Breast density’s effects on cancer risk, detection a ‘fast-moving target’ in research

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.

“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.

Results showed black women had significantly higher absolute breast area (40.1 cm² vs. 33.1 cm²; P < .001) and volume (187.2 cm³ vs. 181.6 cm³; P < .001) than white women. However, white women had a higher area (23.5% vs. 19.6%; P < .001) and volume percent density (13.4% vs. 11.6%; P < .001).

When researchers adjusted for age, BMI and cancer risk factors, black women demonstrated significantly higher breast density in all categories, including absolute area density (P < .001), area percent density (P = .021), absolute volume density (P < .001) and volume percent density (P < .001).

Cancer risk

Associations exist between breast density and established breast cancer risk factors, suggesting these risk factors may influence breast cancer through their influence on breast density, according to Vachon.

“The strongest associations have been observed with age and BMI,” Vachon said. “Reproductive factors such as nulliparity are associated with increased breast density, and breast density decreases with the more children a woman has.”

Boyd and colleagues analyzed the association between mammographic density and breast cancer risk.

The researchers conducted three nested case-control studies in screened populations with 1,112 matched pairs. Investigators used Cumulus — a semiautomated method for measuring breast density — to examine the association of measured percentage of density in baseline mammogram with breast cancer risk.

Their findings revealed that women with at least 75% dense tissue had a nearly five times greater risk for breast cancer than women with less than 10% dense tissue (OR = 4.7; 95% CI, 3-7.4), regardless of whether the breast cancer was detected by screening (OR = 3.5; 95% CI, 2-6.2) or less than 1 year after a negative screening examination (OR = 17.8; 95% CI, 4.8-65.9).

Among women aged younger than 56 years — the median age of the cohort — 26% of all breast cancers and half of cancers detected less than 1 year after negative screening were attributed to mammographic density of 50% or more.

A study published this year showed elevated cancer risk linked to breast density persists among older women.

Braithwaite and colleagues analyzed data from 403,268 women aged 65 years and older in the Breast Cancer Surveillance Consortium who underwent screening mammography at a community practice between 1996 and 2012.

Women with BI-RADS category C or category D breast density demonstrated increased risk for breast cancer (ages 65 to 74 years, HR = 1.39; 95% CI, 1.28-1.51; ages 75 and older, HR = 1.23; 95% CI, 1.1-1.37).

Conversely, women with BI-RADS category A or category B breast density demonstrated reduced risk (ages 65 to 74 years, HR = 0.66; 95% CI, 0.58-0.78; ages 75 years and older, HR = 0.73; 95% CI, 0.62-0.87).

“Dense breast tissue is composed of increased numbers of ductal and epithelial cells; thus, having more cells increases risk for cancer occurrence,” Kerlikowske said. “There also is an increase in collagen and fibroblast tissue.

“Some have hypothesized it is the proteins secreted or not secreted by the stroma that increases breast cancer risk,” she added. “The molecule CD36 is thought to get turned off in women with dense breasts, such that women with dense breasts are not as protected as individuals without dense breast tissue.”

Despite the elevated risk, evidence suggests high mammographic breast density does not increase mortality risk among those who develop breast cancer when other patient and tumor characteristics are taken into account.

Gierach and colleagues examined the association between mammographic density and breast cancer mortality or all-cause mortality within the Breast Cancer Surveillance Consortium.

The researchers used BI-RADS to assess mammographic density of 9,232 women diagnosed with primary invasive breast cancer between 1996 and 2005.

After mean follow-up of 6.6 years, investigators documented 1,795 deaths, of which 889 were due to breast cancer.

Multivariable analyses adjusted for site, age at diagnosis, cancer stage, treatment, BMI and other factors showed high breast tissue density (BI-RADS category D) was not associated with the risk for breast cancer mortality (HR = 0.92; 95% CI, 0.71-1.19) or all-cause mortality (HR = 0.83; 95% CI, 0.68-1.02).

Risk reduction

Researchers are examining approaches aimed at reducing breast cancer risk among women with dense breasts.

