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BREAST CANCER DETECTION TECHNOLOGIES IN DEVELOPMENT

To the extent that it was possible, the committee evaluated the apparent strengths and weaknesses of the new breast cancer detection technologies. However, the experimental evidence available for most new breast cancer detection technologies was not strong enough to support definitive conclusions about their ultimate clinical value and use, as discussed below. None of the newer technologies have been studied to the same extent as conventional mammography.

Advances in breast cancer detection technology include improvements to current techniques, new ways to image the breast, and new detection strategies aimed at finding distinctive “molecular signatures” of a pre-malignant or malignant breast tumor. The Food and Drug Administration (FDA) has approved some of these new techniques for clinical use, but many are in earlier stages of development and have not been used outside a research setting.

Digital Mammography

In an attempt to improve x-ray mammography, several companies have developed digital mammography devices. Unlike film mammography devices that produce an x-ray image of the breast directly on photographic film, digital


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FIGURE 5 Examples of Full-Field Digital Mammography of the breast. SOURCE: General Electric Medical Systems



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Page 9 BREAST CANCER DETECTION TECHNOLOGIES IN DEVELOPMENT To the extent that it was possible, the committee evaluated the apparent strengths and weaknesses of the new breast cancer detection technologies. However, the experimental evidence available for most new breast cancer detection technologies was not strong enough to support definitive conclusions about their ultimate clinical value and use, as discussed below. None of the newer technologies have been studied to the same extent as conventional mammography. Advances in breast cancer detection technology include improvements to current techniques, new ways to image the breast, and new detection strategies aimed at finding distinctive “molecular signatures” of a pre-malignant or malignant breast tumor. The Food and Drug Administration (FDA) has approved some of these new techniques for clinical use, but many are in earlier stages of development and have not been used outside a research setting. Digital Mammography In an attempt to improve x-ray mammography, several companies have developed digital mammography devices. Unlike film mammography devices that produce an x-ray image of the breast directly on photographic film, digital ~ enlarge ~ FIGURE 5 Examples of Full-Field Digital Mammography of the breast. SOURCE: General Electric Medical Systems

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Page 10 mammography devices (which still require breast compression) capture the x-ray image digitally ( Figure 5). An array of detectors creates a digitized image that can be viewed and manipulated on a computer screen. In theory, this could enable better detection of tumors obscured by the dense breast tissue frequently seen in younger women. The ability to enlarge or adjust the contrast of questionable areas without requiring new x-ray exposure may facilitate the detection of lesions that have been missed by film mammography. The technology could also improve screening mammography by allowing electronic storage, retrieval, and transmission of mammograms. However, one important limitation of digital mammograms is that the images are not as finely detailed as film mammograms. Although digital mammography has been promoted as a major technical improvement over conventional mammography, preliminary studies have not yet confirmed a significant improvement in the accurate detection of breast cancers. More studies need to be done to assess its accuracy. One digital mammography machine has been approved by the FDA based on a small study of accuracy. Several other digital mammography units await FDA review and approval. To date, no studies have shown that digital mammography is more accurate or effective in reducing breast cancer deaths than film mammography. Computer-Aided Detection (CAD) Digital mammograms also make the use of computer-aided detection (CAD) systems easier. These systems use sophisticated computer programs to recognize patterns in images that might suggest a malignancy. If such patterns are detected, the CAD system notifies the radiologist, who can then examine the suspicious area more carefully. CAD can be used directly on digital mammograms or on conventional mammogram films that have been converted to a digital format. Several studies suggest CAD can improve a radiologist's ability to detect and classify breast abnormalities on mammograms. One study suggested that CAD could have diminished the number of breast cancers missed in film mammography screening by nearly three-quarters. Other studies indicate that the addition of CAD to mammogram screening does not significantly boost the number of abnormalities inaccurately identified as potential tumors (false positives). More extensive studies must be done, however, to ensure that CAD does not lead to more false positive or negative results, and to define more clearly the value and appropriate use of this technology. The FDA recently approved one CAD detection system for breast cancer screening.

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Page 11 ~ enlarge ~ FIGURE 6 An example of an ultrasound image of the breast. SOURCE: Janet Baum, Director, Breast Imaging, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Ultrasound Imaging X-ray mammograms are frequently followed by ultrasound imaging ( Figure 6) to determine whether a mass that appeared on a mammogram is solid tissue or a harmless cyst containing fluid. Ultrasound imaging devices emit high-frequency sound waves, which penetrate the body. When these waves bounce off the boundaries between tissues in the body, they generate distinctive echoes that a computer uses to generate an image known as a sonogram. Because a fluid-filled cyst has a different “sound signature” than a solid mass, radiologists can reliably use ultrasound to detect cysts, which are commonly found in breasts. Ultrasound imaging of the breast may also help radiologists evaluate some lumps that can be felt (palpable lesions) but are difficult to see on a mammogram, especially in women with dense breasts. One study of women with palpable lesions suggested that ultrasound was very accurate at diagnosing non-malignant abnormalities and could have eliminated the need for more than half the biopsies that were done. Other studies suggest that ultrasound may also be able to characterize non-palpable solid lesions as benign or malignant. Additional research suggests that ultrasound combined with x-ray mammography might improve the accuracy of breast cancer screening and also enable the detection of early-stage tumors in women with dense breasts. Further study is needed to assess the usefulness of ultrasound as a screening method

