This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Note: Separate PDQ summaries on Breast Cancer Prevention ; Breast Cancer Treatment ; Male Breast Cancer Treatment ; and Breast Cancer Treatment and Pregnancy are also available.
Screening by Mammography
Statement of benefit
Based on fair evidence, screening mammography in women aged 40 to 70 years decreases breast cancer mortality. The benefit is higher for older women, in part because their breast cancer risk is higher.
Description of the Evidence
Statement of harms
Based on solid evidence, screening mammography may lead to the following harms:
|Harm||Study Design||Internal Validity||Consistency||Magnitude of Effects||External Validity|
|Treatment of insignificant cancers (overdiagnosis, true positives) can result in breast deformity, lymphedema, thromboembolic events, new cancers, or chemotherapy-induced toxicities.||Descriptive population-based, autopsy series and series of mammary reduction specimens||Good||Good||Approximately 33% of breast cancers detected by screening mammograms represent overdiagnosis.||Good|
|Additional testing (false-positives)||Descriptive population-based||Good||Good||Estimated to occur in 50% of women screened annually for 10 years, 25% of whom will have biopsies.||Good|
|False sense of security, delay in cancer diagnosis (false-negatives)||Descriptive population-based||Good||Good||6% to 46% of women with invasive cancer will have negative mammograms, especially if young, with dense breasts,[8,9]or with mucinous, lobular, or fast-growing cancers.||Good|
|Radiation-induced mutations can cause breast cancer, especially if exposed before age 30 years. Latency is more than 10 years, and the increased risk persists lifelong.||Descriptive population-based||Good||Good||Between 9.9 and 32 breast cancers per 10,000 women exposed to a cumulative dose of 1 Sv. Risk is higher for younger women.[11,12]||Good|
Screening by Clinical Breast Examination
Statement of benefits
Based on fair evidence, screening by clinical breast examination reduces breast cancer mortality.
Description of the Evidence
Statement of harms
Based on solid evidence, screening by clinical breast examination may lead to the following harms:
|Harms||Study Design||Internal Validity||Consistency||Magnitude of Effects||External Validity|
|Additional testing (false-positives)||Descriptive population-based||Good||Good||Specificity in women aged 50 to 59 years ranged between 88% and 99%.[13,14]||Good|
|False reassurance, delay in cancer diagnosis (false-negatives)||Descriptive population-based||Good||Fair||Of women with cancer, 17% to 43% had a negative clinical breast examination.||Poor|
Screening by Breast Self-Examination
Statement of benefit
Based on fair evidence, teaching breast self-examination does not reduce breast cancer mortality.
Description of the Evidence
Statement of harms
Based on solid evidence, formal instruction and encouragement to perform breast self-examination leads to more breast biopsies and to the diagnosis of more benign breast lesions.
Description of the Evidence
|1.||Nyström L, Andersson I, Bjurstam N, et al.: Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 359 (9310): 909-19, 2002.|
|2.||Shapiro S: Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, Md: Johns Hopkins University Press, 1988.|
|3.||Miller AB, To T, Baines CJ, et al.: The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med 137 (5 Part 1): 305-12, 2002.|
|4.||Miller AB, Baines CJ, To T, et al.: Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ 147 (10): 1477-88, 1992.|
|5.||Moss SM, Cuckle H, Evans A, et al.: Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial. Lancet 368 (9552): 2053-60, 2006.|
|6.||Zahl PH, Strand BH, Maehlen J: Incidence of breast cancer in Norway and Sweden during introduction of nationwide screening: prospective cohort study. BMJ 328 (7445): 921-4, 2004.|
|7.||Elmore JG, Barton MB, Moceri VM, et al.: Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 338 (16): 1089-96, 1998.|
|8.||Rosenberg RD, Hunt WC, Williamson MR, et al.: Effects of age, breast density, ethnicity, and estrogen replacement therapy on screening mammographic sensitivity and cancer stage at diagnosis: review of 183,134 screening mammograms in Albuquerque, New Mexico. Radiology 209 (2): 511-8, 1998.|
|9.||Kerlikowske K, Grady D, Barclay J, et al.: Likelihood ratios for modern screening mammography. Risk of breast cancer based on age and mammographic interpretation. JAMA 276 (1): 39-43, 1996.|
|10.||Porter PL, El-Bastawissi AY, Mandelson MT, et al.: Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 91 (23): 2020-8, 1999.|
|11.||Ronckers CM, Erdmann CA, Land CE: Radiation and breast cancer: a review of current evidence. Breast Cancer Res 7 (1): 21-32, 2005.|
|12.||Goss PE, Sierra S: Current perspectives on radiation-induced breast cancer. J Clin Oncol 16 (1): 338-47, 1998.|
|13.||Fenton JJ, Rolnick SJ, Harris EL, et al.: Specificity of clinical breast examination in community practice. J Gen Intern Med 22 (3): 332-7, 2007.|
|14.||Baines CJ, Miller AB, Bassett AA: Physical examination. Its role as a single screening modality in the Canadian National Breast Screening Study. Cancer 63 (9): 1816-22, 1989.|
|15.||Thomas DB, Gao DL, Ray RM, et al.: Randomized trial of breast self-examination in Shanghai: final results. J Natl Cancer Inst 94 (19): 1445-57, 2002.|
Incidence and Mortality
Breast cancer is the most common noncutaneous cancer in U.S. women, with an estimated 226,870 new cases of invasive disease (plus 63,300 cases of in situ disease) and 39,510 deaths in 2012. Males account for 1% of breast cancer cases and breast cancer deaths (refer to the Special Populations section of this summary for more information).
Ecologic studies from the United States  and the United Kingdom  demonstrate an increase in breast cancer incidence during the last three decades, rising from 82 cases per 100,000 people in 1973 to 124 per 100,000 in 2007. Between 1970 and the early 1980s the increase was small and has been attributed to changes in reproductive behavior and hormone use. Since the mid-1980s, with the widespread adoption of screening mammography, the increase has been dramatic. By illustration, the incidence among British women aged 50 to 65 years nearly doubled between 1984 and 1994. Similarly, in Sweden, where more cancers are discovered in younger women, the incidence of breast cancer increased dramatically in counties that adopted screening. Similar findings have been documented in the United States. Mammographic screening has also increased the diagnosis of noninvasive cancers and premalignant lesions. Whereas ductal carcinoma in situ was a rare condition before 1985, it is currently diagnosed in more than 63,000 American women per year (refer to the Ductal Carcinoma In Situ section of this summary for more information).
One might expect that screening will identify many cancers before they cause clinical symptoms, followed by a subsequent compensatory decline in cancer rates, seen either in annual population incidence rates or in incidence rates in older women. So far, no compensatory drop in incidence rates attributable to a change in screening patterns has been observed. This raises concerns about overdiagnosis—screening that identifies clinically insignificant cancers (refer to the Overdiagnosis section of this summary for more information).
The risk of breast cancer depends on age (see Table 3). As shown in Table 3, the interval risk increases with starting age. Thus, a 60-year-old woman has a higher risk of being diagnosed with breast cancer in the next 10 years compared with a 40-year-old woman. Breast cancer is rare among younger women; among women aged 30 years, 4 in 1,000 will develop breast cancer in the next 10 years.
The cumulative lifetime risk decreases across the age groups as shown in Table 3. This is because a woman who is aged 50 years has lived through some of her risk period without having cancer. The common risk cited that one in eight women will develop breast cancer is based on lifetime risk starting from birth and does not account for the woman's current age. For example, women who are aged 60 years have lived a good portion of their life expectancy without cancer, therefore their remaining lifetime risk is less than for women who are aged 30 years (91 per 1,000 vs. 123 per 1,000).
|Current Age in Yearsb||Risk per 1,000 Womenc|
|a Based on an analysis of data from the Surveillance, Epidemiology, and End Results registry for 2005–2007.|
|b Women who are free from invasive breast cancer at their current age.|
|c Number of women in 1,000 who would develop invasive breast cancer in the next period of time.|
|in 10 years||in 20 years||in 30 years||Lifetime|
In 2012, an estimated 39,510 women will die of breast cancer, compared with about 72,590 women who will die of lung cancer. Approximately one in six women diagnosed with breast cancer dies of the breast cancer, while nearly all women with lung cancer die of lung cancer.
Breast cancer mortality increases with age. For a 40-year-old woman without a breast cancer diagnosis, the chance of dying from breast cancer within the next 10 years is extremely small, but for a woman older than 65 years, it is about 1% (see Table 4). Women older than 70 years have an even higher risk of dying of breast cancer, but they are even more likely to die of other causes.
|For Women Aged:||Chance of Dying of Breast Cancer in the Next 10 Years per 1,000 Women||Chance of Dying From Any Cause in the Next 10 Years per 1,000 Women|
|a Adapted from Schwartz, Woloshin, and Welch.|
Other Risk Factors
Additional risk factors include a strong family history of breast or ovarian cancer (particularly first-degree relatives, on either the mother's or father's side); early age at menarche and late age at first birth (reflecting estrogen exposure); and a history of breast biopsies, especially for proliferative benign breast disease,[7,8] including radial scalloping lesions (a pathologic entity also called radial scars, even though unrelated to previous surgeries or scars). The Gail model estimates individual risk over time based on these factors for women aged 40 years or older who receive regular mammography.[10,11,12] (Refer to the Breast Cancer Risk Assessment Tool.)
Women with a personal history of invasive breast cancer, ductal carcinoma in situ, or lobular carcinoma in situ have a 0.6% to 1.0% estimated annual risk of developing a new primary breast cancer.
Women treated with thoracic radiation, especially when younger than 30 years, have a 1% annual risk of breast cancer, starting 10 years after the irradiation.
Radiological breast density [15,16,17] is a strong risk factor for breast cancer and also presents challenges in the interpretation of mammograms. Dense fibroglandular tissue seen on mammography is associated with a threefold to sixfold increased risk of breast cancer compared with fatty breast tissue.
Behavioral factors such as menopausal hormone use, obesity, and alcohol intake are associated with an increased risk of breast cancer. (Refer to the PDQ summaries on Cancer Prevention Overview and Breast Cancer Prevention for more information.)