“Studies consistently have shown decreased density with oral tamoxifen use,” Vachon said. “It’s not clear whether a tamoxifen gel will have the same effects.”

Investigators at University of Southern California launched a randomized, double-blind clinical trial to assess whether BHR-700 (Besins Healthcare) — a proprietary gel that contains 4-hydroxytamoxifen, which has a strong affinity for estrogen receptors in the breast — can effectively reduce breast density among healthy women aged 35 to 75 years.

4-hydroxytamoxifen binds with estrogen receptors in the breast, stopping the cell cycle in breast tissue induced by estradiol, according to researcher Pulin A. Sheth, MD, assistant professor of clinical radiology and director of breast imaging at Norris Breast Center/Keck School of Medicine at USC. This interference may prevent cells from proliferating into cancer cells.

In the trial, 220 patients will receive two actuations of gel per breast containing a total of 8 mg BHR-700. The other 110 patients will receive matching placebo.

Study participants will be treated for 1 year, after which they can choose to receive another year of active treatment in an open-label fashion.

Breast density as determined by standard digital mammogram will serve as the primary outcome measure. Tolerability and safety also will be monitored, and blood levels of circulating 4-hydroxytamoxifen will be measured.

“We hope to find that there is a statistically significant and clinically meaningful reduction in breast density among patients treated with BHR-700,” Sheth told HemOnc Today. “It has been shown in studies with tamoxifen that an overall reduction between 4% and 5% is associated with a reduction in the occurrence of breast cancer. As this study focuses on women with dense or very dense breasts, we are hopeful that the effect could be significantly larger.”

Notification laws

As of early October, 36 states had adopted laws that require some type of breast density notification to women after screening mammograms.

These laws are meant to raise awareness among women receiving mammography and their providers, Vachon said.

“As a result, women have a better understanding of the limitations of mammography for dense breasts, as well as the options available to them,” she said. “A negative mammogram does not mean that a woman should not see her doctor with new symptoms.”

However, there is tremendous variation in notification laws.

Some require that everyone receive a notification letter, whereas others only require it for those found to have heterogeneously dense or extremely dense breasts. The degree of actionable information — such as the effect breast density has on cancer risk, or the importance of discussing supplemental screening with their primary care physician — differs greatly.

Federal lawmakers began introducing legislation in Congress in 2013 to standardize the notification process. The goal is to ensure the notifications educate individuals about breast density; explain how it may mask the presence of breast cancer on mammography; and encourage those who have dense breasts to talk to their health care providers about supplemental breast cancer screening.

“Advocates have tried to get a breast density bill passed but, after 5 years, Congress still has not passed a bill,” Kerlikowske said.

Most women want to know their breast density and favor the concept of notification letters, according to Randy C. Miles, MD, MPH, radiologist in the division of breast imaging at Massachusetts General Hospital.

Source: David Z. Chow.

“However, we need to evaluate how we can best educate women and talk about this issue,” he said. “Legislation is highly variable across states.”

Massachusetts passed a law in 2014 that requires mammography providers to notify individuals in writing if results show dense breast tissue.

Miles and colleagues assessed knowledge of breast density and notification legislation among women who underwent routine mammography after passage of Massachusetts’ notification law.

Researchers administered surveys to women who underwent screening mammography at an academic medical center during two 1-week periods. Investigators administered 1,000 surveys, and 338 women responded.

The results showed 61% of women were surprised to receive a breast density notification letter and 90% were unaware of the newly enacted legislation.

More than half (54.7%; n = 185) of respondents reported having dense breasts; however, only 61% of that group (n = 113) correctly reported that dense breast tissue increased breast cancer risk.

“Despite implementation of state breast density laws since 2009, confusion and misinformation about breast density persists among women receiving mammography screening,” Miles and colleagues wrote.

Christine M. Gunn, PhD, research assistant professor at Boston University School of Medicine, and colleagues analyzed how dense breast notifications affected women’s perceptions and participation in follow-up care.

Researchers conducted phone interviews with 30 English-speaking women aged 40 to 74 years who received dense breast notification from a Massachusetts hospital.

The results showed 81% of women interviewed recalled receiving the notification.

