Appendix A
Breast Cancer Technology Overview

Many new technologies are being developed for the detection and diagnosis of breast cancer, and many of them have been described as “breakthrough” technologies in the media. For a public eager for definitive results, the summary below will be disappointing. Of the 23 technologies described below, only 10 have been approved by the Food and Drug Administration (FDA). And only 3 (screen-film mammography, digital mammography, and computer-aided detection [CAD]) have been approved for use in breast screening. Other technologies are approved only as adjuncts to mammography or for other uses. For example, positron emission tomography (PET) is approved for monitoring response to treatment for breast cancer, but not for screening or diagnosis. As discussed in Chapter 6, FDA approval does not certify that a particular technology improves health outcomes, only that it is safe and meets the manufacturer’s claims for efficacy. As with magnetic resonance imaging (MRI), claims made by groups other than the manufacturer are beyond the purview of FDA.

Over time and with the results of well-designed studies, some of the technologies listed below may earn the title of “breakthrough technology,” but without evidence they remain “promising.” It is not possible to anticipate which of the many promising technologies will realize their expected potation and which will not.



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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Appendix A Breast Cancer Technology Overview Many new technologies are being developed for the detection and diagnosis of breast cancer, and many of them have been described as “breakthrough” technologies in the media. For a public eager for definitive results, the summary below will be disappointing. Of the 23 technologies described below, only 10 have been approved by the Food and Drug Administration (FDA). And only 3 (screen-film mammography, digital mammography, and computer-aided detection [CAD]) have been approved for use in breast screening. Other technologies are approved only as adjuncts to mammography or for other uses. For example, positron emission tomography (PET) is approved for monitoring response to treatment for breast cancer, but not for screening or diagnosis. As discussed in Chapter 6, FDA approval does not certify that a particular technology improves health outcomes, only that it is safe and meets the manufacturer’s claims for efficacy. As with magnetic resonance imaging (MRI), claims made by groups other than the manufacturer are beyond the purview of FDA. Over time and with the results of well-designed studies, some of the technologies listed below may earn the title of “breakthrough technology,” but without evidence they remain “promising.” It is not possible to anticipate which of the many promising technologies will realize their expected potation and which will not.

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis ANATOMICAL TECHNOLOGIES Mammography and Its Improvements Technology Description Developmental Stage First FDA Approval Screen-Film Mammography X-rays are sent through the breast tissue. Denser tissue, which is often associated with cancer, absorbs the x-rays and appears as a white region on the film. Routine clinical use for screening 1969 Computer Aided Detection Uses computer algorithms to highlight suspicious areas on mammograms for the radiologist to review. Clinical use for screening 1998 Digital Mammography Similar to screen-film mammography except x-rays are recorded in digital format instead of on x-ray film. Clinical use for screening 2000 Tomosynthesis A computer assembles information from mammograms taken at several different angles to provide high-resolution cross-sections and three-dimensional images. Experimental use (clinical prototype) — Diffraction Enhanced Imaging A synchrotron-based x-ray machine. Integrates two images, one image based on x-ray absorption (e.g., conventional image from an x-ray) and the other based on refraction. Experimental use —

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Screen-Film Mammography (Conventional X-Ray Mammography) The current standard of care for breast cancer screening is x-ray mammography for women over the age of 40. A technician that compresses the breast and takes pictures from different angles, creating a set of images of each breast, usually performs this technique. In the set of images, called a mammogram, breast tissue appears white and opaque, while fatty tissue appears darker and translucent. X-rays travel unimpeded through soft tissues; however, cancerous tissue absorbs x-rays and can show up on the film as white areas. In a screening mammogram, the breast is x-rayed from center to side. However, a diagnostic mammogram focuses in on a particular lump or area of abnormal tissue. This examination usually takes about 30 minutes. Yearly screening mammography results in sensitivity (proportion tests that correctly indicate a woman has cancer) ranging from 71 to 96 percent and specificity (proportion of tests that correctly indicate that a woman does not have cancer) ranging from 94 to 97 percent.18 However, several factors influence the correct detection of breast cancer, such as age, breast density, hormone replacement therapy, image quality, and experience of the radiologist.18 Computer Aided Detection (CAD) CAD involves the use of computers to identify suspicious areas on a mammogram after the radiologist’s initial review of the mammogram. CAD double-checks the work of the radiologist to help avoid possible oversights. In 1998, the FDA approved the first CAD system, ImageCheckerTM (R2 Technology, Inc., Los Altos, CA). This device can either scan a mammographic film with a laser beam and convert it into a digital image, or obtain images directly from a digital mammography system. The radiologist can see if any of the highlighted areas were missed on the initial review and require further evaluation. Initial studies show CAD technology may improve the accuracy of screening mammography by reducing the number of missed cancers.3,13 A 2004 study reported that the use of CAD was not associated with statistically significant changes in recall or breast cancer detection rates.15 However, all radiologists in that study were considered breast imaging specialists, and the results of this study should not be extrapolated to use by community radiologists who vary widely in their proficiency.11 The greatest clinical value of CAD probably does not lie in its ability to raise the performance level of all breast imagers, but rather in its potential to bring the performance level of general radiologists to that of breast imaging specialists.35