Breast cancer incidence and mortality risk also vary according to geography, culture, race, ethnicity, and socioeconomic status and are discussed more fully below (refer to the Special Populations section of this summary for more information).
|1.||American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed January 5, 2012.|
|2.||Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online. Last accessed December 1, 2011.|
|3.||Johnson A, Shekhdar J: Breast cancer incidence: what do the figures mean? J Eval Clin Pract 11 (1): 27-31, 2005.|
|4.||Hemminki K, Rawal R, Bermejo JL: Mammographic screening is dramatically changing age-incidence data for breast cancer. J Clin Oncol 22 (22): 4652-3, 2004.|
|5.||Kerlikowske K, Salzmann P, Phillips KA, et al.: Continuing screening mammography in women aged 70 to 79 years: impact on life expectancy and cost-effectiveness. JAMA 282 (22): 2156-63, 1999.|
|6.||Schwartz LM, Woloshin S, Welch HG: Risk communication in clinical practice: putting cancer in context. J Natl Cancer Inst Monogr (25): 124-33, 1999.|
|7.||London SJ, Connolly JL, Schnitt SJ, et al.: A prospective study of benign breast disease and the risk of breast cancer. JAMA 267 (7): 941-4, 1992.|
|8.||McDivitt RW, Stevens JA, Lee NC, et al.: Histologic types of benign breast disease and the risk for breast cancer. The Cancer and Steroid Hormone Study Group. Cancer 69 (6): 1408-14, 1992.|
|9.||Jacobs TW, Byrne C, Colditz G, et al.: Radial scars in benign breast-biopsy specimens and the risk of breast cancer. N Engl J Med 340 (6): 430-6, 1999.|
|10.||Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989.|
|11.||Bondy ML, Lustbader ED, Halabi S, et al.: Validation of a breast cancer risk assessment model in women with a positive family history. J Natl Cancer Inst 86 (8): 620-5, 1994.|
|12.||Spiegelman D, Colditz GA, Hunter D, et al.: Validation of the Gail et al. model for predicting individual breast cancer risk. J Natl Cancer Inst 86 (8): 600-7, 1994.|
|13.||Gail MH, Costantino JP, Bryant J, et al.: Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 91 (21): 1829-46, 1999.|
|14.||Goss PE, Sierra S: Current perspectives on radiation-induced breast cancer. J Clin Oncol 16 (1): 338-47, 1998.|
|15.||Ma L, Fishell E, Wright B, et al.: Case-control study of factors associated with failure to detect breast cancer by mammography. J Natl Cancer Inst 84 (10): 781-5, 1992.|
|16.||Goodwin PJ, Boyd NF: Mammographic parenchymal pattern and breast cancer risk: a critical appraisal of the evidence. Am J Epidemiol 127 (6): 1097-108, 1988.|
|17.||Fajardo LL, Hillman BJ, Frey C: Correlation between breast parenchymal patterns and mammographers' certainty of diagnosis. Invest Radiol 23 (7): 505-8, 1988.|
Evaluation of Breast Symptoms
Breast symptoms may suggest a diagnosis of breast cancer. During a 10-year period, 16% of 2,400 women aged 40 to 69 years sought medical attention for breast symptoms at their health maintenance organization. Women younger than 50 years were twice as likely to seek evaluation. Additional examinations were performed in 66% of patients, with 27% undergoing invasive procedures. Cancer was diagnosed in 6.2% of patients with breast symptoms, most being stage II or III. Of the breast symptoms prompting medical attention, a mass was most likely to lead to a cancer diagnosis (10.7%) and pain was least likely (1.8%) to do so.
Pathologic Diagnosis of Breast Cancer
Breast cancer is diagnosed by pathologic review of a fixed specimen of breast tissue. The breast tissue can be obtained from a symptomatic area or from an area identified by a screening test, usually mammography. A palpable lesion can be excised surgically or biopsied with fine-needle aspirate or core needle biopsy (CNBx). Nonpalpable lesions can be excised by surgical needle localization under x-ray guidance (SNLBx). Alternatively, a CNBx of a mammographically suspicious area can be obtained with use of stereotactic x-ray or ultrasound. In a retrospective study of 939 patients with 1,042 mammographically detected lesions who underwent CNBx or SNLBx, sensitivity for malignancy was greater than 95% and the specificity was greater than 90%. Compared with SNLBx, CNBx resulted in fewer surgical procedures for definitive treatment with a higher likelihood of clear surgical margins at the initial excision.
Fine-needle aspiration, nipple aspiration, and ductal lavage are three methods of obtaining cells from breast tissue or ductal epithelium for cytological examination (refer to the Tissue Sampling [Fine-Needle Aspiration, Nipple Aspirate, Ductal Lavage] section of this summary for more information).
None of these technologies has been tested in controlled trials of screening or compared with other breast cancer screening modalities.
Ductal CarcinomaIn Situ
Ductal carcinoma in situ (DCIS) is a noninvasive condition that can progress to invasive cancer, with variable frequency and time course. While some authors include DCIS with invasive breast cancer statistics, it has been suggested that the term DCIS be replaced by a classification system of ductal intraepithelial neoplasia, similar to those used to grade cervical and prostate precursor lesions. DCIS is usually diagnosed by mammography, so it is rare in unscreened women. In the United States in 1983, the prescreening era, 4,900 women were diagnosed with DCIS, compared with approximately 63,300 women who will be diagnosed in 2012.[3,4,5]
The natural history of untreated DCIS is poorly understood because women diagnosed with DCIS undergo surgery, with or without radiation and hormone therapy. According to data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute on women with newly diagnosed DCIS treated between 1984 and 1989, 1.9% died of breast cancer within 10 years of diagnosis. Development of breast cancer after treatment of DCIS varies according to treatment. One large randomized trial found that 13.4% of women treated by lumpectomy alone developed ipsilateral invasive breast cancer by 90 months, compared with 3.9% of those treated by lumpectomy and radiation. Another series of 706 DCIS patients, however, allowed definition of the University of Southern California/Van Nuys Prognostic Scoring Index, which defines the risk of recurrence based on age, margin width, tumor size, and grade. The low-risk group, comprising a third of the cases, experienced few DCIS recurrences (1%) and no invasive cancers, regardless of whether radiation was given. The moderate- and high-risk groups had higher recurrence rates, with a beneficial preventive effect of radiation. Nonetheless, only approximately 1% had death from breast cancer. The addition of tamoxifen also reduces the incidence of invasive breast cancer after excision of DCIS. Because all these studies include excision of mammographically detected DCIS, the natural history of this condition remains unknown.
Some information about the natural history of untreated, palpable DCIS is available. A retrospective review of 11,760 biopsies performed between 1952 and 1968 identified 28 cases of untreated DCIS (noncomedo type).[10,11] All were found by clinical examination, underwent biopsy only, and were followed for 30 years. Nine women (32%) developed invasive breast cancer in the area of previous DCIS. Of these, seven cancers were diagnosed within 10 years of DCIS biopsy, and two were diagnosed between 10 and 30 years after biopsy. Many of the cancers were diagnosed at advanced stages, possibly because of the false reassurance of the previous "negative" biopsy. None of the women with invasive cancer received adjuvant systemic therapy. Four eventually died of the disease. These findings have been used as an argument both for and against aggressive diagnosis and treatment of DCIS.
Many DCIS cases will not progress to invasive cancer, and those that do are likely to be managed successfully at the time of progression. Thus, treatment of all screen-detected DCIS with surgery, radiation, and/or hormone therapy represents overdiagnosis and overtreatment for many. The Canadian National Breast Screening Study-2 of women aged 50 to 59 years found a fourfold increase in DCIS cases in women screened by clinical breast examination plus mammography compared with those screened by clinical breast examination alone, with no difference in breast cancer mortality. (Refer to the PDQ summary on Breast Cancer Treatment for more information.)
|1.||Barton MB, Elmore JG, Fletcher SW: Breast symptoms among women enrolled in a health maintenance organization: frequency, evaluation, and outcome. Ann Intern Med 130 (8): 651-7, 1999.|
|2.||White RR, Halperin TJ, Olson JA Jr, et al.: Impact of core-needle breast biopsy on the surgical management of mammographic abnormalities. Ann Surg 233 (6): 769-77, 2001.|
|3.||American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online. Last accessed January 5, 2012.|
|4.||Allegra CJ, Aberle DR, Ganschow P, et al.: National Institutes of Health State-of-the-Science Conference statement: Diagnosis and Management of Ductal Carcinoma In Situ September 22-24, 2009. J Natl Cancer Inst 102 (3): 161-9, 2010.|
|5.||Virnig BA, Tuttle TM, Shamliyan T, et al.: Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst 102 (3): 170-8, 2010.|
|6.||Ernster VL, Barclay J, Kerlikowske K, et al.: Mortality among women with ductal carcinoma in situ of the breast in the population-based surveillance, epidemiology and end results program. Arch Intern Med 160 (7): 953-8, 2000.|
|7.||Fisher B, Dignam J, Wolmark N, et al.: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16 (2): 441-52, 1998.|
|8.||Silverstein MJ: The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg 186 (4): 337-43, 2003.|
|9.||Fisher B, Dignam J, Wolmark N, et al.: Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 353 (9169): 1993-2000, 1999.|
|10.||Page DL, Dupont WD, Rogers LW, et al.: Intraductal carcinoma of the breast: follow-up after biopsy only. Cancer 49 (4): 751-8, 1982.|
|11.||Page DL, Dupont WD, Rogers LW, et al.: Continued local recurrence of carcinoma 15-25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer 76 (7): 1197-200, 1995.|
|12.||Miller AB, To T, Baines CJ, et al.: Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 92 (18): 1490-9, 2000.|
Mammography utilizes ionizing radiation to image breast tissue. The examination is performed by compressing the breast firmly between a plastic plate and an x-ray cassette that contains special x-ray film. For routine screening in the United States, examination films are taken in mediolateral oblique and craniocaudal projections. Both views should include breast tissue from the nipple to the pectoral muscle. Two-view examinations decrease the recall rate compared with single-view examinations by eliminating concern about abnormalities due to superimposition of normal breast structures.
Under the Mammography Quality Standards Act (MQSA) enacted by Congress in 1992, all facilities that perform mammography must be certified by the U.S. Food and Drug Administration (FDA). This mandate has resulted in improved mammography technique, lower radiation dose, and better training of personnel. Refer to the list of FDA Certified Mammography Facilities. Image contrast has improved with the use of lower voltage, specialized aluminum grids, and higher film optical density. The 1998 MQSA Reauthorization Act requires that patients receive a written lay-language summary of mammography results.
