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Developing Technologies for Early Detection of Breast Cancer: A PublicWorkshop Summary

BACKGROUND

In November 1999, the Institute of Medicine, in consultation withthe Commission on Life Sciences, the Commission on Physical Sciences,Mathematics, and Applications, and the Board on Science, Technologyand Economic Policy launched a one year study on technologies forearly detection of breast cancer. The committee was asked to examinetechnologies under development for early breast cancer detection,and to scrutinize the process of medical technology development,adoption, and dissemination. The committee is gathering informationon these topics for its report in a number of ways, including twopublic workshops that bring in outside expertise. The first workshopon “Developing Technologies for Early Breast Cancer Detection” was held in Washington DC in February 2000. The content of thepresentations at the workshop is summarized here. A second workshop,which will focus on the process of technology development and adoption,will be held in Washington, DC on June 19–20. A formal report onthese topics, including conclusions and recommendations, will beprepared by the committee upon completion of the one-year study.

INTRODUCTION

The goal of early breast cancer detection is to identify cancersat a more curable stage and thus improve disease-specific mortalityand improve other important clinical outcomes. The breast cancerdetection technologies discussed at the workshop may have the potentialto enhance breast cancer detection. Right now, these emerging technologiesshow promise primarily as adjuncts to existing standard detectiontechniques, but with further development, some technologies may perhapseventually replace current early detection modalities. The goal ofthis workshop was to examine a diverse sampling of some of the emergingtechnologies—there are many other novel technologies on the horizonthat could not be covered in the limited time frame of the conference.

The workshop presenters described how far along the technologiesare in development and their potential strengths and weaknesses.They also addressed real-world considerations, such as cost considerationsand current reimbursement. Despite the promise of many of these modalities,adopting these technologies would raise new questions, namely thepotential for both benefit and harm, appropriate case selection,and cost/benefit tradeoffs.

In particular, workshop participants were quick to point out thatimproved methods for early detection of breast cancer bring new challengesas well as opportunities for intervention. If the information generatedby new technologies cannot be acted upon appropriately to improvesurvival, then women are not likely to benefit from the technologicaladvances. Furthermore, as technologies become better and better atfinding very small, early lesions such as carcinoma in



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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary Developing Technologies for Early Detection of Breast Cancer: A PublicWorkshop Summary BACKGROUND In November 1999, the Institute of Medicine, in consultation withthe Commission on Life Sciences, the Commission on Physical Sciences,Mathematics, and Applications, and the Board on Science, Technologyand Economic Policy launched a one year study on technologies forearly detection of breast cancer. The committee was asked to examinetechnologies under development for early breast cancer detection,and to scrutinize the process of medical technology development,adoption, and dissemination. The committee is gathering informationon these topics for its report in a number of ways, including twopublic workshops that bring in outside expertise. The first workshopon “Developing Technologies for Early Breast Cancer Detection” was held in Washington DC in February 2000. The content of thepresentations at the workshop is summarized here. A second workshop,which will focus on the process of technology development and adoption,will be held in Washington, DC on June 19–20. A formal report onthese topics, including conclusions and recommendations, will beprepared by the committee upon completion of the one-year study. INTRODUCTION The goal of early breast cancer detection is to identify cancersat a more curable stage and thus improve disease-specific mortalityand improve other important clinical outcomes. The breast cancerdetection technologies discussed at the workshop may have the potentialto enhance breast cancer detection. Right now, these emerging technologiesshow promise primarily as adjuncts to existing standard detectiontechniques, but with further development, some technologies may perhapseventually replace current early detection modalities. The goal ofthis workshop was to examine a diverse sampling of some of the emergingtechnologies—there are many other novel technologies on the horizonthat could not be covered in the limited time frame of the conference. The workshop presenters described how far along the technologiesare in development and their potential strengths and weaknesses.They also addressed real-world considerations, such as cost considerationsand current reimbursement. Despite the promise of many of these modalities,adopting these technologies would raise new questions, namely thepotential for both benefit and harm, appropriate case selection,and cost/benefit tradeoffs. In particular, workshop participants were quick to point out thatimproved methods for early detection of breast cancer bring new challengesas well as opportunities for intervention. If the information generatedby new technologies cannot be acted upon appropriately to improvesurvival, then women are not likely to benefit from the technologicaladvances. Furthermore, as technologies become better and better atfinding very small, early lesions such as carcinoma in

