2
Plenary Session

Introduction to the Symposium and of the Founder and Chairman of The Breast Cancer Research Foundation Edward Penhoet, Ph.D., Chair, Committee on Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis; and Director, Science and Higher Education Programs, Gordon and Betty Moore Foundation

Good morning and welcome to this symposium to discuss the product of almost two years’ work on saving women’s lives. We are delighted to see so many who have joined us. Before we begin the formal presentations, however, we have a special guest, Evelyn H.Lauder, who has come from New York to say a few words to us. Mrs. Lauder is the Founder and Chairman of The Breast Cancer Research Foundation which has supported work at the Institute of Medicine’s (IOM’s) and National Research Council’s (NRC’s) National Cancer Policy Board on breast cancer research for several years, and in particular has been an important supporter of this project and co-sponsor of this symposium.



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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis 2 Plenary Session Introduction to the Symposium and of the Founder and Chairman of The Breast Cancer Research Foundation Edward Penhoet, Ph.D., Chair, Committee on Saving Women’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis; and Director, Science and Higher Education Programs, Gordon and Betty Moore Foundation Good morning and welcome to this symposium to discuss the product of almost two years’ work on saving women’s lives. We are delighted to see so many who have joined us. Before we begin the formal presentations, however, we have a special guest, Evelyn H.Lauder, who has come from New York to say a few words to us. Mrs. Lauder is the Founder and Chairman of The Breast Cancer Research Foundation which has supported work at the Institute of Medicine’s (IOM’s) and National Research Council’s (NRC’s) National Cancer Policy Board on breast cancer research for several years, and in particular has been an important supporter of this project and co-sponsor of this symposium.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Introductory Remarks Evelyn H.Lauder Founder and Chairman, The Breast Cancer Research Foundation Thank you, Dr. Penhoet, and good morning, everyone. I am very flattered to be introducing this symposium and pleased, on behalf of The Breast Cancer Research Foundation to welcome all of you. We are all here because we share a common goal, to save women’s lives from breast cancer. As founder and chairman of an organization that has raised over $95 million since 1993 to support innovative research in preventing and curing cancer, I know and appreciate the critical role of early detection and diagnosis. In 1992, along with Alexandra Penney, who was then editor of Self magazine, we introduced to people all over the world the pink ribbon which has come to be recognized as a universal sign of breast health and awareness. I’m proud to say that since that time, the Estee Lauder Companies alone have distributed over 45 million of these ribbons at our counters worldwide. In 1993, I led a delegation of Estee Lauder executives and editors from Self magazine to Washington, D.C., and we raised a window shade on which had been pinned 250,000 names. Through coverage of this event in the national press and television and our visit to Hillary Clinton at the White House, we drew attention to the fact that the federal government needed desperately to give more funds for breast cancer research. It was then that Major General Travis was designated to head a study as a result of which substantial new funds were made available for breast cancer research. So from the outset, we have been dedicated to supporting clinical and genetic research into the causes and treatment of breast cancer. Our Foundation’s grants for stellar research projects have really grown. For example, and of particular interest today, we provided major funding for the 2001 IOM and NRC report, Mammography and Beyond (Institute of Medicine and National Research Council, 2001). After its publication, Dr. Larry Norton, our scientific diretor, who is with us today, addressed the Foundation’s board and told us that the IOM was appointing a new committee to embark on a study to expand on that report. Dr. Herdman and Dr. Joy can attest to the enthusiasm with which Dr. Norton’s suggestions were greeted. We called the IOM right after the meeting to say that $100,000 had been pledged on the spot by members of our board for the new committee’s work. Since then, the Foundation has provided steady financial support for the project and has eagerly awaited the committee’s findings, which were released to the public last week, and are being expanded and presented in greater detail at this symposium today. I could not be more proud of the research that Dr. Norton and his colleagues on our Medical Advisory Board have recommended for support by The Breast

