Biological differences suspected but not yet identified

Jennifer Chan, MD, MPH

Researchers at Dana-Farber Cancer Institute have uncovered a cancer paradox: A family history of colon or rectal cancer doubles one's risk of the disease — but improves the odds of survival should the cancer develop.

A study appearing in the June 4 issue of the Journal of the American Medical Association found that patients treated for stage III colorectal cancer fared significantly better if they had a first-degree relative with the disease than if they had no family history of colon or rectal cancer. Having a family history conferred a 28 percent lower risk of a cancer recurrence, being diagnosed with a new tumor, or dying from any cause during the median 5.6-year follow-up.

The researchers do not fully understand the reason for the paradoxical finding of increased risk but better prognosis in the patients who had a family history of colorectal cancer. However they noted there is precedent: A rare inherited condition called Lynch syndrome strongly increases the risk of colorectal cancers that may behave less aggressively than non-inherited "sporadic" cases of colon cancer.

In the new study, the more affected relatives a patient reported, the better his or her odds became. Compared with participants without a family history of colorectal cancer, participants with two or more affected relatives had a 51 percent lower risk for cancer recurrence or death.

"This news may be reassuring to people with a family history, but our hope is that we can discover what underlies this effect of family history in biological terms," said Jennifer Chan, MD, MPH, of Dana-Farber's Center for Gastrointestinal Oncology, first author of the report. It is estimated that more than 153,000 cases of colon and rectal cancer will be diagnosed in 2008, according to the American Cancer Society, with more than 50,000 deaths.

An individual who has a first-degree relative with colorectal cancer faces a doubled lifetime risk of being diagnosed with the disease — approximately 2 in 20 odds, compared to 1 in 20 for those with no family history.

The findings emerged from a prospective study of 1,087 patients enrolled in a randomized trial of two chemotherapy regimens following surgery for stage III colon cancer. These cancers are characterized by their deep penetration into the wall of the colon, or large intestine, and have spread to nearby lymph nodes but not to other organs.

The patients were interviewed about family history of the disease and some had DNA extracted from tumor samples. About 18 percent of the patients reported a diagnosis of colon or rectal cancer in one or more first-degree relatives. The patients were followed for an average of 5.6 years to measure their disease-free survival — the time from enrolling in the study to being diagnosed with a recurrence of the tumor or a new primary colon cancer, or death from any cause.

Examining just the risk for cancer recurrence, patients with a family history of colorectal cancer had a 26 percent reduced risk compared with patients without a family history. Cancer recurrence occurred in 27 percent of patients with a family history of colorectal cancer and 35 percent of patients without a family history. Patients with a family history of colorectal cancer had a 25 percent reduction in risk of dying from their cancer.

The scientists ruled out several explanations for the difference, including the possibility that people with affected relatives adopted healthier life styles or were diagnosed earlier. "We looked at important lifestyle factors like diet, exercise and smoking, and found no association. Since all patients had stage III cancers, earlier diagnosis didn't explain it, either," explained Chan.

They also studied the potential effect of a kind of genetic alteration seen in the tumors of patients with the inherited Lynch syndrome that is associated with the elevated risk of colorectal cancer in these families as well as their more-favorable prognosis. This genetic change, known as microsatellite instability, did not appear to explain the behavior of the more-common cancers associated with family history in the new study.

Charles Fuchs, MD, of Dana-Farber, the senior author of the study, said that the form of colorectal cancer associated with a family history behaves differently because of "something biologic, but we just don't know yet what that is."

In an effort to identify the biologic factor or factors, Fuchs and his colleagues are examining hundreds of colorectal tumor samples for common genetic changes. If some of these changes are found more often in patients having a family history, it could lead researchers to mechanisms in those cancers that explain their distinct behavior. In turn, this understanding could help in devising better treatments.

"Meanwhile," said Fuchs, "the message is that people who have a family history should be screened, and if they do get the cancer, they appear to have a better outlook."

Screening — usually a colonoscopy — is recommended beginning at age 50 for people at average risk, and beginning at age 35 or 40 for those with a family history.

Other authors include Jeffrey Meyerhardt, MD, MPH, and a number of investigators from Dana-Farber and other institutions involved in the treatment study that yielded data used in the analysis.

The treatment study, carried out by Cancer and Leukemia Group B, was supported by grants from the National Cancer Institute and Pharmacia & Upjohn Co., now Pfizer Oncology.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.