6for the ACS Breast Cancer Advisory Group: Stephen Sener, MD; Barbara Andreozzi; Lynn Erdman, RN, MS; W. Phil Evans, III, MD; Hershel W. Lawson, MD; Jeanne Petrek, MD; Maggie Rinehart-Ayres, PhD, PT; Christy A. Russell, MD; Carolyn D. Runowicz, MD; William C. Wood, MD; Sherry Bailey; Debbie Saslow, PhD

An update to the American Cancer Society (ACS) guideline regarding early detection of breast cancer, based on recommendations from a formal review and recent workshop, is presented. The new screening recommendations address screening mammography, physical examination, screening older women and women with comorbid conditions, screening women at high-risk, and new screening technologies.

In 1997, the American Cancer Society (ACS) updated its guidelines for breast cancer screening . The most notable change in the 1997 guideline update was the recommendation that women should begin annual screening at age 40; previous guidelines had recommended mammography every 1-2 years for women beginning at age 40, and annual mammography for women beginning at age 50. The 1997 update also noted that there was no chronological age at which screening should stop, emphasizing that as long as a woman was in good health she likely would benefit from breast cancer screening. Recommendations for breast self-examination (BSE) and clinical breast examination (CBE) remained the same, although the ACS added the advice that women forty and older schedule annual CBE close to the time of and before their annual mammogram.

In 2002, the ACS convened an expert panel to review the existing early detection guideline in the context of evidence that has accumulated since the last revision. The panel was divided into working groups to review the evidence and develop recommendations regarding (1) mammography; (2) physical examination; (3) screening of older women and women with co-morbid conditions; (4) screening high-risk women; and (5) screening tests.

During the current guideline review, literature related to breast cancer screening published between January 1997 and September 2002, including new screening tests, were identified using MEDLINE (National Library of Medicine), bibliographies of identified articles, personal files of panel members, and unpublished manuscripts. Expert panel members reviewed articles using specified criteria and discussed them during a series of conference calls. Each work group developed recommendations, rationale, and evidence summaries, and reviewed the summaries developed by the other work groups prior to a September 2002 workshop. When evidence was insufficient or lacking, the final recommendations incorporated the expert opinions of the panel members. During the conference calls and workshop, consensus was reached on the key issues within the guideline recommendations. Following the workshop, ACS Breast Cancer Advisory Group members deliberated over the guideline modifications. Each work group member and workshop attendee reviewed the draft of this manuscript.

Women at average risk should begin annual mammography at age 40.

Since 1997 there have been several updates in the evidence from clinical trials, and additional literature bearing on a range of issues pertinent to breast cancer screening. Two separate reports by the same authors have challenged the value of screening for breast cancer with mammography, leading to a surge of new literature re-examining the underlying evidence related to breast cancer screening.

The primary evidence supporting the recommendation for periodic screening for breast cancer with mammography derives from 7 randomized controlled trials. Two of the trials took place in North America, one in Scotland, and four in Sweden. One additional trial evaluating the question of benefit from beginning screening early in the forties is underway in the United Kingdom. At the time of the previous guideline update, individual trials and meta-analyses of all trials combined showed statistically significant mortality reductions for women ages 40-69 associated with an invitation to screening.

Long-term follow-up data from the U.K. Trial of Early Detection of Breast Cancer (TEDBC) and from the Edinburgh trial of breast cancer screening were published in the Lancet in 1999. The TEDBC is a non-randomized study comparing observed vs. expected breast cancer mortality in women ages 45-64 in eight centers, consisting of two mammography centers, two BSE centers, and four comparison centers. After adjusting for pre-trial mortality rates, breast cancer mortality was 27% lower in women ages 45-69 in the two centers in which women underwent mammography compared with the comparison centers. A 35% breast cancer mortality reduction was observed in cohorts aged 45-46 at entry into the study, an effect that began to emerge after 3-4 years. In the Edinburgh trial follow-up, the investigators applied an improved method of quantifying socioeconomic status and censored breast cancer diagnoses more than three years after the conclusion of the study; 29% fewer breast cancer deaths were observed in the group invited to screening compared with an initial estimate of 13%.

Updated results from both arms of the Canadian National Breast Cancer Screening Trial (NBSS-1 and NBSS-2) have been reported since 1997. In 2000, Miller et al. reported 13 year follow-up results from the NBSS-2, which compared annual two-view mammography and CBE to annual CBE only in women ages 50-59 at randomization. The authors reported no difference in the breast cancer mortality rate in the group randomized to receive annual mammography and CBE compared with the group invited to receive CBE only (RR=1.02), and concluded that mammography provided no additional advantage compared with carefully conducted CBE. In 2002, the Canadian investigators reported updated results from the NBSS-1, which compared annual mammography and CBE with usual care in women ages 40-49. After 11-16 years of follow-up, and after adjustment of the data to account for members of the control group who actually received mammograms, there was no difference in the breast cancer mortality rate in the group invited to screening compared with usual care (RR=1.06).

Swedish investigators recently updated the overview analysis of the Swedish trials of mammography screening based on follow-up to 1996. With a median follow-up time from randomization to the end of follow-up of 15.8 years, the investigators observed an overall 21% statistically significant reduction in breast cancer mortality associated with an invitation to mammography (RR=0.79).

As part of the evidence review of the U.S. Preventive Services Task Force (USPSTF), new meta-analysis of the randomized controlled trials was conducted by Humphrey, et al. and published simultaneously with the updated USPSTF guidelines. The meta-analysis of trial results (excluding the Edinburgh trial) from all age groups showed a statistically significant 16% mortality reduction associated with an invitation to screening (RR=0.84). Similar meta-analyses were conducted for women ages 40-49 at randomization, with results leading the authors to conclude that the risk reduction from mammography screening does not differ substantially by age, although absolute benefits are lower in women under age 50 compared with women aged 50+. The authors of the updated reports from Edinburgh and the TEDBC reached similar conclusions about age-specific benefits .