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Cancer Research Foundation. In fact, the first scientific presenter this morning will be our dear friend, Dr. Laura Esserman, whose research we have also supported for 10 years. The work that you have all done in assessing the state of breast cancer and early detection in this country and in identifying ways to improve detection and diagnosis is of major importance. Your research will make a huge difference in women’s lives, and for that, I want to thank you personally. You have fueled the determination of volunteers like myself and Peg Mastrianni, the deputy director of the Foundation, and her colleague, Anna DeLuca, who directs public affairs. You encourage us to work toward increasing public awareness and support, though magazine editorials, newspaper reporters, as well as fundraising. So I can’t thank you enough. DR. PENHOET: Thank you, Mrs. Lauder, for your comments and especially for the opportunity you have provided all of us on this committee to work on this project, to join you in the fight against breast cancer. We would also like to acknowledge the other sponsors of our work and the symposium: the Broad Reach Foundation, the Apex Foundation,1 and the National Cancer Institute. In addition, I would like to extend our warm thanks to Dr. Janet Joy, who was our report’s study director. It is hard to imagine anybody working harder for a period of 18 months; she has produced a very fine, readable report. I also recognize the vice chair of this committee, Dr. Diana Petitti, who worked closely with me and with Janet throughout the entire process. Diana, thank you so much for your help with this work today. Due to the shortness of time, I won’t go through the entire roster of participants in this committee, who are listed in the front of the report. This was an extraordinary group of experts who worked really hard to achieve the tasks assigned to this committee. We are grateful to all the participants, especially the sponsors and the staff of the IOM, for bringing us to this point. The report that we are here to discuss is the result of an 18-month study charged with examining existing and evolving approaches—that doesn’t mean just technology—that hold the greatest promise for improving the early detection and diagnosis of breast cancer. The committee focused on identifying which approaches are likely to save the most lives in the near term. This includes technology in the broadest sense—from specific tools such as digital mammography, MRI, biomarkers, and proteomics to how these tools and strategies can be most efficiently deployed in clinical practice. The committee’s recommendations address what we thought were the most important steps that could be taken to improve outcomes of breast cancer in the near term. First, we have not yet optimally used the most powerful tool at our disposal, that is, mammography. So a number of our recommendations relate to the im- 1   The Apex Foundation support was given in memory of Mabel Frost McCaw and Joan Morgan, and in honor of Sallie Nichols, Beth Weibling, Jane Carson Williams, Bonnie Main, and Amy McGraw.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis provement of the practice of screen-film mammography and to better access to mammography. Second, the committee believes we need technology and procedures to develop individually tailored screening strategies so that high, medium and low risk individuals can receive the type of screening that is most appropriate to them. This poses a difficult task—to stratify risk in the population as a whole. We think that the promise of genomic technology has already been realized in a few instances in breast cancer, for example, the BRCA family of genes, and that in the future this might be expanded significantly. Our ultimate objective would be to customize and optimize screening strategies for individual women. Third, we need to address the weakest link in the pathway of technology development, that is, demonstration that a new technology or procedure truly improves health outcomes. Here, we recommend the formation of centers in the United States, either real or virtual, to integrate new technologies, particularly to integrate the basic research findings in biomarkers and proteomics, among other advances that we discuss, with clinical practice, and then once those things have become integrated, to make sure that clinical utility is demonstrated in a convincing way. We believe these recommendations are fully consistent with the new initiative at the National Institutes of Health (NIH), the road map, which seeks to better integrate basic research with clinical practice. The purpose of this symposium then is to discuss the implications of the recommendations in this report, as well as how they might be implemented. Several members of the committee are here today. You will hear from some of them, as well as other experts who have not been directly involved in the report. This symposium also will provide an opportunity to discuss the issues and complexities surrounding the early detection of breast cancer in much greater depth than is possible in a press conference. This morning we will hear from a series of speakers who will be addressing different themes following the outline in the report. In the afternoon, there will be two concurrent group discussions, ending with a plenary wrap-up discussion. The Pros and Cons of Screening Mammography: What Women Need to Know—An Overview of the Report’s Findings on Mammography Laura Esserman, M.D., M.B.A., Director, Carol Franc Buck Breast Care Center and Professor of Surgery and Radiology University of California, San Francisco The first thing that women need to know is that mammography is early detection, not prevention. The World Health Organization has set out principles for