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Digital Mammography Digital mammography, also known as full-field digital mammography (FFDM), is a technique for recording x-ray images in digital format instead of on x-ray film. The images are displayed on a computer monitor and can be adjusted before they are printed on film. Images can be lightened, darkened, and magnified to zoom in on an area of interest. The first digital mammography system, General Electric Medical Systems’ Senographe 2000D, received FDA approval in 2000. From the patient’s perspective, the procedure for a mammogram with a digital system is the same as for conventional mammography. However, the utility of the digital images may provide advantages over conventional mammography. For example, FFDM images can be stored and retrieved electronically, making remote consultations with other mammography specialists easier and lost mammogram films less likely. Despite the benefits of a digital medium, studies have not yet shown that digital mammography is more effective in finding cancer than conventional mammography. Digital mammography systems offer better contrast and lower spatial resolution at a lower radiation dose than traditional screen film mammography.20 However, the relative diagnostic accuracy of digital mammography as compared to traditional mammography has not yet been determined. The results of the Digital Mammographic Imaging Screening Trial, a large trial designed to determine if digital mammography provides any benefit in breast cancer detection over screen-film mammography, are currently being analyzed, and initial results should be available in 2005. Digital Tomosynthesis Mammography Digital tomosynthesis mammography, another modification of x-ray mammography, involves moving the x-ray machinery in an arc around the breast while taking several low-dose images (typically 7-12) at the same overall dose as conventional two-view mammography. The procedure reduces the possibility that overlapping structures from a specific angle will obscure a cancer, potentially making abnormalities more visible.38 With the advent of digital mammography, tomosynthesis to produce a three-dimensional image of the breast tissue became possible. A computer is used to assemble the information to provide high-resolution cross-sectional and three-dimensional images that can be reviewed by the radiologist at a computer workstation. This technique may improve the specificity of mammography with improved lesion margin visibility and may improve early breast cancer detection, especially in women with radiographically dense breasts, by avoiding the limitation of standard mammography, which attempts to project the three-dimensional anatomical information of the breast into a two-dimensional image.38 These three-dimensional image views can bring

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis structures into relief, and the image can be rotated in space for more careful examination. Dr. Daniel Kopans, at Massachusetts General Hospital, and his colleagues are currently conducting clinical trials using a prototype machine derived from the commercially available Senographe 2000D digital mammography system.a Another system, produced by Hologic, Inc., is expected to be available for clinical testing late in 2004. Currently, the most significant barrier to the adoption of the tomographic technology is the amount of time that it takes to reconstruct the image. Multiple images are necessary to reconstruct an adequate three-dimensional image of the breast tissue. Approximately 8 to 10 images are required to maximize contrast and detail. The current computer processing time of two hours will have to be shortened to several minutes to make use of this system feasible in a clinical setting.53 Diffraction Enhanced Imaging Diffraction enhanced imaging (DEI), a modification of the current practice of mammography in very early stages of development, may produce better images of breast tissue.42 Increased radiographic contrast could make this type of mammography more effective in revealing tumors.16 In DEI, a silicon crystal is placed between the object being studied and the x-ray film or digital detector where the image is recorded. The crystal diffracts a particular wavelength of x-ray producing two images. One image is based on x-ray absorption (conventional image from an x-ray) and the other image is based on refraction. Refraction is a process where light, including x-rays, deviates in angle slightly because of differences in the density of the material it passes through.4 Thus, the integration of these two images may provide more detail in the tissue. Researchers used a synchrotron housed at Brookhaven National Laboratory to image seven breast cancer tissue specimens using the DEI technique. The same seven specimens were imaged using conventional x-ray methods at the University of North Carolina at Chapel Hill. Early results indicated that tumor visibility might be superior with DEI in six of the seven specimens.42 Despite increased imaging capabilities, the large task of developing a prototype that can be used in the clinic still remains before clinical investigation can begin. In addition, training of radiologists to interpret the unique image characteristics may not be effective. For example, it will have to be demonstrated that interpretation will not be negatively affected by specific image features, such as microcalcifications. However, DEI is at a much earlier stage of development than the other technologies described in this overview and is not ready for clinical testing. a   Mass Gen news release. Dec 10, 2002. http://www.massgeneral.org/news/releases/121002tomosnythesis.htm.