In October 2001, The Lancet published a research letter by Ole Olsen and Peter Gøtzsche, two researchers from the Nordic Cochrane Centre in Copenhagen. Under the auspices of the Cochrane Collaboration, the authors evaluated the randomized trials of breast cancer screening, and concluded that five of the seven trials were so significantly flawed that they should not be regarded as providing reliable scientific evidence. Olsen and Gøtzsche also argued that breast cancer mortality was an unreliable endpoint, and that only comparison of all-cause mortality between the experimental and control groups could serve as an unbiased endpoint. Based on their meta-analysis, which included only the Malmö and Canadian trials, the authors found no evidence of a reduced mortality associated with an invitation to mammography (RR=1.0), and concluded that there was no reliable evidence that screening reduces breast cancer mortality. Several guideline groups, national boards of health, and numerous individual authors have provided formal critiques of the methodology and conclusions of Olsen and Gøtzsche . The reviews uniformly concluded that the evidence provided by the Cochrane Review did not support the claim that alleged methodological shortcomings in the conduct of the trials were of such significance to invalidate the conclusion that screening for breast cancer with mammography reduces breast cancer mortality.

The most recent results from the trials are shown in Table 1. While there is variation in the observed mortality reductions, meta-analysis of the most recent results shows a 24% mortality reduction associated with an invitation to screening. Although results from individual trials vary, those trials that achieved the greatest reduction in the relative risk of being diagnosed with a node positive tumor also have shown the greatest mortality reductions .

(a) There are more recent publications from the Gothenburg trial but they refer only to the under 50 age group.

The inherent limitations of the breast cancer screening RCT’s to estimate the benefits associated with exposure to modern mammography, as well as the importance of program evaluation, have led to increased interest in evaluating the impact of screening in the community setting, also referred to as service screening. Service screening evaluation can estimate breast cancer mortality for women who actually attend community screening programs and for the population as a whole. It can also be used to attribute differences in mortality over time to screening, improvements in therapy, and increased awareness, although distinguishing between screening and non-screening factors is complex and can be only indirectly estimated.

Banks, et al. reported on the impact of the National Health Service breast cancer screening program in women ages 55-69 years between 1990-1998 , and estimated a 21.3% reduction in breast cancer mortality, with a smaller direct effect of mammography (6.4%) compared with increased awareness and improvements in therapy (14.9%). Jonsson and colleagues have reported on service screening in Sweden for women ages 40-49, and 50-69, and the investigators concluded that the estimated mortality reductions were consistent with the estimates from the randomized controlled trials.

Two additional investigations from Sweden were able to classify breast cancer cases before and after the introduction to screening on the basis of exposure to screening . In the most recent report , which expanded an earlier analysis to seven counties in the Uppsala region, Duffy and colleagues compared breast cancer mortality in the pre-screening and post-screening periods among women aged 40-69 in six counties, and 50-69 in one county. Overall, they observed a 44% mortality reduction in women who underwent screening, and a 39% reduction in overall breast cancer mortality, after adjustment for selection bias, associated with the policy of offering screening to the population. These data demonstrate that organized screening with high rates of attendance in a setting that achieves a high degree of programmatic quality assurance can achieve breast cancer mortality reductions equal to or greater than those observed in the randomized trials.

The evaluation of service screening represents an important new development for several reasons, including the unlikelihood that there will be additional randomized controlled trials of breast cancer screening, the value of measuring the effect of modern mammography in the community, and the value of measuring the benefit from mammography screening to women who actually get screened.

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Mortality reductions for women aged 40-69 have been observed in trials that screened at intervals of 12 and 24+ months, and thus some guidelines recommend screening at an interval of 1-2 years. However, data from two trials, and inferential evidence used to estimate the duration of the detectable pre-clinical phase, or sojourn time, have provided persuasive evidence that younger women likely will benefit from a shorter screening interval compared with older women, a conclusion also reached in the recent USPSTF evidence review. Further, data from both RCT’s and from service screening programs have shown that the proportional incidence of interval cancers in the period after a normal screening examination is higher in younger women compared with older women, suggesting faster growth rates . Tabar and colleagues have estimated that tumor sojourn times increase with increasing age, and using Two County data have estimated the mean sojourn time for women by age as follows: 40-49=2.4 years, 50-59=3.7 years, 60-69=4.2 years, and 70-79=4 years.

Modeling data also have suggested that progressively shorter screening intervals result in detection of tumors at smaller sizes and in decreased mortality. Estimating tumor characteristics associated with screening intervals of 24, 12, and 6 months, Michaelson, et al. showed that shorter screening intervals were associated with greater reductions in the proportion of cases diagnosed with distant metastases. In a subsequent modeling analysis of 1352 women from the Van Nuys Breast Cancer Center between 1966 and 1990, Michaelson, et al. showed that tumor size correlated highly with survival independent of method of detection .

While sojourn times lengthen with increasing age, these data provide only a limited basis for establishing screening intervals, and in particular they provide only a benchmark for an interval that should not be exceeded, since the screening interval should always be shorter than the estimated mean sojourn time. Since the goal of screening is the reduction in the incidence rate of advanced disease, the screening interval should be set for a period of time in which adherence to routine screening is likely to result in the detection of the majority of cancers while still localized. The importance of annual screening clearly is greater in premenopausal women (< 55) compared with post-menopausal women. However, given the prognostic value of smaller tumors, and the finding that annual screening results in more favorable tumor characteristics in women over age 50, annual screening in this group may offer advantages over biennial screening as measured by tumor characteristics, even if the difference is not as great compared with the advantage of a shorter interval in premenopausal women.

The issue of adverse events associated with mammography, primarily in women who do not have breast cancer, has been a source of growing attention, and has commonly been one of the core issues in recent debates about mammography. It must be appreciated that the benefit/harm equation will differ for women of different ages, with different risks, and with different values related to the likelihood of benefit and risk of harm. However, there is general agreement that there is an excess rate of false positives and biopsy that could be reduced with improvements in screening quality. There also is agreement that steps should be taken to reduce anxiety associated with screening, and that there should be conscientious efforts applied toward informing women about the likelihood of both false negative and false positive findings.