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis detection through population-based screening. The disease should be serious and prevalent, like breast cancer. There should be a detection test that is sensitive and specific, well tolerated, inexpensive, and that changes therapy or outcome. This is important, because population-based screening is very different from individual screening. We are going to talk about what that means, and also how our new understanding of the biology of breast cancer should affect our approach to screening. The goal for breast cancer screening is not to detect every possible breast disease or abnormality but rather to prevent deaths from breast cancer. That is the ultimate test of whether screening is of value. What are the pros and cons of mammography? There have now been seven randomized trials that demonstrate 20 to 30 percent reductions in the relative risk of breast cancer mortality depending on age at screening. Mammography finds cancers at an earlier stage than detectable by physical examination. Small cancers are less likely to metastasize and are therefore more likely to have good outcomes. Small cancers are also more amenable to breast conserving treatment approaches and better cosmetic results. There really is no other technology that has been shown to systematically find tumors at an earlier stage, and 12 countries have implemented systematic screening programs. Participants in the global mammography summit in June 2002 reviewed the available evidence and unanimously decided that there was no reason to change screening programs. But they also noted that mammography is only one part of the total management of a woman with breast cancer; integration with further diagnosis and treatment is critical. So, why should there be any controversy? Well, mammography doesn’t find all cancers. The sensitivity is 83 to 97 percent; it depends on age and probably breast density as well, which is related to age. Mammography has a relatively high false positive rate, which is important. Ten percent is high for population-based screening. Mammography is resource intensive. Quality is actually quite variable, depending on how mammography is performed. The absolute number of women benefited by mammography is very different from the relative risk reduction. There is perhaps a four to six percent reduction in absolute mortality as opposed to the 20 to 30 percent reduction in relative risk. The absolute reduction also depends on age, and the value is quite a bit lower for young women, perhaps in the 1 to 2 percent range. Finally and importantly, finding cancers early does not guarantee cure. Biology can trump detection, and better understanding biology is an important theme of this report. Mammography has also led to a very large increase in the detection of in situ cancers; some call this the friendly fire in the war against cancer, an apt description, I think.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis Do we just need a more sensitive screening detection tool? Maybe we should be using ultrasound or magnetic resonance imaging (MRI), even though they are three- to fifteen-fold, respectively, more expensive than screen-film mammography. MRI, for which there has been considerable enthusiasm, can identify tumors that don’t form masses and tumors in dense breast tissue. MRI certainly is useful when we know someone is at extremely high risk for developing breast cancer. For women with genetic susceptibility, some of whom are known to have an 80 percent lifetime risk of developing breast cancer, MRI, even though expensive, has been shown to be much more sensitive than screen-film mammography, particularly because those being screened are young women with dense breast tissue in whom underlying breast tumors are more likely to occur (Kriege et al, 2004) The problem is that MRI is too sensitive. It finds all kinds of things that aren’t cancer, but whose significance is unclear, and its performance in detecting cancer is not better in women with fatty breast tissue who make up the majority of women ages 50 to 70 for whom screening is designed. Furthermore, biopsy tools are not readily available. Lastly, it is also too expensive for a general population screening test. That is probably also true for ultrasound, which is very labor intensive. These factors bear on how we want to think about population-based screening with the objective of saving women’s lives. Screening has enormous impact. Economically, mammography in aggregate U.S. cost is somewhere in the six to ten billion dollar range. Emotionally, women who are called back for low risk lesions or women with indolent disease, who assume they have life threatening disease, pay an enormous price, if in fact these things would not have otherwise come to clinical attention. The sensitivity and specificity of mammography depend to some extent on who interprets the image. High sensitivity, that is, the chance that a mammogram of a woman with breast cancer will be correctly interpreted as positive for cancer, is clearly desirable. But if you find absolutely everything, at some point you are going to pay the price of a high false positive fraction, or 1 minus the specificity (the specificity being the chance that the mammogram of a woman without breast cancer will be correctly interpreted as negative for cancer). Historically, it was thought that this was just a simple tradeoff, but it is not. Sensitivity and specificity are highly variable. Some breast imagers are more experienced and/or skilled than others, and, as exemplified in Figure 2.1, these imagers (represented by the curve for “better” interpreters) have better ratios

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis FIGURE 2.1 Better interpretation means a better ratio between true and false positive cancer readings as shown in this ROC (receiver operating characteristic) schematic. between true positive and false positive readings of mammograms. In short, the chance that a breast cancer will be detected depends in part on who reads the mammogram, and the chance of having a false positive also depends on the quality of the interpretation. (Of course, other factors are important, as well, such as the quality of the image, positioning and compression of the breast, among others.) In the U.S., over 75 percent of biopsies following mammography are not cancer. Although, there is variation in biopsy rates internationally, variation may be greater in the U.S. perhaps than in countries where they have more focused screening programs. The organization of care clearly affects the quality of screening. High volume, experienced mammographers find the most cancers and miss the fewest

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis FIGURE 2.2 Cost differences between programs of varying efficiency. CBR= cancer to biopsy ratio. cancers. Furthermore, coordinated teams make sure that, in the trajectory of care, the right procedure is done at the right time. We think that integration of the various aspects of care and feedback (learning from experience) is critical to optimizing performance. Where there are focused, organized screening programs, the fraction of positive operative breast biopsies can be 80 to 90 percent (UK) or 85 to 95 percent (Sweden) compared to the U.S. fraction of 20 to 70 percent. Data such as these suggest the value of high volume screening programs and support the conclusion that in some countries, mammographic interpretation is more consistent and of greater specificity than in the U.S. Such effective, highly-organized programs can also be more efficient with the potential for significant cost savings as indicated in Figure 2.2, which shows the high aggregate cost differences between high recall, low cancer to biopsy ratio (CBR) and low recall, high CBR programs. Higher quality can also be much more cost-effective (Burnside et al., 2001). We are also beginning to understand, through molecular fingerprinting, that all breast cancers are not the same. We can tell the types of cells from which breast cancers arise—where they are in the milk duct—and these different