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary situ, treatment decisions can be difficult to make because so littleis known about the malignant potential of these premalignant cells.As a result, some women may face the diagnosis of breast cancer andthe subsequent therapy for a lesion that may never have become alethal, metastatic cancer. These issues are revisited frequentlyin the workshop summary. Advances in Traditional Imaging Technologies Full-Field Digital Mammography* Digital mammography consists of a dedicated electronic detector systemthat captures and displays the x-ray signals on a computer ratherthan film. Full-field digital mammography (FFDM) offers new capabilitiesnot provided by conventional film-screen mammography, according toCarl D'Orsi, who described the current status of development of diagnosticfull-field digital mammography. Unlike film-screen mammography, full-fielddigital mammography offers an infinite ability to manipulate contrastand brightness with one exposure. Many investigators in this fieldconsider such flexibility as a critical advance in helping to reducefalse negatives, which are most likely to occur when imaging densebreast tissue. Without the ability to adjust contrast and brightness,dense tissue can obscure precancerous and cancerous lesions. Digital mammography separates the process of image acquisition fromthat of image display. The detector responds to x-ray exposure andthen sends an electronic signal for each pixel to a computer whereit is digitized, processed, and stored. Because the signal for eachpixel is digitally stored, the same image can be manipulated to showdifferent brightness and contrast combinations, allowing radiologiststo more easily see through denser tissues. Digital mammography examinations can be displayed in either hardcopy(laser-printed film) or on screen (using a Cathode Ray Tube (CRT)monitor). With hard copy display, spatial resolution and gray scalerange are comparable to standard film screen mammography. However,laser-printed film is costly, involving significant costs for printing,development, personnel, supplies, and printing more than one versionof the mammogram. With screen display (also known as softcopy), digital mammographycan be used for computer-aided diagnosis, using algorithms similarto those available for reading film screen mammography. A potentialadvantage of softcopy display over conventional film-screen mammographyis that it permits adjustment of magnification, brightness, and contrastafter the mammography examination, thus enabling a more detailedexamination of questionable areas without necessarily requiring additionalimaging. Other potential benefits are its ease of image retrieval and transmission;ability to work in tandem with computer aided detection, and digitaltomosynthesis, a process whereby digitized images of the breast takenat different angles are used to reconstruct a three-dimensional imageor hologram of the breast. Studies on the feasibility of satellitetransmission of digital mammography, or telemammography, are alsocurrently underway. A major limitation, however, is that spatial resolution and luminancerange—even with the most advanced CRT technology—is significantly lower than conventional film screen mammography.The speakers suggested that reading softcopy off a CRT display ultimatelywill prove unattractive to users. Instead, they envision using atechnology that involves liquid crystal displays similar to thoseon laptops because they are likely to provide better image quality.However, an * Based on presentations by Carl D'Orsi and Etta Pisano.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary evaluation of the usefulness of soft copy display system such asvery high resolution CRTs and active matrix screens has not beenreported. If the technology is to pass muster, questions concerning the optimumspatial resolution must be resolved. A major unknown is whether increasedcontrast resolution can compensate for a lower spatial resolution.Pisano believes it will, but only if the image is displayed well.Further, she says that much of the power of digital mammography liesin its ability to distinguish between cancerous tissue and backgrounddense breast tissue. “It is likely that subtle lesions can be seenon digital mammography much more easily,” including diffuse calcifications,she believes. A multicenter trial supported by the U.S. Army Breast Cancer Researchand Materiel Command is currently evaluating full-field digital mammographyagainst film-screen mammography in a population of over 7,000 womenage 40 and older (principal investigator Ed Hendrick, Ph.D., NorthwesternUniversity). Preliminary results based on 4,945 screening exams showthat digital mammography performs no better than standard film screenmammography in detecting malignant lesions, but has so far led tofewer recalls than conventional mammography in a screening population.Sensitivity was 58.3% for digital mammography compared with 63.8%for screen-film mammography (the difference was not statisticallysignificant). Positive predictive value (the proportion of recalledexams that led to a diagnosis of cancer) was 3.7% with digital mammography,compared with 3.3% with screen film mammography. Positive biopsyrate with digital mammography appeared to be higher with digitalmammography than conventional mammography (30% vs. 19.8%), but thisdifference was not statistically significant. Digital mammography's lower recall rate (11.5%) compared to screen-film mammography's (13.9%) was statistically significant (p<0.001). If projected to U.S. women receiving screening mammograms(5 million), this could amount to 50,000 fewer women recalled forfollow-up procedures. Digital mammography has yet to reach its full potential, accordingto results from this trial. D'Orsi cautioned that the study describedabove is not yet completed and may have insufficient statisticalpower to detect a difference in sensitivity. The Department of Defensewill not be supporting further patient accrual to this trial. However,further studies are underway. The American College of Radiology ImagingNetwork (ACRIN) trial of digital mammography will be especially importantin answering many unresolved issues. Thus, the presenters urged thecommittee not to “throw the baby out with the bath water,” not to prejudge digital mammography's effectiveness, and adopt a wait-and-see approachin evaluating it. Currently, at least four manufacturers have digital mammography machineswith differing spatial resolutions: both Fuji and General Electricmachines have a resolution of 100 microns, Fischer's machine is 54microns; and Trex's digital mammography machine can obtain a 41-micronresolution. In January 2000, the Food and Drug Administration approvedthe first digital mammography machine, General Electric's Senographe2000 D digital mammography machine. However, it was approved foruse only with hardcopy display, which eliminates the opportunityfor enhanced softcopy manipulation and computer aided detection.Studies are currently underway to obtain FDA approval for softcopyinterpretation. However, another consideration is that prior filmstaken with standard film screen mammography cannot be imported easilyinto digitized formats for serial comparisons, posing a problem notuncommon in adopting new technologies. Cost may be another significant barrier. The GE digital mammographymachine costs approximately $450,000 per unit. Thus, purchasing themachines will entail significant up-front costs. Current reimbursementfor mammography also makes digital mammography an unappealing investmentfor radiologists, according to D'Orsi and Pisano. Both presenterssaid that