Overall, it is difficult to draw conclusions about the extent of harms associated with mammography and, in particular, harms that may be lasting. In general, the evidence suggests that some women experience anxiety related to screening and to false positive results, but that for most women anxiety is short-lived and does not have lasting consequences on either stress or likelihood of subsequent screening. A recent study by Schwartz and colleagues revealed that women accept false positive results as a part of screening and do not regard false positives as an important harm in the context of the underlying goal of early breast cancer detection, which is to avoid a late stage at diagnosis of breast cancer. Nevertheless, there should be organized efforts to achieve an acceptable rate of false positives in screening programs, and to minimize the spectrum of harms associated with false positives. Health professionals must become more sensitive to both short-term and long-term effects of false positives, whether or not they may be lasting, and women should be fully informed of the range of possible screening outcomes.

Concerns about detection and overtreatment of ductal carcinoma in situ (DCIS) have been raised . The detection of DCIS is an inevitable consequence of screening for invasive disease, which is the principal purpose of a breast cancer screening program. Although the detection of DCIS represents overdiagnosis in some instances, this is a very different situation compared with the potential for overdiagnosis when screening benefits are uncertain. Given the general acceptance that a significant proportion of unexcised DCIS will eventually progress to invasive disease and that the mortality rate from DCIS is still 1-2%, the more important and logical target of concerns about overtreatment rest not with screening, but with therapy. Furthermore, excision of DCIS both permits histological confirmation that the disease is noninvasive and may be thought of as a form of secondary prevention when combined with ipsilateral radiotherapy and tamoxifen.

Recommendations (Note: The changes recommended relate to the periodicity and purpose of CBE and BSE)

Clinical Breast Examination: For average risk asymptomatic women in their twenties and thirties, it is recommended that CBE be part of a periodic health examination, preferably at least every 3 years. Information should be provided about the benefits and limitations of CBE and BSE, and it should be emphasized that breast cancer risk is low for women in their 20s and gradually increases with age. The exam should include patient instruction in BSE for the purpose of gaining familiarity with breast composition. The importance of prompt reporting of any new signs and symptoms to a health professional also should be emphasized.

Asymptomatic women aged 40 and over should continue to receive CBE as part of a periodic health examination, preferably annually. Beginning at age 40, discussion during CBE should include information about screening mammography. Ideally, the CBE should be done shortly before the mammogram. At the time of CBE, the benefits and limitations of physical examination and mammography should be discussed with the patient.

Breast Self Examination: Beginning in their twenties, women should be informed about the benefits and limitations of BSE. The importance of prompt reporting of any new breast signs and symptoms to a health professional should be emphasized. Women who choose to do BSE should receive instruction and have their technique reviewed on the occasion of a periodic health examination. It is acceptable for women to choose not to do BSE, or to do BSE irregularly.

The logic for the earlier detection of breast masses is straightforward and is an extension of the logic for detecting breast cancer before a tumor is palpable. With increasing tumor size, the likelihood of regional and distant metastasis increases. Long-term survival, measured either with registry data or with data from RCTs, is worse with each incremental 5 mm increase in tumor size . For average risk women under age 40, earlier detection of palpable tumors with CBE or BSE can lead to earlier therapy. After age 40, CBE and BSE are regarded as adjunctive because mammography does not achieve perfect sensitivity.

The current evidence supporting the value of CBE and BSE as methods of reducing breast cancer mortality in asymptomatic women is insufficient to warrant recommendation as a screening method. The current recommendations rely in large part on expert opinion.

Today, mammography and clinical breast examination are recommended to women 40 and older because (1) there are randomized controlled trial (RCT) data showing the combination of mammography and CBE was associated with lower breast cancer mortality; and (2) evidence from these RCT’s and demonstration projects showed that some cancers detected by CBE were not detected by mammography.

The USPSTF recommends mammography with or without CBE, and it has concluded that there is insufficient evidence to recommend for or against breast cancer screening with CBE alone. Evaluation of CBE as a detection modality has generally focused on the performance characteristics of the test, i.e., sensitivity, specificity, and positive predictive value. On all aspects, performance characteristics are poorer than those of mammography. Sensitivity of CBE in particular was estimated in a recent meta-analysis to be only 54%. While noting that two trials demonstrate breast cancer mortality reductions associated with the combination of mammography and CBE, the USPSTF concluded there is insufficient evidence to quantify the incremental benefits of adding CBE to mammography. This particular question is more pertinent to the decision to include recommendations for CBE as part of a mammographic screening program. Though the proportion of incident cases detected by CBE in the trials is significant, the proportion not visible with modern, high quality mammography appears to be considerably lower today.

Based on findings from 752,081 CBEs, Bobo and colleagues reported that 6.9% of all CBEs were coded as abnormal, and that 5 cancers were detected per 1,000 examinations. However, only 5.1% of the malignancies (193/3753), or 2.56 per 10,000 CBE exams, were detected in women with an abnormal CBE and benign findings on the mammogram. Since women with self-detected breast symptoms were 7.2 times as likely to have an abnormal exam, it is likely that a significant proportion of these CBE-positive cases were first detected by women themselves, leading to an even lower rate of breast cancer detection attributable to CBE alone. Newcomer, et al. recently reported on the mode of detection in 2341 Wisconsin women ≥ 50 diagnosed with breast cancer between 1988-91. Women were asked how their breast cancer was first discovered—48% were self-detected, 41% were detected by mammography, and 11% were detected by CBE. Since these are first indications of signs or symptoms of breast cancer, some or all of the cancers first apparent by CBE may also have been detectable by mammography.

At this time, it is unclear what CBE contributes to detection of breast cancer, although it is likely that in nominally asymptomatic women the contribution is small. When done prior to mammography, CBE can detect some cancers that will not be visible on mammography, and can guide subsequent imaging exams in women among whom masses are detected. CBE also provides the occasion to educate women about breast health and to raise awareness about breast cancer.

As a growing proportion of women are receiving regular mammograms, the relative contribution of CBE to early breast cancer detection and its cost-effectiveness warrant renewed attention. At this time, the cancer detection rate for CBE appears to be low, and the evidence for breast cancer mortality reduction associated with CBE is weak and indirect. While it is commonly asserted that the value of CBE is measured most in its ability to detect cancers that are not detected by mammography, there are insufficient data to truly measure its unique contribution to early breast cancer detection, or contribution as a complement to other tests. Given the present uncertainty about the contribution to CBE, the fact that women are screened with mammography opportunistically, that across the country mammography sensitivity is variable, and in some settings may be quite low, and the lack of a solid body of evidence pointing to a clear direction, the ACS will continue to recommend CBE. Further, CBE may serve an additional, separate function: it provides the occasion to raise awareness about breast cancer and to provide accurate education on the variety of breast health topics that women commonly ask about, including genetics, the roles of diet and hormones in the etiology of breast cancer, and newer cancer detection and treatment strategies. Until more informative scientific evidence is available, periodic CBE is recommended with the additional endorsement that the occasion of a CBE should be used to raise awareness about the early detection of breast cancer.