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis FIGURE 2.3 All breast cancers are not the same. sources affect the outcomes for patients. As the survival curves in Figure 2.3 show, some types of breast cancer have a much higher risk of progression to distant metastasis and death (Sorlie et al., 2003). For example, new data from the Women’s Health Initiative, shown in Figure 2.4, indicate that some populations, such as African American women, have different types of breast cancer, so that, although the frequency may be lower, more aggressive, poorly differentiated plus estrogen receptor negative tumors are much more frequent. Breast cancer from milk duct luminal cells is more frequent in older women and is more likely to be well differentiated and amenable to treatment. Breast cancer from basal cells, which is more frequent in younger women, is often more aggressive and less likely to be amenable to treatment. Patient populations which are more likely to have aggressive, fast-growing tumors that are discovered when they are larger or have spread and are, therefore, less responsive to treatment, are not as likely to benefit from screening. That is relevant to what Dr. Penhoet was saying about screening and stratifying risk.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis FIGURE 2.4 African American women have significantly more aggressive, poorly differentiated, estrogen receptor (ER) negative breast cancer. So the lessons from biology are that tumors grow at different rates. Fast growing tumors may not be caught in time by mammography. Other slow growing tumors provide time to do interval screening and detection before they are a threat to the patient. And there are still other cancers that may grow so slowly, particularly if they are in older women, that they may never come to clinical attention. So part of our strategy has to be designed in concert with our new understanding of the biology of breast cancer. Returning to the implications of less frequent but more aggressive breast cancer originating in basal cells in African American women, one would expect perhaps that screening would make more of a difference in Caucasian women—more cases to find, more chance of making a difference through early detection. This does appear to be true, at least in part, as indicated by Figure 2.5 from the IOM report. Breast cancer incidence in African American women remains lower than in Caucasian women over time, but mortality is greater and has not been as affected by increasing rates of screening. While other factors may explain some of these effects, such as access and treatment variables, it is also important for us to integrate our understanding of biology when interpreting data like these. We should not expect too much from mammography. We know that mammography is not going to make a difference for all breast cancers, and breast cancer is not one disease. And mammography cannot be expected to find all cancers either. The cost of mammography often exceeds reimbursement, and this is also important in thinking about strategies. Having run a digital mobile van service

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis FIGURE 2.5 Consider biology when interpreting mammography data. SOURCE: Surveillance Epidemiology and End Results Program, NCI. FIGURE 2.6 Poverty is the greatest barrier to mammography screening.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis BOX 2.6 The Five Components of Medicare Reimbursement Regulartory approval (if applicable) Benefit catergory determination Coverage Coding Payment routinely (but not always) cover off-label indications, both diagnostic and therapeutic. But if the technology falls under FDA statutory authority, Medicare requires that it be approved for at least one indication. There are ways in which changes in FDA regulatory policy related to technology can influence payment policy. I will discuss this further later, but it is particularly relevant in the case of breast cancer and the coverage of mammography. The benefit category is the next step, and a major one, in the reimbursement cascade. Medicare is a defined benefits program, meaning the benefit category has to be defined in statute in order for Medicare to pay. Benefit categories include, for example, inpatient treatment, outpatient treatment, or durable medical equipment. And as you know, a prescription drug benefit was added in September 2003. Before the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA, P.L. 108–173), Medicare could not pay for outpatient prescription drugs, no matter how needed or effective they were. Diagnostic services are a Medicare benefit category, but screening and preventive services generally require separate legislation. Definition of a service as diagnostic is important because Medicare can pay for diagnosis but not screening. Medicare could pay for breast cancer diagnosis, therefore, including diagnostic mammography, by the use of new, not currently employed technologies. Screening mammography, however, was added by a change in Medicare law which described screening mammography narrowly and in such a way that the precise definition was left to the public health law and the FDA. That is why Medicare can pay for screening mammograms, but it is also why, as I noted earlier, other technologies besides screening mammography for early detection of breast cancer could not be covered without a statutory or regulatory change at the FDA. The actual language from Medicare law, section 1861(jj) states that the term screening mammography means a radiologic procedure provided to a woman for the purposes of early detection of breast cancer and includes a physician’s interpretation of the result of the procedure. The term radiologic procedure is not

