Breast density changes the breast-imaging landscape

With new laws on breast-density notification sweeping the nation, radiologists are concerned 2-dimensional (2D) digital mammography alone may not be enough for screening patients with dense breasts. Subsequently, many breast-imaging centers are looking to expand their arsenal of screening technologies.

Some of these adjunct-screening tools include automated breast ultrasound (ABUS), tomosynthesis, opto-acoustic imaging, breast magnetic resonance imaging (MRI), and molecular breast imaging (MBI). Each imaging device offers an additional or alternative view that may detect lesions in the breast that might otherwise go unnoticed.

Dense breast awareness

It is well established that mammographic breast density—a reflection of the proportions of fat, connective tissue, and epithelial tissue in the breast—is a risk factor for breast cancer. A recent study found women with dense tissue in 75% or more of the breast have a risk of breast cancer 4 to 6 times as great as the risk among women with little or no dense tissue.¹

A study by doctors at Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, and colleagues, found higher mammographic density is associated with more aggressive tumor characteristics and also with in situ tumors.² The authors wrote: “masking of a tumor can occur because cancerous tissue and mammographically-dense tissue have similar x-ray attenuation, allowing tumors to go undetected on screening mammography examination and progress to a more advanced and aggressive stage before detection.” They recommended “breast density should be included in risk prediction models across tumor subtypes.” 

These and other studies on mammography screening for women with dense breasts have catalyzed a movement for dense breast awareness. Earlier, growing concern over the efficacy of mammograms on women with dense breasts had prompted Connecticut to enact a law in 2009 requiring that women be informed of their breast density when they receive their mammography reports. Related legislation in the same state mandates that insurance companies provide coverage for comprehensive ultrasound screening of an entire breast or breasts if a mammogram demonstrates heterogeneous or dense breast tissue based on the Breast Imaging Reporting and Data System (BI-RADS) established by the American College of Radiology (ACR).³ Since then, several others states have enacted similar breast- density notification laws.

Mammograms plus adjunct exams

An estimated 40% of all women undergoing screening mammography have dense breasts, according to the American College of Radiology Imaging Network (ACRIN).⁴

“There is the issue of masking breast cancer because of the density of the breast. Everyone agrees there is greater risk for breast cancer in women with dense breasts,” said Dennis McDonald, Medical Director for breast imaging for the Sutter Medical Center Sacramento, Sacramento, CA.

To address the problem, the center implemented Volpara objective breast-density measurement software, a breast-density assessment tool designed to improve early detection among women with dense breasts.

Volpara automatically generates objective, automatic measurement of volumetric breast density values under the Volpara Density Grade (VDG^®), a grading system that correlates with the American College of Radiology BI-RADS Density Grading Classifications. Volpara is FDA cleared for all digital mammography units, and integration with other digital mammography systems, CAD systems, and mammography reporting solutions are also underway.

“We purchased the Volpara software to give a more objective estimation of the breast density because it’s a volumetric measurement. In our experience, there is really good correlation with our visual interpretation; it lent some consistency to the whole process of density determination,” said Dr. McDonald.

Adjunct imaging

Nonetheless, as such a large percentage of the screening population has dense or heterogeneous breast tissue, many radiologists believe mammography for those patients should be followed up with an adjunct imaging test, such as ultrasound or MRI.

A recent trial by ACRIN⁵ reported that there is a significant breast cancer detection benefit of supplementing annual mammography screening with ultrasound in women at elevated risk due to dense breast tissue. The same study also found that a single screening MRI following 3 years of annual mammography and ultrasound screenings identified additional cancers.

“This and other studies confirm that mammography fails to see about half of the cancers present in women with dense breasts. These women tend to be diagnosed with more advanced cancers often detected clinically in the interval between annual mammography screenings,” said Wendie Berg, MD, PhD, and Professor of Radiology at the University of Pittsburgh School of Medicine, Magee-Womens Hospital of UPMC, Pittsburgh, PA, and the trial’s principal investigator.