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary mammography reimbursement has remained unchanged over the last 10years and that mammography facilities are having a difficult timemeeting their expenses. They also suggested that radiologists intraining are pursuing other more lucrative areas of radiology, atrend that could erode access to mammography. Although the price could drop with broad use, insurers are likelyto take a hard look at whether the machine offers added value. Respondingto the mammographers' reimbursement concerns, a managed care representativesaid that many physicians have a “cottage industry mentality” that should be abandoned. In medicine,he offered, providers need to learn how to do more for less or insurerswill redirect their patients to providers who can offer more valuefor less money. He noted that technologies are unlikely to be attractiveto insurers unless they can improve upon existing technology, demonstratecost-effectiveness, save lives, or show improvements in importantclinical endpoints. Thus, if digital mammography cannot show superiorperformance in early detection by improving the sensitivity and specificity,insurers won't find it attractive in replacing conventional filmscreen mammography. However, if it can be better exploited to permittomosynthesis (3-D imaging), digital subtraction mammography withx-ray-based contrast agents, computer-aided detection, multimodalityimaging, or telemammography, it might offer added value over existingfilm-screen mammography. Computer-Aided Detection* Computer-aided detection (CAD) systems for screening mammographyconsist of sophisticated computer programs that are designed forrecognizing features of breast cancer, that is, microcalcificationsand masses. They are intended to help radiologists identify suspiciousareas that may otherwise be overlooked. CAD software works similarlyto a spellchecker, according to Ronald A. Castellino, M.D., and hasthe potential to increase the detection of cancer. The interpretation of screening mammograms is particularly challenging,since a large number of cases are viewed to detect a small numberof cancers (3–10 cancers per 1,000 women screened), which are oftenmanifest by subtle alterations superimposed upon the complex radiographicstructure of the breast. As a result, some cancers are missed. Studiesshow that a significant number of cancers (as many as 30–65%) canbe visualized on prior mammograms in retrospective review. Doublereading of mammograms by two radiologists can improve the detectionrate of cancer (which yields a 4–15% increase in cancers detected),but is expensive and time consuming. The goal of CAD is to improvedetection rates in a more efficient and cost-effective manner. Dr. Castellino summarized the results of a large clinical trial (subsequentlypublished in Radiology, May 2000) consisting of all breast cancercases diagnosed at 13 clinical sites by screening mammography (1,083,Current mammograms) over a two year period, and the most recent availableprior screening exam (427, Prior mammograms). The CAD system correctlymarked 99% of the 406 microcalcification cases and 75% of the 677mass cases, or 84% of the 1,083 Current mammograms. Subsequent algorithmimprovements marked 86% of the mass cases. The original radiologist's sensitivity for screening mammography was determined to be 79%(21% false negative rate). The CAD system correctly marked 77% ofthese cases. The sensitivity and specificity of CAD in a general screening population,however, has not yet been defined. Further research is needed toresolve these issues. * Based on a presentation by Ronald A. Castellino.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary Initially, there was some concern that CAD might result in a higherrecall rate for suspicious lesions. However, according to Castellino,data on recall rates at five clinical sites before (23,682 cases)and after (14,817 cases) the installation of a CAD system showedno increase the recall rate (overall preinstallation recall rate8.3% vs. postinstallation recall rate 7.6%) for any individual radiologistor for the group overall. Further studies of CAD with digital mammography also are underway.Several CAD systems are being developed by a number of companiesand are being tested on populations around the world. Magnetic Resonance Imaging Magnetic resonance imaging is the creation of images from signalsgenerated by the excitation (the gain and loss of energy) of elementssuch as the hydrogen of water in tissue in a magnetic field. Thesignals have characteristics which are reflective of the types oftissues (e.g., fat, muscle, fibrotic tissue, edema, etc). The methodhas no hazards from magnetic field effects and does not use ionizingradiation. Breast magnetic resonance (MR) imaging was first attemptedin the 1980s, but early results were disappointing. Subsequently,intravenous contrast agents were used with MR in the late 1980s,offering a clear advance: in general, malignant tumors showed intenseuptake of contrast, while surrounding normal tissue did not enhance.Following this discovery, MR has been studied as an emerging, butas yet unproven technology for breast cancer detection. Recently,a number of investigators in this field have demonstrated the potentialof breast MRI, but it is currently confined to experimental protocols.Improvements in specificity, and optimal acquisition protocols, examinationand interpretation standards remain as ongoing areas of investigation. MRI Screening in High-Risk Women* Contrast-enhanced magnetic resonance imaging is currently under activeinvestigation for several applications, notably for imaging densebreast tissue in younger women; surveillance of high-risk women;presurgical planning and surgical guidance; evaluation of recurrenceand drugtherapy monitoring; and for imaging elastography. Contrast-enhanced magnetic resonance breast imaging requires an intravenousinjection of Gadolinium chelate contrast agent and a dedicated breastcoil. The technique is often performed one of two ways: (1) by usinghigh-resolution three-dimensional magnetic resonance imaging capableof rendering the details of lesion morphology with a resolution of300 microns, or (2) using high-speed, lower resolution (~1mm), two-dimensionalmagnetic resonance imaging, to collect multiple images to track thekinetics of uptake and washout of contrast media in tumors. Theseare currently the best achievable resolutions on a very limited numberof MR scanners. The three-dimensional technique takes approximately4–7 minutes to collect detailed images of both breasts, while thetwo-dimensional technique requires 5–20 seconds per image section. Recent studies have shown that contrast-enhanced magnetic resonanceimaging confers a greater than 90% sensitivity in detecting lesions,according to Donald Plewes, but the specificity can be lower, rangingbetween 60% and 90%, depending on the patient population and interpretationtechnique used. * Based on a presentation by Donald B. Plewes, Ph.