The manifest goal of periodic BSE is to detect palpable tumors. An additional role of BSE is to increase awareness of normal breast composition, so that there is heightened awareness of changes that may be detected during BSE or at some other time.

The first studies suggesting possible effectiveness of BSE were published in 1978. These two studies and many additional studies in the pre-mammography era found that in general women who reported that they had been BSE performers had their breast cancers detected at a smaller size and at earlier clinical and/or pathologic stage. Regular performance of BSE did not mean that the breast cancer was necessarily self-detected during a formal BSE procedure. Even regular BSE performers commonly detected their breast cancer incidentally, suggesting that there was a component of increased body awareness (or perhaps increased awareness of subtle signs) in addition to the self-performed physical examination. Studies of the technique of BSE performers have found many to be using improper techniques. The results of several studies suggest that women who practice BSE regularly with technique that is judged to be adequate are more likely to self-detect their tumors.

The literature on the effectiveness of BSE as a detection modality has shown mixed results, but the more recent evidence reviews have focused on the absence of direct evidence of benefit in two RCTs, and data indicating that the rate of benign biopsy is higher in women who regularly perform BSE. The USPSTF concluded that the evidence is insufficient to recommend for or against teaching or performing routine BSE. The Canadian Task Force on Preventive Health Care went a step further and recommended against routine instruction in BSE in periodic health examinations on the basis of fair evidence of no benefit, and good evidence of harm (false positives) . The Canadian Task Force did recommend that women should be taught to promptly report any breast changes or concerns, and those women who choose to practice BSE should receive careful instruction as well as information about risks and benefits. However, Nekhlyudov and Fletcher argued that the existing data do not provide a sound basis for dismissing the value of BSE, based on both the limitations in the RCT data and observational studies, and on the basis of a principle of the USPSTF that when evidence is lacking it is best to err on the side of prudence.

There are a number of methodological challenges to the evaluation of BSE. While early and recent null results from the Shanghai trial are commonly cited as evidence that BSE is ineffective, these findings still may be limited by the duration of follow-up, as well as lack of direct applicability to screening programs in which BSE is not the primary mode of detection. On the other hand, the findings do suggest that in populations where heightened awareness and prompt reporting of breast symptoms is common, BSE may offer less potential for earlier interventions than in populations where presentation of large, advanced tumors is more common.

Baxter and others have emphasized that among regular practitioners of BSE, a significant percentage of women detect new symptoms incidentally rather than on the occasion of their regular BSE. However, rather than refuting the value of instruction, one might also interpret this finding as a measure of heightened awareness resulting from periodic BSE, as well as the underlying greater probability that normal activities (bathing, dressing, etc.) could result in detection during any of 29-30 other days of the month.

As with CBE, it is unclear what BSE contributes to early detection of and reduced mortality from breast cancer, and it is likely that the contribution is small. Women therefore should be encouraged to be aware of how their breasts look and feel in order to be able to recognize any changes and promptly report them.

The evidence supporting the value of CBE and BSE is largely inferential, and of the two, CBE generally has greater acceptance. Even so, the most recent literature reviews reveal the limitations of the current data for drawing evidence-based conclusions about the value of physical exams. However, for our purposes here, there are several fundamental questions about the value of physical examinations in average-risk asymptomatic women. First, what does screening CBE contribute over and above self-detection of breast cancer in women (regardless of age)? Second, apart from the basic role of screening with CBE, are there other aspects of the exam (i.e. patient education) that can contribute to early detection? Third, after decades of promoting BSE, does monthly BSE, occasional BSE, or even instruction to perform BSE offer a measurable advantage over the gains that have been made in increased awareness about breast cancer signs and symptoms and the importance of reporting breast signs/symptoms to a health care professional? Finally, should heightened awareness of changes in breast composition be an important element in a breast cancer control strategy, and if so, how can it be achieved?

Recommendation: Breast cancer screening decisions in older women should be individualized by considering the potential benefits and risks of mammography in the context of estimated life expectancy. As long as a woman is in reasonably good health and has life expectancy exceeding three to five years, and is treatable and willing to be treated, she should continue to be screened with mammography. However, if an individual has a life expectancy of less than three to five years, multiple or severe comorbidities, and/or functional limitations likely to limit life expectancy, it may be appropriate to consider discontinuing screening. Chronological age alone should not be the reason for the cessation of regular screening.

The size of the older population is growing exponentially. Persons over age 65 years currently represent approximately 1/8^th of the U.S. population (35 million), and their numbers are expected to double in the next 20 years (accounting for 1 in 5 Americans) . Increasing numbers of women and their healthcare providers are faced with questions about whether and when to end breast cancer screening. They will be required to make judgments on the balance between the potential benefits of screening, where early breast cancer detection could reduce the risk of breast cancer morbidity and mortality, and potential harms, which among women with comorbidity or limited longevity could cause suffering and diminished quality of life in remaining years without appreciable benefit. The balance of this equation shifts with chronological age, life expectancy, comorbidity, and functional limitation.

Breast cancer is the second leading cause of cancer death in U.S. women and disproportionately affects older women: diagnosis of breast cancer in women age 60+ accounts for approximately half of all breast cancer deaths . Breast cancer mortality increases with advancing age, ranging from 86 deaths per 100,000 women aged 65-69 years to 200 deaths per 100,000 women aged 85 years and older . Although the risk of death from breast cancer is higher in older women, the question of screening in this population must be considered in the context of competing risks of death from comorbid conditions and/or limited longevity.