She noted, “For women who have dense breasts, adding ultrasound to mammography will increase the chance of finding invasive cancer before it spreads to lymph nodes,” said Dr. Berg.

Automated ultrasound

Currently, there is only one ultrasound system approved in the United States for breast cancer screening as an adjunct to mammography for asymptomatic women with > 50% dense breast tissue and no prior breast interventions. This system, the somo•v^® Automated Breast Ultrasound (ABUS) (recently acquired by GE Healthcare) has made significant improvements in the visualization of cancer-hiding tissue in dense breasts.

“Mammography is an effective tool at finding breast cancer, but it doesn’t work equally well in everyone,” noted Rachel F. Brem, MD, Director, Breast Imaging and Interventional Center, Professor of Radiology, Vice Chair, Research and Faculty Development, The George Washington University Medical Center, Washington, DC. Dr. Brem was the principal investigator of the SOMO-INSIGHT clinical study examining whether full-field digital mammography along with the somo•v could improve breast cancer detection when compared to mammography alone in women with dense breasts.

“In recently completed studies demonstrated with the addition of somo•v ABUS, we find about 30% more cancers in women who have a normal mammogram, normal physical examination, and dense breasts. For the > 40% of women who have dense breasts, this is a significant advancement in their breast healthcare,” said Dr. Brem.

She added, “What ABUS does is solves the problem of how to find cancer in dense breasts and at an earlier stage.”

As new breast-density legislation is adopted nationwide, increasing numbers of women with dense breasts will require ultrasound screenings in addition to mammography. The challenge in the clinical setting is how to streamline the process. The standard procedure today is to use hand held ultrasound, which is very operator dependent. Comparatively, automated breast ultrasound systems lend themselves better to the screening environment, according to Dr. Brem.

With somo•v ABUS, the scanner is positioned on the breast and the technologist presses a button to begin a 3-dimensional (3D) ultrasound scan of the front, outer, and inner sides of the breast. Siemens Healthcare also offers an automated ultrasound, the ACUSON S2000™ Automated Breast Volume Scanner (ABVS).

In a new study, Marcela Böhm-Vélez, MD, of Weinstein Imaging Associates in Pittsburgh, PA, and Ellen B. Mendelson, MD, a Diagnostic Radiologist at Northwestern Memorial Hospital, Chicago, IL, are using the ABVS for screening and comparing hand held with automated breast ultrasound. The design of the study is to show that they can detect as many lesions with the ABVS system as with hand held ultrasound.

“With 40% to 50% of the population with dense breasts, there are not enough trained sonographers available to do breast ultrasound for all of these women. That is why hand held ultrasound would be a good option for screening all of these women with dense breasts without requiring a technologist there doing it,” said Böhm-Vélez. “We hope that this technology could replace hand held ultrasound, especially for the screening patient.”

Another important feature with ABVS is the additional coronal view. “The ABVS technology provides the coronal view, which we can’t view with hand held ultrasound, and the coronal view better shows the pulling of the Cooper’s ligaments, which is an indirect sign that there may be a cancer there,” said Böhm-Vélez. “Since you have 3D reconstruction, you can look at images from any view—coronal, transverse, longitudinal, whatever you want—instead of looking at 2D static images with the hand held ultrasound.”

She added, “I think for a large screening program, there is a role for this technology, especially for women with dense breasts.”

Opto-acoustic imaging: A new angle on ultrasound

A new approach to ultrasound is opto-acoustic imaging technology, which is designed to improve accuracy. Opto-acoustic imaging technology combines optical imaging with ultrasound to provide blood maps of the body. It uses very short pulses of laser light directed at the region of interest, which are converted into a real-time image. The colors (wavelengths) of the light pulses are chosen due to their ability to be preferentially absorbed either by oxygenated blood or by deoxygenated blood. The acoustic waves that result from the light absorption travel to the transducers. By using this array of transducers, it is possible to reconstruct 2D images.