Mammography can identify breast cancers too small to palpate on physical examination and can also find ductal carcinoma in situ (DCIS), a noninvasive condition. Because all cancers develop as a consequence of a series of mutations, it is theoretically beneficial to diagnose these noninvasive lesions. A large increase in the frequency of DCIS diagnosis occurred in the United States beginning in the early 1980s  because of the increased use of screening mammography. Appropriate management of DCIS is not well understood because its natural history is incompletely defined. (Refer to the PDQ summary on Breast Cancer Treatment for more information. Also refer to the Ductal Carcinoma In Situ section of this summary for more information.)
Numerous uncontrolled trials and retrospective series have documented the capacity of mammography to diagnose small, early-stage breast cancers, including those that have a favorable clinical course. These trials also show that cancer-related survival is better in screened women than in nonscreened women. These comparisons are susceptible, however, to a number of important biases:
|1.||Lead-time bias: Survival time for a cancer found mammographically includes the time between detection and when the cancer would have been detected because of clinical symptoms, but this time is not included in the survival time of cancers found because of symptoms.|
|2.||Length bias: Mammography detects a cancer while it is preclinical, and preclinical durations vary. Cancers with longer preclinical durations are more likely to be detected by screening; these cancers tend to be slow growing and to have good prognoses, irrespective of screening.|
|3.||Overdiagnosis bias: An extreme form of length bias; screening may find cancers that are very slow growing and that would never have become manifest clinically.|
|4.||Healthy volunteer bias: The screened population may be healthier or more health conscious than the general population.|
Because the extent of these biases is never clear in any particular study, one must rely on randomized controlled trials to assess the benefits of screening. (Refer to the Effect of Screening on Breast Cancer Mortality section of this summary for more information.)
The sensitivity of mammography is the proportion of breast cancer detected when breast cancer is present. Sensitivity depends on several factors, including lesion size, lesion conspicuity, breast tissue density, patient age, the hormone status of the tumor, overall image quality, and interpretive skill of the radiologist. Sensitivity is of great importance to patients and physicians alike; failure to diagnose breast cancer is the most common cause of medical malpractice litigation. Half of the cases resulting in payment to the claimant had false-negative mammograms.
Overall sensitivity is approximately 79% but is lower in younger women and in those with dense breast tissue. Overall specificity is approximately 90% and is lower in younger women and in those with dense breasts (see the Breast Cancer Surveillance Consortium).[6,7,8] Using data from screened women in the Group Health Cooperative of Puget Sound health maintenance organization, characteristics of 150 cancers not detected at screening but diagnosed within 24 months of a normal screening examination (interval cancers) were compared with those of 279 screen-detected cancers. Interval cancers were much more likely to occur in women younger than 50 years and to be of mucinous or lobular histology, high histologic grade, and high proliferative activity. Screen-detected cancers were more likely to have tubular histology; to be smaller, of low stage, and hormone sensitive; and to have a major component of in situ cancer.
Mammography is a less sensitive test for women aged 40 to 49 years than for older women. The authors of one study examined 576 women who developed invasive breast cancer following a screening mammogram to determine whether greater breast density or faster growing tumors among younger women explained the lower sensitivity. They found that more younger women with cancer had developed interval cancers. They also found that greater breast density explained most (68%) of the decreased mammographic sensitivity in younger women at 12 months, whereas at 24 months, rapid tumor growth and breast density explained approximately equal proportions of the interval cancers.
Screen-detected cancers have a more favorable prognosis than do interval cancers, even when matched for size and stage; this is an expression of length bias. These cancers have favorable cellular characteristics, including lower histologic grade, higher rate of hormone sensitivity, and lower proliferative indices. A 10-year follow-up study of 1,983 Finnish women with invasive breast cancer demonstrated that the method of cancer detection is an independent prognostic variable. When controlled for age, node involvement, and tumor size, screen-detected cancers had a lower risk of relapse and better overall survival. The hazard ratio (HR) for death was 1.90 (95% confidence interval [CI], 1.15–3.11) for women whose cancers were detected outside screening, even though they were more likely to get adjuvant systemic therapy. Similarly, an examination of the breast cancers found in three randomized screening trials (Health Insurance Plan, National Breast Screening Study [NBSS]-1, and NBSS-2—see below) accounted for stage, nodal status, and tumor size and determined that patients whose cancer was found via screening enjoyed a more favorable prognosis. Namely, the HRs for death were 1.53 (95% CI, 1.17–2.00) for interval and incident cancers in comparison with screen-detected cancers and 1.36 (95% CI, 1.10–1.68) for cancers in the control group in comparison with screen-detected cancers. A third study compared the outcomes of 5,604 English women with screen-detected or symptomatic breast cancers diagnosed between 1998 and 2003. After controlling for tumor size, nodal status, grade, and patient age, researchers found that the women with symptomatic cancers fared worse. The HR for survival was 0.79 (95% CI, 0.63–0.99). Thus, method of cancer detection is a powerful predictor of patient outcome, which is useful for prognostication and treatment decisions.
A critical factor determining mammographic sensitivity is the radiologist's interpretation. Studies have shown substantial variability in interpretation and reading accuracy among radiologists.[14,15,16,17,18,19,20,21,22,23] Some evidence suggests that using physician interpretation of actual mammograms influences sensitivity, specificity, or both, and a learning curve has been noted during the first few months of experience interpreting mammography examinations.[17,18,24,25] Whether this results from different overall accuracy or a shift in the trade-off between sensitivity and specificity, however, is not certain. The clinical significance of variability in radiologists' interpretations is not clear. Identifying a radiologist who is more accurate than another is difficult.
High breast density is associated with low sensitivity. At all ages, regardless of hormone therapy (HT), high breast density is associated with 10% to 29% lower sensitivity. HT, which increases breast density, is associated with both lower sensitivity and an increased rate of interval cancers. High breast density is an inherent trait, which can be familial [28,29] but also may be affected by age, endogenous  and exogenous [31,32] hormones, selective estrogen receptor modulators such as tamoxifen, and diet. Strategies have been proposed to improve mammographic sensitivity by altering diet, by timing mammograms with menstrual cycles, by interrupting HT use before the examination, or by using digital mammography machines.
The specificity of mammography is the likelihood of the test being normal when cancer is absent, whereas the false-positive rate is the likelihood of the test being abnormal when cancer is absent. If specificity is low, many false-positive examinations result in unnecessary follow-up examinations and procedures. (Refer to the Harms of Screening section of this summary for more information.) An improvement in reporting mammography results has been the adoption of Breast Imaging Reporting and Data System (BI-RADS) categories, which standardize the terminology used in assessing the significance of the findings and recommending future action. A study correlating needle localization biopsies with BI-RADS categories showed that categories 0 and 2 yielded benign tissue in 87% and 100%, respectively, of 65 cases. Category 3 (probably benign) yielded benign tissue in 98% of 141 cases, category 4 (suspicious) yielded benign tissue in 70% of 936 cases, and category 5 (highly suspicious) yielded benign tissue in only 3% of 170 cases. Studies have shown relatively little impact of false-positive test results on the use of subsequent mammography screening behavior, but false-positive test results may have long-term consequences, such as anxiety about breast cancer.
International comparisons of screening mammography have found that specificity is greater in countries with more highly centralized screening systems and national quality assurance programs.[39,40] For example, one study reported that the recall rate is twice as high in the United States as it is in the United Kingdom, with no difference in the rate of cancers detected. Such comparisons may be confounded, however, by other social, cultural, or economic factors that can influence the performance of mammography screening. No improvement in cancer detection was noted in these studies despite the higher recall rate.
The Million Women Study in the United Kingdom revealed three patient characteristics that decrease the sensitivity and specificity of screening mammograms in women aged 50 to 64 years: use of postmenopausal HT, prior breast surgery, and body mass index below 25. Another factor that affects sensitivity and specificity is the interval since the last examination. One study used data from seven registries in the United States to examine mammographic data and cancer outcomes in 1,213,754 screening mammograms in 680,641 women. With longer intervals between mammograms, sensitivity increased, specificity decreased, recall rate increased, and cancer detection rate increased.
The optimal interval between screening mammograms is unknown. In particular, each of the breast cancer mortality-focused, randomized, controlled trials (RCTs) used single screening intervals with little variability across the trials. A prospective trial that was undertaken in the United Kingdom randomly assigned women aged 50 to 62 years to annual or the standard 3-year interval for screening mammograms. More cancers of slightly smaller size were detected in the annual screening group with a lead time of approximately 7 months in comparison with triennial screening; however, the grade and node status were similar in the two groups. A large observational study found a slightly increased risk of late-stage disease at diagnosis for women in their 40s who were adhering to an every-2-year versus every-1-year schedule (28% vs. 21%; odds ratio = 1.35; 95% CI, 1.01–1.81). A 2-year interval was not associated with late-stage disease for women in their 50s or 60s.
A Finnish study of 14,765 women aged 40 to 49 years assigned women born in even-numbered years to annual screens and women born in odd-numbered years to triennial screens. The study was small in terms of number of deaths, with low power to discriminate breast cancer mortality between the two groups. There were 18 deaths from breast cancer in 100,738 life-years in the triennial screening group and 18 deaths from breast cancer in 88,780 life-years in the annual screening group (hazard ratio, 0.88; 95% CI, 0.59–1.27).
The optimal screening interval has been addressed by modelers. Modeling makes assumptions that may not be correct; however, the credibility of modeling is greater when the model produces overall results that are consistent with randomized trials overall and when the model is used to interpolate or extrapolate. For example, if a model's output agrees with RCT outcomes for annual screening, then it has greater credibility in comparing the relative effectiveness of biennial versus annual screening. In 2000, the National Cancer Institute formed a consortium of modeling groups (Cancer Intervention and Surveillance Modeling [CISNET]) to address the relative contribution of screening and adjuvant therapy to the observed decline in breast cancer mortality in the United States. (Refer to the Randomized Controlled Trials section of this summary for more information.) These models gave reductions in breast cancer mortality similar to those expected in the circumstances of the RCTs but updated to the use of modern adjuvant therapy. In 2009, CISNET modelers addressed several questions related to the harms and benefits of mammography, including comparing annual versus biennial screening. The proportion of reduction in breast cancer mortality maintained in moving from annual to biennial screening for women aged 50 to 74 years ranged across the six models from 72% to 95%, with a median of 80%.
As a general rule, cancers that arise between screening examinations (interval cancers) have characteristics of rapid growth [9,48] and are frequently of advanced stage. The likelihood of diagnosing cancer is highest with the prevalent (first) screening examination, ranging from 9 to 26 cancers per 1,000 screens, depending on age. The likelihood decreases for follow-up examinations, ranging from one to three cancers per 1,000 screens.