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary In the trial taking place at Dr. Plewes's institution, 200 women are undergoing four different detectionstrategies: mammography, clinical breast examination, ultrasound,and magnetic resonance imaging, to determine the relative sensitivityof each method. In addition, clinical trials are underway in othercountries throughout the world. In the US, a study is being conductedunder the aegis of the International Consortium on Breast MagneticResonance Imaging, the National Cancer Institute, and the NationalInstitutes of Health's Office of Women's Health. Similar studies in the UK and Europeare also underway or being planned. According to Dr. Plewes, withinthe next three years, approximately 5,000 high-risk women will havebeen scanned with MRI. MR Spectroscopy* Magnetic resonance spectroscopy uses MR to measure the biochemicalcomposition of tissues. It is under active investigation as an adjunctto mammography and other accepted imaging techniques. According toMitchell Schnall, M.D., MR spectroscopy research is in the earlystages of development but research with human subjects is underway. MR spectroscopy is being explored to help characterize human breasttissue. According to recent studies, MR spectroscopy has successfullycharacterized breast lesions of 1 centimeter or more. Dr. Schnallbelieves that the technique has the potential to offer much moreprecise information about the signature of tumors. For example, inan investigational setting, researchers are looking at the chemicalconstituents, such as choline content, of cancerous tissue. One hypothesisgenerated from animal studies suggests that the more choline foundin breast tissue, the more likely that it is cancerous. However,the technology is not yet far enough advanced for clinical use. Thereare many challenges that must be overcome if it is to prove beneficialas an adjunct to other detection techniques. For example, the sensitivityand specificity of MR spectroscopy need to be improved for smalllesions. At present, the International Consortium on Breast Magnetic ResonanceImaging, the National Cancer Institute, and National Institutes ofHealth are supporting research aimed at standardizing lesion characterization. MR spectroscopy is costly and it will be very important to determineits place among the emerging breast cancer detection modalities.Head-to-head trials of alternative detection techniques may answerunresolved questions about how the technology could be optimallyused. Such studies would also help determine its use as an adjunctto existing technologies. MR Imaging of Angiogenesis* Imaging of tumor angiogenesis, or new blood vessel formation, usingmagnetic resonance imaging also shows promise for detection of breastcancer lesions.. Using dynamic contrast technology and kinetic analysis,scientists are able to derive quantitative parameters, which correlateto the histopathology of angiogenesis. State-of-the-art MR scannerscan be used to image angiogenesis. There are several potential advantages of this emerging technology,according to Michael Knopp, M.D. With further study, Knopp hopesthat MR imaging of angiogenesis might permit more precise depictionof how tumors evolve at the molecular level. Another potential advantage * Based on a presentation by Mitchell Schnall, M.D. * Based on a presentation by Michael Knopp, M.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary is that angiogenesis studies provide a noninvasive assessment oftumor biology. The clinical utility of this method has not yet beendemonstrated, but in the future, the technique could establish itselfin the setting of predicting response to and in monitoring therapy.In high-risk populations and patients with highly aggressive tumors,this modality might prove particularly beneficial, according to Knopp.It has the potential to aid in surveillance and in developing moretargeted therapies that are not currently available, he says. Important drawbacks must be overcome if the technology is to passmuster. Current research shows that the technology is not yet ableto detect very small tumors and won't work unless angiogenesis isinduced or revascularization occurs. Scientists have recently learned that contrast agents that work wellin MR angiography also have the potential for imaging angiogenesis.Gadolinium chelates are the contrast agents most commonly used today,but newer compounds are available in Europe, and are entering theFDA pipeline in the US. Examples include the supraparamagnetic compoundsNC100150 (Clariscan (Tradename), Nycomed-Amersham, Oslo) and SHU555 (Resovist (Tradename), Schering, Berlin). These compounds arein various stages of clinical trials relevant for angiogenesis imaging.New classes of Gd-chelates that exhibit some reversible protein interactionsare also being developed, such as Gd-BOPTA (Multihance (Tradename),Bracco SpA, Milan), which was the first available agent and has weakinteraction, and MS-325 (Angiomark (Tradename), EPIX Medical, Cambridge),which is a complex Gd-agent with strong interaction. Other examplesof agents with potential for tumor imaging include Gadomer 17 (Schering,Berlin) and B-22956/1 (Bracco SpA, Milan). Recent research shows that MR coupled with new contrast agents candetect angiogenesis induced by factors such as VEGF (vascular endothelialgrowth factor) and FGF (fibroblast growth factor). Accuracy is above90% in most cases, with a 95% sensitivity or higher in patients withinvasive ductal cancers, 90% or greater for lobular cancers. However,in noninvasive cancers, its sensitivity(about 50%) is low. If the technique is to be used effectively, good case selection mustbe established. The National Cancer Institute is supporting researchon the pharmacokinetics and standardization of the nomenclature forMR imaging of angiogenesis. Ultrasound* Ultrasound waves are high frequency sound waves that reflect at boundariesbetween tissues of different acoustic properties. The depth of theseboundaries is proportional to the time intervals of reflection arrivals.Thus, ultrasound can map an image of tissue boundaries. Ultrasoundcan also provide information about blood flow by mapping the amountof acoustic frequency shift as a function of position in tissue,the Doppler effect. Within the category of non-ionizing radiationimaging techniques, ultrasound has been the most widely used. Traditionallyused as an adjunct to mammography in the identification of cystsand in guiding aspiration and biopsy, improvements in ultrasoundtechnology may expand the role of ultrasound in the differentiationof benign and malignant breast lesions and selection of patientsfor biopsy, according to Christopher Merritt, M.D. Ultrasound hasalso been shown, in limited studies, to hold promise as a methodfor early detection of cancers in women with dense breast tissue,which is often problematic with conventional film-screen mammography. * Based on a presentation by Christopher Merritt, M.