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis ANATOMICAL TECHNOLOGIES Approaches Based on Physical Properties Technology Description Developmental Stage Approval First FDA Sonography Noninvasive modality that uses a handheld probe to reflect sound waves, not radiation, off of breast tissues, constructing an image of the breast based upon the physical properties (e.g., reflection of sound waves) of the underlying anatomy. This technique is FDA approved for adjunctive use in the clinic to clarify abnormalities initially detected by screening mammography. Routine adjunctive clinical use for diagnosis 1977 Electronic Palpation Electronic version of the clinical breast exam performed by a physician that measures the resistance of breast tissue, providing a quantitative characterization of breast “lumps.” Experimental use (clinical prototype) — Elastography Measures stiffness of breast tissue in response to a mechanical stimulus, developing a map of the mechanical properties of the tissue; thus, assisting the identification of abnormal tissue (e.g., hardened lesions). Experimental use —

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Technology Description Developmental Stage First FDA Approval Infrared Thermography Heat radiating from breast tissue can be imaged using infrared sensors. Regions of increased surface temperature are often associated with increased vascular activity supplying tumors with sufficient nutrients for sustained growth. Rare adjunctive clinical use 1982 Thermorhythmometry Uses several heat sensing probes to measure the surface temperature of the breast tissue over a 24-hour period to identify suspicious areas of the breast. Experimental use (clinical prototype) — Sonography (Ultrasound) Sonography, also known as ultrasound, is an imaging technique in which high-frequency sound waves are reflected from tissues and internal organs. Their echoes produce a picture called a sonogram based upon the properties of the tissue. Ultrasound can be used as an adjunct to mammography to evaluate suspicious areas on a mammogram, increasing the accuracy of the combined technologies.17 It can be of particular use in distinguishing between solid tumors and fluid-filled cysts because differences in reflective characteristics between the tissues are discernable on the sonograph. Ultrasound does not use any radiation and is usually pain-free. The exam may take between 15 and 30 minutes to complete depending on how difficult it is for the operator to find the breast abnormalities being examined, such as a lesion deep within the breast. Ultrasound is not currently used for routine breast cancer screening because it does not consistently detect certain early signs of cancer such as microcalcifications, which are deposits of calcium in the breast that cannot be felt but can be seen on a conventional mammogram, and are the most common indicator of ductal carcinoma in situ (DCIS). However, the technique is quite useful in conducting image-guided biopsy.26,33 Many techniques are being developed to

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis enhance the capability of ultrasound to detect cancer single-handedly; however, they are still under clinical investigation and will require further study to determine their utility.49 Electronic Palpation Sensors that record the resistance of tissues to applied pressure can be used to develop density maps of the breast that can be used to detect lumps in the breast. This technique is essentially an electronic version of the manual clinical breast exam, in which the physician applies pressure in a circular pattern over the breast to detect lumps, possibly indicating cancer. The electronic palpation device provides quantitative measurement of the hardness and size of lesions, opposed to the subjective manual breast exam. Several companies have developed palpation devices and received FDA approval. This technique is promising because it does not use radiation or require uncomfortable breast compression, yet its accuracy will have to be proven in clinical trials for widespread clinical adoption. In addition, it is relatively inexpensive. Elastography Mapping the mechanical properties (such as stiffness or elasticity) of breast tissue can identify abnormal tissue properties that are often associated with cancer growth.30 This method of cancer detection is known as elastography. Elastography couples mechanical stimulus (vibrations) with imaging modalities, such as ultrasound or magnetic resonance. Thus, imaging the behavior of the breast tissue in response to mechanical vibrations can discover abnormalities in the elasticity of the breast tissue (e.g., hard tumors) that may not be detected by mammography or are too deep in the tissue to be palpated. Such lesions hidden deep within breasts may not be palpable until they are quite large and difficult to treat.37 Magnetic resonance elastographic imaging of biopsy-proven breast tumors has demonstrated stiffness two to three times greater than the surrounding fibrous tissue.46,50 Although the proof of concept for this technology has been established, extensive clinical trials will be required to determine whether application in the clinic will be possible. Infrared Thermography (Digital Infrared Imaging) Infrared thermography is based on the principle that chemical and blood vessel activity in both precancerous tissue and the areas surrounding a developing breast cancer is often higher than in the normal breast. Precan-