“The difference in frequency that the ultrasound wave sends back depends on the characteristics of that tissue. When tissue has cancer, one of the hallmarks of cancer is that it does not regulate blood flow well because it uses up large amounts of oxygen,” explained Mike Ulissey, MD, a medical consultant to Seno Medical Instruments Inc., San Antonio, TX.

“Using laser light at different frequencies, we can also co-register it with ultrasound imaging so that the radiologist can look at the lesion and identify its location, and use the laser wavelength from opto-acoustic imaging to analyze that specific mass or region of concern. With ultrasound, it looks at structural information, evaluating the morphology of the lesion at the margins.”

Opto-acoustic imaging can be used not only for cancer detection but also to analyze a potentially suspicious breast lump.

“While opto-acoustic imaging is a functional technology, it is similar to MR spectroscopy and hybrid positron emission tomography / computed tomography (PET/CT) in that it provides functional and anatomical data with what seems to be a similar level of accuracy. However, we anticipate it will be less expensive and will not use radiation, radioisotopes, and no contrast agents,” said Dr. Ulissey.

Combo-mode imaging with tomosynthesis

One of the most logical extensions of 2D mammography is 3-dimensional mammography, or breast tomosynthesis. While breast tomosynthesis has been in use in Europe for several years, it only recently became available for breast screening in the U.S., opening up new possibilities for women with dense breasts.

Hologic Inc.’s Selenia Dimensions 3D mammography system, the first device of its kind to receive FDA 510(k) clearance, is indicated for diagnostic performance. Technologists can use a one-touch control to transition between imaging modes: FFDM (2D imaging), tomosynthesis (3D imaging), or “combo-mode” imaging (2D+3D imaging). The latter feature quickly acquires a digital mammogram and a tomosynthesis scan in the same compression (a screening exam consists of a digital mammogram and breast tomosynthesis image set).

A recent study analyzed results from 12,631 examinations interpreted by using mammography alone and mammography plus tomosynthesis. Researchers found that with mammography plus tomosynthesis there was a 31% increase in the cancer detection rate; the false-positive rate was 13% less; and there was a 26% increase in the detection of higher-grade cancers.⁶

In another study, led by Liane Philpotts, MD, Chief of Breast Imaging at the Yale University School of Medicine, New Haven, CT, investigators concluded that adding 3D to a screening exam reduced recall rates by 40%.⁷

“With Hologic’s 3D technology, we can see the entire breast more clearly in 1-mm slices,” said Dr. Philpotts. “This allows us to find additional cancers earlier and also dismiss ambiguous spots that are actually normal breast tissue.”

Roles of breast MRI and MBI

Breast MRI is the gold standard for acquiring functional data for high-risk patients with dense breasts and patients with a strong family or genetic history (BRCA1 or BRCA2 genes) of breast disease. Although breast MRI is not a routine screening procedure, the study led by Dr. Berg⁵ found MRI detected additional invasive cancers not seen on mammography or ultrasound.

Still, there has been criticism of breast MRI for its high false-positive rates, resulting in unnecessary biopsies, surgical procedures, and anxiety for the patient. “Those false-positive rates are higher in conventional breast MRI systems than in dedicated breast MRI units,” said Alan Hollingsworth, MD, Medical Director, breast surgeon at Mercy Women’s Center at Mercy Health Center, Oklahoma City, OK.

In a recent multi-center trial,⁸ managed by ACR Image Metrix (the American College of Radiology’s clinical research organization), Dr. Hollingsworth and other researchers found that dedicated breast MR systems led to better diagnostic performance for sensitivity, specificity, negative predictive value, positive predictive value, and area under the receiver operating characteristic curve than what has been reported for breast MR imaging on conventional breast MRI systems.

“False-positive rates from previously reported trials using whole-body breast MRI have typically been between 30% to 50%. The dedicated breast MRI system offers a significant improvement in performance,” noted Dr. Hollingsworth. “Even within the 93 false positives, 27% were high-risk histologies, for which excision is often recommended.⁸ This kind of performance should provide breast radiologists and surgeons alike with a higher level of diagnostic confidence, and could have significant impact on the role of breast MRI.”