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary Among the recent technological advances showing potential in expandingthe capability of ultrasound are methods for improving image qualitythrough use of high frequency transducers with improved spatial andcontrast resolution and by reducing noise through compound imaging.Enhanced detection of tumor vascularity through use of echo enhancingcontrast agents and improved Doppler techniques, three-dimensionalimaging, and novel approaches such as elastography may further expandthe role of breast ultrasound in the near future. A limitation of conventional ultrasound has been its poor abilityto detect small calcifications in the breast (microcalcifications).Usually identifiable with mammography, these tiny calcificationsrange from 50 to several hundred microns in diameter and may be animportant early indication of breast cancer. Contributing to thedifficulty of identifying small calcifications with ultrasound isa phenomenon called “speckle” that arises from the interaction of the ultrasoundfield with tissue. In the breast speckle may produce small brightechoes within tissue that have an appearance quite similar to smallcalcification, making detection of true calcifications difficult.Speckle and other forms of noise also degrade the definition andcharacterization of very small breast cysts and solid masses. Conventional ultrasound generates images using a beam that strikestissues from a single direction. Recent developments have made itpossible to generate an ultrasound image using several beams thatstrike the tissue from several angles. This technique, called compoundimaging, significantly reduces speckle in images of the breast andimproves the contrast and definition of small breast masses. Limitationsof compounding include a reduction in the display of shadowing andenhancement from some masses. The detection of tumor blood supply may be important both in theearly diagnosis of cancer and in the differentiation of benign andmalignant masses. Assessment of tumor vascularity may also be importantin predicting the biological activity of tumors and in monitoringresponse to treatment. Doppler ultrasound permits the identificationof blood flow within some breast masses, but has limited sensitivity.Ultrasound contrast agents might substantially improve the ability of Doppler ultrasound to evaluatetumor blood supply, particularly when coupled with new signal processingmethods such as harmonic and pulse inversion contrast imaging. Severalcontrast agents are now in the pipeline and are undergoing clinicaltrial. Innovations in three-dimensional ultrasound imaging are also proceedingrapidly. Three-dimensional ultrasound permits the examination ofa volume of tissue, rather than a single slice. Researchers at theUniversity of Michigan have developed innovative techniques for registrationof images from 3-D data sets, permitting more accurate measurementof tumor volume and comparison of changes in the size of masses overtime. In contrast to fetal and gynecological ultrasound, where 3-D methodshave received considerable attention, 3-D scan of the breast is inan early stage of development. In the breast, 3-D imaging deservesevaluation for early breast cancer detection as in serial studies,according to Merritt. Coupled with contrast agents, 3-D Doppler imagingmay provide more detailed assessment of tumor vascularity than iscurrently possible. However, additional research in the use of ultrasoundcontrast agents and three-dimensional ultrasound imaging is neededto fully define the contributions of these methods to detection,diagnosis, and assessment of treatment response. A novel use of ultrasound in the breast currently under developmentis elastography. Elastography uses information from the ultrasoundsignal to produce an image displaying the elastic properties of breasttissue. Like palpation, elastography is able to detect and displaydifferences in tissue stiffness. Since most cancers are hard in comparisonto the tissues that surround them, elastography provides a high contrastimage, in some cases revealing features that may not be

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary visible with conventional ultrasound or mammography. Investigatorsin the field are optimistic that elastography may improve upon conventionalultrasound's specificity and sensitivity, but further study is needed. According to Dr. Merritt, clinical trials that allow head-to-headcomparisons of these innovative technologies with conventional screeningtechniques are needed, particularly in settings where conventionalmethods are limited, such as in high-risk young women with densebreast tissue and for detection of multifocal disease in women withdense breasts. Ultrasound should also be investigated aggressivelyas an adjunct to mammography among patients with suspicious breastlesions, he says. Looking further into the future, it is possible to envision othernew approaches to cancer treatment aided by ultrasound technology.High intensity focused ultrasound (HIFU) is currently under investigationas a noninvasive method for the tumor ablation that may lead to nonsurgicaloptions for treatment of breast cancers in some patients, and ultrasonicdestruction of microbubbles carrying chemotherapeutic or gene therapyproducts is an intriguing possibility that could substantially increasethe dose of the agent delivered to the area of the tumor with minimalsystemic toxicity. However, the clinical utility of these novel methodshas not yet been determined. Functional Imaging* Traditional early cancer detection technologies use an anatomicalimaging approach, but a new era in medical oncology that focuseson imaging of molecular markers is under active development. Benchresearchers suggest that it has the potential to identify the molecularchanges in breast cancer much earlier than with conventional anatomicalimaging techniques, but this potential is still far from being realized. Imaging Molecular Markers* Scintimammography uses radioactive tracers that are taken up morereadily by breast tumors compared to normal breast tissues to producean image of a tumor. This is a relatively new technology that someclinicians may use as an adjunct to standard x-ray mammography tohelp localize tumors, to distinguish malignant and benign lesions,and to identify lymph node metastases. Studies indicate that theoverall sensitivity of scintimammography ranges from 75 percent to94 percent, and the specificity ranges from 80 percent to 89 percent.However, one limitation of scintimammography is its resolution, whichis between .8 and 1 cm. As a result, the scans cannot detect tumorssmaller than 1 cm. Developments in positron tomography and compact,special purpose devices may improve detection capabilities. In the future, it may be possible to advance this technology by combiningit with a molecular biology approach. Scientists are examining specificmolecules that define cancer and the transformed cancer cell. Usingradiopharmaceuticals in conjunction with nuclear medicine imagingtechniques such as positron emission tomography (PET), and singlephoton emission computed tomography (SPECT), they are just beginningto examine those molecules in living tissues. David Piwnica-Worms, M.D., suggested that if scientists can identifyearly markers of tumor aggressiveness—depending on receptor and enzymelevels, for example—they may be able to establish biochemical mapsthat could help individualize treatments. Currently, this technology is * Based on a presentation by David Piwnica-Worms, M.D, Ph.