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis defined in the statute or any Medicare regulations. Instead, it is defined in the Public Health Service Act and FDA regulations pursuant to that Act which limit the term to the standard mammogram, not PET scan, not CT, not MRI, and not ultrasound, among others. There is nothing, then, in the Medicare statute or regulations that would prevent inclusion of a much broader range of imaging technologies under the current statutory authority for paying for screening mammography if the FDA changed the definition of a screening mammogram as embedded in FDA regulations defining a radiologic procedure. Otherwise, it would probably require a statutory change to have any new breast cancer screening techniques paid for beyond the standard mammogram. At least, as I surveyed relevant staff in CMS, this seems to be the correct interpretation. As I said, the definitions of screening and diagnosis are important in determining Medicare payment. Diagnosis means a test that is done in the presence of signs or symptoms of disease. In other words, if there is an abnormal finding on a mammogram, any technology used to evaluate that abnormal finding is considered diagnostic and a coverable benefit. Medicare may refuse to pay for a diagnostic technology or procedure based on a decision that it is not reasonable and necessary, but at least it is a coverable benefit as opposed to a screening procedure in a healthy woman that discovered the abnormal finding (unless that screening procedure had been added by specific statute). For example, a very strong family history does not qualify any test as diagnostic. A woman could have the strongest possible family history of cancer and performing what could be considered a diagnostic study in the absence of signs or symptoms of disease or personal history of cancer would be considered screening and would not be coverable by Medicare (again, unless that kind of study had been specifically added to coverage by special statute). Last year, CMS considered adding testing for diabetes as a benefit for patients with risk factors, but no signs or symptoms of the disease, and explored a regulatory change to achieve this. We discovered we could not add this benefit without a statutory change, and so diabetes screening was included in the MMA. I suppose that, in theory, Medicare might change the rules to consider interventions to discover disease in a particularly high-risk situation as diagnostic (and reimbursable), but such a rulemaking process would not necessarily be a more efficient, faster process than a legislative change. Unlike mammography, the statutory benefit for colorectal cancer screening provides that lab-based fecal occult blood testing and other screening tests as determined by the Secretary in consultation with experts are covered. Therefore, if additional new technologies, virtual colonoscopy, for example, met the standard of reasonable and necessary, they would be potentially coverable under the statutory authority for colorectal cancer screening. But, unfortunately, to emphasize what I have said, the mammography screening benefit’s statutory language does not allow Medicare to add other breast cancer screening technologies.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis I have talked a little of the reasonable and necessary concept, which is the subject of technology assessment and evaluating medical benefits. The Medicare statute provides payment only for things that are reasonable and necessary for diagnosis and treatment of illness and injury. That term is not further defined in any official legal documents. CMS, however, uses a standard definition, which is that there has to be adequate evidence to conclude that the item or service improves net health outcomes experienced by patients (such as improved function, quality of life, morbidity, or mortality), generalizable to the Medicare population, and as good or better than currently covered alternatives. CMS uses a standard evidence-based-medicine framework, relying on the usual rules of evidence, no different than the U.S. Preventive Services Task Force. There is no formal economic analysis done as part of a reasonable and necessary determination. Although, there is no legal prohibition against considering costs, it is longstanding Medicare practice not to do so when making coverage decisions. A technology or procedure could cost $5,000, $50,000, or $500,000 per life year saved; it would meet the test of reasonable and necessary in any of these instances if it improved health outcomes. Coverage decisions can be made at the local and/or national level. Many people think that reasonable and necessary reviews at the local level apply a somewhat lower evidence standard of proof and may rely more on expert opinion. The usual view, therefore, is that, in terms of introducing new technologies, bringing those in through the local contractor process is less burdensome than coming in for a national coverage decision. The national coverage process is diagramed in Figure 2.14. It involves a formally defined series of steps for submitting a request for coverage, so that an evidence review can be referred to an outside advisory committee or a formal technology assessment carried out. In reasonable and necessary decisions for diagnostic tests (like diagnostic mammography, for example), CMS looks for studies of test performance, classic sensitivity and specificity, for impact on patient management and outcomes, which may depend on whether or not there is a beneficial intervention available, or asks if the information itself provides a benefit. Certainty in diagnosis may be useful by itself, or information about diagnosis or prognosis may influence decisions about the use of other health care services, institutionalization, or other care. If there is empirical evidence that knowledge of diagnosis influences the care or quality-of-life of the patient, that certainly would be a potential basis for meeting the reasonable and necessary standard. In some situations, however, like PET scanning for Alzheimer’s disease, where treatments are relatively ineffective and not particularly toxic, it is preferable simply to go ahead and treat based on the clinical story rather than run the risk of withholding treatment based on a possible false negative scan. In this situation, therefore, the test does not actually improve a health outcome.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis FIGURE 2.14 The national process for determining Medicare payment coverage. Sometimes, a CMS review of coverage results in a split decision, such as the coverage decision on PET for breast cancer. It is covered for diagnosis not for screening, consistent with the usual rules on benefit categories I discussed earlier, but it is covered as an adjunct to standard staging in loco-regional or distant recurrence and monitoring for response to therapy. It is not covered for evaluating abnormal mammograms or palpable breast masses or for evaluation of axillary lymph nodes to decide on lymph node dissection. Assuming that CMS could make reasonable and necessary decisions about screening and early detection of breast cancer, we still need to know who is doing the evidentiary studies, what is the quality of the studies, and what methods are required to study comparatively sequences of multiple studies. It appears that handling these questions is not part of anybody’s research agenda. As the IOM report points out, the funding for applied clinical research, how to use technologies once they are developed, is really nobody’s domain. This is what I am calling the systematic gap in evidence from applied clinical research. Decision makers are interested in using high quality evidence to support clinical and health policy choices, but the quality of available evidence is inadequate (Tunis et al., 2003). The whole concept of practical or pragmatic clinical