Digital mammography is rapidly increasing in use. Digital mammography is more expensive than screen-film mammography (SFM), but more amenable to data storage and sharing. Performance of both technologies has been compared directly in three trials with similar results noted in the studies.
A large cohort of women undergoing both types of mammography was evaluated at 33 U.S. centers in the Digital Mammographic Imaging Screening Trial, showing no differences in mammographic sensitivity and specificity. Digital mammography had a higher sensitivity in premenopausal and perimenopausal women, in women younger than 50 years, and in women with dense breasts, according to a planned subset analysis.
An Italian trial of parallel cohorts of 14,385 women matched for age and interpreting radiologist were screened by either full-field digital or SFM. Recall rate and cancer detection rate, especially for clustered microcalcifications, were higher for digital mammography, whereas the recall rate for poor technical quality was higher for SFM. There was no difference in positive predictive value (PPV).
The Oslo II Study randomly assigned women to screening by digital mammography (n = 6,944) versus SFM (n = 16,985) with soft-copy double reading by experienced radiologists. Recall and cancer detection rates were higher for digital mammography, but there was no difference in PPV or incidence of interval cancers.
A study in a single screening center in the Netherlands compared women (aged 50–75 years) attending a population-based screening program who were screened on a new full-field digital mammography (FFDM) unit (that included computer-aided detection [CAD]) with women being screened by SFM. For a period of 5 years, a total of 311,082 screening examinations were done by SFM and 56,518 by FFDM. The groups were assembled without obvious bias but without randomization. The recall rate was higher in the FFDM group (4.41% vs. 2.32% at first screen and 1.70% vs. 1.17% at subsequent screens, both P < .001). There was no statistically significant difference in the detection of invasive breast cancer (4.9 per 1,000 SFM vs. 5.4 per 1,000 FFDM at first screen [P = .46] and 4 per 1,000 SFM vs. 4 per 1,000 FFDM [P = .96] at subsequent screens between the groups). There was higher detection of DCIS in the FFDM group (2.2 per 1,000 FFDM vs. 1.2 per 1,000 SFM [P = .015] at first screen and 1.2 per 1,000 FFDM vs. 0.8 per 1,000 SFM [P = .007] at subsequent screens). Most of this increased detection of DCIS appears to be caused by increased detection of clustered microcalcifications by FFDM compared with SFM.
A review of ten controlled studies of various designs found that, overall, the literature supports an increase in breast cancer detection (combining invasive cancer and DCIS), and that the evidence is mixed concerning which modality is associated with higher recall rates.
The performance of mammography is very different in the United States as compared with the Netherlands. Specifically, the recall rates are much higher, and with similar cancer detection rates, the PPVs are much lower. Thus, the impact of digital mammography with CAD versus SFM in the United States may be different.
CAD systems are designed to assist radiologists in reading mammograms. The goal is to help identify suspicious regions such as clustered microcalcifications and masses. The use of CAD systems increases sensitivity but decreases specificity. Several CAD systems are in use. One large population-based study comparing recall rates and breast cancer detection rates before and after the introduction of CAD systems questions their utility; there was no change in either rate.[55,57] Another large study noted an increase in recall rate, no improvement in cancer detection rate, and an increased detection of DCIS compared with invasive cancers. Because no mortality studies have been conducted, the impact of CAD on breast cancer mortality is uncertain. CAD systems seem to increase detection of DCIS more than invasive breast cancers.
Clinical Breast Examination
No randomized trials of clinical breast examination (CBE) as a sole screening modality have been done. The Canadian National Breast Screening Study compared CBE plus mammography to CBE alone in women aged 50 to 59 years (refer to the Effect of Screening on Breast Cancer Mortality section of this summary for more information). CBE was conducted by trained health professionals with periodic evaluations of performance quality. The frequency of cancer diagnosis, stage, interval cancers, and breast cancer mortality were similar in the two groups and compared favorably with other trials of mammography alone. One explanation for this finding was the careful training and supervision of the health professionals performing CBE. Breast cancer mortality with follow-up 11 to 16 years after entry (mean = 13 years) was similar in the two screening arms (mortality rate ratio, 1.02 [95% CI, 0.78–1.33]). The investigators estimated the operating characteristics for CBE alone. For 19,965 women aged 50 to 59 years, sensitivity was 83%, 71%, 57%, 83%, and 77% for years 1, 2, 3, 4, and 5 of the trial, respectively, and specificity ranged between 88% and 96%. PPV, which is the proportion of cancers detected per abnormal examination was estimated to be 3% to 4%. For 25,620 women aged 40 to 49 years, who were examined only at entry, the estimated sensitivity was 71%, specificity 84%, and PPV 1.5%. Among community clinicians, screening CBE has higher specificity (97%–99%)  and lower sensitivity (22%–36%) compared with examiners in clinical trials of breast cancer screening.[63,64,65,66] A study of screening in women with a positive family history of breast cancer showed that, after a normal initial evaluation, the patient or CBE identified more cancers than did mammography. Another study examined the usefulness of adding CBE to screening mammography. Among 61,688 women older than 40 years and screened by mammography and CBE, sensitivity and specificity for mammography and for combined mammography-CBE were calculated. Specificity for mammography was 78% and for both modalities 82%. The increased sensitivity was greatest for women aged 60 to 69 years with dense breasts (6.8%), compared with women aged 60 to 69 years with fatty breasts (1.8%). Specificity was lower for women undergoing both screening modalities compared with mammography alone (97% vs. 99%). The duration of examination in the trials was 5 to 10 minutes per breast.
Monthly breast self-examination (BSE) is frequently advocated, but evidence for its effectiveness is weak.[69,70] The only large, well-conducted, randomized clinical trial of BSE that has been completed, randomly assigned 266,064 women according to workplace in Shanghai to receive either BSE instruction, reinforcement and encouragement, or instruction on the prevention of lower back pain. Neither group received breast cancer screening through other modalities. After 10 to 11 years of follow-up, 135 breast cancer deaths occurred in the instruction group and 131 in the control group (relative risk [RR] = 1.04; 95% CI, 0.82–1.33). Although the number of invasive breast cancers diagnosed in the two groups was about the same, women in the instruction group had more breast biopsies and more benign lesions diagnosed than did women in the control group.
Case-control studies, nonrandomized trials, and cohort evidence about the effectiveness of BSE is mixed; results are difficult to interpret because of selection and recall biases. For example, a small case-control study in Seattle, Washington, compared self-reported practice of BSE in women with advanced breast cancer with that in age-matched controls. The frequency of practicing BSE did not differ in these groups, and there was no decrease in the risk of advanced-stage breast cancer associated with BSE (RR = 1.15; 95% CI, 0.73–1.81). BSE proficiency was low in both groups of women.
In the U.K. Trial of Early Detection of Breast Cancer, two districts invited more than 63,500 women aged 45 to 64 years to educational sessions about BSE. After 10 years of follow-up, there was no difference in mortality rates in these two districts compared with four centers without organized BSE education (RR = 1.07; 95% CI, 0.93–1.22).
A case-control study nested within the Canadian NBSS suggests that well-performed BSE may be effective. This study compared self-reported BSE frequency before enrollment in the trial with breast cancer mortality. Women who examined their breasts visually, used their finger pads for palpation, and used their three middle fingers had a lower breast cancer mortality.
A device called the Sensor Pad was designed to improve the accuracy of BSE and has been approved by the FDA; however, there is no evidence on its efficacy to decrease breast cancer mortality.
The primary role of ultrasound is the evaluation of palpable or mammographically identified masses. A review of the literature and expert opinion by the European Group for Breast Cancer Screening concluded that there is little evidence to support the use of ultrasound in population breast cancer screening at any age.
Magnetic Resonance Imaging
There is increasing interest in using breast magnetic resonance imaging (MRI) as a screening test for breast cancer among women at elevated risk of breast cancer based on BRCA1/2 mutation carriers, a strong family history of breast cancer, or several genetic syndromes such as Li-Fraumeni or Cowden disease.[76,77] Breast MRI is a more sensitive modality for breast cancer detection as compared with screening mammography, but it is also less specific.[78,79]
Direct back-to-back comparisons of breast MRI and mammography in young high-risk women report MRI sensitivities ranging from 71% to 100% versus mammography sensitivities of 20% to 50%. The low sensitivities of mammography are consistent with previous experience in young women and those with dense breasts. Contrast-enhancing foci are normal in healthy breasts, and false-positive results are common.[80,81] These same studies show that MRI is also associated with threefold to fivefold higher recall rates, higher false-positive rates (with specificities varying from 37%–97%), and substantially worse PPVs. Thus, women who are screened with MRI have more negative surgical biopsies.
It is unknown whether the increase in cancer detection confers a mortality benefit given the large increase in false-positive rates, and the possibility of overdiagnosis. All of the published studies are observational studies, and none of the published studies have assessed whether patient outcomes (including morbidity, survival, or mortality) are improved when women are screened with breast MRI. It is likely that MRI screening may lead to overdiagnosis (i.e., the detection of lesions that would remain asymptomatic in the absence of screening).
Therefore the clinical role of MRI in breast imaging for average-risk women is still generally reserved for diagnostic evaluation, including evaluating the integrity of silicone breast implants, assessing palpable masses following surgery or radiation therapy, and detecting mammographically and sonographically occult breast cancer in patients with axillary nodal metastasis and preoperative planning for some patients with known breast cancer. The role of MRI in screening high-risk women or very high-risk women (such as BRCA1/2 carriers) remains uncertain. There is no clear evidence of a mortality benefit among these women, yet the very high burden of breast cancer, and attendant anxiety, has led to MRI screening among these women due to its high sensitivity for cancer detection at the cost of low specificity.
Studies of screening MRI in women of high genetic risk are ongoing.
Scintimammography, using technetium-99m sestamibi or technetium-99m tetrofosmin, scans the axilla and supraclavicular region while simultaneously imaging the breast tissue. In staging women with a known breast cancer, the contralateral arm is injected with the radionuclide, and lateral and anterior projections are imaged with a gamma camera, with both arms raised. The theoretical advantage of this technology is the potential to obtain staging information, but only small clinical series have been described.
Tissue Sampling (Fine-Needle Aspiration, Nipple Aspirate, Ductal Lavage)
Random periareolar fine-needle aspirates were performed in 480 women at high risk for breast cancer, and the women were followed for a median of 45 months. Twenty women developed breast neoplasms (13 invasive and 7 DCIS). Using multiple logistic regression and Cox proportional hazards analysis, a diagnosis of hyperplasia with atypia was found to be associated with the subsequent development of breast cancer.
