Move Over Mammo
As the number and type of breast imaging modalities have multiplied and research has demonstrated their effectiveness, it may be time for women's imaging practices to consider the role of new technologies in breast cancer screening and detection.

In the last 18 months, regulatory, technical and legislative developments have occurred at a head-spinning pace. The FDA approved tomosynthesis, and an FDA advisory panel recommended approval of automated ultrasound as an adjunct to mammography for women with dense breasts.

From 2D to 3D

When the FDA approved breast tomosynthesis in February 2011, Houston Breast Imaging in Texas was poised to take advantage of the 3D development. Stephen L. Rose, MD, president and CEO of the practice, served as principal investigator in clinical trials of the technology. The practice has deployed four tomosynthesis systems, and its three affiliated hospitals own another four.

Many practices in the U.S. that have invested in tomosynthesis operate in a hybrid environment, with a single tomosynthesis system mixed with digital mammography, and have not devised a true tomosynthesis screening program. In contrast, by May 2011, Houston Breast Imaging began delivering tomosynthesis to its screening population.

In preparation for a clinical trial, Rose and colleagues have off-loaded 2D mammography data from 10,000 screening patients to a separate workstation to inform an "apples to apples comparison" of 3D and 2D exams. As the researchers evaluate the data, the early findings are compelling.

In the 2D environment, the 14-radiologist practice had a callback rate of approximately 10 percent. Since transitioning to screening tomosynthesis, its rate has hovered in the 5 to 6 percent range. Similarly, a study conducted at Yale University School of Medicine in New Haven, Conn., and presented at the annual meeting of the American Roentgen Ray Society in May, showed that the patient recall rate dropped from 11.1 percent with 2D mammography to 6.6 percent with 2D mammography and tomosynthesis.

"It isn't just that we are reducing the callback rate. When we call patients back, we don't have to do as many exams," says Rose. The conventional diagnostic model typically requires additional mammography views followed by ultrasound in most cases. With tomosynthesis, the patient typically proceeds directly to ultrasound and a same-day biopsy if needed.

Furthermore, positive predictive value has improved. "Traditionally, 20 percent of biopsies in a screening population are actually malignant. Our data show this rate is 45 to 50 percent with tomosynthesis," says Rose.

However, it is critical that imaging modalities detect malignancies of consequence to the patient's health, Rose says. "We are finding the same spectrum of tumors we see in the regular population, such as infiltrating lobular cancers or high-grade tumors. They are just smaller."

Rose and his colleagues had expected tomosynthesis to assist in the evaluation of women with dense breasts. A somewhat unexpected finding is its role in detection of cancers in women who don't have dense breasts. In some of these women, findings that seem to be an area of asymmetry have been diagnosed as 2 mm to 4 mm tumors.

However, Rose acknowledges the technology is not perfect. For starters, false-negative results are always a possibility.

Workflow presents another challenge. Tomosynthesis allows the radiologist to view data in 1 mm slices. In settings where radiologists can use the vendor workstation, Rose estimates that it takes 30 percent longer to review tomosynthesis images than conventional mammography results. In one location where the breast imaging workstation cannot display tomosynthesis images, data must be sent to a separate workstation. In that model, it takes two to three times as long to review tomosynthesis data. The situation is expected to improve when the tomosynthesis vendor releases a DICOM format for its data.

The efficiency hit is exacerbated by a reimbursement catch-22. The FDA requires that women have a standard mammogram in addition to a tomosynthesis study, yet the Centers for Medicare & Medicaid Services (CMS) and private payors do not reimburse radiologists to read tomosynthesis images. However, the increased diagnostic confidence in both negative findings and callbacks outweigh the downsides, says Rose.

MR, US & the intermediate-risk conundrum

Supplementing screening mammography with ultrasound or MRI improved breast cancer detection among women with dense breasts and at least one additional risk factor (intermediate-risk women), according to the ACRIN 6666 study published April 4 in the Journal of the American Medical Association. Adding screening ultrasound to annual mammography increased the cancer detection rate 4.3 cancers per 1,000 screens each year over three years. A single screening MR screening revealed additional cancers not seen by mammography or ultrasound at a rate of 14.7 per 1,000 screens. Applying the finding in practice, however, illustrates the complex web of breast cancer screening.

