Up to half of U.S. women aged 40 to 74 years have dense breasts, meaning the proportion of fibrous and glandular tissue exceeds that of fatty tissue.
This common inherited trait is associated with elevated risk for breast cancer, and it also can limit the effectiveness of breast cancer screening.
Fatty tissue appears almost black on mammograms. Dense breast tissue appears white — the same color as breast tumors or masses — making it more difficult for radiologists to see cancers and potentially leading to delayed diagnosis.
Nearly three dozen states have passed legislation that requires some level of notification to women determined by mammography to have dense breasts.
However, the type of information in these notices varies greatly.
Some do not include a woman’s breast density category, which indicates the extent of dense tissue. Others do not explain the link between breast density and cancer risk or encourage women with dense breast tissue to discuss supplemental screening strategies with their primary care physician.
Karla Kerlikowske“All women having mammography should know their category of breast density so they or their provider can calculate their breast cancer risk. Simply telling a woman she has dense breasts is not helpful without knowing the category of breast density, which determines risk for breast cancer and missed cancer,” Karla Kerlikowske, MD, professor in the departments of medicine and epidemiology/biostatistics at University of California, San Francisco, told HemOnc Today.
HemOnc Today spoke with radiologists, epidemiologists and other experts about the biologic link between breast density and cancer risk; research efforts to reduce cancer risk among women with dense breasts; the limitations of mammography for this population and the possibility that other screening modalities may be more effective; and the need for standardized notification laws.
Classification and prevalence
The Breast Imaging Reporting and Data System (BI-RADS) — established by American College of Radiology in 1986 — classifies breast tissue into four main density categories:
Category A — almost entirely fatty;
Category B — scattered fibroglandular densities;
Category C — heterogeneously dense; and
Category D — extremely dense.
“Radiologists review screening results and place women in one of these four categories,” Jack Cuzick, PhD, FRS, CBE, director of Wolfson Institute of Preventive Medicine and head of Centre for Cancer Prevention at Queen Mary University of London, told HemOnc Today. “Areas that appear white on film consist of both epithelial cells and fibrous tissue.
“Breast density measures both of these cells, but this is thought to be the best available, albeit indirect, measure of the number of epithelial cells,” Cuzick added. “These are the cells that can divide and become cancer. The more cells a person has that can possibly divide, the greater risk that one of the cells will have a mutation and become a cancer.”
More than 30 million American women fall into the two most extreme breast density categories, according to a study by Sprague and colleagues.
Researchers reviewed data from 1.51 million mammograms conducted from 2007 to 2010 at Breast Cancer Surveillance Consortium facilities.
Results showed 43.3% (95% CI, 43.1-43.4) of women aged 40 to 74 years had heterogeneously dense or extremely dense breasts. The proportion appeared inversely associated with age and BMI.
Investigators estimated that 27.6 million American women aged 40 to 74 years had dense breasts. When researchers included women aged 75 years or older in their analysis, the number reached 30.8 million.
Several factors — including younger age, lower BMI and receipt of hormone therapy for menopause — increase risk for dense breasts. Conversely, two strategies to reduce breast cancer recurrence — tamoxifen for premenopausal women and aromatase inhibitors for postmenopausal women — have been shown to reduce breast density.
However, genetics may explain much of the risk.
In the Healthy Twin study, Sung and colleagues assessed the role of genetic factors on mammographic density measurements among 730 Korean women. The analysis included 122 monozygotic twin pairs, 28 dizygotic twin pairs and 430 first-degree relatives.
The researchers determined the covariance between dense and nondense area had a significant genetic basis (correlation coefficient=– 0.25; standard error=.06).
“The Healthy Twin study showed that, if one identical twin has a certain level of breast density, then the other twin has a very similar level,” Kerlikowske said. “It is even true among fraternal twins, and the same has been found between mothers and daughters.”
Additional research has revealed genes associated with breast density.
For instance, Lindström and colleagues identified common variants in ZNF365 as associated with breast density and breast cancer risk. Later, researchers identified genome-wide significant loci associated with breast density measures, including dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B and SGSM3/MKL1), nondense area (8p11.23) and percent density (PRDM6, 8p11.23 and TMEM184B).
“Several studies have shown evidence for familial aggregation of breast density and genes underlying breast density, and several of these genes are also associated with breast cancer,” Celine M. Vachon, PhD, professor of epidemiology and chair of the division of epidemiology at Mayo Clinic in Rochester, Minnesota, told HemOnc Today.
The prevalence of breast density also varies by race and ethnicity.
McCarthy and colleagues determined black women had a higher prevalence of dense breasts than white women, even after adjustments for age, BMI and other breast cancer risk factors.
The researchers evaluated data from 2,845 women (1,589 black and 1,256 white; mean age, 57 years) with no history of breast cancer.
Investigators used a software algorithm developed at their institution to evaluate absolute and percent area density. They used FDA-approved software (Quantra, Hologic) to calculate volumetric estimates of absolute and percent dense tissue.
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