Theoretical considerations suggest that older women may have a higher prevalence of less aggressive tumors than younger women. In general the growth rate of a tumor is related to its aggressiveness: if less aggressive tumors have a longer sojourn times (i.e., mammographically-detectable pre-clinical phase), they are also more likely to become manifest later in life and to be more prevalent among older individuals. Clinical observations support this hypothesis. Nixon et al and Lyman et al have shown that compared with younger women, the prevalence of poorly differentiated (grade 3) tumors decreases, and the prevalence of hormone-receptor-rich tumors increases, with the age of the patient population. Evidence suggests that the growth and the metastatic spread of breast cancer are slower in older women compared with younger women. In a series of 819 Finnish women, Holmberg et al found that for tumors of similar size, the prevalence of axillary lymph node involvement decreased with the age of the patient after age 55. Similar findings have been reported by Tabar and colleagues, who showed that for any given size, the presence of grade 3 tumors and the likelihood of nodal involvement are lower in older women compared with younger women. These data indicate that the prevalence of less aggressive tumors increases with age.

There is suggestive evidence that host characteristics in older women are somewhat less favorable to tumor growth. The extent to which these tumor characteristics translate into a more benign natural course of breast cancer in some older individuals, vs. slower growth towards the same potentially lethal endpoint, is unclear. It is important to emphasize that breast cancer is a potentially lethal disease at any age. Regardless of patient age, larger tumor size is associated with higher nuclear grade and greater nodal involvement, all of which are associated with poor outcomes. In the context of the increased burden of disease with age, it is clear that even relatively more favorable tumor characteristics do not translate into a condition that can be regarded as less worthy of attention.

There are limited data on the efficacy of screening mammography in women over the age of 69. Only two of the published randomized controlled trials included women older than 69. Published screening studies have concluded that the performance and effectiveness of mammography is similar in women aged 70 and older compared with younger women; in the absence of more definitive data, various groups that have issued guidelines have reached the same conclusion.

As noted earlier, the length of the mammographically-detectable pre-clinical phase increases with increasing age, and is estimated to be approximately 4 years for women ages 70-79. Longer sojourn times in older women have raised the question of whether a subset of screen-detected incidence cases represent overdiagnosis, i.e., detection of cases that would not have presented clinically in the patient’s lifetime. One method of estimating overdiagnosis is the prevalence screen predictive index (PSPI), which is the proportion of tumors diagnosed at a prevalence screen that would have arisen clinically if screening had not taken place. From evaluation of Two-Country Trial data, Tabar and colleagues estimated that the percentage of the PSPI tumors for women 70-79 is 87%, and for women 50-69 it is 100%. Thus there is little or no evidence to suggest that overdiagnosis of breast tumors in older women is a problem.

As noted above, Field et al showed that shorter screening intervals in women aged 65+ also were associated with more favorable tumor characteristics. The average tumor size in women who had undergone annual screening (N = 93) was 10.7 mm (median = 9.5) and for women who had undergone biennial screening (N = 27) the average tumor size was 16.5 mm (median = 15 mm). Seventy two percent of the women who had undergone annual screening had a tumor T1bN0 or less, whereas only 44% of the women who underwent biennial screening were of comparable stage. Thus, even though older women have a longer detectable pre-clinical phase, annual screening still will result in more favorable tumor characteristics at the time of detection.

Rosenberg et al used a population-based database and statewide tumor registry in New Mexico to study the factors affecting mammography sensitivity and stage at diagnosis. Among women 65+ (47,000 examinations), sensitivity was 81%; the sensitivity for women 50-64, 40-49, and less than 40 was 78%, 77% and 54% respectively. Faulk divided women into the age groups 50-64 and 65+. Abnormal interpretations and number of biopsies were comparable among the women in both groups, but positive predictive value, biopsy yield, and rate of cancers per thousand screens were higher in the older age group. In the same study, there also was a tendency toward lower stage at diagnosis among the older group of women.

Data from the screening mammography program of British Columbia show comparable abnormal interpretation rates for women 70 and above compared with women 40-69, but higher cancer detection rates. Medical audit data from the University of California, San Francisco on a small number of older women show similar results. In other words, while the likelihood of an abnormal mammogram is similar across age groups, the cancer yield is greater with increasing age.

Smith-Bindman et al studied female California Medicare beneficiaries aged 66-79 years. In this series, the risk of detecting metastatic breast cancer was significantly reduced among women 60-79 years who underwent screening mammography with a RR 0.57 (CI 0.45-0.72). Although these data are indirect, these findings are consistent with evidence from the randomized trials demonstrating that mortality reductions are achieved through a reduction in the incidence rate of advanced disease.

For women older than 65 who did not have dense breasts, Rosenberg’s study showed that the sensitivity for the detection of breast cancer was comparable regardless of whether the women used hormone replacement therapy (83% versus 86%). However, for women over age 65 with dense breasts, screening mammography sensitivity was lower among women on HRT (64% vs. 84%).

With advancing age, incidence of breast cancer remains high, the breast cancer mortality rate increases, but overall life expectancy decreases. Because the survival benefit from screening mammography takes several years to emerge, consideration of the effectiveness of screening mammography in older women must address issues of comorbidity and life expectancy as well as questions of test performance .

In the National Health Interview Survey (NHIS), the percentage of women who reported two or more comorbid conditions increased from 45% among those aged 60-69 years, to 61% for those aged 70-79, to 70% for those aged 80 years and over. Results of one national study indicate that many older people with cancer are concurrently being treated for other conditions that include arthritis, hypertension, and heart disease . However, these data also reveal that there are significant numbers of older individuals that are in good health, and more recent data indicate that the proportion of older individuals without significant co-morbidity is increasing. (reference)

A central issue is whether detecting early-stage breast cancer confers an advantage among women with comorbidity, as it does among women without comorbidity. If there is no significant difference in the length and quality of survival by stage of disease among women with comorbidity, then the rationale for regular screening in this group is reduced.

Breast cancer patients with comorbidity have poorer chances of survival, measured in terms of both the quality and duration of life, than patients without comorbidity, after adjustment for other prognostic indicators, such as stage of disease at diagnosis, tumor grade, and histology . Diabetes, renal failure, stroke, liver disease, and a previous cancer were among the conditions that predicted early mortality among women with breast cancer . Satariano and Ragland found that the relative risk of breast cancer death declined with the number of comorbid conditions. In a study by Lee and colleagues based on data from the Upper Midwest Oncology Registry System, there was no improvement in survival with mammographically-detected tumors in women with severe or multiple comorbidities. However, this group constituted only 13% of the sample of 5,186 women ages 65 to 101.

