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Mammography and Beyond: Building Better Breast Cancer Screening Tests

Linda Wang

Recent clashes in the medical literature provide a reminder that mammography is far from a perfect screening test. Newer technologies such as magnetic resonance imaging and protein-based assays may ultimately offer some advantages over mammography, but it is still too early to tell whether any of these tools will prove superior to mammography, the gold standard for breast cancer screening for decades.

In fact, there may never be a perfect test. Rather, experts say, the future of breast cancer screening may lie in not one, but a series of tests—with mammography securing a place somewhere in between.

The problem with mammography is that it raises more questions than it answers. About 75% of masses that are biopsied after a mammogram turn out to be benign, and mammography misses about 20% of tumors, particularly those that are fast-growing and those buried in dense breasts.

Despite these limitations, mammography remains the best available tool for breast cancer screening, many experts say.

"Mammography, while it gets beat up, is pretty good in a lot of ways," said Keith D. Paulsen, Ph.D., of Dartmouth College in Hanover, N.H., who is working on alternate breast cancer detection methods. He pointed out that, unlike other breast cancer screening methods, mammography has benefited from more than three decades of experience and fine tuning.

Improving Mammography

To improve mammography, some researchers are looking to full-field digital mammography, which has been approved by the U.S. Food and Drug Administration.



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This image, taken from a digital mammogram, shows clustered calcifications. This patient was diagnosed with high-grade ductal carcinoma in situ.

 
Digital mammography has the advantages of speed and higher contrast resolution. Further, capturing images on the computer instead of on film makes it easier for radiologists to send images to other radiologists for a second opinion.

However, growing evidence suggests that digital mammography may be no more effective at spotting breast cancers than film mammography. A recent study involving about 4,500 women found that digital mammography missed more cancers than film mammography; however, digital mammography was more specific and resulted in fewer biopsies than film.

Etta D. Pisano, M.D., chief of breast imaging at the University of North Carolina, Chapel Hill, cautioned that the study, published in the September 2002 issue of the American Journal of Radiology, was limited by a small sample size and included only one of several federally approved digital mammography machines. "I don’t think we should take this as the definitive word on digital mammography," she said. "At this point it’s still an open question."

Answers may be forthcoming. In the Digital Mammographic Imaging Screening Trial (DMIST), 49,500 female volunteers will undergo both conventional mammography and digital mammography to determine whether digital mammography is as good as or better than film mammography. Results may be available as early as 2005.

But even if digital ultimately proves to be better than film, digital mammography costs much more, and experts question whether the benefits will justify the costs. Pisano pointed out that if digital mammography can result in a smaller biopsy-to-cancer ratio, the cost savings may compensate for the increased cost of the technology. Cost-effectiveness will also be studied in the DMIST trial.

Because accurate mammography interpretations depend heavily on the reader, some researchers advocate double reading of films by separate radiologists. But the problem, said Maryellen Giger, Ph.D., a professor of radiology at the University of Chicago, is that there is a major shortage of radiologists, particularly mammographers, in the United States.

One solution is computer-aided diagnosis (CAD), which involves the use of a computer to bring suspicious areas on the mammogram to the radiologist’s attention.

In a prospective study published in the September 2001 issue of Radiology, Timothy W. Freer, M.D., and Michael J. Ulissey, M.D., of the Women’s Diagnostic and Breast Health Center in Plano, Texas, found that the use of CAD increased the number of cancers detected by radiologists by nearly 20%, compared with the performance of radiologists who did not use CAD.

And where CAD may be most valuable is in the community setting. In a study published in the August 2002 issue of Radiology, Giger and her colleagues showed that CAD could raise the performance of community radiologists to the level of expert mammographers in distinguishing between malignant and benign masses seen on mammograms.

Beyond Mammography

In January 2003, the Institute of Medicine and the National Research Council held a workshop to discuss how to move these technologies more swiftly into clinical relevancy. Recommendations from an expert panel may be available as early as fall 2003.

One technology gaining attention is magnetic resonance imaging (MRI). This approach can provide higher soft tissue resolution of the breast than mammography. However, MRI is much slower than mammography, it may have lower specificity than other imaging techniques, and the machines are still quite expensive.



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Magnetic resonance elastography, performed with the equipment shown above, is being tested as a method of breast cancer screening.

 
"Even if we prove that MRI is close to the perfect screening test, we’d really have to think hard about whether we want to produce machines that are so cheap that they could be implemented at a lower cost," said Pisano. "But odds are [MRI machines] won’t come down to the price of a mammography unit."

The International Breast MRI Consortium is conducting trials to evaluate MRI screening in a high-risk population, compare MRI with ultrasound (another imaging tool) in a high-risk population, and evaluate MRI screening of the opposite breast in women with unilateral breast cancer.

Other technologies attempt to capitalize on physical differences between tumor tissue and normal tissue, such as tissue elasticity (magnetic resonance elastography), electrical conductivity (electrical impedance spectral imaging), water content (microwave imaging spectroscopy), and blood volume (near-infrared spectral imaging).

If successful, these approaches may someday lead to new options for breast cancer screening, said Dartmouth’s Paulsen, whose team is examining each of these techniques in small-scale preliminary studies.

"I think all of them offer something interesting and unique," he said. "But I think there is some prospect that if we could put them all together, we might have something better than any one of them alone."

Back to Basics

An ideal screening test should be cheap, easy to administer, and both sensitive and specific, said Laura Esserman, M.D., an associate professor of radiology and surgery at the University of California San Francisco. She noted that many of the current tests, however, are limited by high cost.

One potentially inexpensive test involves the analysis of specific protein patterns in the blood. Lance Liotta, M.D., Ph.D., of the National Cancer Institute, and his colleagues, have developed a test to recognize specific protein patterns in a drop of blood that may help identify cancer.

Last year, Liotta and his colleagues showed that in a training set of blood samples from 66 healthy women and 50 women with ovarian cancer, their assay correctly identified 100% of the ovarian cancers and 95% of the non-cancers. Their test has shown similar success in identifying prostate cancer.

Liotta and his colleagues are now testing their method on breast cancer. Clinical trials are ongoing to see whether results from their assay can correlate with results from breast biopsies.

If successful, Esserman envisions a reordering of tests with the serum proteomics assay being the first in a series of tests to screen for breast cancer. For example, people who test positive for breast cancer with the protein test could go on to mammography, MRI, or some other test to confirm and localize the cancer, she added.

"You don’t have to wait for the magic bullet," said Esserman. "If you could get a cheap test where you could funnel the group of people at risk and make it much smaller, then you can afford to be looking with all these other tests."

But Liotta cautioned that it is much too early to say whether their test will be appropriate for mass screening.

"It’s completely unknown whether we’ll ever be able to replace these imaging methods or to be able to triage patients into those who should get imaging and those who shouldn’t," he said. "But at some point we’ll know whether our test correlates with what the biopsy shows."

He added that there a lot of questions to be answered and that the development of screening strategies should be approached very carefully. "We’ve been looking for the elusive single cancer test for too long, and it doesn’t exist," said Liotta.

Esserman suggested that people think less about defending one test or another and more about how best to order the tests. "How do you figure out how to tie all these things in together?" Esserman asked. "That’s what’s exciting."



             
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