The use and effect of mammography (Chapter 1)

1.

Mammography is used to detect, localize, and characterize breast abnormalities, especially cancer. It is routinely used for breast cancer screening and diagnostic follow-up.

2.

Mammography is federally regulated, including standards for equipment, personnel, reporting, and rates of reimbursement for the procedure.

• It is the only medical imaging procedure used for breast cancer screening and the only procedure regulated in this way.
• The Mammography Quality Standards Act is central to the regulation of device quality and clinical practice of mammography.

3.

The evidence definitively indicates that screening mammography, when properly performed at recommended intervals and combined with appropriate interventions, can reduce, but not eliminate, breast cancer mortality. This conclusion is based on evidence of efficacy in clinical trials and evidence of effectiveness in the general population.

• In randomized clinical trials, screening mammography reduced the rate of mortality from breast cancer mortality by ∼25 to 30 percent for women ages 50 to 70 and ∼16 to 18 percent for women ages 40 to 49.
• The time lag between initiation of screening and documentation of a significant reduction in breast cancer mortality in these trials is longer for women under age 50 (10 to 12 years) than for women over age 50 (∼5 years).
• Most randomized clinical trials excluded women over age 70, even though the risk of breast cancer increases with age and thus is more prevalent among women in this age group. Recent observational studies suggest that mammography is also beneficial for women over age 70, but further documentation of benefit is important.
• Mortality from breast cancer in the United States has been decreasing over the last decade, and some of this reduction is consistent with the effect of screening.
• Mortality from breast cancer has been decreasing in some other industrialized countries as well, and studies from the United Kingdom and Finland indicate that, in practice, screening programs can decrease breast cancer mortality.

4.

There is clearly room for improvement in the screening and diagnosis of breast cancer because of both technical and biological limitations of the current methods.

• It is technically difficult to consistently produce mammograms of high quality, and interpretation is subjective and can be variable among radiologists.
• Mammography does not detect all cancers, including some that are palpable.
• As many as three-quarters of all breast lesions biopsied turn out to be benign.
• Mammograms are particularly difficult to interpret for women with dense breast tissue. The dense tissue interferes with identification of abnormalities associated with tumors, despite the increased risk of breast cancer in these women. This leads to higher rates of false-negative and false-positive findings among these women.
• Optimal screening intervals are not well defined. Some tumors may develop too quickly to be identified at the current screening intervals.

Evolving imaging technologies (Chapter 2)

1.

Since the 1960s there have been many technical improvements in film-screen mammography that have allowed for more consistent detection of breast cancers at an earlier stage than that possible by physical examination.

• Investigators have not systematically studied whether the improvements already realized have further augmented the survival benefits seen in the earlier randomized screening trials.
• Technical improvements have greatly reduced the dose of radiation necessary to obtain quality mammograms, and most experts agree that the potential benefits of mammography outweigh the risks from radiation. Nonetheless, the risk from radiation may not be uniform across all women. (For example, women with certain germ-line mutations may be at higher risk, but current data are not definitive.)

2.

A number of promising new imaging technologies have been developed, and some are already in use as adjuncts to mammography for the diagnosis of breast cancer. Some may have particular potential for augmenting the benefits of mammography in certain subsets of women (e.g., women with dense breasts).

• Technologies approved by the Food and Drug Administration (FDA) include ultrasound, magnetic resonance imaging (MRI), scintimammography, computer-aided detection and diagnosis, thermography, electrical impedance imaging, and full-field digital mammography (FFDM). Many additional technologies are at earlier stages of development.
• FFDM represents a technical advance over traditional film-screen mammography, but studies to date have not demonstrated a meaningful improvement in sensitivity and specificity. However, these studies have not been designed to test the full potential of FFDM with the use of “softcopy” interpretation (on a computer screen rather than on film). The technology could also potentially improve the practice of screening and diagnostic mammography in other ways, for example, by facilitating electronic storage, retrieval, and transmission of mammograms.
• Computer-aided detection has the potential to improve the accuracy of the interpretation of screening mammography, at least among less experienced readers, but questions remain as to how this technology will ultimately be used and whether it will have a net beneficial effect on current screening practices.
• MRI shows promise for the screening of women at high risk (those with BRCA mutations or a strong family history of breast cancer who want to begin screening at an earlier age and who are thus more likely to have dense breast tissue). Preliminary results of MRI studies are encouraging, and computer modeling suggests that MRI screening of high-risk women may be cost-effective, but more study is needed to define its use and value for this population. It also has shown potential as a diagnostic adjunct to mammography, especially for women in whom the sensitivity of mammography is not optimal, such as those with dense breasts or breast implants.
• Ultrasound has traditionally been used to differentiate between cystic and solid lesions. More recently, it has been used to distinguish between benign and malignant solid lesions as well. With newer ultrasound techniques, the vascularity of tumors can be assessed and micro-calcifications can be detected. Recent technical advances have renewed interest in the development of the technology for screening purposes as well, particularly for women with dense breast tissue.
• MRI and ultrasound imaging may facilitate new minimally invasive methods for the ablation of early lesions, and such methods are under investigation. The development of more acceptable interventions for early lesions could reduce some of the problems associated with “overtreatment,” but clinical trials are needed to assess the potential of these new technologies.