At age 70, the average life expectancy for a woman in the U.S. is 15.4 years, well exceeding any proposed threshold for a mortality benefit from breast cancer screening. Indeed, even women at very advanced ages may be expected to have considerable additional years of life, as is shown in Table 2.

Adding to the complexity of cancer screening decisions in older women, though, is the heterogeneity in health status of this population. As noted above, there is great variation in amount and severity of comorbidity, functional status, and in how long people of similar ages live, suggesting that screening guidelines based solely on chronological age cut-offs are not appropriate. Figure 1 shows the distribution of life expectancy for U.S. women according to the upper, middle and lower quartiles of life expectancy at each age. For example, approximately 25% of 75-year-old women will live more than 17 years, 50% will live at least 11.9 years and 25% will live less than 6.8 years.

Figure 1. Upper, middle, and lower quartiles of life expectancy for women at selected ages.

In using Figure 1 to anchor life expectancy estimates, physicians can assess many clinical variables to estimate whether a woman is typical of someone in the lower quartile of life expectancy for her age or is more like someone in the middle or upper quartile. For example, when clinicians are considering recommending screening mammography to an older woman, they should consider whether she has a severe comorbid condition, such as congestive heart failure (class III or IV), end-stage renal disease on dialysis, oxygen-dependent chronic obstructive pulmonary disease, or moderate to severe dementia. These are all examples of conditions that would cause a woman to have a life expectancy in the lowest 25^th percentile for her age. Figure 1 shows that the majority of such older women 80 years old and older will have life expectancies less than 5 years, so the likelihood that they will benefit from screening mammography is comparatively lower . Conversely, Figure 1 also illustrates that there is a large group of older women who have substantial life expectancies. Up until age 85 most women have a life expectancy exceeding 5 years, as do some very healthy 90 year-old women. These women potentially may benefit from screening mammography.

There is great variability in life expectancy of older women, and individual variability in health status and disability increases with age. Though estimations of life expectancy that incorporate severity of comorbidity and functional impairments are imperfect predictors of longevity, they allow for better consideration of the potential benefits and harms of screening mammography than simply focusing on chronological age.

Although a majority of women are accepting of high rates of false positive tests, on a population-basis, abnormal screening tests can have a large short-term impact on health, well being, and health care utilization and costs. Previous work has identified a number of domains, particularly psychosocial spheres of function, that are affected during the interval from notification of an abnormal mammogram to determination that cancer is absent. Though the overwhelming majority of these studies have been conducted in younger women, there is no reason to believe that the effects of a false positive screen will vary substantially by age. These effects, when noted, are generally transient, , have no effect on endocrine and immunological function (Linbrink et al, 1995) and are inversely related to the time from abnormal notification to resolution as normal. These short-term experiences following falsely abnormal mammography have not been consistently linked to future screening behaviors.

One concern frequently raised about screening women with a life expectancy of 5-10 years is detection and treatment, including overtreatment, of DCIS. Detection rates of DCIS are similar across age groups. Field et al. showed that biennial screening increases the percentage of invasive disease in women over 65 compared with detection of DCIS, suggesting that less screening does lead to more tumor progression in this population. It is particularly important that older women be informed about possible harms associated with screening, including identification and potential over-treatment of some DCIS lesions. However, it is important to note that the purpose of breast cancer screening is the detection of invasive disease, that the incidence of invasive disease dwarfs that of DCIS, and that it is not currently possible to identify which in situ cancers will progress. Thus, while women should be informed about the potential for identification of abnormalities that ultimately are revealed to be benign or DCIS, it would be shortsighted to decide to forgo screening on this basis. Concerns about overtreatment of DCIS are best focused on treatment decisions, not screening.

Some groups of older women with physical or cognitive problems may be particularly vulnerable to the burdens, discomfort, and anxiety associated with screening and associated testing. On the other hand, some studies have demonstrated that physicians over-estimate physical and financial burdens of screening, and may fail to refer older women for mammography based on anticipated patient refusal.

Recommendation: Women at increased risk of breast cancer might benefit from additional screening strategies beyond those offered to women of average risk, such as earlier initiation of screening, shorter screening intervals, or the addition of screening modalities other than mammography and physical examination. However, the evidence currently available is insufficient to justify recommendations for any of these screening approaches. In lieu of recommendations, points of discussion have been developed for women at increased risk and their healthcare providers when considering screening options. These points are based on the limited available evidence and expert opinion. Decisions about screening options for women at increased risk of breast cancer should be based on shared decision-making after a review of potential benefits, limitations, and harms of different screening strategies and the degree of uncertainty about each. In order to pursue answers to unresolved questions, important elements of a research agenda are identified and efforts to collect needed outcome data are encouraged.

Over the years, a number of risk factors have been identified for breast cancer . The most important risk factors are age and sex. Although approximately 1% of all cases are male, the majority are female, and risk increases with age. After controlling for age, the greatest increase in risk has generally been associated with a family history of breast and/or ovarian cancer, with the number, type and age at onset of affected relatives being important modulators of risk . Within the group of women with a family history of breast and/or ovarian cancer, a relatively small subset of women deserves special mention. Over the past decade, two breast/ovarian cancer susceptibility genes have been identified, named BRCA1 and BRCA2 . Women who are known carriers of mutations in either of these two genes have particularly high risks of breast and ovarian cancer. Although only laboratory testing can confirm that a woman carries a deleterious mutation in one of these genes, genetic and epidemiologic studies document several family history characteristics that suggest an increased risk of breast cancer. These include:

• Two or more relatives with breast or ovarian cancer;
• Breast cancer occurring before age 50 in an affected relative;
• Relatives with both breast and ovarian cancer;
• One or more relatives with two cancers (breast and ovarian cancer, or two independent breast cancers);
• Male breast cancer;
• A family history of breast or ovarian cancer and Ashkenazi Jewish heritage.

