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Institute of Medicine (US) and National Research Council (US) Committee on New Approaches to Early Detection and Diagnosis of Breast Cancer; Joy JE, Penhoet EE, Petitti DB, editors. Saving Women's Lives: Strategies for Improving Breast Cancer Detection and Diagnosis. Washington (DC): National Academies Press (US); 2005.

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Saving Women's Lives: Strategies for Improving Breast Cancer Detection and Diagnosis.

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Appendix ABreast 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.


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

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

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 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.


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
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
ThermorhythmometryUses 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 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.


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. Precancerous 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.


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


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)

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 breast cancer, and is recommended to be used when mammography or other findings clearly indicate the need for a biopsy.

In a separate study comparing EIS to sestimibi scans, the T-scan had 72.2 percent sensitivity and 67 percent specificity in detecting breast cancer and sestamibi had 88.9 percent sensitivity. The T-scan detected one more breast cancer than sestamibi, at the expense of 27 additional false-positive results.34

Based on his studies of electrical impedance spectroscopy (the technology on which T-Scan is based), Keith Paulsen concluded that more work needs to be done with this technology. The placement of the electrodes on the breast, which determine the signal, depends on the operator and the impact of this on the test accuracy needs to be tested further. The technique is generally a low resolution, at best detecting tumors that are 1 cm or larger (about pea-sized). Because the technique loses sensitivity as the distance from the electrode increases, lesions deep in the breast will be harder to detect than those close to the skin surface. Finally, although the technique is potentially very high contrast, this remains somewhat controversial. Furthermore, this technology has not been evaluated by any large clinical trials and its lack of widespread acceptance might be due to the extraordinarily high reliability and accuracy of biopsy.

Microwave Imaging

Mapping the differences in the electrical properties can be accomplished by using low-energy electromagnetic waves, known as microwaves. Due to higher water content in tumors as compared with healthy tissue, differences in the electrical-conducting properties of breast tissue can be analyzed. Two to three times the amount of electrical conductivity is observed through microwave imaging of cancerous breast tissue when contrasted with surrounding normal tissue.5,23,27,48

While researchers are still years away from clinical trials, they have studied the technique using breast phantoms (test objects that simulate the radiographic characteristics of normal and cancerous breast tissue) and excised breast samples. Researchers were able to identify tumors as small as 6 mm in diameter (comparable to x-ray mammography for masses). But microcalcifications, which are often signs of early breast cancer, can be found much smaller than 6 mm with mammography.

However, breast cancers have the potential to show more contrast at microwave frequencies than at the x-ray frequencies used for mammograms.12 Also, the sometimes painful breast compression associated with x-ray mammography is not required for the conformal microwave imaging. Women can recline comfortably on their backs during the procedure. Microwaves imaging also avoids the use of radiation (see Harms of Mammography in Chapter 2).


Approaches Based on Optical Properties

Technology Description Developmental Stage First FDA Approval
Optical Infrared light is passed through the breast tissue identifying areas of high vascular activity that have been shown to correlate with the rapid growth of tumors. Experimental use (clinical prototype)
Computed Laser Mammography A modification of conventional optical imaging in which harmless optical lasers penetrate the three-dimensional surface of the breast to identify areas of high vascular activity. Thus, along with the use of a computer program, a three-dimensional image of the breast and the location of possible abnormalities is created. Experimental use (clinical prototype)

Optical Imaging

Optical imaging is a method by which near-infrared light is used to image the hemoglobin content of tissue, identifying possible malignancies. Imaging the absorption of near-infrared light in breast tissue can quantify the hemoglobin content and volume of blood perfusing the tissue, providing contrast between the dense vasculature often associated with cancer and healthy tissue.21 Since most tumors require an abundance of nutrients delivered through the vasculature of the capillary bed for accelerated growth, the high oxygen content and blood volume has been demonstrated to correlate with malignancy.21,39 Furthermore, using a technique called diffuse optical tomography, three-dimensional visualizations can be constructed to improve visualization of abnormalities in the tissue.21,22,39 Only mild breast compression is required for this technique and the breast tissue is not exposed to radiation. This method is favored for its speed, low cost, safety, and noninvasiveness; however, optical imaging has not been validated in large clinical trials and problems of low image resolution and difficulties with image reconstruction will have to be overcome.21,39 Several companies are in the late stages of development of this technology and are conducting clinical trials for submission to the FDA to obtain marketing approval. Despite the progress made in developing optical imaging, clinical validation of the technology has not occurred to date.