3.

Several new image-guided biopsy techniques offer a less invasive alternative to open surgical biopsy for many women.

4.

There are difficulties associated with the comparison of new technologies with the imperfect “gold standard” of film-screen mammography.

• There is inherent variability in the production and interpretation of mammograms and other breast images.
• This variability makes it difficult to accurately determine the sensitivity and specificity of imaging modalities.
• This variability caused major difficulties and delays in the FDA approval process for FFDM and thus greatly increased the cost and time required to gain approval.

5.

Improved imaging technologies that allow clinicians to detect more lesions at an earlier, preinvasive stage may or may not lead to reduced breast cancer mortality, and may lead to more overtreatment of women unless they are coupled with biologically based technologies that can determine which lesions are likely to become metastatic and lethal.

• A better understanding of the biology and etiology of breast cancer will be critical for increasing the net benefit of screening protocols.

Technologies based on the molecular biology of breast lesions (Chapter 3)

1.

The malignant potential of early-stage lesions (invasive and noninvasive) is not well understood.

• It is likely that some early lesions have very little potential to cause the death of the patient, and labeling these women as cancer patients and treating them for breast cancer may lead to increased morbidity without decreasing breast cancer mortality. The magnitude of this dilemma is not known, but the prevalence of ductal carcinoma in situ (a preinvasive lesion that may or may not progress to invasive or metastatic cancer) has quadrupled since the adoption of screening mammography.
• Currently, methods for the classification of lesions detected by mammography are based on morphology, and the ability to determine the malignant and metastatic potential of breast abnormalities from this classification is crude at best.

2.

Technologies that might help define the biological nature of lesions found by imaging technologies and that might also help advance the field of functional imaging are being developed. These include culture of breast cancer cells in vitro, measurement of protein expression in cancer cells, identification of markers of cancer cells (or their secreted proteins) in blood, and the identification of tumor genotypes.

• In many instances these technologies could potentially identify fundamental changes in the breast that appear before a lesion can be identified. Thus, they may identify women at high risk of developing breast cancer (or, more importantly, women at high risk of dying from breast cancer).
• The distinction between “early breast cancer” and “high-risk breast tissue” is important but still imprecise.

3.

Technologies not based on traditional imaging modalities could potentially contribute to improved patient outcomes in several ways:

• They could distinguish between lesions that require treatment because of a high potential for malignancy and those that do not (e.g., some forms of carcinoma in situ, or even some very slow growing or low grade invasive carcinomas).
• They could identify women who should undergo more frequent screening or who might benefit from newer imaging modalities.
• They could identify women who should explore a “risk reduction” strategy that will affect all breast cells. (However, current strategies for risk reduction are less than ideal. Improved understanding of the biology could also lead to better prevention strategies.)

4.

Certain germ-line mutations such as BRCA1, BRCA2, p53, and PTEN mutations are the only markers identified thus far that have some of these characteristics (specifically, the last two bullets under item 3 above).

5.

Further progress in this field will be dependent on the establishment, maintenance, and accessibility of tissue specimen banks, as well as access to new high-throughput technologies and bioinformatics.

• Access to these resources continues to be problematic for many reasons.
• More could be done to ensure the privacy of genetic information and protection from genetic discrimination.

Development of new technologies: requirements and barriers (Chapter 4)

1.

The potential barriers to the development of new technologies include the high economic risk of the development and approval process, the length of time that it takes to get a new technology onto the market, and the size of the market.

• The technology development process is complex and costly, and the end results of research are unpredictable, making it a financially risky undertaking.
• For medical devices, the requirements for FDA approval and insurance coverage have been variable and unpredictable, adding additional levels of risk to the development process.