However, most could not remember specific content, and many indicated they struggled to interpret what breast density meant. The majority of women planned to or did talk with their physicians about breast density as a result of receiving the notification.

A previous analysis by Gunn and colleagues showed readability of breast density notifications ranged from seventh-grade to college levels.

“Notifications tend to be written at a very high literacy level, and some women have difficulty understanding them,” Gunn told HemOnc Today. “Women may not be prepared to receive such communication, and early research shows notifications alone do not sufficiently explain what women should do and what exactly breast density is. When coupling this with providers not being able to counsel patients on the topic, this can create a lot of confusion.”

Supplemental screening

Mammography is the primary screening modality for U.S. women aged 40 to 74 years, including those determined to have dense breasts.

However, mammography is less accurate for women with dense breast tissue, creating the potential for overlooked cancers or false-positive results that require additional follow-up.

Supplemental screening may offer benefits, but there are disadvantages, too.

“The costs associated with supplemental screening for women with dense breasts are high, if we consider 40% to 50% of women will have dense breasts,” Vachon said. “Also, the additional imaging procedures are not without their risks — including false positives, which result in additional clinical workup and anxiety. We have to do a better job of stratifying women by risk for both routine and supplemental screening.”

Molecular breast imaging has shown the ability to detect breast cancers missed by conventional mammography, but the approach is used only by a few screening centers.

MRI often is used to complement mammography for women at high risk for breast cancer; however, that approach is costly.

Tomosynthesis — also called 3-D mammography — has been shown to increase the number of cancers detected among women with dense breasts compared with traditional 2-D mammography, while also reducing unnecessary recall rates. This modality is becoming standard for breast screening for a majority of U.S. practices, according to Vachon.

However, radiologists need significantly more time to interpret the results with this approach. Also, screening is costlier and women are exposed to high doses of radiation.

The U.S. Preventive Services Task Force guideline on breast cancer screening includes a section for women with dense breasts, but there is no formal guidance on supplemental screening.

“Current evidence is insufficient to assess the balance of benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, MRI, tomosynthesis or other methods [for] women identified to have dense breasts on an otherwise negative screening mammogram,” the guideline states.

Supplemental screening can improve cancer detection among women with dense breast tissue, but more evidence-based research is necessary, Miles said.

“Breast density is a fast-moving target in research,” he said. “Not only are women confused about their breast density, but they are also confused about whether they should receive additional imaging with breast ultrasound or breast MRI. This is largely due to variability in supplemental screening recommendations used across the country. At Massachusetts General Hospital, we recommend high-quality screening mammography with 3-D tomosynthesis for women with dense breasts. Based on existing evidence, we do not perform whole-breast screening ultrasound in these women. We do, however, recommend that women discuss with their doctor about their personal risk for developing breast cancer to determine if they meet criteria for supplemental breast MRI.

“Some of the anxiety women feel when they hear about breast density will be calmed, as the breast imaging community develops consistent guidelines and recommendations about supplemental screening in women with dense breasts,” he added.

Considerable research is underway to compare screening modalities, many of which are still under development, Vachon said.

“Several groups are working on liquid biopsy tests that detect tumor shedding in the blood,” she said. “This noninvasive test may complement imaging modalities for early breast cancer detection, especially among women with dense breasts.”

Automated breast ultrasound — an imaging technique that provides volumetric ultrasound data of the entire breast — in combination with mammography has demonstrated the potential to improve breast cancer detection among women with dense breast tissue compared with mammography alone.

In South Korea, every woman of screening age receives breast ultrasound as a primary screening modality, with tomosynthesis as an adjunct test.

“There is resistance in the United States to provide supplemental ultrasound because it takes more time to perform and interpret an ultrasound than mammography,” Kerlikowske said. “However, there are promising data being published for automated ultrasound, so maybe this new technology will continue to improve as it disseminates into clinical practice. Automated ultrasound has the potential to be more reproducible than handheld ultrasound. Supplemental ultrasound has three advantages: there is no radiation exposure, the breasts are not compressed and it is a relatively quick examination compared with breast MRI.”