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary in the laboratory, but with continued research, he believes it mightbe sufficiently developed to enter the clinic within the next fiveto ten years. One example of this type of molecular imaging research has focusedon the imaging of multidrug resistance. Piwnica-Worms and other investigatorsare actively studying the fundamental mechanisms of radiopharmaceuticalsand multidrug resistance. The radiopharmaceutical 99m-Tc-sestamibiis selectively taken up by tumor cells compared to normal cells.Recent research in the laboratories of Silvana Del Vecchio, Ph.D.(Naples, Italy), Piwnica-Worms, and others suggests that the radiopharmaceuticalis pumped out of cells just like the chemotherapeutic agent adriamycin.Piwnica-Worms demonstrated in humans that excretion of 99m-Tc-sestamibiis mediated by P glycoprotein function. Del Vecchio subsequentlycarried out the pilot clinical research that correlated very rapid99m-Tc-sestamibi washout rates with treatment failure. This processcan be imaged with 99m-Tc-sestamibi using SPECT. Previous research suggests that approximately 25% of patients withstage I breast cancer overexpress P-glycoprotein and are at increasedrisk for failing conventional chemotherapy. Preliminary scintigraphicresearch has shown that patients who fail breast cancer chemotherapyclear the radiopharmaceutical 99m-Tc-sestamibi three times fasterif they overexpress the multidrug resistance P glycoprotein (MDR1). Piwnica-Worms suggested that these MDR imaging trials might permitmolecular characterization of breast tumors and aid in early detection.Novel interventions, yet to be fully developed and proven effective,could then be combined with molecular detection to improve treatment.For example, researchers are now beginning to test P-glycoproteininhibitors in phase II/III clinical trials. Such inhibitors may increasethe efficacy of chemotherapy regimens in women who overexpress MDR. This is a burgeoning area of research and studies with other molecularmarkers are actively underway. Work with other contrast agents andPET imaging is also under active investigation (e.g., labeled endothelialgrowth factor and labeled steroids). If molecular imaging ultimately proves to aid in prognostic stratificationand more targeted molecular therapies become widely available, healthoutcomes might improve, while subsets of women could be spared iatrogenicmorbidity, and costs could be reduced. However, much more bench researchand clinical trials are necessary to prove efficacy and effectivenessbefore this technology enters the clinic. Imaging Gene Expression by MR* Another emerging imaging technique uses “smart” magnetic resonance contrast agents to reveal biochemical and physiologicalinformation, such as gene expression and other physiological processesin the form of a 3D-MR image. This approach is similar to some ofthe radiopharmaceutical techniques described above, but in this case,the technology uses gadolinium contrast agents within a molecularshell. Specific biochemical processes open the protective shell,allowing hydrogen nuclei to interact with the gadolinium, which changesthe MRI signal.. This work is under active study in the laboratoryof Thomas Meade, Ph.D., at Caltech. He sees its development as afundamental key to a future in which we can detect cancer and otherdisease processes much earlier than shown with conventional anatomicalimaging techniques. * Based on a presentation by Thomas Meade, Ph.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary Imaging gene expression that can be correlated to disease statesis in the very early stages of development and is being pursued commerciallyby a company founded by Dr. Meade known as Metaprobe (Pasadena, CA).With further development, Meade says the novel imaging techniquecould track cell growth and behavior in breast and other cancers,including imaging of intracellular protein communication, apoptosis(or programmed cell death), and angiogenesis. With more precise imagingof cancer cell biology and function, the goal is to intervene earlierin the cascade of breast cancer progression, hopefully resultingin better clinical outcomes. If the technology proves to better stratifycancers early on, he says it may permit better targeting of therapies.However, so far, all research has been conducted on animals and testingin humans in clinical trials is still a long way off. Thus, littleis known about the technology's sensitivity, specificity, toxicity,and prognostic value. Optical Scanning* Optical scanning uses non-ionizing radiation and a variety of contrastagents to produce an image of the breast. Potential advantages ofthe technology include speed, comfort, noninvasiveness, and easyaccess to the breast. Optical scanning is able to penetrate deeplyinto the breast and do so without using ionizing radiation. To takean optical scan of the breast, an image pad is simply placed overthe breast. An image can be taken in less than 30 seconds withoutbreast compression. Using a near-infrared light probe and novel contrastagents, the technology has the potential to show the key molecularand enzymatic events involved in cancer development and progression.Optical contrast agents (termed “molecular beacons”) fluoresce (or light up) aftercleavage with specific enzymes. Optical scanning images can alsobe digitized, thus allowing image manipulation and serial studies.Hurdles that must be overcome before this technology reaches theclinic relate to accuracy and resolution, which are not yet optimized. The technique is actively under investigation for a variety of cancers,including breast and prostate cancer, and in the assessment of lymphnode metastases, according to Britton Chance, Ph.D., a pioneer inthe field who spoke on behalf of the seven other laboratories andindustries developing breast imaging optical devices. With opticalscanning, he says, it may be possible to obtain a coherent imageof enzymatic and molecular processes, offering depiction of abnormalcells before conventional anatomic imaging would be able to detectthem. Dr. Chance said that the technique is very inexpensive andsimple to use, especially in comparison to many other imaging modalities. Proponents of the technique hope that with further research, it maybecome possible to use optical scanning to enhance cost effectivenessof early detection and treatment. In the future, optical scans mightprove capable of enhancing the sensitivity and specificity of otherdetection techniques, and thus might help reduce unnecessary biopsies.The technique has already been shown to be relatively unaffectedby the problem of dense breast tissue, a limitation of mammography. Biological Detection The recognition that breast cancers of the same stage progress withwidely varying rates underlies much research into biological detection.Current staging techniques are considered relatively imprecise inpredicting prognosis. The goal of biological research is to classify tumors * Based on a presentation by Britton Chance, Ph.