New Models of Breast Cancer Risk Focus on Breast Density

Two new models for assessing a patient's risk of developing breast cancer focus on breast density as an important predictor. The two studies are reported in the September 6 Journal of the National Cancer Institute.

CCR Grand Rounds September 12: Dr. Steven M. Larson, Chief, Nuclear Medicine Service; Memorial Sloan-Kettering Cancer Center. "Molecular Imaging in Drug Discovery." September 19: Dr. Samuel Strober, Professor of Medicine, Stanford University School of Medicine. "Harnessing the Power of Graft Anti-tumor Activity after Bone Marrow Transplantation." CCR Grand Rounds are held 8:30 to 9:30 a.m. at the NIH campus in Bethesda, Md., in the Clinical Center's Lipsett Amphitheater.

In the first study, Dr. William E. Barlow of Cancer Research and Biostatistics, and Group Health Cooperative in Seattle, and colleagues identified 11,638 women diagnosed with breast cancer within the Breast Cancer Surveillance Consortium, a large prospective study of mammography in clinical practice in the United States. The study developed prediction models for pre- and postmenopausal women and used breast density reported as part of routine screening mammography by radiologists in clinical practice. The factors predicting risk in premenopausal women were limited to age, breast density, family history of breast cancer, and prior breast procedure. These factors also predicted risk for postmenopausal women, as did the additional risk factors of ethnicity, body mass index, natural menopause, use of hormone therapy, and a prior false-positive mammogram.

"The models establish breast density as a highly clinically significant predictor of breast cancer risk that is almost as powerful a risk factor as age...Nonetheless, ability to accurately predict breast cancer at the individual level remains limited," the authors wrote. However, these models may be helpful in identifying women at high risk for breast cancer who may benefit from preventive interventions or more intensive surveillance.

The second study, headed by Drs. Jinbo Chen and Mitchell H. Gail of NCI's Division of Cancer Epidemiology and Genetics, assessed the absolute risk of developing breast cancer using an updated version of the Gail model. The Gail model was developed in the 1980s to assess the risk of breast cancer for women who undergo annual mammography screening.

The new model included breast density, weight, age at first live birth, number of benign breast biopsy examinations, and number of first-degree relatives with breast cancer. The researchers investigated whether information on breast density, which was available for 7,251 women in the Breast Cancer Detection Demonstration Project (BCDDP), could improve absolute breast cancer risk projections compared with an earlier version of the Gail model, which was also based on BCDDP data.

The new model predicted higher risks than the previous model in women with high breast density, and previous analyses indicated that the new model had modestly higher discriminatory accuracy. However, Dr. Gail cautioned, "Independent validation studies are needed before we would recommend using this model for counseling."

Celecoxib Significantly Reduces the Risk of Precancerous Colorectal Polyps

The final results of two phase III clinical trials indicate that regular use of the COX-2 inhibitor celecoxib (Celebrex) significantly reduces the risk of precancerous polyps reoccurring in the colon or rectum.

In the NCI and Pfizer cosponsored APC trial and the Pfizer-sponsored PreSAP trial, risk reductions as great as 45 percent were seen in patients taking celecoxib compared with placebo. Participants receiving celecoxib in both trials had fewer new adenomas and, perhaps more importantly, fewer new advanced adenomas than those on placebo. The results were published in the August 31 New England Journal of Medicine (NEJM).

As reported previously, celecoxib use in both trials was also associated with a statistically significant increased risk of cardiovascular events. According to an NCI-funded independent safety analysis of the trials' results, published in the September 5 Circulation, when event data from both trials were combined, there was a nearly twofold increased risk of cardiac events in patients taking celecoxib.

The analysis also revealed dose-related increases in cardiovascular events and blood pressure, leading the authors to speculate that the increased cardiac events might be related to elevated blood pressure and that lower doses of the drug might have a wider safety margin with respect to cardiovascular disease while still reducing cancer risk.

In an NEJM editorial, Drs. Bruce Psaty from the University of Washington and John Potter from the Fred Hutchinson Cancer Research Center argued that, based on the available evidence, celecoxib "has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or in the general population."

But in the view of APC co-author Dr. Ernie Hawk, director of NCI's Office of Centers, Training & Resources, a more complex set of conclusions is warranted. "Celecoxib is already used by patients with familial adenomatous polyposis, who have a much higher risk of cancer than patients on the APC and PreSAP trials do. The high degree of efficacy demonstrated in the APC and PreSAP trials should provide major incentive for researchers to define the agent's mechanisms of action more fully with regard to benefits as well as risks."

Overweight, Obesity in Midlife Increases Risk of Mortality

NCI researchers, in collaboration with AARP, found that being overweight during midlife is linked to an increased risk of death, according to study results in the August 24 New England Journal of Medicine.

The study, led by Dr. Kenneth Adams of NCI's Division of Cancer Epidemiology and Genetics (DCEG), monitored the health status of 527,265 Americans aged 50-71 from 1995 to 2005 using mailed questionnaires and death records. The study's participants included 186,000 nonsmoking men and women. This allowed researchers to account for confounding factors of smoking, preexisting disease, age, race/ethnicity, education, physical activity, and alcohol consumption. The study accounted for preexisting chronic disease by asking participants to report their weight at age 50. Examining weight at an earlier age provides a measure of typical adult weight that is largely unaffected by the onset of chronic disease.

"We reasoned that BMI at age 50 gives a more accurate representation of the amount of excess weight a person was exposed to over many years," said Dr. Michael F. Leitzmann of DCEG, the study's senior author.

BMI analysis of nonsmokers at age 50 found that the risk of mortality among participants who were overweight increased by 20 to 40 percent, while mortality risk among obese participants increased two- to threefold.

Excess body weight is known to increase the risk of several cancers as well as heart disease, stroke, high blood pressure, pulmonary disease, and diabetes.

Suicidality Increased in Adult Survivors of Childhood Cancer

Even modern cancer treatments can result in significant, lasting physical and emotional side effects. Previous studies have shown that individuals diagnosed with cancer have an increased risk of suicide, but few studies have focused on the risk in cancer survivors years later. A new study in the August 20 Journal of Clinical Oncology indicates that adult survivors of childhood cancer have an increased risk of suicidal thoughts and suicide attempts.

Researchers from Dana-Farber Cancer Institute conducted the study, which included 226 survivors of childhood cancer participating in routine psychological screening at a multidisciplinary cancer survivor clinic. Patients provided demographic information; treatment methods were determined from medical records. All patients were asked standard questions designed to measure physical functioning, mental health, and suicidality.

Out of the 226 participants, 29 (12.83 percent) reported suicidality. Longer time since diagnosis and treatment with cranial radiation were both associated with suicidality, as were the self-reported variables of depression, hopelessness, pain, and concern about appearance. Only 11 out of the 29 patients with suicidal symptoms were clinically depressed, indicating that factors such as physical functioning and pain should also be monitored during follow-up care.

The authors acknowledge that their study may be limited by the fact that all participants were taken from a single survivorship clinic, and may not be representative of cancer survivors from other institutions or socioeconomic backgrounds. Patients actively seeking follow-up care may also have more physical and emotional problems than the general population of survivors. Nonetheless, stated the authors, "This study demonstrated that suicidal symptoms are meaningfully related to cancer treatments and post-treatment health, even many years after completion of therapy."