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis cerous and cancerous masses have high metabolic rates, and they need an abundant supply of nutrients to grow. In order to do this they increase circulation to their cells by sending out chemical signals to keep existing blood vessels open, recruit dormant vessels, and create new ones (neoangiogenesis).b The increased vascular activity often results in an increase in surface temperatures of the breast near the location of tumor, which can be imaged through thermographic devices. In 1982, the FDA approved the first breast thermography device as an adjunctive breast cancer screening procedure.c Since then, several devices have been approved under the FDA’s 510(k) equivalent device review. However, to date, no thermographic device has gained clinical acceptance. Definitive clinical trials of this technology have never been conducted to determine its effectiveness in detecting breast cancer. Thermorhythmometry Although thermorhythmometry relies upon similar principles as infrared thermography to help identify breast cancer, the technique uses a different approach. Instead of imaging the breast, probes are placed on the breast that monitor the skin temperature over a 24-hour period (known as a circadian rhythm) to identify variances which may correspond to neoangiogenesis and cancer.24,44 This approach aims to identify abnormalities that could be missed with tests that only examine the breast for a brief period of time, potentially missing warning signs that are only evident by analyzing the daily temperature cycles of patients.52 b   International Academy of Clinical Thermography What is Breast Thermography. http://www.iact-org.org/patients/breastthermography/what-is-breast-therm.html [Accessed April 29, 2003]. c   A Review of Breast Thermography. International Academy of Clinical Thermography. http://www.iact-org.org/articles/articles-review-btherm.html [Accessed April 29, 2003].

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis ANATOMICAL TECHNOLOGIES Approaches Based on Electrical Properties Technology Description Developmental Stage First FDA Approval Electrical Potential Measurement Electrodes placed on the breast measure the small amount of natural electric charge at various locations on the breast. The abnormal growth of cancer cells may produce imbalances in the ionic gradients of cells that can theoretically be detected by the electrodes. Experimental use (clinical prototype) — Electrical Impedance Scanning Uses the electrical conducting properties of the breast tissue to identify tumors. A small amount of current is introduced into the body using a handheld probe; the breast tissue is then imaged using a technician-held device. Approved for clinical use No units sold in the United States 1999 Microwave Imaging Microwave pulses are used to image the conductivity of the breast. Since the water content of tissue largely determines the conductivity, researchers may be able to discriminate between the low water content of healthy cells and high water content in tumors to detect malignant breast tissue. Experimental use (clinical prototype) —

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Electrical Potential Measurement This technology involves use of electrodes applied to the skin to obtain measurements of electrical potential (differences in electric charge) at various locations on the breast. The difference in electric charge is measured in areas of suspicious findings in comparison with electrodes placed elsewhere on the chest. The abnormal growth of cancer cells may result in an ionic gradient with potassium moving out of the cells and sodium moving into cells. The difference in ionic concentration creates an electrical potential that theoretically could be measured by electrodes placed on the breasts.d This approach is proposed for examination of a suspicious finding based on either physical examination or breast imaging. A technician can perform this noninvasive procedure in less than 20 minutes and test results are available for radiologist interpretation within five minutes after the procedure. This technology is currently under clinical investigation to gather data to submit to the FDA. However, initial studies report a sensitivity of 90 to 95 percent and a specificity of 40 to 65 percent for palpable lesions.8 Additional studies will have to be conducted to verify the detection capability of this device for broad application/adoption. Electrical Impedance Scanning Different tissues have different levels of electrical impedance (resistance to conducting electricity). Electrical impedance is lower in cancerous breast tissue than normal breast tissue; therefore, electrical impedance scanning (EIS) devices can be used along with conventional mammography to help detect breast cancer. The electrical impedance scanning device consists of a hand-held scanning probe and a computer screen that displays two-dimensional images of the breast. The device does not emit radiation; rather, a very small amount of electric current, similar to a small battery, is transmitted into the body. The current travels through the breast, where it is measured by the scanning probe. Areas of low impedance, which may correspond to cancerous tumors, show up as bright white spots on a computer screen. The scanner sends the image directly to a computer, allowing the radiologist to move the probe around the breast to get the best view of the area being examined. The device is intended to reduce the number of biopsies needed to determine whether a mass is cancerous. The FDA approved an EIS device called the T-Scan 2000, in 1999, as an adjunct to mammography. However, none of the devices have been sold in the United States to date.36,e The scanner is not approved by the FDA as a screening device for d   See www.biofield.com [Accessed May 9, 2003]. e   Twenty-five T-Scan units have units been sold internationally.

