Screening women with dense breasts with both molecular breast imaging (MBI) and digital breast tomosynthesis (DBT) significantly increased the detection of invasive cancers compared with DBT alone, according to a major multicenter trial published in Radiology.
The study, known as the Density MATTERS (Molecular Breast Imaging and Tomosynthesis to Eliminate the Reservoir) trial, is the first prospective, multicenter evaluation of MBI as a supplement to DBT in women with dense breasts. It was led by Carrie B. Hruska, PhD, professor of medical physics at Mayo Clinic, and included participants from five U.S. screening sites.
“Someone who’s having their routine annual screen every year should not be diagnosed with advanced breast cancer. That’s just unacceptable,” Hruska said. “With a supplemental screening every few years, we hope to find cancers earlier and see the diagnosis of advanced cancer go way down.”
Dense breast tissue challenges
Nearly half of women undergoing mammography have dense breast tissue, according to the Centers for Disease Control and Prevention. Dense tissue can mask tumors on mammograms, reducing the effectiveness of even advanced technologies such as DBT, which reconstructs 3D images from multiple X-ray views.
Federal law now requires breast density notification after mammography, alerting patients that dense tissue “makes it harder to find breast cancer on a mammogram.” But Hruska noted that the mandated language falls short of conveying the magnitude of the problem.
“What we and others have found is that you are missing about half of the breast cancers that are there if you only screen with DBT,” she said. “Supplemental tests like MBI or MRI can reveal this whole other reservoir of undetected cancers.”
How MBI works
Unlike mammography, which relies on X-rays, MBI uses a small intravenous dose of technetium-99m sestamibi, a radiotracer routinely used in cardiac stress testing. The tracer accumulates in areas of high mitochondrial activity and blood flow—both hallmarks of cancerous tissue. Specialized gamma cameras optimized for breast imaging then detect the tracer.
“MBI kind of fills that gap for people who are looking for additional screening,” Hruska explained. “It’s well tolerated, relatively inexpensive, and can be adopted by community practices more easily than MRI.”
Study design and findings
Between 2017 and 2022, 2,978 women aged 40–75 with dense breasts were enrolled at five sites. Participants underwent two annual screening rounds combining DBT and MBI.
Across both rounds, 30 breast cancer lesions in 29 participants were detected by MBI but missed by DBT. Most (71%) were invasive cancers, with a median size of 0.9 cm. 90% were node-negative, suggesting earlier detection, while 20% were node-positive, indicating clinically significant disease that had escaped DBT.
At the first screening round, MBI identified an additional 6.7 cancers per 1,000 screenings beyond DBT. At the second round, the incremental detection was 3.5 per 1,000. Researchers believe the drop reflects the elimination of previously “hidden” cancers during the initial round, a pattern also observed with MRI and contrast-enhanced mammography.
Importantly, MBI increased the recall rate modestly: 9.4% at the first screening, declining to 4.8% at the second. “That decrease reflects the benefit of having prior MBI images to compare against,” Hruska said.
Implications for screening
The trial showed that DBT alone detected only 57% of node-positive cancers at the first round, compared with 100% detection when combined with MBI. In the second round, DBT alone found just 16% of node-positive cancers, while DBT plus MBI detected 67%.
“These results demonstrate that functional imaging approaches like MBI uncover cancers that mammography simply can’t see in dense tissue,” Hruska said.
While MRI remains the gold standard for supplemental screening, it is costly, less accessible, and not well tolerated by some patients. Contrast-enhanced mammography is another option, but it carries risks related to iodinated contrast. By comparison, sestamibi has a strong safety record, with no contraindications except pregnancy.
Hruska emphasized that mammography should not be abandoned. “If you have dense breasts, you should still get your mammogram—it does find cancers and it’s usually covered by insurance,” she said. “But you should also understand that you’re only detecting about half of the cancers that may be there, and supplemental tests like MBI can be really helpful.”
The Density MATTERS trial, supported by NIH funding and earlier grants from Susan G. Komen, provides critical evidence for policymakers, insurers, and health systems weighing supplemental screening options. Its inclusion of both academic centers and community hospitals, along with 12% minority enrollment, strengthens the generalizability of findings.
For Hruska, who has worked on MBI development since her graduate school days, the study’s publication marks a milestone. “It’s really exciting to see a technology we’ve nurtured for years now tested in a grown-up, multicenter way,” she said.
With breast density notifications now mandatory, patients and clinicians alike are seeking clearer guidance. The new data suggest that MBI could become an important, accessible tool for women at average risk with dense breasts—helping to shift diagnoses toward earlier, more treatable stages.