Nipple aspirate fluid cytology was studied in 2,701 women who were followed for subsequent incidence of breast cancer, with an average of 12.7 years of follow-up. Breast cancer incidence overall was 4.4%, including 11 cases of DCIS and 93 of invasive cancer, and was associated with abnormal nipple aspirate fluid cytology. Whereas the breast neoplasm rate was only 2.6% for 352 women in whom no fluid could be aspirated, it was 5.5% for 327 women with epithelial hyperplasia and 10.3% for 58 women with atypical hyperplasia.
One study reported results of nipple aspiration followed by ductal lavage in 507 women at high risk for breast cancer. Nipple aspirate fluid was obtained from 417 women, but only 111 (27%) were adequate samples. Ductal lavage samples were evaluated in 383 women, 299 (78%) of which were adequate for diagnosis. Abnormal cells were found in 92 (24%) ductal lavage samples, including 88 (17%) with mild atypia, 23 (6%) with marked atypia, and 1 (<1%) malignant. The corresponding numbers and percentages for nipple aspiration fluid were 16 (6%), 8 (3%), and 1 (<1%). Although ductal lavage was associated with some discomfort, it was judged by participants to be comparable to mammography. Whether this procedure led to the detection of any cancers earlier than mammography alone would have done is not known, and no data are available to determine the efficacy or mortality reduction of ductal lavage use as a screening or diagnostic tool. Therefore, the use of this procedure as a screening tool remains investigational.
Thermography of the breast looks for temperature hot spots on the skin as an indicator of vascular proliferation induced by an underlying tumor. Thermographic devices use infrared imaging techniques to detect changes in the temperature of the skin surface and displays these changes in color patterns. Thermographic devices have been approved by the FDA under the 510(k) process, which does not require evidence of clinical effectiveness. There have been no randomized trials of thermography to evaluate the impact on breast cancer mortality or the ability to detect breast cancer. Small cohort studies do not suggest any additional benefit for the use of thermography as an adjunct modality for breast cancer screening.[86,87]
|1.||Sickles EA: Findings at mammographic screening on only one standard projection: outcomes analysis. Radiology 208 (2): 471-5, 1998.|
|2.||Lillie-Blanton M: Mammography Quality Standards Act : X-ray Quality Improved, Access Unaffected, but Impact on Health Outcomes Unknown: Testimony Before the Subcommittee on Health and the Environment, Committee on Commerce, House of Representatives. Washington, D.C.: Committee on Commerce, 1998. Available online. Last accessed January 23, 2012.|
|3.||Ernster VL, Barclay J, Kerlikowske K, et al.: Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 275 (12): 913-8, 1996.|
|4.||Moody-Ayers SY, Wells CK, Feinstein AR: "Benign" tumors and "early detection" in mammography-screened patients of a natural cohort with breast cancer. Arch Intern Med 160 (8): 1109-15, 2000.|
|5.||Physician Insurers Association of America.: Breast Cancer Study. Washington, DC: Physician Insurers Association of America, 1995.|
|6.||Carney PA, Miglioretti DL, Yankaskas BC, et al.: Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med 138 (3): 168-75, 2003.|
|7.||Rosenberg RD, Hunt WC, Williamson MR, et al.: Effects of age, breast density, ethnicity, and estrogen replacement therapy on screening mammographic sensitivity and cancer stage at diagnosis: review of 183,134 screening mammograms in Albuquerque, New Mexico. Radiology 209 (2): 511-8, 1998.|
|8.||Kerlikowske K, Grady D, Barclay J, et al.: Likelihood ratios for modern screening mammography. Risk of breast cancer based on age and mammographic interpretation. JAMA 276 (1): 39-43, 1996.|
|9.||Porter PL, El-Bastawissi AY, Mandelson MT, et al.: Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst 91 (23): 2020-8, 1999.|
|10.||Buist DS, Porter PL, Lehman C, et al.: Factors contributing to mammography failure in women aged 40-49 years. J Natl Cancer Inst 96 (19): 1432-40, 2004.|
|11.||Joensuu H, Lehtimäki T, Holli K, et al.: Risk for distant recurrence of breast cancer detected by mammography screening or other methods. JAMA 292 (9): 1064-73, 2004.|
|12.||Shen Y, Yang Y, Inoue LY, et al.: Role of detection method in predicting breast cancer survival: analysis of randomized screening trials. J Natl Cancer Inst 97 (16): 1195-203, 2005.|
|13.||Wishart GC, Greenberg DC, Britton PD, et al.: Screen-detected vs symptomatic breast cancer: is improved survival due to stage migration alone? Br J Cancer 98 (11): 1741-4, 2008.|
|14.||Kerlikowske K, Grady D, Barclay J, et al.: Variability and accuracy in mammographic interpretation using the American College of Radiology Breast Imaging Reporting and Data System. J Natl Cancer Inst 90 (23): 1801-9, 1998.|
|15.||Elmore JG, Wells CK, Lee CH, et al.: Variability in radiologists' interpretations of mammograms. N Engl J Med 331 (22): 1493-9, 1994.|
|16.||Elmore JG, Wells CK, Howard DH, et al.: The impact of clinical history on mammographic interpretations. JAMA 277 (1): 49-52, 1997.|
|17.||Barlow WE, Chi C, Carney PA, et al.: Accuracy of screening mammography interpretation by characteristics of radiologists. J Natl Cancer Inst 96 (24): 1840-50, 2004.|
|18.||Smith-Bindman R, Chu P, Miglioretti DL, et al.: Physician predictors of mammographic accuracy. J Natl Cancer Inst 97 (5): 358-67, 2005.|
|19.||Esserman L, Cowley H, Eberle C, et al.: Improving the accuracy of mammography: volume and outcome relationships. J Natl Cancer Inst 94 (5): 369-75, 2002.|
|20.||Kan L, Olivotto IA, Warren Burhenne LJ, et al.: Standardized abnormal interpretation and cancer detection ratios to assess reading volume and reader performance in a breast screening program. Radiology 215 (2): 563-7, 2000.|
|21.||Beam CA, Conant EF, Sickles EA: Association of volume and volume-independent factors with accuracy in screening mammogram interpretation. J Natl Cancer Inst 95 (4): 282-90, 2003.|
|22.||Coldman AJ, Major D, Doyle GP, et al.: Organized breast screening programs in Canada: effect of radiologist reading volumes on outcomes. Radiology 238 (3): 809-15, 2006.|
|23.||Elmore JG, Jackson SL, Abraham L, et al.: Variability in interpretive performance at screening mammography and radiologists' characteristics associated with accuracy. Radiology 253 (3): 641-51, 2009.|
|24.||Miglioretti DL, Gard CC, Carney PA, et al.: When radiologists perform best: the learning curve in screening mammogram interpretation. Radiology 253 (3): 632-40, 2009.|
|25.||Théberge I, Hébert-Croteau N, Langlois A, et al.: Volume of screening mammography and performance in the Quebec population-based Breast Cancer Screening Program. CMAJ 172 (2): 195-9, 2005.|
|26.||Nass S, Ball J, eds.: Improving Breast Imaging Quality Standards. Washington, DC: National Academies Press, 2005.|
|27.||Crouchley K, Wylie E, Khong E: Hormone replacement therapy and mammographic screening outcomes in Western Australia. J Med Screen 13 (2): 93-7, 2006.|
|28.||Pankow JS, Vachon CM, Kuni CC, et al.: Genetic analysis of mammographic breast density in adult women: evidence of a gene effect. J Natl Cancer Inst 89 (8): 549-56, 1997.|
|29.||Boyd NF, Dite GS, Stone J, et al.: Heritability of mammographic density, a risk factor for breast cancer. N Engl J Med 347 (12): 886-94, 2002.|
|30.||White E, Velentgas P, Mandelson MT, et al.: Variation in mammographic breast density by time in menstrual cycle among women aged 40-49 years. J Natl Cancer Inst 90 (12): 906-10, 1998.|
|31.||Harvey JA, Pinkerton JV, Herman CR: Short-term cessation of hormone replacement therapy and improvement of mammographic specificity. J Natl Cancer Inst 89 (21): 1623-5, 1997.|
|32.||Laya MB, Larson EB, Taplin SH, et al.: Effect of estrogen replacement therapy on the specificity and sensitivity of screening mammography. J Natl Cancer Inst 88 (10): 643-9, 1996.|
|33.||Baines CJ, Dayan R: A tangled web: factors likely to affect the efficacy of screening mammography. J Natl Cancer Inst 91 (10): 833-8, 1999.|
|34.||Brisson J, Brisson B, Coté G, et al.: Tamoxifen and mammographic breast densities. Cancer Epidemiol Biomarkers Prev 9 (9): 911-5, 2000.|
|35.||Boyd NF, Greenberg C, Lockwood G, et al.: Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breast: results from a randomized trial. Canadian Diet and Breast Cancer Prevention Study Group. J Natl Cancer Inst 89 (7): 488-96, 1997.|
|36.||Pisano ED, Gatsonis C, Hendrick E, et al.: Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med 353 (17): 1773-83, 2005.|
|37.||Orel SG, Kay N, Reynolds C, et al.: BI-RADS categorization as a predictor of malignancy. Radiology 211 (3): 845-50, 1999.|
|38.||Brewer NT, Salz T, Lillie SE: Systematic review: the long-term effects of false-positive mammograms. Ann Intern Med 146 (7): 502-10, 2007.|
|39.||Smith-Bindman R, Chu PW, Miglioretti DL, et al.: Comparison of screening mammography in the United States and the United kingdom. JAMA 290 (16): 2129-37, 2003.|
|40.||Elmore JG, Nakano CY, Koepsell TD, et al.: International variation in screening mammography interpretations in community-based programs. J Natl Cancer Inst 95 (18): 1384-93, 2003.|
|41.||Banks E, Reeves G, Beral V, et al.: Influence of personal characteristics of individual women on sensitivity and specificity of mammography in the Million Women Study: cohort study. BMJ 329 (7464): 477, 2004.|
|42.||Yankaskas BC, Taplin SH, Ichikawa L, et al.: Association between mammography timing and measures of screening performance in the United States. Radiology 234 (2): 363-73, 2005.|
|43.||The Breast Screening Frequency Trial Group.: The frequency of breast cancer screening: results from the UKCCCR Randomised Trial. United Kingdom Co-ordinating Committee on Cancer Research. Eur J Cancer 38 (11): 1458-64, 2002.|