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary based on their molecular biology rather than their morphology asis currently done. If this goal can be achieved, then this new knowledgecould potentially be used to develop new methods for earlier detectionand also better stratifying cancers. However, biological analysisis most likely to be used as an adjunct to imaging technologies oncea lesion has been located based on its morphology. In some cases,the techniques might also be used to identify women who need furtherevaluation in addition to the usual screening mammography, whichis unable to detect certain breast tumors. Biology of Early Breast Cancer* Understanding the molecular biology of premalignant breast diseaseand early breast cancer is in its infancy and is relatively unchartedterrain, according to D. Craig Allred, M.D. “We are a long way offfrom a major paradigm shift in how we treat patients with these lesionsand translating knowledge about their biology from the bench to thebedside,” he observes. However, in pursuing research on the molecularbiology of premalignant disease and early breast cancer, it may becomepossible to prevent or delay more advanced invasive breast cancer. Conventional imaging techniques offer relatively imprecise estimatesof those premalignant lesions most likely to progress to invasivebreast cancer (IBC) or those IBC's most likely to metastasize. Tremendousbiological variability exists in these lesions and the ways in whichthey grow and spread. Identifying the molecules associated with invasivebreast cancer could open the door to developing more targeted preventionstrategies and could potentially aid in stratifying an individual's risk for invasive breast cancer and response to therapy. As Allred described, pathologists have long understood that breastlesions exist on a histological continuum. Cells in the stem cellcompartment, the normal terminal duct lobular units, begin to undergoa hyperplastic proliferative response, the first phase in the continuum.However, in conceptualizing breast cancer in terms of a linear processcarries with it an oversimplification of the development of breastcancer. Just in the past decade, there has been an explosion in researchon the biological determinants of breast cancer. Scientists are investigatingbreast cancer biology in studies examining the growth of premalignantlesions, the estrogen receptor, other growth factors, and genetics,for example. Immunohistochemistry on tissue sections is a technologythat can show tumor marker expression in cells, and along with histologicalgrading systems, can partially convey the morphological and biologicalheterogeneity of lesions. So far, the most thoroughly studied moleculesare the estrogen receptor, HER-2/neu, and p53. Both apoptosis and proliferation are under hormonal regulation innormal breast epithelial cells. Preliminary studies suggest thataverage rates of growth are higher and apoptosis is lower in premalignantcells compared to normal cells, which may be important in the developmentand progression of premalignant disease. In studying the genetics of breast cancer, loss of heterozygosity(LOH) is an intriguing area of research, according to Allred. LOHoccurs when one copy of a gene is deleted from a cell's genome. Theremaining copy is often mutated. The studies are based on DNA isolatedfrom archival tissue samples that are microdissected, allowing independentexamination of lesions. They are incubated with primers for differentmicrosatellite markers, PCR-amplified, and separated on a gel. Therehave been at least thirty studies that have found significant ratesof loss of heterozy * Based on a presentation by Craig Allred, M.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary gosity at dozens of genetic loci in premalignant disease and earlybreast cancer. However, the contribution of these genetic alterationsto the initiation or progression of breast cancer is largely unknown. One impediment to moving ahead in our understanding of early breastcancer is that researchers have been largely restricted to workingwith small archival tissue samples from premalignant breast tissue,which means that scientists have been limited to doing correlativestudies. Such studies do not provide information on mechanisms, andthere is a lack of animal models or cell lines to address these mechanisticquestions. Microarray Analysis* DNA chips, or cDNA microarray analysis, holds promise for pinpointingwhich genes are differentially expressed in cancer compared to normaltissue, according to Stefanie Jeffrey, M.D. Microarrays display thousandsof DNA dots on a single slide. Each dot represents an individualgene, and as many as 24,000 dots make up a gene chip. The microarraytechnology enables researchers to look at thousands of genes at onceand obtain a tumor “signature.” Scientists working in this field believe thatthe technology will eventually be able to differentiate tumors thatare aggressive from those that might lie dormant. In the future,it may also be able to determine how a given tumor will respond tosystemic therapy, but currently, applications of the technology arein very early stages of investigation. The technology first emerged in the mid-1990s. Early pioneers includePatrick Brown, Ph.D., and David Botstein, Ph.D., from Stanford UniversitySchool of Medicine. They have been using microarrays to study a varietyof cancers. Jeffrey is using the technology to study breast cancer.She is now studying late-stage breast tumors (generally greater than2 cm), using frozen breast tumor tissue. As of now, Jeffrey saysthat her group has been making microarrays with 23,000 genes. Withthe microarrays, it is possible to analyze tumors for expressionof specific gene markers, such as HER-2/neu and ER. It may also bepossible to identify new genes involved in breast cancer progression.Once genes are identified, researchers can conduct verification studiesusing a variety of techniques to see whether it is important in cancer. So far, Jeffrey's lab has been able to develop a cluster scheme that groups togethertumors that are similar in gene expression. To further develop thistechnology, Jeffrey believes that examining normal breast tissue,as well as earlier stage cancers, is important. Currently, she islooking at RNA that is harvested from core needle biopsies. Anotherapproach uses a technique known as laser capture microdissectionto collect cells. The technique permits examination of small clustersof cells, and can be used to collect pure samples of endothelialcells, stromal cells, as well as epithelial cells, which cannot bedone with other techniques. The high costs associated with DNA chipsand banking sufficient tissue for study are potential barriers tomoving this research forward. The need for better “bioinformatics” was also raised as an issue that must be reconciled to allow furthertechnology assessment. Another unrelated technique that Jeffrey and others are using involvesNASA-type “smart probes,” which differentiate tumor from benign tissue. These minimallyinvasive probes identify physiologic properties of tumors, such asoptical reflectance, intratumor O2 measurements, electric potentialdifferences, and laser doppler bloodflow of tumor vascularity. Otherways to potentially exploit the technology include measuring temperaturechanges, drug levels, and serial * Based on a presentation by Stefanie Jeffrey, M.