Modifiable-risk biomarkers are increasingly being used in early-phase research to guide larger prevention trials.
ABSTRACT: Modifiable-risk biomarkers are increasingly being used in early-phase research to guide larger prevention trials.
A woman's breast density changes over her lifetime, decreasing with age and correlating with her menopausal status. Breast health specialists are focusing on how much breast density augurs a risk for breast cancer. Two recent studies offered some insights into the link between mammographic density and disease risk.
Researchers at the Mayo Clinic suggested that a reduction in breast density over time conferred a lower breast cancer risk, while investigators at Georgetown University hypothesized that increases in breast density may be associated with estrogen and progestin therapy.
CELINE VACHON, PHD
Celine Vachon, PhD, and colleagues tapped into the Mayo Mammography Health Study of nearly 20,000 women. "Breast density is not a static trait," said Dr. Vachon, an associate professor of epidemiology at the Mayo Clinic in Rochester, Minn. "We know that it changes. We have seen that it decreases with increasing age and with postmenopausal status."
The women included in this analysis underwent a screening mammogram between October 2003 and September 2006. Women were eligible if they were 35 years of age or older, had no personal history of breast cancer, and lived in Minnesota, Iowa, or Wisconsin (all three states have breast cancer registries).
Did You Know? Density disclosure The state of Connecticut passed a law mandating that women undergoing mammography be informed of their breast tissue density rating. S.B. 458 requires all mammography reports given to a patient, on and after October 1, 2009, to include information about breast density. The report must include a notice that, if the mammogram demonstrates dense breast tissue, the woman might benefit from supplementary screening tests, such as ultrasound or MRI. Proponents of the law called it a first step toward educating the general population on the connection between breast density and cancer risk. Opponents say that it will only lead to a higher workload for already-stressed and understaffed screening programs.
"We were able to access mammograms as early as 1996 for the women in the study to assess change in density," Dr. Vachon said. "Change in density was measured over an average of six years between the earliest and the enrollment mammograms." Women were followed for an average of four years for breast cancer. Breast density categories, as determined by the Breast Imaging Reporting and Data System (BI-RADS), are: primarily fatty breast tissue, scattered densities, heterogeneously dense, and extremely dense.
Dr. Vachon reported on 219 women with new breast cancers and compared their outcomes with 1,900 women selected randomly from the mammography cohort. Dr. Vachon noted a reduced risk in those women who had decreased one BI-RADS category or more over an average six years (hazard ratio = 0.72). These women were at reduced risk of breast cancer compared with those whose density was unchanged (AACR 2010 abstract 4828).
The researchers also observed an increased risk of 52% for women whose breast density increased by one BI-RADS category or more, but it did not achieve statistical significance (HR = 1.52), she said.
When the researchers looked at women's menopausal status, "the decreased risk associated with decreased density appears to be significant only among postmenopausal women," Dr. Vachon said. But she noted that the figures were derived using 62 cases among premenopausal women and 157 cases among postmenopausal women. "So it could be that we were not powered to detect an association in the premenopausal group," she said.
Her group suggested that measures of breast density at two time points may inform women's risk beyond a measure at one point in time.
Density and hormone therapy
CELIA BYRNE, PHD
In 2002, results from the Women's Health Initiative (WHI) reported an increased rate of breast cancer with estrogen and progestin therapy (EPT). Celia Byrne, PhD, and colleagues at Georgetown University in Washington, DC, used data from WHI and identified 339 women who developed breast cancer, including 224 women who were prescribed EPT and 174 women from the placebo arm of the study.
Dr. Byrne was able to collect baseline and one-year postrandomization mammograms for 174 women who developed breast cancer and 733 controls. Four independent radiologists then read the mammograms and, assisted by computer-aided detection software, calculated the breast density percentage.
"Within the estrogen plus progestin arm, even a 1% change in breast density was associated with a significant increase in risk," said Dr. Byrne, who is an associate professor of oncology at Georgetown's Lombardi Cancer Center. "We calculated that a 1% increase in breast density was equal to a 3% increase in the risk of breast cancer."
Compared with the women in the lowest quartile of breast cancer density increase, those women in the highest quartile-who experienced a greater than 19% increase in breast density-had a 3.6-fold increased risk of breast cancer (AACR 2010 abstract 5741).
Dr. Byrne noted that while there was an increased risk for women on EPT, it was breast density changes that increased the risk, not necessarily the hormone therapy. "Breast density appears to be an appropriate intermediate marker of risk among postmenopausal women using EPT," she said. n
CAROL J. FABIAN, MD A new tool to better define short-term risk
These studies bolster the hypothesis, that, under some conditions, higher breast density is associated with higher breast cancer risk," said Dr. Fabian, a professor of medicine in the division of clinical oncology at the University of Kansas Medical Center in Kansas City.
While high breast density is a known risk factor for breast cancer, a lower breast density doesn't necessarily mean a low risk, according to Dr. Fabian, who is also director of the Breast Cancer Prevention Center at the University. Women with a BRCA 1or 2 mutation, who have one of the highest risks for breast cancer, have a similar range of breast density as lower risk women. Postmenopausal obese women have a higher risk of breast cancer than lean women and yet have lower mammographic density. Many factors go into determining risk, and mammographic density is just one of them, she said.
"The cancer research community is always looking for new methods to refine short-term risk estimates to supplement the known risk factors for breast cancer like family history, hereditary breast cancer genes, reproductive variables, and age," Dr. Fabian said. Mammographic density appears to be one of those tools. "Modifiable-risk biomarkers like mammographic density are, in addition, increasingly being used in small early-phase prevention trials to help us decide which interesting strategies should be carried further into very large phase III studies with cancer incidence as an endpoint."