Despite its additional diagnostic utility, screening MRI is not the right exam for intermediate-risk women. For starters, researchers reported that MRI was less tolerable than mammography or ultrasound. In ACRIN 6666, 58 percent of intermediate-risk women offered screening MRI at no out-of-pocket cost accepted.

Ultrasound may fill the gap. This middle group of women—who have dense breasts and possibly another risk factor such as an intermediate family history or personal history—has posed a lingering problem, says Wendie A. Berg, MD, PhD, professor of radiology at Magee-Womens Hospital, University of Pittsburgh School of Medicine (UPMC). Women with dense breasts, approximately one-third of women over the age of 50 and half of the women younger than 50, are at increased risk for developing breast cancer. Plus, dense breasts may obscure malignancies on a mammogram.

"For the first time, we know that performing screening ultrasound each year significantly increased cancer detection in these women. Nearly all of the ultrasound-detected cancers were invasive and node negative, which are the ones we are most interested in finding," says Berg.

Breast density, one factor in the risk assessment, may be challenging for some radiologists to apply in practice. According to the American College of Radiology, the assessment of breast density is not reliably reproducible.

Although individual radiologists may differ on borderline cases, they can agree on women with extremely dense breasts who are at higher risk than women with heterogeneously dense breasts, explains Berg. Moreover, screening ultrasound improves cancer detection even among women with minimally dense tissue. In ACRIN 6666, ultrasound provided significant increased cancer detection among women with heterogeneously dense tissue in one quadrant. Breast density software, marketed by at least two vendors, may help provide a standardized measure.

Identifying and educating high-risk women represents an additional hurdle. It's difficult to implement the American Cancer Society guidelines, which recommend screening MRI for high-risk women in practice, says Berg.

A mere 14 percent of high-risk women completed recommended breast MRI screening within one year after Invision Sally Jobe Breast Centers in Denver implemented risk assessments and informed primary care providers that high-risk women should undergo breast MRI, according to a study published in Academic Radiology in January. Part of the problem is lack of consensus on the optimal risk model, and these models predict only half of breast cancers.

A personal touch may help high-risk women follow through with MR screening, says Patricia A. Somerville, MD, a radiologist at Elizabeth Wende Breast Care (EWBC) in Rochester, N.Y. The clinic has seen its high-risk screening MR program grow from less than 10 percent of its MR volume in 2005 to more than half in 2012. The practice provides risk assessments to the wide pool of women who qualify for them and a genetic counselor corresponds directly with patients to educate them about the role of supplemental screening.

EWBC radiologists manage the workflow crush of the 2,000-plus images generated by breast MR by deferring image review to the end of the day and employing computer-aided detection to assist with image review.

New life for gamma imaging

Another relatively new arrow in the quiver is dedicated breast gamma camera imaging. Researchers realized the potential of scintimammography technology using 99m Tc-sestamibi to detect pathological areas in the late 1990s. However, adoption was hindered by the large size of gamma cameras coupled with their inability to detect lesions smaller than 2 cm.

A few companies focused on developing detectors, but by the time prototypes were developed in 2005, MRI seemed to have a firm grip on the market.

There are some critical differences between dedicated breast gamma camera imaging and MRI, says Jean M. Weigert, MD, a radiologist at Hospital of Central Connecticut in New Britain. She and her colleagues reviewed 800 cases after installing a breast gamma camera system in 2005, and found sensitivity and specificity in the 90 percent range. The results were reported at RSNA 2006 and the annual meeting of the American Society of Breast Disease in 2007. "The sensitivity of breast MRI is 93 to 95 percent, but specificity is 50 to 70 percent, depending on the reader."