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis trials is one that has been talked about since the original discussion of pragmatic attitudes and therapeutic trials in 1967 (Schwartz and Lellouch, 1967). I am talking about the gap in studies in which the hypothesis and design are developed specifically to answer the questions faced by decision makers. These trials select clinically relevant alternative interventions to compare, include a diverse study population with broad patient eligibility recruited from heterogeneous “real world” practice settings, allow natural variation and are minimally intrusive on care, and collect data on a broad range of health outcomes both functional and economic (Tunis et al., 2003). I emphasize that the key is clinical research that is designed to answer the questions of decision makers like patients, like clinicians, and like payors and purchasers. That research looks very different from clinical research that is designed to answer fundamental questions about etiology, causation, and the like. CMS, under Dr. McClellan, is very interested, given that we are a major consumer of information needed to make decisions about payment and coverage, in trying to find ways to get into this business. We are working in a number of ways to try to facilitate the support and infrastructure for practical clinical research, research on comparative effectiveness, through Section 1013 of the MMA. We have new collaborations with NCI, NHLBI, and FDA to focus on this issue, looking into alternatives or modifications to clinical trials, registries, quasi-experimental studies, among others, to try to improve the evidence base. We also have a lot of interest in exploring coverage under protocol, that is, paying for emerging and promising technologies, but only in the context of a clinical trial or some kind of clinical study with systematic collection of evidence. I would like to conclude with some general comments on health care costs. We all know that we are spending a lot of money on health care, so it is important that we know the risks and benefits of the interventions we are using. While I said there is no explicit consideration of costs in Medicare coverage and payment, cost is the universal context of health care decision making. Both in the IOM report as well as in any other discussion, we must think about the economic implications of new or added technologies, the additional clinical value or the additional social value, and how that is related to the investment. There are many other unmet needs in society for health care services that should be balanced against additional spending for improvements in breast cancer technology or increases in payment to improve the quality of mammography. DR. PENHOET: We have time now for questions and answers from our last three speakers. DR. DUNNICK: What is the timing regarding the suggestion about testing technologies in practical clinical trials since we cannot test these with the classical randomized controlled trials or we will be waiting 10 or 15 years for results?

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis DR. TUNIS: One of the limitations of the evidence-based framework for coverage and payment policy is the long time it can take to prove something actually works, time during which introduction into practice should have occurred. The answer to getting relatively quickly from proof of principle at the bench to early experience at the bedside is to have some framework, as I have described, where there is a subset of technologies that look promising and could be reimbursed in the context of defined protocols in order to find out which actually work and which do not. So often at present as technologies are first introduced into practice, there is uncoordinated trial and error that produces no information about whether they are or value, and that wastes a lot of money and time. DR. ESSERMAN: Our report states that the organization of screening mammography and breast cancer care is important and could make for greater cost-effectiveness and better quality. But there is no funding or infrastructure to support that. I’d like to hear you comment on that. DR. TUNIS: I think we are actually at an inflection point in terms of payors thinking more about how payment policy might promote the efficient organization of care. Historically, Medicare has been a resource-based payor, that is, paying for resource consumption. In that context, there is no place for discussing how to pay for delivery of a service in a high quality way. Now, however, there may be an opportunity to make a case to both private payers and CMS for payment for models of care that are efficient. We can look at our regulatory and statutory authority and find out how we might facilitate that. Medicare now has a new Section 721 which allows a new payment mechanism for coordinated care for chronic illness, moving away from resource consumption. If you can do it better and cheaper, we will find a way to financially reward that. DR. ESSERMAN: In the committee, we considered whether proteomics would have to go head-to-head with mammography, that is, would have to have equivalent sensitivity and specificity. But that could hamper development of inexpensive and easy tests that have very high sensitivity and low specificity for use in a primary-secondary screen system. That is partly an FDA issue and partly a CMS issue; but what would enable or support this kind of integrated approach to combining tests and looking at more clever ways of harnessing technology? DR. TUNIS: The standard framework for evaluating new technologies does not easily apply to such staging of tests. I don’t have the answer to how to do that. If you came up with a framework by which that kind of question could be answered, we payors would have to look at it, but at the moment we have rather simple-minded evidence standards that do not apply very well. DR. SMITH: Dr. Fletcher, I thought you addressed the issue of risk stratification very nicely in terms of the Gail model in context and its application to identify a population for study. The problem is, short term risk is deceptively

