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May 24, 2004

Functional Mammotomogram
Nuclear Medicine Research Seeks Earlier Detection
By Beth W. Orenstein
Vol. 5 No. 11 p. 14

Duke University scientists hope to soon launch clinical trials for a test using radioactive tracers to identify cellular changes in breast tissue that precede malignancy.

What if you could detect tumors in the breast before you could see them on a mammogram or feel a lump? To do so, you would need a device sensitive enough to detect some of the earliest chemical changes that precede malignancy. Martin Tornai, PhD, an associate professor of radiology and biomedical engineering at Duke University in Durham, N.C., has been working on such a nuclear imaging device for the past several years.

Tornai is pursuing the device because “if we can detect subtle changes in cells before a tumor has developed, we have a better and earlier chance of treating the abnormal cells,” he says. “By the time structural changes are detected using mammography, the traditional tool for breast cancer detection, they have been going on for a while.”
It has been well established in oncology that the earlier physicians detect breast cancer, the more successful the treatment. Breast cancer is the most common non-skin cancer and second-leading cause of cancer mortality in women, accounting for approximately 40,000 deaths per year in the United States.

Small Gamma Camera
The system consists of a miniature gamma camera mounted on a rotating platform and uses radiopharmaceuticals to detect chemical changes to breast cells that signal the cells are becoming or already are malignant. Tornai and colleagues hope to launch clinical trials in patients soon.

Prior to the exam, a cancer-specific radioactive tracer is attached to technetium-99m, a widely used radionuclide, and injected into the patient’s bloodstream. The tracer, called sestamibi, is absorbed more quickly by cancer cells because they have large numbers of mitochondria, the powerhouses of the cells. Cancer cells have more mitochondria than normal cells because they are more metabolically active and require more energy to grow and spread.

The camera system encircles the breast, looking at it from many angles, ultimately producing a high-resolution, 3-D image. The camera obtains its images by detecting the gamma rays—high-energy photons or units of light—emitted by the radioactive atom attached to the sestamibi.

“Nuclear imaging tracers such as sestamibi show up in both premalignant and malignant breast cells as a little light bulb in the middle of a dim space,” says Tornai, who presented his findings at the 26th Annual San Antonio Breast Cancer Symposium in December 2003.

3-D Images
The 3-D images obtained in this way are called emission or functional mammotomograms, says Tornai, who was among the first, if not the first, to use that term. (Tornai published a paper in The Journal of Nuclear Medicine in January 2003 using the term functional mammotomograms.)

Functional mammotomograms have several advantages over traditional mammography, which uses 2-D x-rays or projection images. The gamma camera can detect tumors in large or dense breasts, which are difficult to image using traditional mammography because x-rays often cannot penetrate them.

Moreover, the geometry of the dedicated breast imaging system allows for imaging small breasts and the nearby chest wall. “It can even image the axillary lymph nodes to look for evidence of metastasis, which traditional mammography cannot do,” Tornai says.

Thus, he says, the new device could be particularly useful in screening women at high risk for breast cancer, especially younger women who have denser breast tissue that x-ray mammography cannot easily penetrate. Women at high risk include those with a family history of breast cancer or who test positive for the breast cancer gene.

Mammotomograms could also help reduce the number of biopsies women must undergo.
While mammograms are highly sensitive—they detect 85% of breast lesions—they are not very specific for breast cancer. In fact, only 30% of patients who have biopsies because of suspicious findings on mammograms actually have breast cancer.

“Nuclear medicine projection images [scintimammograms] for breast cancer are pretty good,” Tornai says. “Sensitivity and specificity are both above 90% for tumors greater than 1 centimeter.”

Having the breast scanner technology in place in the mammography suite could eliminate the delays and anxiety that sometimes result if a woman is asked to return for a repeat test, Tornai says.

More Comfortable Test
Another potential advantage to women is that a mammotomogram should provide a more comfortable exam than mammography because the device works without compressing the breast. Indeed, women may not even be required to remove their bras. Many women complain about the pain involved in mammography and may avoid them for that reason.
“We believe the comfort aspect is something that might actually make someone more amenable to coming for their breast exams,” Tornai says. The ability to perform imaging without compressing the breast as mammograms do will also provide a more precise idea about the location of the tumor, he adds.

Because the device detects changes to cancer cells, it could prove useful in monitoring the patient undergoing chemotherapy or radiation therapy for breast cancer.
“During and after chemotherapy, if you take an x-ray mammogram of the same cancerous tissue, it looks identical to its pretreatment size,” Tornai says. “But if you take a nuclear medicine image, the affected tissue doesn’t take up the tracer, so you can see if the therapy is having an effect very early on, much sooner than waiting for tumor shrinkage.”

In a clinical setting, the functional mammotomogram, which Tornai expects to take approximately 10 to 20 minutes per breast, should prove relatively safe, he says. Because of the radioactive tracer, the breasts are imaged one at a time.

Gamma ray tracers such as sestamibi have a short half-life and are broken down quickly by the liver and excreted. The amount of radiation exposure from a single diagnostic procedure is roughly the same as one year’s exposure from the natural background radiation found in the environment, Tornai says.

Early Work
Tornai began doing breast cancer research while a graduate student at the University of California, Los Angeles, in 1992.