Reese and colleagues showed Videssa Breast (Provista Diagnostics) — a combinatorial proteomic biomarker assay comprised of serum protein biomarkers and tumor-associated autoantibodies, as well as patient-specific clinical data — yields a diagnostic score that reliably detects breast cancer, making it a potentially viable supplemental screening tool for those with dense breast tissue.

The researchers evaluated the test in a study that included 545 women aged 25 to 50 years.

Among 454 women for whom breast density information was available, the test showed an 88.9% sensitivity and 81.2% specificity for dense breasts, and a 92.3% sensitivity and 86.6% specificity for nondense breasts.

Negative predictive values were 99.1% among those with dense breast tissue and 99.3% among those with nondense breast tissue.

“Unlike imaging, Videssa Breast does not appear to be impacted by breast density. It can effectively detect breast cancer in women with dense and nondense breasts alike,” Reese and colleagues wrote. “Thus, Videssa Breast provides a powerful tool for health care providers when women with dense breasts present with challenging imaging findings.”

A personalized approach

Most experts with whom HemOnc Today spoke supported a personalized screening approach.

“Decisions about supplemental imaging cannot be based upon age or breast density alone. Full risk assessment needs to be performed accounting for other risk factors, such as family history of breast cancer, history of breast biopsy and body mass index,” Kerlikowske said.

Several tools take lifestyle and personal health factors, family history and breast density into account to estimate 5-year, 10-year or lifetime breast cancer risks, Gunn said.

“Although some women have dense breasts, overall they still may have a very low risk for breast cancer,” Gunn said. “These women may not benefit from additional screening, which can be accompanied by its own set of costs. However, women with dense breasts who do have an elevated risk for breast cancer may find additional screening beneficial.”

Cuzick also addressed the benefits of risk-adaptive screening.

“If a woman is at high risk for breast cancer, she should consider screening more often, whereas those at low risk should be screened less often,” Cuzick said.

“Those at the highest risk should be considered for preventive therapy with tamoxifen if they are premenopausal and an aromatase inhibitor if they are postmenopausal,” he added. “Integrating the idea of renaming the breast cancer screening program to be considered a breast cancer prevention program — through which we not only try to detect cancer early but also identify ways in which we can prevent it — is one of the exciting new areas in this field.” – by Jennifer Southall

Click here to read the , “Is automated whole-breast ultrasound a valid supplemental screening modality for all women with dense breasts?”

References:

Boyd NF, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa062790.

Braithwaite D, et al. Cancer Epidemiol Biomarkers Prev. 2018;doi:10.1158/1055-9965.EPI-18-0044.

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Gunn CM, et al. Patient Educ Couns. 2018;doi:10.1016/j.pec.2018.01.017.

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McCarthy AM, et al. Abstract 6580. Presented at: American Association for Cancer Research Annual Meeting; April 18-22, 2015; Philadelphia.

Miles RC, et al. Acad Radiol. 2018;doi:10.1016/j.acra.2018.07.004.

Reese DE, et al. PLoS One. 2017;doi:10.1371/journal.pone.0186198.

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For more information:

Jack Cuzick, PhD, FRS, CBE, can be reached at Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; email: j.cuzick@qmul.ac.uk.

Christine M. Gunn, PhD, can be reached at Boston University School of Medicine, 72 E. Concord St., Boston MA 02118; email: cgunn@bu.edu.

Karla Kerlikowske, MD, can be reached at University of California, San Francisco, VAMC 111A1, San Francisco, CA 94143; email: karla.kerlikowske@ucsf.edu.

Randy C. Miles, MD, MPH, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 2114; email: randy.miles@mgh.harvard.edu; Twitter: @rmilesmd.

Pulin A. Sheth, MD, can be reached at Keck School of Medicine of USC, 1975 Zonal Ave., Los Angeles, CA 90033; email: pulin.sheth@med.usc.edu.

Celine M. Vachon, PhD, can be reached at Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; email: vachon.celine@mayo.edu.

Disclosures: Cuzick, Gunn, Kerlikowske, Miles and Vachon report no relevant financial disclosures.