A number of statistical models exist that attempt to predict the risk of breast cancer for women with risk factors for the disease . A quantitative evaluation of family history, to determine the likelihood of BRCA1/2 mutations and to estimate lifetime risk of breast cancer, can be accomplished with the BRCAPRO statistical model . The Claus statistical model can also be used to estimate either short-term or lifetime risk of breast cancer based on family history ; this model is most appropriate for patients with one or two affected relatives. A third statistical model, the Gail model , can also be used to estimate short-term and lifetime risk of breast cancer. The Gail model estimates five-year and lifetime risk of breast cancer based on age of menarche, age at menopause, age at birth of first child, number of breast biopsies, whether or not breast biopsies conferred a finding of atypia, and family history (scored as 0, 1, or 2 first-degree relatives with breast cancer). Because the Gail model uses limited family history information, it is helpful in assigning risk when family history is not the primary risk factor of interest.

Each of these models has strengths and weaknesses, and a woman’s risk estimates may vary with different models . In addition, it has been shown that while these models predict well for groups of women with a particular risk factor, they are less successful in estimating risk for an individual woman . Thus the risks generated from these models should not be considered precise estimates but rather a means to identify a subset of women at significantly increased risk.

The threshold for defining a woman as having significantly elevated risk of breast cancer is based on expert opinion. Any woman with a BRCA1 or BRCA2 mutation should be considered at significantly increased risk. If mutation testing is not available, or has been done and is non-informative, pedigree characteristics suggesting high risk (as noted above) are also an indicator of significantly increased risk. The age group for which risk assessment is likely to be most important is women aged less than 40, because it is in this age range that beginning screening earlier may offer the greatest potential benefit.

Additional factors that increase the risk of breast cancer and thus may warrant earlier or more frequent screening include previous treatment with chest irradiation (e.g. for Hodgkin’s Disease) and a personal history of breast cancer.

Four screening options may be considered for women at significantly increased risk of breast cancer:

• Initiation of screening at age 30 or, rarely, at younger ages;
• Shorter screening intervals – e.g., every 6 months;
• Addition of MRI screening;
• Addition of ultrasound screening.

There are no randomized controlled trial data and few observational data to assess mammography screening in high-risk women younger than age 40. A number of prospective and case-control studies of good quality have evaluated screening in young women at increased risk, but most of the subjects in these studies have been between the ages of 40 and 50. The breast cancer incidence observed in these studies confirms that family history indicators and BRCA1/2 mutation status can identify women at significantly increased risk of breast cancer, and that mammography has performance characteristics in young women at increased risk similar to its characteristics in women from the general population at older ages. . Women under age 50 who are at increased risk and are undergoing regular screening are more likely to be diagnosed at earlier stages of invasive or in situ disease and tend to have more favorable tumor characteristics.

Early initiation of mammography screening may permit the identification of early breast cancer in women at high risk. In particular, women with BRCA1 and BRCA2 mutations are at risk for breast cancer at an early age: cumulative risk to age 40 could be as high is 20% in some mutation carriers.

Sensitivity and specificity of mammography are not well established in young women. In general, accuracy measured by both sensitivity and specificity is lower in younger women compared with older women, but still is favorable in all age groups, and both sensitivity and specificity improve incrementally as women get older. However, screening in younger women generally will have higher false positive results, which result in excess workups. Alternatively, false negative results may lead to false reassurance in the presence of a subsequent palpable mass, although the degree to which this occurs is uncertain.

Several studies have provided evidence for an increased risk of breast cancer after therapeutic radiation exposure or multiple exposures to diagnostic radiation . Overall, risk from single and cumulative exposures is small, but risk increases with the amount of exposure and with younger age at exposure. It is theoretically possible that cumulative radiation exposure associated with screening mammography increases the risk of breast cancer, and the relative risk increases depending on model assumptions of carcinogenesis at very low doses. It has also been hypothesized that some women at increased risk for breast cancer may also have increased radiation sensitivity, which could increase their risk for radiation-induced breast cancer. One indicator for this possibility is that studies of BRCA1 and BRCA2 suggest that these genes code for functions related to repair of radiation damage to DNA. However, in a report from a multi-institutional study, there was no evidence of increased radiation sensitivity in BRCA 1/2 carriers receiving radiotherapy after breast-conserving surgery, nor did family history influence treatment outcome among women at a referral center who received breast-conserving surgery and radiation therapy . Even if the highest estimates of increased risk of radiation-induced cancers from low mammographic doses beginning at a younger age are true, the risk-benefit equation is still in favor of mammography screening for most or all women, particularly if radiation exposure from the screening process is kept as low as possible. However, given concerns and uncertainties about possible radiation risk, it is important not to screen young women for whom there is not a firm basis for assigning high risk, and to limit radiation exposure during the screening process to the lowest level that still insures a favorable image. Further, as part of a decision-making process, women should be informed about the unlikely, but uncertain, potential for radiation-induced cancers as a possible harm associated with regular screening beginning at young ages.

There are limited data on the effectiveness of CBE and BSE (see section on physical examination). Data specific to high-risk women are particularly limited. A recent study from Memorial Sloan-Kettering Cancer Center suggested a value for BSE, in that 5 breast cancers were detected by BSE less than a year after a previous screen among a cohort of high-risk women (as compared with 1 cancer detected by clinical exam and 11 cancers detected as a result of mammographic screening). However, it is not clear in this study whether the detection of interval cancers occurred through deliberate self-examination according to instruction or whether discovery occurred during the course of normal activities. There are no systematic studies looking at harms (including anxiety, false positive work-ups, and complacency) associated with physical exam, and there has been no systematic comparison of different screening intervals.

There are no known studies evaluating a semi-annual vs. annual screening interval, although those comparing annual vs. biennial definitely favor more frequent screening. Recommendations for shorter intervals have generally been based on interval cancer and modeling data. An important research question is to what extent interval cancer diagnoses should be used as a basis for recommending more frequent screening. There is disagreement about the extent to which interval cancers in younger women at increased risk are attributable to faster tumor growth rates and shorter sojourn times versus greater difficulty in imaging dense parenchyma. Data from the Two-County trial showed that women with family histories had tumors with faster growth rates, but the difference was not large. If cancers are missed due to density, then, theoretically, another modality should add more to detection than a more frequent screening interval with a less sensitive test.

Five separate groups have evaluated the relative contributions of mammography, magnetic resonance imaging (MRI) and ultrasound in women with either a family history of breast cancer or a documented BRCA1/2 mutation. In addition to the published studies, there are several ongoing MRI high-risk screening studies throughout the world, including the US, Canada, England, Germany, the Netherlands, France and Italy. These studies suggest that MRI or ultrasound may be beneficial if used as an additional screening method for women with a significantly increased risk of breast cancer.