When he came to Duke in 1997, the lab he began working at was involved in a National Institutes of Health study on breast cancer using gamma cameras. The problem was that the standard nuclear medicine gamma cameras are large whole-body scanners that take a single, 2-D image and generally cannot take multiple views of the breast. Also, their cumbersome size—they can weigh up to a couple of tons—makes it difficult to obtain a close image of the breast from all sides, which is critical to obtaining a complete, 3-D picture.

In 2000, Tornai received an almost $210,000 grant from The Whitaker Foundation over three years to investigate and develop a more user-friendly nuclear imaging system specifically for the breast. Tornai and his Duke colleagues, Caryl Archer, MS, a graduate student, and James Bowsher, PhD, an assistant research professor of radiology and a co-inventor on the patent pending for the device, built a prototype using a 40-pound commercially available camera they integrated into the compact system.

The researchers leased a camera from Gamma Medica, Inc., a start-up based in Northridge, Calif. Its small gamma camera is approved by the FDA for 2-D nuclear imaging, Tornai says. They mounted the camera on a rotating platform that allows the camera to completely and closely orbit the breast.

Flexible Positioning
“The system gives us tremendous flexibility,” Tornai notes. It can even be positioned under the patient’s arm for lymph node imaging. The camera has a higher resolution than conventional gamma cameras, which is crucial when trying to image the small lesions that are the early stages of breast cancer.

The Duke researchers tested their system using an artificial breast that they implanted with phantoms—small spheres that simulate cancerous growths. Made of plastic and filled with water and radioactive material, the spheres ranged from 4 millimeters, roughly the size of an early cancerous lesion, up to 1 centimeter.

“The main reason to use a phantom is that you know what the answer is and [thus] can determine the lower limits of detectability,” Tornai says.

Their studies demonstrated that, in principle, it is possible to locate even a pinhead-sized lesion using their new device.

Tornai expects to begin using the device at Duke to image breast cancer patients shortly. His group is putting finishing touches on the bed where the patient will lie so her breast is isolated for imaging.

The next step in the development of the device will be combining the nuclear medicine image with a dedicated CT scan, which will provide a structural mammotomogram. The information can then be overlaid with the functional information on the same 3-D image, Tornai says.

“One of the criticisms of nuclear medicine is that it is hard for physicians to read the grainy images,” Tornai says. “For example, an x-ray will exquisitely show the bones in my hand [while] a nuclear medicine [image] will show the ring on my finger, which will appear to be floating in space. We need an imager that will show where the ring sits on my hand, and we can achieve that with a dual imager.”

Not a Replacement
Tornai doesn’t expect that this approach would ever replace traditional mammography as a general screening tool, but it could become a useful adjunct device in the mammography clinic. “If and when the breast imaging system is fully developed, it won’t replace mammograms but instead would offer women with inconclusive results an alternative to biopsies,” he says. “It also could potentially be used to screen women at high risk for breast cancer.”

Cost should not be an issue in its usage and acceptance because the tracer is fairly inexpensive, he says. “I don’t see this costing but a few hundred dollars. That’s my guess. That depends on if this gets commercialized and how much the camera sells for.”

Colleagues praise Tornai’s research and development of the nuclear imaging device for breast cancer but are cautious about its potential benefits at this point.

Preliminary Research
R. Edward Coleman, MD, director of the division of nuclear medicine at Duke University Medical Center, agrees that Tornai’s new scanner offers much promise for earlier detection of breast cancer. However, he says, “we still have a lot to learn about it before it can be used for routine clinical studies.” One area that still needs exploration is the tracers that are used, Coleman says.”We may need radiopharmaceuticals that have better localization in breast cancer than the ones that we are now using for us to take full advantage of what this system can do.”

Also, Coleman says, clinical studies “are needed before we know its contribution to the evaluation of women with suspected breast cancer.”

David Mankoff, MD, PhD, an assistant professor of nuclear medicine at the University of Washington in Seattle, agrees that radiotracer imaging may someday prove an attractive complement to more traditional methods of screening for breast cancer and staging the disease. However, he says, while early studies were promising, subsequent studies showed that radioactive tracers were not as good at detecting smaller or nonpalpable breast cancers, which are the cancers most important to detect to reduce breast cancer mortality.

Researchers claim that the reduced sensitivity for smaller breast lesions is the result of using general purpose radiotracer imaging devices. They believe designing devices more tailored to breast imaging might be able to improve detection of breast lesions, Mankoff says.

However, he adds, there are several reasons to believe that limited sensitivity of radiotracer imaging for early breast cancer is not simply the result of the limits of the instrumentation.

Radiotracer Research
Additional studies, including those at the University of Seattle, show that most radiotracers currently used in breast imaging, including sestamibi, are seen more clearly when the tumors are aggressive and that early-stage breast cancers may not be that aggressive, Mankoff says.

The problem may lie not only in the instrumentation but also in a mismatch between the tracers and early breast cancer biology, he says. “To have an impact on early breast cancer detection, radiotracer breast cancer imaging will require the combined efforts of tumor biologists, radiopharmaceutical chemists, and the instrumentation physicists.”

The studies by Tornai and his colleagues show a promising effort on the physics front, Mankoff says. “Similar successes will be needed in biology and chemistry before radiotracer imaging will gain widespread use in early breast cancer detection.”

— Beth W. Orenstein is a freelance health writer and regular contributor to Radiology Today.

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