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis small, long term risk is deceptively large, and that makes it very hard for women to get a handle on how to think about risk mathematically for a disease that means a lot to them. As risk grows over time, screening needs to be thought of in terms of social insurance. Most women will not develop breast cancer in their lifetime, but screening can measurably reduce the risk of being diagnosed with advanced breast cancer that could result in a premature death. With respect to all-cause mortality, ultimately only about three and a half percent of women die of breast cancer, but that is not nearly as important as the contribution that breast cancer makes to premature mortality. In any given year, deaths of women diagnosed with breast cancer in their forties account for about 16 or 17 percent of all breast cancer deaths. We looked at the two-county trial to estimate the effect of a reduction of risk of dying of breast cancer on all-cause mortality. As you said, women in their forties have a very low risk of dying of anything. But among the causes of death breast cancer is quite a significant factor. The breast cancer mortality reduction we saw in that group meant a reduction in risk of dying of anything by about 50 percent. I am wondering how you would reconcile the near-term risk versus the long-term risk against the background of something simple to do that can ensure, even though you have a low probability of dying of anything, that you have significantly reduced your risk of dying of breast cancer by participating in screening. DR. FLETCHER: I think you are illustrating why this is such a complicated, almost counterintuitive area. The prevention paradox is that for the vast majority of people undertaking an intervention, for example, screening for breast cancer, there is no benefit. Yet, for the women who do benefit, it may be quite substantial. As you said, in the younger age groups, we are talking about 10 to 15 percent of deaths caused by breast cancer. I think what I showed reaches the same conclusion as what you said. Stratification of risk is going to be tougher than at least I had previously thought. We need groups of risks that are really quite a bit more substantial than most of the risks we have so far identified. Furthermore, regardless of what we come up with in terms of a new model incorporating brand-new technologies, we must validate it not only in terms of calibration, but in terms of the ability to discriminate among women if it is to be used for risk stratification. DR. PETITTI, Kaiser Permanente: The promise of the ultra-low breast cancer risk group is demonstrated by the study of Cummings and colleagues showing that at some age there is a serum marker (serum estradiol level), which is not based on proteomics, that identifies a group of women that have a very low risk of developing breast cancer over some reasonable time frame, say 4

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis years (Cummings et al., 2002). When you think about it, the ability to decide when you have the risk of a 70-year-old man and don’t need to have mammography is very important. There are analogies in other fields of cancer screening; we are now finding that a 55-year-old woman who is human papilloma virus negative might not need a Pap smear every year, and there are analogies from the cardiovascular field, where someone who has a low density lipoprotein of 80 and a high density lipoprotein of 100 probably would not be a candidate for a screening test for early cardiovascular disease. So I think the ultra-low risk group is as important as the high risk group. DR. WARRICK: Are low risk, high perception women disproportionately utilizing mammography capacity, and if so, does this explain 60 percent of women reporting having had mammograms to the Behavioral Risk Factor Surveillance System, and only a little more than 30 percent of Medicare eligible beneficiaries getting screened. Should the Breast and Cervical Cancer Early Detection Program be modified based on these findings? DR. FLETCHER: As mammography utilization increased in this country, for a long time women in their 40s utilized it more than women over 50. I think now, the women over 50 have a slightly higher percentage utilization. And the women over 65 do not utilize it nearly as much. DR. DUNNICK: Women at a higher risk do have mammography more frequently, but still, 30 percent of them do not have periodic mammography. This difference is present from 41 to 49, but not over 50, which is interesting. I wanted to ask Dr. Hanash about the exciting material he presented; when can we expect a fusion between basic bench science and a clinically usable test, given the problems of looking at probes for breast cancer, and also the problems that we see with PET scanning and with BRCA positive women. DR. HANASH: Aside from funding problems, there is a major issue with respect to validation of interesting markers. The initial discovery work is usually done with very contrasting groups, those with overt disease and those who are completely normal, and in the disease group something promising shows up. But if our goal is early detection, the disease group is not representative of an early detection population. Having access to samples from an appropriate early detection population could be highly informative, but those types of samples are scarce and access to them is limited. For example, we found a few potential lung cancer markers, and asked if we could have access to samples taken over a period of time from subjects who later were diagnosed with lung cancer to see if our markers worked to identify early disease. We were asked about evidence that our markers were effective for early detection. We answered that we did not have such evidence; we hoped testing the samples would provide the evidence. The people controlling the samples would not allow them to be used without some data on our markers’ effectiveness in early detection. So, although we ultimately did get some access, initially