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis MRS is a method of diagnosing breast cancer using biological factors, such as metabolism, that are intrinsic properties of the disease, not possible by imaging the anatomy of the breast. Comparison of the MR spectroscopic technique with the fine-needle aspiration biopsy findings in lymph nodes revealed a sensitivity of 82 percent, specificity of 100 percent, and accuracy of 90 percent.55 As with an MRI exam, MRS does not expose the patient to radiation, and takes about 45 minutes to perform. However, this technique is expensive and unproven, and therefore limited to academic medical centers conducting research in this area. Gene Profiling Genetic profiling allows for the characterization of a tissue sample based upon the genetic makeup and activity of the sample. For example, tissue samples from an invasive cancer and from a benign cyst will have very different growth characteristics determined by the genetic makeup of the tissue and more importantly the expression of that genetic code (the relative level of gene activity). The relative activity of thousands of genes on a microarray (glass slide with many spots each individually representing one gene) can be analyzed by computer algorithms to predict the behavior of the tissue. A recent study (2002) demonstrated the potential of genetic profiling to predict the clinical outcome of breast cancer.51 Microarray DNA expression profiles can be used on primary breast tumors to identify a signature expression profile (“poor prognosis signature”) of 70 genes strongly predictive of a short interval to distant metastases (<5 years). The “poor prognosis signature” consists of genes regulating cell cycle, invasion, metastasis, and angiogenesis. The gene expression profile outperformed all currently used clinical parameters in predicting outcome of disease, such as lymph node status and histological grade. A large unselected “cohort” of breast cancer patients may be required to validate the findings and bring this approach closer to the clinic. Eventually this technique may be used to select patients who would benefit from adjuvant therapy and avoid ineffective treatments. This approach may also prove useful in assessing prognosis prior to biopsy, helping to reduce the number of open surgical biopsies of benign tissue. Genetic Testing Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The BRCA genes are tumor suppressor (control the growth of cells) genes that in their mutated forms become cancer susceptibility genes increasing the risks of developing breast and

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis TABLE A-1 A Mutation-Positive Result May Have Both Benefits and Problems BENEFITS PROBLEMS Resolve uncertainty Increased fear, anxiety, depression, or guilt Lead to early diagnosis through increased screening Make medical decisions more pressing Identify relatives at increased risk Affect family relationships (pressure on relatives to get tested, guilt about children, etc.) Help make decisions about cancer treatment, chemoprevention, prophylactic surgery Possible employment or insurance discrmination Decrease risky health behaviors Fear of screening for fear of finding cancer Improve healthy behaviors     SOURCE: Greater Baltimore Medical Center (GBMC) Harvey Institute of Human Genetics. http://www.gbmc.org/genetics/harveygenetics/cra/brcatest.cfm [Accessed May 16, 2003]. ovarian cancer in people that carry the mutation. Women who have BRCA mutations have a 36 to 85 percent lifetime chance of developing breast cancer while the general population has only a 13 percent chance.j In testing for these mutations, a small sample of blood is drawn, and the DNA is analyzed for genetic defects in the BRCA1 and BRCA2 genes. The test results can be either mutation-positive or mutation-negative (see Tables A-1 and A-2). A negative result does not completely eliminate the chance that a genetic mutation exists within a family. Another breast cancer predisposing mutation may be present. Twenty percent of hereditary breast cancer families have mutations in genes other than BRCA1 and BRCA2. The identity of many of these other hereditary breast cancer genes is currently unknown.k Despite the fact that there is no proven approach to prevent breast cancer, there are interventions that may decrease an individual’s chance to develop cancer. Major interventions include chemoprevention (use of drugs j   Breast and ovarian cancer gene testing: Is it right for you? http://www.mayoclinic.com/invoke.cfm?objectid=015A9CD3-3654-4EE8-B8AA87FC0323F818 [Accessed June 10, 2003]. k   Greater Baltimore Medical Center (GBMC) Harvey Institute of Human Genetics. http://www.gbmc.org/genetics/harveygenetics/cra/brcatest.cfm [Accessed May 16, 2003].