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary changes within a tumor. With this technology, it is may be possibleto show very small physiological differences within a breast tumorand at its margin. Jeffrey noted that she has been testing the smartprobe technology in only in rats so far.. Nipple Aspiration of Fluids and Cells* Nipple aspiration is another early breast cancer detection modalityunder investigation. Nipple aspiration uses breast massage and amodified breast pump to aspirate fluid and cells for determininga cytological diagnosis. It can also facilitate measurement of proteinmarkers such as growth factors and tumor-specific antigens, whichare likely to be more concentrated in the breast fluid than in serum.However, to date, analyses such as these have not demonstrated thesensitivity necessary to accurately predict the presence of breastcancer, and thus further research will be required to develop thetechnology. According to Edward Sauter, M.D., the technique could serve as anadjunct to mammography and other conventional imaging studies. Hesuggests that it might be particularly useful for detection of breastcancer in young women with dense breasts or women who have undergoneradiation for breast cancer, both of which are not as easily monitoredby mammography. Potential strengths of this evolving technology arethat it can be done inexpensively by trained nurses and there areno age limits in using it. Proponents of the technique say it isnoninvasive, painless, and nontoxic. Early studies of the technology have stymied development becauseinitial data showed a poor yield of cells and low sensitivity andspecificity. According to Dr. Sauter, there is a learning curve inperforming the technique. After performing approximately 30 to 40cases, nurses become proficient at aspirating fluid successfully. Culturing Breast Cells† According to Jean Latimer, Ph.D., bench researchers are also developingnovel ways of culturing the specific cells that develop into breastcancer, the mammary epithelial cells. These cells make up the three-dimensionalplumbing system for milk in the breast. Latimer reported that herlaboratory has developed a cell culture system that is able to maintainviable primary human mammary epithelial cultures from breast reductionmammoplasty surgeries for at least three months in a laboratory incubator.These normal cultures grow and differentiate into three-dimensionalstructures similar to those seen in the breast, she says. Progressiveduct formation and branching are manifested in these cultures, aswell as the organization of lobules (epithelial structures at theends of ducts, which are necessary for milk production). In addition, Latimer's laboratory is also obtaining and studying fresh cells taken frommalignant breast tissues. The tumor primary cultures generally donot form the same complex architectures seen in the nonmalignantcultures, but manifest more independent cell behavior, dependingon the stage of the tumor, she says. Understanding the cellular communication factors in the normal breastis essential to producing and maintaining organotypic in vitro models,according to Latimer. Knowing how these factors lead to the differentiationof epithelial architecture and the corresponding cascades of geneexpression may be important for determining the pathway leading tobreast cancer. * Based on a presentation by Edward Sauter, M.D. † Based on a presentation by Jean Latimer, Ph.D.

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Developing Technologies for Early Detection of Breast Cancer: A Public Workshop Summary In addition, Latimer indicated that her laboratory has extended thelife-span of these primary cultures to develop 70 immortalized celllines from nonmalignant breast epithelium as well as tumors fromstage 0 (Ductal Ccarcinoma In Situ) to stage IV. Every primary cultureis now being extended for the production of an immortal cell line.All of these cell lines are available to the scientific communityand primary cultures are available upon request through a materialtransfer agreement or collaboration. With further research, the technology shows promise in stratifyingtumor cell aggressiveness and possibly in predicting metastatic potential,says Latimer. At present, tumor aggressiveness varies widely withina given stage. For example, although some 75% to 80% of stage I breastcancers can be cured with lumpectomy, 15% to 20% will recur, despitesurgery. If the more aggressive tumors can be distinguished fromthose that are slow-growing or less likely to metastasize, womenwith less aggressive tumors could eventually be spared the morbidityof high-cost therapies that also compromise their quality of life,while not enhancing clinical outcomes. At the same time, in betteridentifying more lethal, aggressive tumors, researchers might bebetter able to deliver systemic therapy earlier on, optimizing outcomes. This technology is in a very early stage of development. Using time-lapsedigital movies of the live cells taken from tumors, it is possibleto capture living cell movements and cell-to-cell interactions. Sofar, the time-lapse live cell videos have revealed markedly differentbehavior and cell-to-cell interaction in tumor cells compared withnormal cells, according to Latimer. Normal cells retain contact witheach other and form three-dimensional structures. Breast tumor cellsoften behave quite differently, with the cultures containing a highproportion of rapidly moving, independent cells, which do not retaincontact with each other. Significant variability among similarlystaged tumors has been documented in these time-lapse digital movies.At present, Latimer is prospectively following patients whose tumorshave been captured in movies to determine whether more aggressivetumors demonstrate more aggressive behavior in culture. Results ofthis ongoing investigation will dictate the chemical utility.