|44.||White E, Miglioretti DL, Yankaskas BC, et al.: Biennial versus annual mammography and the risk of late-stage breast cancer. J Natl Cancer Inst 96 (24): 1832-9, 2004.|
|45.||Parvinen I, Chiu S, Pylkkänen L, et al.: Effects of annual vs triennial mammography interval on breast cancer incidence and mortality in ages 40-49 in Finland. Br J Cancer 105 (9): 1388-91, 2011.|
|46.||Berry DA, Cronin KA, Plevritis SK, et al.: Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353 (17): 1784-92, 2005.|
|47.||Mandelblatt JS, Cronin KA, Bailey S, et al.: Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med 151 (10): 738-47, 2009.|
|48.||Hakama M, Holli K, Isola J, et al.: Aggressiveness of screen-detected breast cancers. Lancet 345 (8944): 221-4, 1995.|
|49.||Tabár L, Faberberg G, Day NE, et al.: What is the optimum interval between mammographic screening examinations? An analysis based on the latest results of the Swedish two-county breast cancer screening trial. Br J Cancer 55 (5): 547-51, 1987.|
|50.||Kerlikowske K, Grady D, Barclay J, et al.: Positive predictive value of screening mammography by age and family history of breast cancer. JAMA 270 (20): 2444-50, 1993.|
|51.||Del Turco MR, Mantellini P, Ciatto S, et al.: Full-field digital versus screen-film mammography: comparative accuracy in concurrent screening cohorts. AJR Am J Roentgenol 189 (4): 860-6, 2007.|
|52.||Skaane P, Hofvind S, Skjennald A: Randomized trial of screen-film versus full-field digital mammography with soft-copy reading in population-based screening program: follow-up and final results of Oslo II study. Radiology 244 (3): 708-17, 2007.|
|53.||Karssemeijer N, Bluekens AM, Beijerinck D, et al.: Breast cancer screening results 5 years after introduction of digital mammography in a population-based screening program. Radiology 253 (2): 353-8, 2009.|
|54.||Skaane P: Studies comparing screen-film mammography and full-field digital mammography in breast cancer screening: updated review. Acta Radiol 50 (1): 3-14, 2009.|
|55.||Gur D, Sumkin JH, Rockette HE, et al.: Changes in breast cancer detection and mammography recall rates after the introduction of a computer-aided detection system. J Natl Cancer Inst 96 (3): 185-90, 2004.|
|56.||Ciatto S, Del Turco MR, Risso G, et al.: Comparison of standard reading and computer aided detection (CAD) on a national proficiency test of screening mammography. Eur J Radiol 45 (2): 135-8, 2003.|
|57.||Elmore JG, Carney PA: Computer-aided detection of breast cancer: has promise outstripped performance? J Natl Cancer Inst 96 (3): 162-3, 2004.|
|58.||Fenton JJ, Taplin SH, Carney PA, et al.: Influence of computer-aided detection on performance of screening mammography. N Engl J Med 356 (14): 1399-409, 2007.|
|59.||Baines CJ: The Canadian National Breast Screening Study: a perspective on criticisms. Ann Intern Med 120 (4): 326-34, 1994.|
|60.||Miller AB, To T, Baines CJ, et al.: Canadian National Breast Screening Study-2: 13-year results of a randomized trial in women aged 50-59 years. J Natl Cancer Inst 92 (18): 1490-9, 2000.|
|61.||Baines CJ, Miller AB, Bassett AA: Physical examination. Its role as a single screening modality in the Canadian National Breast Screening Study. Cancer 63 (9): 1816-22, 1989.|
|62.||Fenton JJ, Rolnick SJ, Harris EL, et al.: Specificity of clinical breast examination in community practice. J Gen Intern Med 22 (3): 332-7, 2007.|
|63.||Fenton JJ, Barton MB, Geiger AM, et al.: Screening clinical breast examination: how often does it miss lethal breast cancer? J Natl Cancer Inst Monogr (35): 67-71, 2005.|
|64.||Bobo JK, Lee NC, Thames SF: Findings from 752,081 clinical breast examinations reported to a national screening program from 1995 through 1998. J Natl Cancer Inst 92 (12): 971-6, 2000.|
|65.||Oestreicher N, White E, Lehman CD, et al.: Predictors of sensitivity of clinical breast examination (CBE). Breast Cancer Res Treat 76 (1): 73-81, 2002.|
|66.||Kolb TM, Lichy J, Newhouse JH: Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology 225 (1): 165-75, 2002.|
|67.||Gui GP, Hogben RK, Walsh G, et al.: The incidence of breast cancer from screening women according to predicted family history risk: Does annual clinical examination add to mammography? Eur J Cancer 37 (13): 1668-73, 2001.|
|68.||Oestreicher N, Lehman CD, Seger DJ, et al.: The incremental contribution of clinical breast examination to invasive cancer detection in a mammography screening program. AJR Am J Roentgenol 184 (2): 428-32, 2005.|
|69.||Baxter N; Canadian Task Force on Preventive Health Care.: Preventive health care, 2001 update: should women be routinely taught breast self-examination to screen for breast cancer? CMAJ 164 (13): 1837-46, 2001.|
|70.||Humphrey LL, Helfand M, Chan BK, et al.: Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 137 (5 Part 1): 347-60, 2002.|
|71.||Thomas DB, Gao DL, Ray RM, et al.: Randomized trial of breast self-examination in Shanghai: final results. J Natl Cancer Inst 94 (19): 1445-57, 2002.|
|72.||Newcomb PA, Weiss NS, Storer BE, et al.: Breast self-examination in relation to the occurrence of advanced breast cancer. J Natl Cancer Inst 83 (4): 260-5, 1991.|
|73.||Ellman R, Moss SM, Coleman D, et al.: Breast cancer mortality after 10 years in the UK trial of early detection of breast cancer. UK Trial of Early Detection of Breast Cancer Group. The Breast 2 (1): 13-20, 1993.|
|74.||Harvey BJ, Miller AB, Baines CJ, et al.: Effect of breast self-examination techniques on the risk of death from breast cancer. CMAJ 157 (9): 1205-12, 1997.|
|75.||Teh W, Wilson AR: The role of ultrasound in breast cancer screening. A consensus statement by the European Group for Breast Cancer Screening. Eur J Cancer 34 (4): 449-50, 1998.|
|76.||Warner E, Plewes DB, Hill KA, et al.: Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA 292 (11): 1317-25, 2004.|
|77.||Kriege M, Brekelmans CT, Boetes C, et al.: Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med 351 (5): 427-37, 2004.|
|78.||Lord SJ, Lei W, Craft P, et al.: A systematic review of the effectiveness of magnetic resonance imaging (MRI) as an addition to mammography and ultrasound in screening young women at high risk of breast cancer. Eur J Cancer 43 (13): 1905-17, 2007.|
|79.||Lehman CD, Gatsonis C, Kuhl CK, et al.: MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med 356 (13): 1295-303, 2007.|
|80.||Lawrence WF, Liang W, Mandelblatt JS, et al.: Serendipity in diagnostic imaging: magnetic resonance imaging of the breast. J Natl Cancer Inst 90 (23): 1792-800, 1998.|
|81.||Kuhl CK, Bieling HB, Gieseke J, et al.: Healthy premenopausal breast parenchyma in dynamic contrast-enhanced MR imaging of the breast: normal contrast medium enhancement and cyclical-phase dependency. Radiology 203 (1): 137-44, 1997.|
|82.||Bermejo-Pérez MJ, Márquez-Calderón S, Llanos-Méndez A: Cancer surveillance based on imaging techniques in carriers of BRCA1/2 gene mutations: a systematic review. Br J Radiol 81 (963): 172-9, 2008.|
|83.||Fabian CJ, Kimler BF, Zalles CM, et al.: Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J Natl Cancer Inst 92 (15): 1217-27, 2000.|
|84.||Wrensch MR, Petrakis NL, King EB, et al.: Breast cancer incidence in women with abnormal cytology in nipple aspirates of breast fluid. Am J Epidemiol 135 (2): 130-41, 1992.|
|85.||Dooley WC, Ljung BM, Veronesi U, et al.: Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. J Natl Cancer Inst 93 (21): 1624-32, 2001.|
|86.||Wishart GC, Campisi M, Boswell M, et al.: The accuracy of digital infrared imaging for breast cancer detection in women undergoing breast biopsy. Eur J Surg Oncol 36 (6): 535-40, 2010.|
|87.||Arora N, Martins D, Ruggerio D, et al.: Effectiveness of a noninvasive digital infrared thermal imaging system in the detection of breast cancer. Am J Surg 196 (4): 523-6, 2008.|
Randomized Controlled Trials
Randomized controlled trials (RCTs), with participation by nearly half a million women from four countries, examined the breast cancer mortality of women who were offered regular screening. One trial (the Canadian National Breast Screening Study [NBSS]-2) compared mammogram plus clinical breast examination (CBE) with CBE alone, but the other eight compared screening mammogram with or without CBE with a control consisting of usual care. The trials differed in design, recruitment of participants, interventions (both screening and treatment), management of the control group, compliance with assignment to screening and control groups, and analysis of outcomes. Some trials used individual randomization while others used cluster randomization in which cohorts were identified and then offered screening, and in one case, nonrandomized allocation by day-of-birth in any given month. Cluster randomization sometimes led to imbalances between the intervention and control groups. Age differences have been identified in several trials, although the differences were probably too small to have a major effect on the trial outcome. In the Edinburgh Trial, socioeconomic status differed markedly between the intervention and control groups. Since socioeconomic status is associated with the risk of breast cancer mortality, this difference makes it difficult, if not impossible, to interpret the trial results.
Since breast cancer mortality is the major outcome parameter for each of these trials, the methods used to determine cause of death is critically important. Efforts to reduce bias in the attribution of mortality cause have been made, including the use of a blinded monitoring committee (New York) and a linkage to independent data sources, such as national mortality registries (Swedish trials). Unfortunately, even these attempts may be unable to avoid prior knowledge of women's assignment to screening or control arms. Evidence of possible misclassification of breast cancer deaths in the Two-County trial that could bias results in favor of screening has been reviewed.