While most conventional MRI systems have special coils for breast imaging, there is only one FDA-approved MRI device designed specifically for breast imaging. The unit is the Aurora 1.5T Dedicated Breast MRI System with Bilateral SpiralRODEO, and it was the MRI system used in the study. The low frequency of false-positive and false-negative findings associated with this dedicated breast MRI system may allow for use of breast MRI with low-risk patients in both the screening and diagnostic environments.

Where does MBI fit in?

With the widespread availability of breast MRI, many radiologists may be wondering where MBI fits in. Much like breast MRI, MBI is a tool that is a supplement to mammography. But where MBI is especially useful in the clinical setting is for imaging patients who cannot have an MRI.

In the study led by Dr. Berg,⁵ she noted, “MRI detected additional invasive cancers not seen on mammography or ultrasound; however, we found that MRI was significantly less tolerable than mammography or ultrasound for many study participants. Of those participants offered an MRI, only 58% accepted the invitation.”

Similarly, for patients at Karmanos Cancer Center, Detroit, MI, problems with undergoing MRI were the impetus for seeking out a solution in terms as a multidisciplinary approach to breast cancer. For Sharon Helmer, MD, clinical Service Chief, Imaging Department, and Director, Breast Imaging, Karmanos Cancer Center, 2 key scenarios encouraged her to consider MBI for screening her patients.

“We wanted to use another tool to examine their breasts with MR to see beyond mammography and ultrasound. But I practice with an urban population with rising obesity rates, and we found a significant number of patients who are candidates for MRI, but couldn’t have MRI for various reasons: renal function, implants or pacemakers, claustrophobia, and weight issues,” explained Dr. Helmer. “We were interested in MBI because about 20% of our patients are high-risk patients with dense breasts, who would normally get a biopsy and an MR for extent of disease.”

While the center has a dedicated 3.0T MR, for a large number of patients, doctors could not provide surgeons with additional metabolic information for treatment planning. Therefore, doctors at Karmanos Cancer Center advocated for MBI as a solution, and implemented the Discovery* NM750b, a dual-head CZT unit by GE Healthcare. The CZT detectors fit into a compact device, allowing users to image the breast up close, right up to the chest wall.  In a recent study,⁹ comparing performance characteristics of dedicated dual-head gamma imaging and mammography in screening women with mammographically dense breasts, researchers found that the addition of gamma imaging to mammography significantly increased detection of node-negative breast cancer in dense breasts by 7.5 per 1000 women screened (95% CI: 3.6, 15.4). However, to be clinically important, gamma imaging will need to show equivalent performance at decreased radiation doses. Regarding radiation, Dr. Helmer points out that recent low-dose protocols developed by the Mayo Clinic have helped in safely conducting MBI procedures.  

“The unit provides high-resolution imaging, and great functionality, and the patients are really comfortable walking into a room that looks very much like a mammogram unit. Also, there is very minimal compression of the breast, and the responses from patients have been very positive,” said Dr. Helmer.

Both MRI and MBI are indicated for patients who have extremely dense breasts or have a strong family history of breast cancer. According to Dr. Helmer, MRI and MBI serve very similar functions. “MR gives you exquisite anatomic detail, but MBI also captures clear, precise images, even for those with dense breast tissue,” she said.

“Obviously, MR gives you chest wall information in addition to the liver, which we can’t get with MBI. As a radiologist, you look at all the film. You’re not seeing the full extent of the anterior lungs and upper part of the liver that you would be able to include in your assessment on an MR. If the patient has an invasive carcinoma, the patient will be assessed and staged with CT and other exams,” said Dr. Helmer.