2.

In the private sector, investment in breast cancer imaging technologies is less attractive than investment in other areas of the health care industry. The reasons for this appear to be multifactorial and include the following:

• Relatively less return on investment because of limits on rates of reimbursement coupled with regulatory requirements that increase costs for mammographic examinations.
• Delays in FDA approval and confusion about the requirements for approval of new imaging technologies.
• Increasing requirements for evidence of efficacy to obtain a positive technology assessment and thus insurance coverage.
• The relatively small size of the potential market for new breast cancer detection devices is small (the United States has about 10,000 certified breast screening centers).
• Effectively less patent exclusivity for devices and diagnostics than for drugs (because of the nature of the technology).

3.

Government funding of research in the health care sector has traditionally focused primarily on basic scientific discovery.

• Recently, a new emphasis on the translation of science through the development of technology has received considerable attention, including the creation of joint public- and private-sector initiatives.
• Technical advances in computer-aided detection and diagnosis and digital mammography are examples of the successes of such initiatives.

4.

Based on the findings of the National Cancer Institute's (NCI's) Breast Cancer Review Group, NCI has launched several new funding initiatives in the last year aimed at increasing the understanding of breast cancer initiation and progression.

5.

Investment from public resources for the development of new imaging technologies for early detection has been substantially increased as a result of U.S. Department of Defense Breast Cancer Research Funds.

• The program has included innovative and nontraditional approaches to grant application and peer review.
• The initiation and continuation of this program have largely been due to the efforts of advocacy groups.

Evaluation of the effects of new imaging technologies on patient outcomes (Chapter 5)

1.

Early randomized trials of screening mammography were the first to demonstrate that early detection of any cancer would reduce mortality from that cancer. Unfortunately, no similar evaluations on the effectiveness of newer technologies on health outcomes have been performed during the past 15 years.

• The evidence for the benefit of screening mammography was based on the use of technologies that are very crude compared with those in use today.
• The net effect of technological changes could be either positive (more accurate detection, leading to lower breast cancer mortality) or negative (capable of identifying more lesions but not changing mortality and thus leading to greater morbidity and higher costs for screening).

2.

Screening trials that could evaluate the effects of recently introduced technologies on patient outcomes have not been designed.

• Data on sensitivity and specificity are necessary but not sufficient to assess the potential value of the newer technologies for screening purposes.
• Thus far, all new technologies have been or are being evaluated by diagnostic studies rather than screening studies, even if they ultimately are intended to be used for screening.
• Adoption of new detection technologies for screening purposes before assessment of their effects on clinical outcomes has been common and very problematic for other diseases.

3.

The dominant framework for medical technology development and evaluation has historically been based on therapeutics, whereas early detection relies on screening and diagnostic methods. The evaluation of such methods may be intrinsically different.

• The stages of development for drugs are more standardized, and therapeutic interventions generate direct outcomes that can be observed in patients.
• Most patient-level effects of diagnostic devices are mediated by subsequent therapeutic decisions. Diagnostic tests generate information, which is only one of the inputs into the decision-making process. Hence, the evaluation of diagnostic tests is fundamentally the assessment of the value of information.
• The development process for devices is iterative. That is, most technologies that ultimately achieve widespread use go through successive stages of development, variation, and appraisal of actual experience in the marketplace.

4.

NCI's Breast Cancer Surveillance Consortium was established in 1994 to study the effectiveness of breast cancer screening practices in the United States through an assessment of the accuracy, cost, and quality of screening programs and the relation of these practices to changes in breast cancer mortality or other shorter-term outcomes, such as stage at diagnosis or survival. A secondary goal of the program is to provide an infrastructure for the conduct of clinical and basic research.

5.

The first large-scale collaborative clinical trials group devoted to medical imaging (American College of Radiology Imaging Network) was launched in 1999 with $22 million in initial support from NCI. One of its first studies will evaluate the sensitivity and specificity of digital mammography for the detection of breast cancer in asymptomatic women. This could become a stable infrastructure for the evaluation of patient outcomes as new imaging technologies are tested for screening use.

6.

Recently, there has been an increased interest in using cost-effectiveness analysis to assess new technologies. A number of cost-effectiveness analyses of breast cancer detection technologies have been carried out, including computer modeling of screening technologies, whose effect on patient outcome (disease-specific mortality) has not been demonstrated. The assumptions regarding the effect of a technology on mortality have not been uniformly accepted. The result of cost-effectiveness analysis is also dependent on what stage of development the analysis of a new technology is carried out. To date, a consensus has not been reached as to how to use the information generated by the analyses. Neither the Health Care Financing Administration (HCFA) nor other third-party payers use cost-effectiveness analysis to make coverage decisions.