Computed Tomography Laser Mammography

Computed tomography laser mammography (CTLM) visualizes the blood supply of tumors, without the use of x-rays and without breast compression. As with optical imaging, increased blood supply indicates the presence of a tumor, based upon the assumption that the rapid growth of tumor must be supported by increased vascularization. Lasers are used to illuminate the breast in 4-mm increments scanning the breast tissue from the chest wall to the nipple. Algorithms are then used to create three-dimensional cross-sectional images of the breast. The technology is designed to be used as an adjunct to mammography for women who have dense breasts and/or whose mammograms are otherwise difficult to interpret. CTLM can potentially provide additional information to radiologists to guide biopsy recommendations.f The technology is not yet available because the FDA has not completed its review for approval of this technology. Research began in November of 1999 at the University of Virginia, yet as of March 2004, no published studies of CTLM indicate the accuracy of detecting breast cancer or the size of the lesions that can be detected.g


Approaches Based on Magnetic Resonance Properties

Technology Description Developmental Stage First FDA Approval
Magnetic Resonance Imaging Type of anatomical imaging that involves using an RF pulse-response in a very strong uniform magnetic field. Various tissue types exhibit unique resonance characteristics which can be displayed with differing contrast properties and allow breast lesions to be identified. Adjunctive clinical use along with mammography 1985

Magnetic Resonance Imaging (MRI)

In MRI, a powerful magnet linked to a computer creates detailed images of the breast without the use of radiation. Each MRI produces hundreds of images of the breast from side-to-side, top-to-bottom, and front-to-back. A radiologist then interprets the images to identify abnormal regions that may require further investigation. During an MRI of the breast, the patient lies on her stomach on the scanning table. The breast hangs into a depression or hollow in the table, which contains coils that detect the magnetic signal. The table is moved into a tube-like machine that contains a powerful magnet. After an initial series of images has been taken, the patient may be given a contrast agent intravenously to enhance the visibility of tissue characteristics. The contrast agent is not radioactive; and can be used to improve the visibility of a tumor. Additional images can be taken after administering the contrast agent. The entire imaging session takes about one hour.

Breast MRI is not FDA approved for routine breast cancer screening, but clinical trials are being performed to determine if MRI is valuable for screening certain women, such as young women at high risk for breast cancer.h MRI cannot always accurately distinguish between cancer and benign (noncancerous) breast conditions. Uses of MRI may include assessment of abnormalities that are unclear on a mammogram, determination of the extent of tumor growth after initial diagnosis, and for evaluation of the effectiveness of treatments. MRI may also be useful in imaging augmented breast tissue, dense breast tissue (often found in younger women), and viewing breast abnormalities that can be felt but are not visible with conventional mammography or ultrasound.43 While contrast-enhanced MRI is statistically significantly more accurate than mammography for detecting multicentric DCIS, it was significantly less specific than mammography for detecting associated invasive disease in one published series.19 MRI is expensive, about 10 times the cost of conventional mammography and, because it will generate more false-positive results, it generates added costs of additional biopsies and/or other diagnostic follow-up. Ultimately more research on the proper application of MRI is needed. The technique may prove useful for special cases, such as screening women with very high risk of developing breast cancer, examining breast implant integrity, and for determining the extent of disease in women with cancer.43


Technology Description Developmental Stage First FDA Approval
Ductal Lavage Involves the collection of cells for microscopic examination by washing the breast ducts with a saline solution. The sample is then analyzed by a pathologist to identify abnormalities. Limited clinical use 1999
Scintimammography (99m Tc-sestimibi) A harmless radioactive tracer is administered to the patient, which may accumulate differently in cancerous and noncancerous tissue. This accumulation of the tracer can then be imaged using a gamma camera to identify breast lesions. Adjunctive clinical use along with mammography, but rarely used 1999
FDG-PET Radioactive compounds are injected into the blood stream and as they are metabolized, the biochemical activity of the tissue can be imaged. Thus, more active tissues may indicate suspicious areas. Clinical use for monitoring treatment, but not for screening or diagnosis 1976*
Magnetic Resonance Spectroscopy Type of biological imaging that analyzes the specific molecular components of a tissue by identifying alterations in the biochemistry of the tissue and identifying intrinsic properties of breast cancer. Experimental use
Gene Profiling Characterizes tissue samples based upon the activity of various genes that play a role in developing and invasive breast cancer. The relative activity of thousands of genes on a microarray (glass slide with many spots, each individually representing one gene) is analyzed by computer algorithms to predict the behavior of the tissue. Experimental use Not FDA regulated
Genetic Testing This technique uses a blood test to identify genetic mutations that have been associated with an increased risk of developing breast cancer. To date, the only clinically validated genes have been BRCA1 and BRCA2. Clinical use for risk assessment Not FDA regulated
Serum Proteomic Profiling The relative amounts of various proteins in the blood are measured by mass spectrometry. Computer algorithims are then used to identify patterns that may be indicative of the possible presence of cancer. However, this technique will only indicate the presence of cancer. Another modality will have to be used to image the tissue and determine the locations of the cancer. Experimental use

PET technology was originally approved in 1976; however, in 2000 the FDA issued a notice that FDG-PET was safe and effective for imaging cancer in patients with a known diagnosis of cancer.