Differences exist in the methodology used to analyze the results of these trials. Four of the five Swedish trials were designed to include a single screening mammogram in the control group, timed to correspond with the end of the series of screening mammograms in the study group. The initial analysis of these trials used an "evaluation" analysis, tallying only the breast cancer deaths that occurred in women whose cancer was discovered at or before the last study mammogram. In some of the trials a delay occurred in the performance of the end-of-study mammogram, resulting in more time for control group women to develop or be diagnosed with breast cancer. Other trials used a "follow-up" analysis, which counts all deaths attributed to breast cancer, regardless of the time of diagnosis. This type of analysis was used in a meta-analysis of four of the five Swedish trials in response to previously expressed concerns about the effect of a delay in control group mammograms upon evaluation analyses.
The accessibility of the data for international audit and verification also varies, with formal audit having been undertaken only in the Canadian trials. In fact, the author of one trial (Kopparberg) refused to respond to queries about methodology or to submit raw data for independent review.
All of these studies are designed to study breast cancer mortality rather than all-cause mortality, because of the infrequency of breast cancer deaths relative to the total number of deaths. When all-cause mortality in these trials was examined retrospectively, only the Edinburgh trial showed a significant difference, which could be attributed to socioeconomic differences. The meta-analysis (follow-up methods) of the four Swedish trials also showed a small but significant improvement of all-cause mortality.
The trials are listed chronologically.
|Age at entry: 40 to 64 years.|
|Randomization: Individual, but with significant imbalances in the distribution of women between assigned arms, as evidenced by menopausal status (P< .0001) and education (P = .05).|
|Sample size: 30,000 to 31,092 in study group and 30,565 to 30,765 in control group.|
|Consistency of reports: Variation in sample size reports.|
|Intervention: Annual two-view mammography (MMG) and CBE for 3 years.|
|Control: Usual care.|
|Compliance: Nonattenders to first screening (35% of the screened population) were not reinvited.|
|Contamination: Screening MMG was not available outside the trial, but frequency of CBE performance among control women is unknown.|
|Cause of death attribution: Women who died of breast cancer that had been diagnosed before entry into the study were excluded from the comparison between the screening and control groups. However, these exclusions were determined differently within the two groups. Women in the screening group were excluded based on determinations made during the study period at their initial screening visits. These women were dropped from all further consideration in the study. By design, controls did not have regular clinic visits, so the prestudy cancer status of control patients was not determined. When a control patient died and her cause of death was determined to be breast cancer, a retrospective examination was made to determine the date of diagnosis of her disease. If this was prior to the study period then she was excluded from the analysis. This difference in methodology has the potential for a substantial bias in comparing breast cancer mortality between the two groups, and this bias is likely to favor screening.|
|External audit: No.|
|Follow-up duration: 18 years.|
|Relative risk of breast cancer death, screening versus control (95% confidence interval [CI]): 0.71 (0.55–0.93) at 10 years and 0.77 (0.61–0.97) at 15 years.|
|Comments: The MMGs were of poor quality compared with those of later trials, because of outdated equipment and techniques. One should remember that the intervention consisted of both MMG and CBE. Major concerns about trial performance are the validity of the initial randomization and the differential exclusion of women with a prior history of breast cancer.|
|Age at entry: 45 to 69 years.|
|Randomization: Individual, within each birth year cohort for the first phase, MMG screening trial (MMST I). Individual for the entire birth cohort 1933 to 1945 for MMST II, but with variations imposed by limited resources. Validation by analysis of age in both groups shows no significant difference.|
|Exclusions: In a Swedish meta-analysis, there were 393 women with pre-existing breast cancer excluded from the intervention group, and 412 from the control group. Overall however, there were 86 more women excluded from the intervention group than from the control group.|
|Sample size: 21,088 study and 21,195 control.|
|Consistency of reports: No variation in patient numbers.|
|Intervention: Two-view MMG every 18 to 24 months × 5.|
|Control: Usual care, with MMG at study end.|
|Compliance: Participants migrating from Malmo (2% per year) were not followed. The participation rate of study women was 74% for the first round and 70% for subsequent rounds.|
|Contamination: 24% of all control women had at least one MMG, as did 35% of the control women aged 45 to 49 years.|
|Cause of death attribution: 76% autopsy rate in early report, lower rate later. Cause of death assessment blinded for women with a breast cancer diagnosis. Linked to Swedish Cause of Death Registry.|
|Analysis: Evaluation, initially. Follow-up analysis, as part of the Swedish meta-analysis.|
|External audit: No.|
|Follow-up duration: 12 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): 0.81 (0.62–1.07).|
|Comments: Evaluation analysis required a correction factor for the delay in the performance of MMG in the control group. The two Malmo trials MMST I and MMST II have been combined for most analyses.|
|Age at entry: 40 to 74 years.|
|Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors and size. Baseline breast cancer incidence and mortality were comparable between the randomly assigned geographic clusters. The study women were older than the control women,P< .0001, but this should not have had a major effect on the outcome of the trial.|
|Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers are reported differently in different publications. The Swedish meta-analysis excluded all women with a prior breast cancer diagnosis, regardless of group assignment.|
|Sample size: Variably reported, ranging from 38,405 to 39,034 in study and from 37,145 to 37,936 in control.|
|Consistency of reports: Variable.|
|Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women 50 years and older.|
|Control: Usual care, with MMG at study end.|
|Compliance: 89% screened.|
|Contamination: 13% of women in the Two-County trial had MMG as part of routine care, mostly in 1983 and 1984.|
|Cause of death attribution: Determined by a team of local physicians. When results were recalculated in the Swedish meta-analysis, using data from the Swedish Cause of Death Registry, there was less benefit for screening than had been previously reported.|
|Analysis: Evaluation initially, with correction for delay in control group MMG. Follow-up analysis, as part of the Swedish meta-analysis.|
|External audit: No. However, breast cancer cases and deaths were adjudicated by a Swedish panel that included the trial's investigators.|
|Follow-up duration: 12 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): 0.82 (0.64–1.05) Ostergotland.|
|Comments: Concerns were raised about the randomization methodology and the evaluation analysis, which required a correction for late performance of the control group MMG. The Swedish meta-analysis resolved these questions appropriately.|
|Age at entry: 40 to 74 years.|
|Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors and size. The process for randomization has not been described. The study women were older than the control women,P< .0001, but this should not have had a major effect on the outcome of the trial.|
|Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers are reported differently in different publications.|
|Sample size: Variably reported, ranging from 38,562 to 39,051 in intervention and from 18,478 to 18,846 in control.|
|Consistency of reports: Variable.|
|Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women aged 50 years and older.|
|Control: Usual care, with MMG at study end.|
|Compliance: 89% participation.|
|Contamination: 13% of women in the Two-County trial had MMG as part of routine care, mostly between 1983 and 1984.|
|Cause of death attribution: Determined by a team of local physicians (see Ostergotland).|
|External audit: No. However, breast cancer cases and deaths were adjudicated by a Swedish panel that included the trial's investigators.|
|Follow-up duration: 12 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): 0.68 (0.52–0.89).|
Edinburgh, United Kingdom 1976 
|Age at entry: 45 to 64 years.|
|Randomization: Cluster by physician practices, though many randomization assignments were changed after study start. Within each practice, there was inconsistent recruitment of women, according to the physician's judgment about each woman's suitability for the trial. Large differences in socioeconomic status between practices were not recognized until after the study end.|
|Exclusions: More women (338) with pre-existing breast cancer were excluded from the intervention group than from the control group (177).|
|Sample size: 23,226 study and 21,904 control.|
|Consistency of reports: Good.|
|Intervention: Initially, two-view MMG and CBE; then annual CBE, with single-view MMG in years 3, 5, and 7.|
|Control: Usual care.|
|Compliance: 61% screened.|
|Cause of death attribution: Cancer Registry Data.|
|External audit: No.|
|Follow-up duration: 10 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): 0.84 (0.63–1.12).|
|Comments: Randomization process was flawed. Socioeconomic differences between study and control groups probably account for the higher all-cause mortality in control women compared with screened women. This difference in all-cause mortality was four times greater than the breast cancer mortality in the control group, and therefore, may account for the higher breast cancer mortality in the control group compared with screened women. Although a correction factor was used in the final analysis, this may not adjust the analysis sufficiently.|
The study design and conduct make these results difficult to assess or combine with the results of other trials.