Diffusion of technologies (Chapter 6)

1.

Use of screening mammography has increased greatly in the last decade, but it has not been universally adopted and accepted by women.

• The percentage of women age 50 and over who reported having a recent mammogram rose to 69 percent in 1998, up from 27 percent in 1987. However, an estimated 12 million women in this age group have not had a mammogram within the last 2 years.
• Access to screening facilities is an issue for some women. Currently, the Centers for Disease Control and Prevention (CDC) screening program reaches only 12 to 15 percent of eligible women without health insurance. Treatment of cancers identified through the screening program was not initially covered, but federal legislation allowing Medicaid coverage of treatment was recently passed. Adoption of this new program by individual states is pending.
• Of those women who have been screened, a significant number do not undergo screening at the recommended interval.
• Physician recommendation is the most important factor in determining whether women are screened.
• Women over age 65 are less likely to undergo screening mammography, although the risk and incidence of breast cancer are higher among women in this age group. Physicians are less likely to recommend screening to older women, perhaps because of the lack of consensus guidelines and data on the effectiveness of screening for women in this age group.
• Mammography is less than an ideal test. Women express concerns about discomfort from the procedure, inconvenience of scheduling an annual test, and fear of what could be found, including false-positive results. (However, fear of cancer and the inconvenience of annual tests may be characteristic of any screening test.)

2.

As the number of women eligible for screening mammography increases (because of the changing age distribution of the U.S. population) and more women adopt the practice of routine screening, there will be increased demand for trained mammographers and certified screening facilities.

• The current screening facilities may already be operating at or near full capacity, as waiting times for appointments appear to be increasing over the last 2 years.
• There are anecdotal reports that inadequate numbers of mammographers and mammography technologists are being trained to fill the current and future needs. Quantitative data to substantiate these concerns are not currently available.
• Radiologists and health care administrators have expressed concern that the reimbursement rate for mammography is too low to cover the actual costs of the procedure (including the cost of meeting federally mandated requirements promulgated under the Mammography Quality Standards Act) and that this situation could lead to a reduction in screening services. Quantitative data are currently unavailable to confirm or refute these assertions.

3.

When film-screen mammography was introduced (before FDA regulation of medical devices), it was a “void-filling” technology.

• New technologies face a different level of evaluation that will likely include comparison with mammography.
• If the rate of reimbursement for mammography is in fact artificially low, then cost comparisons with new technologies will unfairly favor mammography.
• Many new technologies may be first introduced as an adjunct to mammography (to improve its sensitivity or specificity, or both, and its positive predictive value).
• their physicians, allowing an individualized approach to screening and diagnosis depending on a woman's specific needs and characteristics. At the same time, new technologies may add layers of complexity to the decision-making processes associated with screening and diagnosis, making it more challenging to establish practice guidelines and to define a “standard of care.”

4.

Currently, mammography is one of the few screening tests that are reimbursed.

• Preventive services are not routinely covered by HCFA because the U.S. Congress deliberately crafted the Medicare statute to preclude preventive services, reflecting the practice of commercial insurers at the time.
• Congress and state legislatures have mandated coverage for mammography (as well as some other preventive services, including screening tests for cervical, prostate, and colon cancers).

The “ideal” screening tool

1.

All of the tests available for the screening and diagnosis of breast cancer have different strengths and limitations. The ideal test would combine the following characteristics:

• The test should present a low risk of harm from screening
• The test should have high degrees of specificity and sensitivity (low rates of false-positive and false-negative results).
• The test results should have uniform high quality and repeatability.
• Interpretation of test results should be straightforward (objective).
• The test should be simple to perform.
• The test should be noninvasive.
• The test should be able to find breast cancer at a stage that is curable with available treatments.
• The test should have the ability to distinguish life-threatening lesions from those that are not likely to progress.
• The test should be cost-effective (usually considered <$50,000 per quality-adjusted life year saved).
• The test should be widely available.
• The test should be acceptable to women.

2.

The “ideal” breast cancer screening tool has not yet been developed.

3.

Because each technology has different strengths and limitations, a multimodality approach that includes multiple tests in one examination may, in theory, be the best way to optimize the characteristics listed above.