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis TABLE A-2 A Mutation-Negative Result Also Has Benefits and Problems BENEFITS PROBLEMS Relief False sense of security, still have background risk for cancer Cancer risk is similar to general population, normal cancer surveillance Mary cause some people to stop screening for cancer Prophylactic surgery may not be needed Survivor guilt Children of non-carrier not at increased risk Altered family relationships   SOURCE: Greater Baltimore Medical Center (GBMC) Harvey Institute of Human Genetics. http://www.gbmc.org/genetics/harveygenetics/cra/brcatest.cfm [Accessed May 16, 2003]. to reduce the risk of cancer) and prophylactic (preventative) surgery. The use of tamoxifen may be offered to reduce the risk of cancer in high risk women.7 Women at high risk may also be considered for the Study of Tamoxifen and Raloxifene trial,l which is evaluating the effectiveness of the drugs tamoxifen and raloxifene together in preventing breast cancer. Increased screening surveillance by mammography to detect cancer at an earlier stage may also increase breast cancer survival. Other changes may include lifestyle changes such as a balanced diet, limiting alcohol consumption, exercising, maintaining a healthy weight, quitting smoking, and avoiding known carcinogens (substances that are known to damage DNA and cause cancer). Serum Proteomic Profiling The pattern of proteins in blood serum (protein-containing portion of blood) may prove useful in identifying diseases, such as cancer. The development of cancer may signal a cascade of small changes to the proteins circulating in the blood serum that are detectable through mass spectroscopy (sensitive method for identifying substances by their molecular weight). Using computer algorithms, the relative levels of ionized proteins are measured and can be associated with the possible presence of a disease. l   Eligible women are 35 years of age or older, postmenopausal and considered at high risk of breast cancer based upon the NCI risk assessment score (>1.66%) or having already had lobular carcinoma in situ. The trial has been open since 3 years and will continue through the end of 2004. National Surgical Breast and Bowel Project. Study of Tamoxifen and Raloxifene. http://www.nsabp.pitt.edu/STAR/Index.html [Accessed June 10, 2003].

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Analysis of serum proteomic patterns which comprise many individual proteins, each of which independently were not able to differentiate diseased from healthy individuals, has recently been shown to provide a diagnostic endpoint for cancer detection.40 For example, certain patterns associated with the presence of cancers are under clinical investigation. From the patient’s perspective, the test is as simple as giving blood. Nipple aspirant fluid (fluid secreted through nipple duct openings in a nonlactating breast) is obtained using a noninvasive pump. Using serum proteomic patterns to identify breast cancers from 317 samples showed a sensitivity of 90 percent and specificity of 70 percent. However, even better results were achieved in the detection of ovarian cancer with 99 percent sensitivity and 99 percent specificity.29 Although studies have shown progress in this area, clinical proteomics (bedside application of protein pattern diagnostic tests) is not in the near future and large-scale clinical trials will have to be conducted to validate this technique for use as a routine screening tool. In addition, serum proteomics can only reveal that there is high possibility of cancer within the body. It cannot localize the cancer, and therefore must be used adjunctively with some sort of imaging modality. The whole process can take less than a minute from obtaining a sample to interpreting the results. BIOPSY TECHNOLOGIES Technology Description Developmental Stage Surgical Biopsy The gold standard in breast biopsy. Requires a surgical incision to completely remove the lesion (excisional biopsy) or obtain a sample from the lesion (incisional biopsy) to allow the pathologists to make a definitive diagnosis. Clinical use Core Needle Biopsy Larger needle used to obtain tissue samples from a breast lesion. This procedure usually obtains enough tissue to allow a pathologist to make a definitive diagnosis. Clinical use