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Page 12 used along with mammography. Although ultrasound may be useful as an addition to mammography, it has limitations for breast cancer detection when used alone. Ultrasound often cannot detect small tumors (less than 5 mm or about one-quarter inch) and abnormalities (microcalcifications) linked to certain types of breast cancers. Recent improvements in ultrasound technology have the potential to overcome some of these limitations and to expand its usefulness in breast cancer detection. But their ultimate usefulness in breast cancer detection cannot be predicted at this stage of development. Magnetic ResonanceImaging (MRI) Physicians have been using MRI for a wide variety of medical applications since it was FDA-approved for body imaging in 1985. MRI, generally considered to be a safe procedure, generates an image by measuring the responses of tissue components to a magnetic field. Specialized MRI systems, designed for breast imaging ( Figure 7) and approved by the FDA, show promise as a detection method to be used with mammography, especially for dense breasts. Studies suggest that although MRI is highly sensitive at detecting tissue abnormalities that indicate cancer, it is sometimes unable to distinguish malignancies from other harmless tissue abnormalities in the breast. Also, like ultrasound, it cannot detect microcalcifications. Despite this limitation, an MRI ~ enlarge ~ FIGURE 7 Example of a magnetic resonance image of the breast. SOURCE: Drs. D. Plewes and R. Shumak of Sunnybrook and Women's College Health Centre, University of Toronto.

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Page 13 could potentially detect the presence of a breast cancer in a patient whose mammogram, sonogram, and physical exam are not definitive. Another possible use for MRI is to detect recurrent breast cancer in breasts previously subjected to lumpectomies, because unlike mammography, MRIs are usually not limited by scarring that can occur after surgery. Also, MRI can detect tumors in women with breast implants or dense breasts, both of which can interfere with interpretation of x-ray mammograms. Consequently, MRI may prove useful in the screening of high-risk young women (based on genetic testing or strong family history), who tend to have dense breasts. Preliminary results are encouraging in this regard, but further studies are needed to define the usefulness of MRI breast cancer screening in this population. Other Imaging Technologies Under Development for Breast Cancer Detection Several other imaging systems have been developed for breast cancer detection. These systems include some that use radioactive compounds that concentrate in cancerous tissue to image breast cancer, such as scintimammography and positron emission tomography (PET). Others aim to identify cancerous tissue by analyzing temperature, optical, electrical, or elastic properties. Many of these systems are being developed as additions to film mammography, but studies have yet to demonstrate definitively their usefulness for this purpose. Because no single imaging device can accurately detect all types of breast abnormalities in all kinds of breast tissue (for example, in dense as well as fatty breasts, or in breasts with implants or significant scarring), the committee noted that ideal breast cancer detection may ultimately require the use of multiple imaging techniques. In summary, after reviewing all the evidence to date, the committee concluded that despite its limitations, x-ray mammography is currently the only imaging technology that has been adequately studied and is suitable for breast cancer screening in the general population. The Potential of Molecular-Based Detection Knowledge about the genetic basis of cancer has grown dramatically over the past two decades. Scientists now believe that cancer develops in an individual only after a number of steps have occurred. These steps involve a series of genetic changes that trigger cells to make too much or too little of a protein, or to make a malfunctioning protein. The result of these changes is that normal breast cells grow uncontrollably into malignant tumors. By inheriting a changed gene that can foster breast cancer, some women are born with one of the steps on the path to cancer already taken. Researchers are

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Page 14 beginning to uncover some of these inherited genetic changes linked to a high risk of developing breast cancer, including changes in the BRCA1 and BRCA2 genes. But only about 10 percent of breast cancer cases stem from inherited susceptibility. Most breast cancers arise from genetic changes that occur during a person's lifetime. Researchers are currently trying to detect markers of such genetic damage. Newly developed methods for growing breast cells in culture and new automated systems for screening large numbers of genes or proteins in cells should aid this endeavor. Currently, abnormalities detected with mammography are crudely classified as malignant or benign based on their structural appearance under the microscope, and not by what genetic changes they may have. If reliable markers of breast cancer progression can be identified, tests for such markers may play a role in determining whether doctors should treat the pre-malignant abnormalities and early-stage lesions that are now so commonly identified by screening mammography. Many of these abnormalities may not progress to life-threatening disease. The discovery and development of molecular markers for breast cancer, consequently, might help reduce the “overtreatment” of harmless abnormalities. They might also be able to identify women who should undergo more frequent screening or consider prophylactic treatment (for example, mastectomy or tamoxifen), or those who might benefit from newer imaging technologies. If and when these molecular markers prove useful for diagnosing or predicting the aggressiveness of breast cancers, researchers could then also examine their usefulness in breast cancer screening. There are many ways that gene or protein screens could be used for breast cancer detection. Researchers are trying to develop specialized imaging systems that can use “smart” contrast agents to reveal telltale genes that may be activated in cancerous breast tissue, or other biochemical markers of early breast cancer. Such systems might eventually be used in breast cancer screening, but their development is too preliminary at this point to assess their usefulness for this purpose. Other researchers are trying to develop screening tests for tumor markers or tumor cells in breast fluid or blood serum. Breast fluid can be obtained from women who are not pregnant or breast-feeding with the aid of breast massage and a modified breast pump. In addition, researchers have recently developed a device that is inserted into the nipple and uses salt water to flush breast duct cells out of some of the breast ducts (a process known as ductal lavage). The FDA recently approved this device for breast fluid removal. More studies need to be done to