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis we were in a catch-22, having to do our discovery work with samples from not the most appropriate study subjects. For prospective validation of markers for screening, obviously it is impractical to embark on a validation study in a very low risk population. So there, I think you would have to consider strategies demonstrating that a marker builds on existing tests by improving sensitivity and specificity. It would expedite things if you could demonstrate early on that your panel of markers improved specificity and sensitivity of CT based screening for lung cancer or mammography based screening. DR. FLETCHER: Randomized trials were mentioned in validating new technologies which, especially for prevention, take decades to complete. But relatively simple evaluations that do not take so long and do not require randomized trials can be carried out for new screening technologies. For example, for any new screening test, it is important to determine the test characteristics, sensitivity and specificity. Sometimes, even if sensitivity and specificity are determined for a new test, the evaluation is carried out in a diagnostic situation on patients who are symptomatic and/or have an abnormality. Assuming that the results of such an evaluation would generalize to a screening situation is dangerous. It may be reasonable to start out evaluating a new test in a diagnostic situation, in which you quickly know those who have cancer and those who do not, to learn how the test performs. But then the test’s accuracy must be evaluated in a screening situation, because the spectrum of cancers is likely to be very different in that group. Too often, this kind of evaluation is not being done in a systematic way with newer screening technologies. I do not want us to think that we cannot know anything without a randomized trial. Systematic evaluation of the accuracy of a screening test does not require a randomized trial. Finally, I just want to remind everybody that sometimes randomized trials end up with rather unexpected results. The Women’s Health Initiative (WHI) leaps to mind. Here we thought women my age were supposed to be on long-term hormone replacement therapy to prevent several important chronic diseases, and all of a sudden not only the WHI but the Heart and Estrogen/Progestin Replacement Study and the Million Women Study are giving the lie to that conclusion. I was on the Board of Scientific Advisors at NCI, and there was concern about the high cost of the WHI. In retrospect, the cost was nothing compared to the billions of dollars being spent every year by women for a prevention therapy that we now see in an entirely different light. This teaches us to persist with randomized trials every once in awhile, even if they are expensive. DR. ESSERMAN: I wonder whether there is a benefit to having a lot of these test sets public, whether something like the NCI’s Early Detection Research Network is going to facilitate making the data available not just to the

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis researchers, but to the scientific community in general? Will that approach to keeping track of and sharing data early on accelerate discovery and deployment? DR. HANASH: There is this notion that one gene, one protein, one marker may not be enough, hundreds of them together might be required to be informative. If this is the case, obviously having all of the data in the public domain would be extremely useful so others could mine the same set of data using different kinds of software tools and different statistical approaches. Others have thought, that patterns could emerge that are not understood, and that they will represent the diagnosis for various cancers. I hesitate to recommend that we rely on patterns that are not understood for a diagnosis. I think the resources and technology are available to decipher the unknown features and patterns, to link back to the disease process, so that if it does not look very plausible early on, we know there is a problem. DR. NORTON, Memorial Sloan-Kettering Cancer Center: I would second that. Whole books have been written about how misleading blind looking at patterns can be and how not understanding the mechanism can lead you far astray in applications of technology developed in one area to other areas. I want to emphasize that one of the important things about IOM reports is that they can influence policy makers. We have examples in this report of recommendations that I think should be publicized and acted on. One of them is the notion that breast cancer screening, when applied in other countries in an organized fashion, has clearly been shown to reduce mortality. The British epidemiologist, Richard Peto, has shown elegantly over time that as you introduce existing technology and do it in the proper fashion, you see a reduction in mortality. You deal with a country like ours, where screening is not well reimbursed, you see the response. It is a regulatory issue and a statutory issue. The fact is, we know that people are dying because of the mis-application or the lack of application of the technology. It conceptualizes a very important area that we have to address, which is, how do we effect societal change, which means governmental change as well. I also think that probably the data already exist to answer many of our questions, or at least, the samples already exist. But we haven’t heard about HIPAA, the Health Insurance Portability and Accountability Act, which prevents us from doing a lot of the retrospective work that is necessary, to correlate data from samples in serum banks with outcomes to try to address some of the important questions. There, too, we have a barrier that is getting between us and the ability to solve problems DR. FLETCHER: From the perspective of an epidemiologist, we are running more and more into trouble with HIPAA regulations, too. I certainly hope the research community is going to be able to work to correct some of those.

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Saving Woman’s Lives: Strategies for Improving Breast Cancer Detection and Diagnosis DR. HANASH: The research community is vested in this, so it has to come from a third party, as opposed to we researchers trying to make a plea with the regulatory agency. The consumer and the public have to participate.