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Technology Description Developmental Stage Fine Needle Aspiration Biopsy Small needle used to collect fluid or a small sample of cells from a breast lesion. This minimally invasive procedure allows for a pathologist to make a diagnosis; however, a larger sample size obtained through a more invasive biopsy procedure may be required. Clinical use Image Guided Biopsy Subset of needle biopsy procedures that use imaging techniques to guide needles into lesions and obtain samples from nonpalpable lesions. These imaging techniques typically include mammography, ultrasound, and MRI. Clinical use SmartProbe Real-time tissue identification using a 20gauge needle probe. The needle incorporates information from three spectroscopic fibers and an impedance microelectrode for breast cancer diagnosis. Experimental use (clinical prototype) Biopsy is a procedure that involves obtaining a tissue sample for further analysis to establish a precise diagnosis. Surgical Biopsy Traditional open surgical biopsy is the gold standard to which other methods of breast biopsies are compared.25 Surgical biopsy requires a 1.5-to 2.0-inch incision in the breast to remove suspicious tissue for pathologi-

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis cal examination. Surgical biopsy can take the form of either an excisional biopsy (complete removal of the lesion) or an incisional biopsy (only a sample of the lesion is removed for examination). Surgical biopsy takes place in an operating room. Most often a local anaesthetic (the breast only is numbed) is most often used, as opposed to a general anaesthetic (patient is asleep). The shape of the breast may change after removal of the tissue depending on the size of the lesion. Stitches will be required to close the incision and a scar might be left at the point of incision. If the lesion is nonpalpable, wire localization biopsy will be used with mammography or sonography to locate the area of concern before the operation. Open surgical biopsy requires a longer period of recovery than percutaneous (performed through the skin) breast biopsy procedures (such as fine needle aspiration or core needle biopsy). Usually, at least one full day of recovery is required and significant bruising can last several months. Core Needle Biopsy A core needle biopsy is a percutaneous (“through the skin”) procedure that involves removing small samples of breast tissue using a hollow “core” needle. For palpable (able to be felt) lesions, the radiologist or surgeon locates the lesion with one hand and performs a freehand needle biopsy with the other. In the case of nonpalpable lesions (those unable to be felt), image guidance is used most frequently with ultrasound, mammography, or MRI. The core biopsy needle can be from 11 to 16 gauge (outer diameter of 2.77 and 1.65 mm, respectively), while the fine aspiration needle is only 20 or 28 gauge (outer diameter of 0.89 and 0.36 mm, respectively). The core needle biopsy needle also has a special cutting edge. Typically, samples approximately 2.0 cm long are removed. The samples are then sent to the pathology laboratory for diagnosis. The core needle biopsy procedure typically only takes a few minutes, and most patients are able to resume normal activity the same day. Core needle biopsy usually allows for a more accurate assessment of a breast mass than fine needle aspiration because the larger core needle usually removes enough tissue for the pathologist to evaluate abnormal cells in relation to the surrounding small sample of breast tissue taken with the specimen.45 Biopsy results are usually available within several days. Fine-Needle Aspiration Biopsy Fine needle aspiration (FNA) biopsy is a percutaneous (performed through the skin) procedure that uses a fine-gauge needle and a syringe to sample fluid from a breast cyst or remove clusters of cells from a solid mass.

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis With FNA, the cellular material taken from the breast is usually sent to the pathology laboratory for analysis. The needle used during FNA is smaller than a needle that is normally used to draw blood. FNA needles are usually 20 or 28 gauge (0.89 and 0.36 mm, respectively), the size of needles typically used to draw blood. If a breast lump is palpable, the physician will guide a needle into the lesion. If the lump is nonpalpable, the needle will have to be image-guided. The samples are then smeared on a microscope slide, fixed or air dried, stained, and then examined by a pathologist under the microscope, a process similar to the examination of a Pap smear for the early detection of cervical cancer. FNA is the least invasive method of breast biopsy, and the results are available within minutes if a cytopathologist is available to interpret the results. FNA is a good technique for confirming breast cysts, and since the procedure does not require stitches, patients recover almost immediately. One disadvantage of FNA is that the procedure only removes very small samples of tissue or cells from the breast. If the FNA diagnosis is positive, this procedure can result in an incomplete assessment because the cells cannot be evaluated in relation to the surrounding tissue, which is crucial to establishing the stage of cancer and prognosis. Yet, insufficient sample rates for nonpalpable lesions and lower relative diagnostic accuracy reduce the clinical utility of FNA.41 Larger samples from a more accurate core needle biopsy or open surgical biopsy may be needed to make a definitive diagnosis. Image-Guided Biopsy Imaging techniques play an important role in helping doctors perform breast biopsies, especially of abnormal areas that cannot be felt but can be seen on a conventional mammogram or with ultrasound, such as those DCIS. One type of needle biopsy, the stereotactic-guided biopsy, involves the precise location of the abnormal area in three dimensions using conventional imaging approaches. Stereotactic refers to the use of a computer and scanning devices to gain information about the precise location of parts of the image in three dimensions. A needle is then inserted into the breast and a tissue sample is obtained for a definitive diagnosis from the pathology laboratory. SmartProbe Following a suspicious mammogram, a tiny 20-gauge disposable probe connected to a computer is inserted into the suspicious lesion. Measurements of oxygen partial pressure, electrical impedance, temperature, and