Ductal Lavage

Ductal lavage is a technique for collecting samples of cells from breast ducts for analysis under a microscope. A saline (salt water) solution is introduced into a milk duct through a catheter (a thin, flexible, tube for adding or withdrawing fluids from a cavity) that is inserted into the opening of the duct on the surface of the nipple. The saline solution, which contains cells from the duct, is then withdrawn through the catheter. The breast cells that are washed out are sent to the pathology laboratory for analysis. This technique may be able to identify breast duct cells that have certain abnormal characteristics which may cause them to later develop into cancer. Although the ductal lavage device is approved by the FDA, it is still limited mainly to clinical trials to determine the sensitivity, specificity, and appropriate application in clinical use.9,10 As of this writing, no federal public health agencies or leading professional medical organizations have recommended ductal lavage as a screening test for women at high risk for breast cancer. Recently published evidence-based guidelines from the American Cancer Society concluded that there are currently insufficient data to recommend the use of ductal lavage either as an independent screening modality or in combination with screening mammography.47


Scintimammography involves injecting a radioactive tracer into the patient, which accumulates differently in cancerous and noncancerous tissues, to help physicians determine the presence of cancer. Currently, the technitium-99m sestamibi compound is the only radioactive tracer approved by the FDA for breast imaging.

This technique may be useful in patients who have dense breast tissue that makes their mammograms difficult to interpret or in patients with palpable abnormalities (i.e., those able to be physically felt) but whose mammograms do not reveal any abnormalities.17,28,32 Scintimammography may be used to determine whether a patient has a suspicious breast abnormality that would require a biopsy to confirm the presence of breast cancer. The test requires 45 minutes to perform and costs approximately $150 per exam.6 Nuclear medicine involves the use of radiation, but the dose is very low and presents minimal risk to patients. The half-life of the compound is six hours; thus, most of the compound leaves the body within a day.

To perform the exam, a radioactive tracer (Tc-99m sestamibi) is injected in the patient's arm opposite of the breast being studied. The radioactive tracer travels throughout the body, including the breast under examination, and accumulates in tissue present. Approximately five minutes after the injection, a gamma camera (device that takes pictures of radioactive distribution) is used to capture images of the breast from several angles. Dense breast tissue, common in young women, can obscure x-ray mammograms.31 Hence, scintimammography, which is less affected by breast density, may have potential as an adjunct to diagnostic mammography by helping to characterize larger lesions.17,32

Positron Emission Tomography (PET)

PET is a method by which cellular and molecular events can be evaluated. Radiolabeled molecular probes (radioactive tracers) injected into the blood stream are used to map out the underlying biochemistry.14 PET scans create live computerized images of chemical changes that take place in tissue. The patient is given an injection of a substance that consists of a sugar attached to a small amount of radioactive material. A common sugar probe used, 2-18F-fluoro-2-deoxy-D-glucose (FDG), is FDA approved and considered safe for administering into the blood stream.

The radioactive sugar is then absorbed at a higher rate by cells with higher metabolism, such as tumors. The radioactivity localized in the tumor acts as a beacon to help radiologists identify suspicious areas. However, clinical use of PET is generally limited to finding metastatic cancer that has traveled from the breast to another location in the body.

After receiving the radioactive drug, the patient lies still for about 45 minutes while the drug circulates throughout the body. The patient then lies on a table, which gradually moves through the PET scanner 6 to 7 times during a 45-minute period to detect the distribution of radiation. A computer translates this information into the images that are interpreted by a radiologist. PET scans are more accurate in detecting larger and more aggressive tumors associated with metastatic cancers than they are in locating tumors that are smaller (less than 8 mm) and less aggressive tumors.i

Magnetic Resonance Spectroscopy (MRS)

This spectroscopic technique can measure the metabolism of pathological specimens and identify biochemical changes, which closely correspond with the presence of tumors. For example, breast tissue with a high concentration of choline has been shown to be indicative of invasive breast cancers.54 Thus, by identifying alterations in the biochemistry of the tissue, 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 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).

TABLE A-1 A Mutation-Positive Result May Have Both Benefits and 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. [Accessed May 16, 2003].

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 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).

TABLE A-2 A Mutation-Negative Result Also Has Benefits and Problems

Relief False sense of security, still have background risk for cancer
Cancer risk is similar to general population, normal cancer surveillance May 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. [Accessed May 16, 2003].

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.

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.


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
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 pathological 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. 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.


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 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.


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Copyright © 2005, National Academy of Sciences.
Bookshelf ID: NBK22310


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