Unlike other breast imaging modalities that show anatomy (and vascularity in the case of MRI), sestamibi-based imaging depicts physiology. The positive predictive value of sestamibi-based imaging is approximately 50 percent as some benign lesions are metabolically active. But its negative predictive value is 97 percent.

One of the pluses of sestamibi-based imaging, says Weigert, is that data are reviewed in parallel on a multimodality workstation with mammography images. "They are the same kind of images, so the radiologist can go back to the mammogram or ultrasound to evaluate suspicious findings." That is, if the radiologist is mildly suspicious about a finding on a mammogram or ultrasound, he or she can immediately determine if there is uptake in that area on the exam.

Sestamibi-based imaging also has demonstrated high uptake in lobular cancers, which are notoriously hard to detect via mammography because they spread as sheets rather than a true mass.

However, sestamibi-based imaging is not a screening exam, says Weigert. "By definition, a screen has to be low cost, noninvasive and readily available. It requires an injection, exposes the patient to radiation, costs approximately $500 and takes 40 minutes to acquire," says Weigert. "This is an adjunct. The only way it will ever be a screen is if the radiation exposure is reduced and costs fall to the range of a screening mammography."  

Berg points out that sestamibi-based imaging is being evaluated as screening exam where MRI is not available or feasible and adds that it is better tolerated than MRI.

Newer technology, consisting of dual-headed detectors, increases sensitivity and reduces radiation dose. Sestamibi-based imaging, using a 20 mCi dose of sestamibi, delivers approximately 6 mSv of radiation to the body, while newer systems drop dose to as low as 2 mSv (8 mCi dose).

As vendors refine the technology, molecular options seem to be gaining traction. Capital Health in Hopewell Township, N.J., installed a dual-head gamma camera in January to meet the practice's patient and business goals, says Yaakov N. Applbaum, MD, chairman and medical director of radiology at Capital Health.

The practice had opened a women's imaging center in November 2011, and wanted to differentiate itself from the competition.

Applbaum and other leaders recognized the pitfalls of screening mammography and searched for supplemental options. They ruled out screening MRI for its extensive list of downsides, including a high false-positive rate, lengthy exam time, spotty reimbursement and lengthy review time.

However, molecular breast imaging bubbled to the surface. Its 90 percent sensitivity for breast cancer nearly triples that of screening mammography in dense-breasted women.

Unlike MRI, the exam is tolerable for most women. It takes approximately 40 minutes to perform; patients are seated with the breast stabilized, but not compressed, between two plates to hold it in position. The standard exam produces eight images, compared with approximately 1,500 to 2,000 or more with MRI. In addition, newer systems can trim whole-body radiation exposure to 1.3 mSv.

Capital Health plans to recommend the adjunctive exam to women with dense breasts and those with a questionable finding or palpable abnormality. Studies are interpreted according to a scale from negative to weakly, moderately or strongly positive.

"If it's moderately positive, the radiologist can review the mammogram retrospectively to determine if there is a finding," says Applbaum. The next step in the diagnostic pathway is a focused ultrasound to evaluate the lesion. If neither mammography nor ultrasound exams show the lesion, the patient can be referred for an MRI. Women with suspicious results are referred for biopsy. If additional results are negative, the gamma camera exam study will be repeated in six months.

The molecular breast imaging camera represents a $600,000 investment, says Applbaum. The women's imaging center persuaded the hospital to invest in the camera by detailing its collateral economic benefit. With Medicare reimbursement of $495 per exam, Applbaum noted the hospital could pay for the system in three years. However, because molecular breast imaging is more sensitive than mammography, it will detect more cancers and generate more diagnostic and therapeutic revenues. "ROI should not be calculated by simply dividing the number of studies by revenue and subtracting costs. Every woman, who undergoes molecular breast imaging also has to have a mammogram. Every woman who has positive findings will require clarification via ultrasound or MRI."

There is no easy or universal fix to augment screening mammography. Although new tools continue to make their mark and deliver added detection capabilities, mammography remains the only screening exam proven to save lives.