Five studies of screening MRI in younger high-risk women have found sensitivities and cancer yields significantly improved over those of mammography. Specificity varies according to how centers manage follow-up, but is generally lower than screen-film mammography. All prior and current studies indicate the cancer yield with MRI is higher than with mammography and ultrasound. In studies in which both prevalent (first) and incident (subsequent) screens were performed, the higher yield of cancers detected with MRI was true for both prevalent and incident screens. There is a need for longer-term studies that include both prevalent and incident screens.

Even as studies report high sensitivity with MRI, there are substantial concerns about costs and limited access for women with familial risk. In addition, a criterion for a screening modality is that any suspicious lesion that is identified can be biopsied, but MRI-guided biopsies are not widely available. Since false positive results appear to be common, more data are needed on factors associated with lower specificity rates. Among higher risk women undergoing MRI, there are no data on anxiety and quality of life effects related to false positives.

Studies of ultrasound imaging have shown an ability to find cancers not found on mammography but with sensitivity inferior to that of MRI. The value of ultrasound is greatest for women with significant breast density. Ultrasound is less sensitive than MRI, but has the advantage of being more widely available and considerably less expensive. Also, ultrasound-guidance for needle biopsy is easily done, and allows histologic assessment for abnormalities detected during the screening process. There is concern about operator dependence and the difficulty of following up on masses not biopsied. Like mammography, ultrasound has a lower specificity in younger women.

In order to address the unanswered clinical research questions, women at increased risk should be enrolled in protocols assessing early screening, more intensive screening, and the use of new screening modalities, where feasible. Screening MRI should take place in centers with biopsy capability and extensive experience in diagnostic MRI. Many high-risk women are currently being screened with MRI outside of clinical trials. Collection of observational data and development of a national MRI screening registry should be strongly encouraged.

Screen-film mammography is the current gold standard for breast cancer screening. New technologies proposed for breast cancer screening must equal or, preferably, exceed the performance of screen-film mammography to find acceptance as a screening tool. New technologies for breast cancer screening should aim at identifying a higher fraction of early stage cancers, identifying cancers that are likely to progress to become lethal cancers, identifying early changes before the appearance of true malignancies, and identifying more of the cancers that are missed by screen-film mammography (SFM). In addition, any new technology should meet the goals of an ideal screening tool, be associated with low risk, simple to perform, non-invasive, cost-effective, widely available, and acceptable to women.

A list of potential new technologies for breast cancer screening is included in Table 3. Several of these modalities have been FDA-approved for clinical use, but in most cases not explicitly for breast cancer screening. One recently approved technology that also has been approved for breast screening and diagnostic use is full-field digital mammography (FFDM). To obtain FDA approval, FFDM manufacturers had to demonstrate that their digital mammography systems were not significantly inferior to screen-film mammography, in terms of sensitivity, specificity, and receiver-operator characteristic (ROC) curve areas. Three manufacturers have received FDA approval to use FFDM for screening and diagnostic mammography. As of September 2002, there were approximately 300 FFDM systems in clinical use in the US.

The only completed study comparing FFDM to SFM in a screening cohort was done on a single manufacturer’s prototype system at two sites. FFDM had a significantly lower recall rate (11.8% vs. 14.9%, p > 0.001) and significantly lower biopsy rate than SFM (94 vs. 143 out of 6,736 exams, p<0.001). However, FFDM had insignificantly lower sensitivity. The American College of Radiology Imaging Network (ACRIN) is conducting a larger study of similar design. The digital mammographic screening trial (DMIST) is a paired design to compare FFDM (from 4 different manufacturers) to SFM. Enrollment should be completed in late 2003.

A – Strong clinical evidence for effectiveness in screening; technology is routinely used for screening

B - Some clinical evidence for effectiveness or equivalence to screen-film mammography for screening

C - Preclinical data suggest possible promise, but clinical data are sparse or non-existent; more study is needed

D - Clinical evidence indicates that modality is ineffective as a screening tool

E - Technology is not to the stage that data are available

*Adapted, with additions and minor changes, from Table 2-1, Institute of Medicine Report on New Technologies in Breast Imaging, 2001 (reference 1).

Over the last two decades, computer-aided detection and diagnosis (CAD) has been developed to aid radiologists in detecting mammographic abnormalities suspicious for breast cancer. The FDA has approved several commercial systems to aid radiologists in reviewing screening mammograms obtained on screen-film mammography systems. Three commercial systems designed to digitize screen-film mammograms and analyze them for suspicious lesions have received FDA approval for clinical use. There are approximately 500 CAD systems installed in the US. Only one commercial CAD system has been approved by the FDA for use with digital mammography.

Several important clinical studies have been conducted to evaluate the effectiveness of commercial CAD systems in aiding radiologists in the performance of screening mammography. In the largest clinical series to date, radiologists reading with CAD increased their overall screening recall rate from 6.5% to 7.7% (an 18.5% increase), while increasing the number of detected cancers from 41% to 49% (a 19.5% increase) compared to interpretation without CAD. Use of CAD increased overall detection rate from 3.2 to 3.8 cancers per 1,000 women screened. These results suggest that CAD systems may aid the average radiologist by substantially improving detection of early-stage malignancies, with no more than a proportionate increase in recall rate.

Ultrasound has become an extremely valuable diagnostic adjunct to mammography. Usually, however, breast ultrasound is used clinically as a targeted exam, limiting scanning to the area of concern. Recent improvements in breast ultrasound technology and its application have demonstrated that ultrasound can help distinguish not only between cyst and solid masses, but also between benign and malignant masses. Prevalence screening studies in women with dense breasts have reported 3 to 4 breast cancers per 1,000 women that were detected by ultrasound only. Despite these findings, breast ultrasound has known limitations as a screening tool. Breast ultrasound requires a skilled operator and the numbers of radiologists and technologists trained to perform the exam is limited. Other concerns include the lack of standardized exam techniques and interpretation criteria, the inability of breast ultrasound to detect microcalcifications, the variability of equipment, and preliminary data suggesting a substantially higher rate of false positive exams than mammography.