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Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis light scattering and absorption properties are made and instantly displayed on the computer screen. The “smart probe” makes continuous measurements (100 per second) as it moves from the surface of the breast to the center of a suspicious lesion. The entire procedure takes only a few minutes to complete, and the instant display of results will help the physician properly locate the probe within the suspicious tissue. Preliminary clinical investigations are under way at the University of California, San Francisco. Specificity and sensitivity of core needle biopsies are approximately 85 percent, and the gold standard surgical biopsy is 98 percent. The manufacturer of the biopsy probe, Bioluminate, Inc., hopes that the SmartProbe will exceed the accuracy achieved by the core needle procedure and approach the high levels realized by surgical biopsies. However, only a few small studies of the prototype technology have been published.1,2 Trials of this technology are in very early stages; no evidence of clinical validity has been published as of March 2004. REFERENCES 1. Andrews R, Mah R, Aghevli A, Freitas K, Galvagni A, Guerrero M, Papsin R, Reed C, Stassinopoulos D. 1999. Multimodality stereotactic brain tissue identification: the NASA smart probe project. Stereotact Funct Neurosurg 73(1-4):1-8. 2. Andrews RJ, Mah RW. 2003. The NASA Smart Probe Project for real-time multiple microsensor tissue recognition. Stereotact Funct Neurosurg 80(1-4 Pt 1):114-119. 3. Burhenne LJ, Wood SA, D’Orsi CJ, Feig SA, Kopans DB, O’Shaughnessy KF, Sickles EA, Tabar L, Vyborny CJ, Castellino RA. 2000. Potential contribution of computer-aided detection to the sensitivity of screening mammography. Radiology 215(2):554-562. 4. Chapman D, Thomlinson W, Johnston RE, Washburn D, Pisano E, Gmur N, Zhong Z, Menk R, Arfelli F, Sayers D. 1997. Diffraction enhanced x-ray imaging. Phys Med Biol 42(11):2015-2025. 5. Chaudhary SS, Mishra RK, Swarup A, Thomas JM. 1984. Dielectric properties of normal & malignant human breast tissues at radiowave & microwave frequencies. Indian J Biochem Biophys 21(1):76-79. 6. Chen YS, Wang WH, Chan T, Sun SS, Kao A. 2002. A review of the cost-effectiveness of Tc-99m sestamibi scintimammography in diagnosis of breast cancer in Taiwanese women with indeterminate mammographically dense breast. Surg Oncol 11(3):151-155. 7. Chlebowski RT, Col N, Winer EP, Collyar DE, Cummings SR, Vogel VG 3rd, Burstein HJ, Eisen A, Lipkus I, Pfister DG. 2002. American society of clinical oncology technology assessment of pharmacologic interventions for breast cancer risk reduction including tamoxifen, raloxifene, and aromatase inhibition. J Clin Oncol 20(15):3328-3343. 8. Cuzick J, Holland R, Barth V, Davies R, Faupel M, Fentiman I, Frischbier HJ, LaMarque JL, Merson M, Sacchini V, Vanel D, Veronesi U. 1998. Electropotential measurements as a new diagnostic modality for breast cancer. Lancet 352(9125):359-363. 9. Domchek SM. 2002. The utility of ductal lavage in breast cancer detection and risk assessment. Breast Cancer Res 4(2):51-53.

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