But she noted that one of the unexpected benefits of MBI is that it is very good for lobular carcinoma. “That’s good because often it’s difficult to determine the exact extent of disease of a lobular carcinoma on a mammogram and ultrasound. Yet, unlike MRI, MBI is safe for those who have pacemakers, metal implants or other foreign bodies, and patients with renal challenges,” she said.

Dr. Helmer believes MBI fits into the niche that complements mammography and ultrasound, and like breast MRI, provides data on the metabolic activity of an abnormality in the breast or an area of interest that may be of concern.

“Compared to mammography, MBI allows better detection of very small lesions in women with dense breast tissue. Not only will this help eliminate false positives, it may help to detect breast cancers earlier when the disease is highly survivable,” she said. “It’s not a replacement of mammography, but it does offer us another a chance to look at a patient with dense breasts or other problems with the breast. It’s another tool in our armamentarium, and it gives us data, much like MRI.”

MBI is also useful for following up response to noeadjuvent chemotherapy. “Sometimes when you follow patients with mammography or ultrasound to see response to their chemotherapy, the tumor may not appear that different size-wise because we are not able to really assess how it’s responding to the chemotherapy. Whereas with MRI and MBI, we can see that it is less vascular, and that it is responding to the chemotherapy. MBI is a more cost-effective way to do that follow-up,” she said.

For Dr. Helmer and the other radiologists at Karmanos Cancer Center, MBI is another tool in their imaging arsenal that enables them to offer more diagnostic and therapeutic services and to give patients more choices for better care.

Conclusion

Today, mammography remains the first line of defense for detecting breast cancer in its earliest stages.

“It is important to emphasize that an annual mammogram is still recommended and neither ultrasound nor MRI is meant to replace mammography,” remarked Ellen Mendelson, MD, co-investigator and Lee F. Rogers Professor of Radiology at the Feinberg School of Medicine, Northwestern University, Chicago, IL.

Nonetheless, there are limitations to 2D mammography, and supplemental ultrasound and MRI screening help detect more cancers, as do tomosynthesis and MBI, when combined with mammographic data.

With the growing trend in patient advocacy extending the conversation on breast screening into the public domain, radiologists are responding by expanding their portfolio of imaging services. As such, there is an important role adjunct technologies will play in the future of breast screening.

References

1. Boyd NF, Guo H, Martin LJ, et al. Mammographic density and the risk and detection of breast cancer. N Engl J of Med. 2007;356:227-236M.
2. Yaghjyan L, Colditz GA, Collins LC, et al. Mammographic breast density and subsequent risk of breast cancer in postmenopausal women according to tumor characteristics. J Natl Cancer Inst. 2011;103:1179-1189. doi: 10.1093/jnci/djr225. Epub 2011 Jul 27.
3. Are you dense? http://www.areyoudense.org/. Accessed Feb. 4, 2013.
4. Stomper PC, D’Souza, DJ, DiNitto PA, Arredondo MA. Analysis of parenchymal density on mammograms in 1353 women 25-79 years old. AJR Am J Roentgenol. 1996;167:1261-1265.
5. Berg WA, Zhang Z, Lehrer D, et al. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307:1394-1404. doi:10.1001/jama.2012.388.
6. Skaane P, Gullien R, Eben EB, et al. Reading time of FFDM and tomosynthesis in a population-based screening program. Radiological Society of North America annual meeting. Chicago, IL, 2011.
7. Philpotts, L, Raghu, M, Durand, M, et al. Yale University School of Medicine. Initial experience with digital breast tomosynthesis in screening mammography. Presented May 3, 2012 at American Roentgen Ray Society Annual Meeting.
8. Hillman BJ, Harms SE, Stevens G, et al. Diagnostic performance of a dedicated 1.5-T breast MR imaging system. Radiology. 2012;265:51-58.
9. Rhodes DJ, Hruska CB, Phillips SW, et al. Dedicated dual-head gamma imaging for breast cancer screening in women with mammographically dense breasts. Radiology. 2011 Jan;258(1):106-118. doi: 10.1148/radiol.10100625. Epub 2010 Nov 2.