Study finds racial differences in response to treatments for advanced colon cancer

Genetic factors may play a role

(Embargoed) CHAPEL HILL In recent years, reports have emerged showing that Americans with colorectal cancer who are black have a lower rate of survival compared with other racial or ethnic groups.

For both black men and women, cancers of the colon and rectum are the third most common cause of cancer deaths, according to the American Cancer Society. Additionally, death rates for cancer of the colon and rectum among blacks are about 30 percent higher than among whites, and more than two times higher than for Asian Americans, Pacific Islanders, American Indians, and Hispanics.

Several reasons have been suggested to explain these differences, including diagnosis at a later stage of disease, having more aggressive disease and having less access to screening tests for earlier diagnosis. Results of a multicenter study in the United States and Canada point to another possibility: response differences among blacks to standard chemotherapy treatments for advanced colorectal cancer.

The results also suggest that genetic differences in metabolism of chemotherapy drugs may play a role.

"The aim of this research was to compare African American with Caucasian patients with respect to responses, to the time it took for their cancers to become worse, and their overall survival. We also wanted to see if there was any difference in the side effects profile," said Dr. Richard M. Goldberg, professor of medicine and hematology-oncology division chief at the University of North Carolina at Chapel Hill and associate director of clinical research at UNC Lineberger Comprehensive Cancer Center.

Patients in the study donated a tube of blood for DNA studies. "We were looking at their DNA, focusing on minor differences called polymorphisms, or variations in DNA sequences that are present in specific genes in every cell in the patient's body," Goldberg said. "The genes that we were particularly interested in are those genes coding for key enzymes involved in drug activation, metabolism and disposition," Goldberg said.

The findings were presented as an abstract Sunday (June 4) at the American Society of Clinical Oncology meetings in Atlanta.

Participants in the study were a subset of those who had enrolled in a clinical trial that began in the 1990s and was conducted in 155 locations nationwide and in Canada.

The trial helped establish the value of the now-standard chemotherapy regimen known as FOLFOX4, a combination of the standard anticancer drugs 5-fluorouracil (5-FU), leucovorin (LV) and the new drug oxaliplatin.

In that trial, patients were assigned to one of three chemotherapy programs. Each program called for the patient to receive two of three drugs; 5 Fluorouracil, irinotecan or oxaliplatin.

The 1,412 participants reported on in this study all had advanced colorectal cancer. Blacks were similar to whites in extent of disease, gender, age-range and prior treatment.

But blacks had a "significantly lower response rate" overall, both when all three treatment programs were analyzed together and when each chemotherapy combination was analyzed separately. When results of the three treatment arms were analyzed together, blacks showed a 29 percent response rate versus whites' 41 percent response rate.

When FOLFOX was analyzed separately, the 119 black patients enrolled showed a response that was 15 percent lower than that of white patients.

As to time to progression or worsening of disease, the study found no significant differences between the racial groups. The time it took from study enrollment until their cancer became worse was significantly longer for FOLFOX compared with the other chemotherapy combinations, IFL (irinotecan and 5FU/LV) and IROX (irinotecan and oxaliplatin). In terms of overall survival, the comparison between all patients showed about a 1.5 month difference in overall survival favoring white patients, but that finding was not statistically significant.

Blacks did fare better when it came to adverse side effects. "African Americans had significantly less severe toxicity, mainly due to less severe diarrhea," Goldberg said.

"This study suggests that since African Americans don't respond as well to these chemotherapies as Caucasians but don't have as much toxicity, we may not have arrived at the optimal strategy for their treatment," Goldberg added. "It would certainly be worth exploring other strategies, including dose-escalation."

To understand these clinical results further, Goldberg and colleagues performed genetic tests looking for differences in the frequencies of DNA polymorphisms on blood samples of some of the participants, black and white. About 500 participants provided blood samples for this use.

"We looked at 21 genes that we knew were involved in transporting these drugs into the cell, converting them to active products, de-toxifiying them and preparing them for excretion," Goldberg said. "And then we correlated the frequencies of polymorphisms in these genes with our clinical endpoints."

The study found that blacks and whites had "significantly different frequencies of polymorphisms in candidate genes coding for key enzymes involved in drug activation, metabolism and disposition," Goldberg said.

He added, however, that while different frequencies of polymorphisms in genes relevant to drug metabolism "may help explain" the clinical differences found in the study, they are based on correlations and, therefore, don't imply cause-and-effect.

"Perhaps, in time, we'll be smarter about how we prescribe drugs by doing an analysis of DNA ahead of time, thereby allowing us to individualize the most effective and tolerable drug therapy on a patient-by-patient basis," Goldberg said.

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Along with UNC, study collaborators included 150 other institutions with key members of the investigative team hailing from Washington University in St. Louis; the Mayo Clinic in Rochester, Minn.; Iowa Oncology Research Association in Des Moines; Cancer and Leukemia Group-B in Boston; Eastern Cooperative Oncology Group in Pittsburgh; University of Kansas in Kansas City; National Cancer Institute of Canada and St. Catherine's Hospital in Ontario.

The research was funded by the National Cancer Institute, a component of the National Institutes of Health.

Note: From Saturday (June 3) through Monday (June 5) during the ASCO meetings in Atlanta journalists seeking an interview with Goldberg should contact Tom Hughes at (919) 741-8840 or tahughes@unch.unc.edu.

UNC Medicine contacts: Les Lang, (919) 843-9687 or llang@med.unc.edu; Dianne Shaw, (919) 966-7834 or dgs@med.unc.edu

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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