person, ERCC1 helps cells repair damaged DNA, while the body uses TS to make DNA. 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 DNA damaged through chemotherapy.

The more the genes can give orders to make the two enzymes, the more the cancerous tumors can successfully resist certain anti-cancer drugs, Lenz explains. By using a unique technology to test tumor tissue samples, the USC/Norris researchers were able to determine the amount of TS and ERCC1 expressed by the genes in each patient’s tumors.

In the USC/Norris study, the median survival time for patients with low TS gene expression was 311 days, significantly longer than the 57 days survived by the typical patient with high TS gene expression. Similarly, the median survival time for patients with low ERCC1 expression was 311 days, more than five times longer than the 57 days survived by the typical patient with high ERCC1 gene expression.

"These data strongly indicate that if considered separately, either ERCC1 or TS gene expression levels in those heavily pretreated patients with metastatic colorectal tumors predict for clinical outcome," Lenz says.

Such information could help patients and physicians make treatment decisions, including which chemotherapy drugs to administer and whether more chemotherapy is the right choice.

The USC/Norris oncologists conducted the research in cooperation with colleagues at Response Genetics Inc. The company was founded by Kathleen Danenberg, research laboratory specialist at USC/Norris, and Peter Danenberg, Ph.D., USC professor of biochemistry and molecular biology, and focuses on molecular services for oncologists and cancer patients.

Colorectal cancer is the third most common cancer in the United States, and experts expect 130,000 new cases to be diagnosed this year. The five-year survival rate for patients with advanced or metastatic disease is less than 10 percent.












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