NBSS-1, Canada 1980 
|Age at entry: 40 to 49 years.|
|Randomization: Individual volunteers, with names entered successively on allocation lists. Although criticisms of the randomization procedure have been made, a thorough independent review found no evidence of subversion and that subversion on a scale large enough to affect the results was unlikely.|
|Exclusions: Few, balanced between groups.|
|Sample size: 25,214 study (100% screened after entry CBE) and 25,216 control.|
|Consistency of reports: Good.|
|Intervention: Annual two-view MMG and CBE for 4 to 5 years.|
|Control: Usual care.|
|Compliance: Initially 100%, decreased to 85.5% by screen five.|
|Contamination: 26.4% in usual care group.|
|Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.|
|External audit: Yes. Independent, with analysis of data by several reviewers.|
|Follow-up duration: 13 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): 0.97 (0.74–1.27).|
|Comments: This is the only trial specifically designed to study women aged 40 to 49 years. Cancers diagnosed at entry in both study and control groups were included. Concerns were expressed prior to completion of the trial about the technical adequacy of the MMGs, the training of the radiologists, and the standardization of the equipment, which prompted an independent external review. The primary deficiency identified by this review was the use of the mediolateral view from 1980 to 1985 instead of the mediolateral oblique view, which was used after 1985.Subsequent analyses found the size and stage of the cancers detected mammographically in this trial to be equivalent to those of other trials.This trial and NBSS-2 differ from the other RCTs in the consistent use of adjuvant hormone and chemotherapy following local breast cancer therapy in women with axillary node-positive disease.|
NBSS-2, Canada 1980 
|Age at entry: 50 to 59 years.|
|Randomization: Individual volunteer (see NBSS-1).|
|Exclusions: Few, balanced between groups.|
|Sample size: 19,711 study (100% screened after entry CBE) and 19,694 control.|
|Intervention: Annual two-view MMG and CBE.|
|Control: Annual CBE.|
|Compliance: Initially 100%, decreased to 86.7% by screen five in the MMG and CBE group. Initially 100%, decreased to 85.4% by screen five in the CBE only group.|
|Contamination: 16.9% of the CBE only group.|
|Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.|
|External audit: Yes. Independent with analysis of data by several reviewers.|
|Follow-up duration: 11 to 16 years (mean 13 years).|
|Relative risk of breast cancer death, screening versus control (95% CI): 1.02 (0.78–1.33).|
|Comments: This trial is unique in that it compares one screening modality to another, and does not include an unscreened control. Regarding criticisms and comments about this trial, see NBSS-1.|
Stockholm, Sweden 1981 
|Age at entry: 40 to 64 years.|
|Randomization: Cluster by birth date. There were two subtrials with balanced randomization in the first and a significant imbalance in the second with 508 more women in the screened group than the control.|
|Exclusions: Inconsistently reported.|
|Sample size: Declined from 40,318 to 38,525 in intervention group and rose from 19,943 to 20,978 in control, between published reports.|
|Consistency of reports: Variable.|
|Intervention: Single-view MMG every 28 months × 2.|
|Control: MMG at year 5.|
|Compliance: 82% screened.|
|Contamination: 25% of women entering the study had MMG in the 3 years before entry.|
|Cause of death attribution: Linked to Swedish Cause of Death Registry.|
|Analysis: Evaluation, with 1-year delay in the posttrial MMG in control group. Follow-up analysis as part of the Swedish meta-analysis.|
|External audit: No.|
|Follow-up duration: 8 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): 0.80 (0.53–1.22).|
|Comments: There are concerns about randomization, especially in the second subtrial, about exclusions, and about the delay in control group MMG. Inclusion of these data in the Swedish meta-analysis resolves many of these questions.|
Gothenberg, Sweden 1982
|Age at entry: 39 to 59 years.|
|Randomization: Complex; cluster randomly assigned within birth year by day of birth for older group (aged 50–59 years) and by individual for younger group (aged 39–49 years); ratio of study to control varied by year depending on MMG availability (randomization took place 1982–1984).|
|Exclusions: A similar proportion of women were excluded from both groups for prior breast cancer diagnosis (1.2% each).|
|Sample size: Most recent publication: 21,650 invited; 29,961 control.|
|Consistency of reports: Variable.|
|Intervention: Initial two-view MMG, then single-view MMG every 18 months × 4. Single-read first three rounds, then double-read.|
|Control: Control group received one screening exam approximately 3 to 8 months after the final screen in study group.|
|Cause of death attribution: Linked to Swedish Cause of Death Registry; also used an independent endpoint committee.|
|Analysis: Both evaluation and follow-up methods.|
|External audit: No.|
|Follow-up duration: 12 to14 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): Aged 39 to 59 years: 0.79 (0.58–1.08) [evaluation]; 0.77 (0.60–1.00) [follow-up].|
|Comments: No reduction for women aged 50 to 54 years, but similar reductions for other 5-year age groups.|
|Conclusions: Delay in the performance of MMG in the control group and unequal numbers of women in invited and control groups (complex randomization process) complicates interpretation.|
|Age at entry: 39 to 41 years.|
|Randomization: Individuals from lists of general practitioners in geographically defined areas of England, Wales, and Scotland; allocation was concealed.|
|Exclusions: Small (n = 30 in invited group and n = 51 in not invited group) number excluded in each group because could not locate or deceased.|
|Sample size: 160,921 (53,884 invited; 106,956 not invited).|
|Consistency of reports: Not applicable.|
|Intervention: Invited group aged 48 years and younger offered annual screening by MMG (double-view first screen, then single mediolateral oblique view thereafter); 68% accepted screening on first screen and 69% to 70% were reinvited (81% attended at least one screen).|
|Control: Those who were not invited received usual medical care, unaware of their participation, and few screened prior to randomization.|
|Cause of death attribution: From the National Health Service (NHS) central register, death certificate code accepted.|
|Analysis: Follow-up method intention-to-treat (though all women aged 50 years would be offered screening by NHS).|
|External audit: None.|
|Follow-up duration: 10.7 years.|
|Relative risk of breast cancer death, screening versus control (95% CI): 0.83 (0.66–1.04).|
|Conclusions: Not a statistically significant result, but fits with other studies.|
Screening for breast cancer does not affect overall mortality, and the absolute benefit for breast cancer mortality appears to be small.
A way to view the potential benefit of breast cancer screening is to estimate the number of lives extended because of early breast cancer detection.[20,21] Harris  estimated the outcomes of 10,000 women aged 50 to 70 years who undergo a single screen. Mammograms will be normal (true negatives and false negatives) in 9,500 women. Of the 500 abnormal screens, between 466 and 479 will be false-positives, and 100 to 200 of these women will undergo invasive procedures. The remaining 21 to 34 abnormal screens will be true positives, indicating breast cancer. Some of these women will die of breast cancer in spite of mammographic detection and optimal therapy, and some may live long enough to die of other causes even if the cancer has not been screen detected. The number of extended lives attributable to mammographic detection is between two and six. Another expression of this analysis is that one life may be extended per 1,700 to 5,000 women screened and followed for 15 years. The same analysis for 10,000 women aged 40 to 49 years, assuming the same 500 abnormal examinations, results in an estimate that 488 of these will be false-positives, and 12 will be breast cancer. Of these 12, there will probably be only one to two lives extended. Thus, for women aged 40 to 49 years, it is estimated that one to two lives may be extended per 5,000 to 10,000 mammograms.
A meta-analysis of randomized controlled trials conducted for the U.S. Preventive Services Task Force in 2009 (including the AGE trial) found that the number needed to invite to screen for 10 years to avoid or delay one death from breast cancer was 1,904 for women in their 40s, 1,339 for women in their 50s, and 377 for women in their 60s. A 2009 combined analysis by six Cancer Intervention and Surveillance Modeling Network modeling groups found that screening every 2 years maintained an average of 81% of the benefit of annual screening with almost half the false-positive results. Screening biennially from age 50 to 69 years achieved a median 16.5% reduction in breast cancer deaths versus no screening. Initiating biennial screening at age 40 years (vs. age 50 years) reduced breast cancer mortality by an additional 3%, consumed more resources, and yielded more false-positive results.
Population-Based Screening Programs, Including Studies of Effectiveness of Screening
Although the RCTs of screening have addressed the issue of the efficacy of screening (i.e., the extent to which screening reduces breast cancer mortality under the ideal conditions of an RCT), they do not provide information about the effectiveness of screening (i.e., the extent to which screening is reducing breast cancer mortality in the U.S. population). Studies that provide information on this issue include nonrandomized controlled studies of screened versus nonscreened populations, case-control studies of screening in real communities, and modeling studies that examine the impact of screening on large populations. An important issue in all of these studies is the extent to which they can control for additional effects on breast cancer mortality such as improved treatment and heightened awareness of breast cancer in the community.
Two population-based, observational studies from Sweden compared breast cancer mortality in the presence and absence of screening mammography programs. One study compared two adjacent time periods within 7 of the 25 counties in Sweden and concluded a statistically significant breast cancer mortality reduction of 18% to 32% due to screening. The most important bias in this study is that the advent of screening in these counties occurred over a period during which dramatic improvements were being made in the effectiveness of adjuvant breast cancer therapy. The authors do not present data on treatment received, nor do they address differences in treatment that could at least partially explain the observed reduction in breast cancer mortality. The second study considered an 11-year period and compared seven counties that had screening programs with five counties that did not. It concluded that there was a statistically nonsignificant reduction of 16% to 20% in favor of screening. The most important bias in this study was similar to that in the first study. The counties in the control group were rural. Those in the screening group included some urban areas and in general they were largely in the southern, more densely populated part of the country in comparison with the control counties. Participants were accrued over a 7-year period (about 1980–1987) during which effective adjuvant hormonal therapy and chemotherapy were being introduced. The authors do not address differences in treatment in the various geographic areas that could explain the observed reduction in breast cancer mortality.
In Nijmegen, the Netherlands, a population-based screening program was undertaken in 1975, and breast cancer mortality rates were compared with those in the neighboring town Arnhem and to all of the Netherlands. No difference in breast cancer mortality could be identified, although case-cohort studies showed that screened women have decreased mortality. One such study was performed in Nijmegen itself, with an odds ratio of 0.48, for screened versus unscreened women. Explanations for the lack of demonstrable benefit include earlier diagnosis of breast cancer in the general population (due to increased public awareness) and documented trends for the diagnosis of cancers with favorable prognostic indicators. Furthermore, adjuvant systemic therapy decreases breast cancer mortality, and its use may decrease the impact of early detection.
A community-based case-control study of screening as practiced in excellent U.S. health care systems between 1983 and 1998 found no association between previous screening and reduced breast cancer mortality. Mammography screening rates, however, were generally low.
Since 1990, there has been a sustained reduction in age-adjusted breast cancer mortality in the United States of about 2% per year. Between 1990 and 2000, the cumulative reduction was 24%. To address the contribution of screening and adjuvant therapy to this decline, the National Cancer Institute formed a consortium of seven modeling groups . These groups developed independent statistical models of female breast cancer incidence and breast cancer mortality in the United States. They used common inputs for the dissemination of screening mammography, chemotherapy, and hormonal therapy and for the benefits of treatment interventions. All seven models ascribed some benefit to both screening and adjuvant treatment, but their estimates of the relative and absolute contributions varied considerably. The estimated proportion of the total mortality reduction contributed by screening varied from 28% to 65%, with adjuvant treatment contributing the rest. The variability across models for the absolute contribution of screening was larger than it was for treatment, reflecting the greater uncertainty and higher complexity associated with estimating screening benefit.
A well-conducted ecologic study compared three pairs of neighboring European countries, matched on similarity in health care systems and population structure, one of which had started a national screening program some years earlier than the others. The investigators found that each country had experienced a reduction in breast cancer mortality, with no difference between matched pairs that could be attributed to screening. The authors suggested that improvements in breast cancer treatment and/or health care organizations were more likely responsible for the reduction in mortality than screening.
A systematic review of ecologic and large cohort studies published through March 2011 compared breast cancer mortality in large populations of women aged 50 to 69 years who started breast cancer screening at different times. Seventeen studies met inclusion criteria. All studies had methodological problems, including control group dissimilarities, insufficient adjustment for differences between areas in breast cancer risk and breast cancer treatment, and problems with similar measurement of breast cancer mortality between compared areas. There was great variation in results among the studies, with four finding a relative reduction in breast cancer mortality of 33% or greater (with wide confidence intervals) and five studies finding no reduction in breast cancer mortality. As only a part of the overall reduction in breast cancer mortality could possibly be attributed to screening, the review concluded that any relative reduction in breast cancer mortality due to screening would likely be no greater than 10%, less than predicted by the RCTs.
|1.||Gøtzsche PC, Olsen O: Is screening for breast cancer with mammography justifiable? Lancet 355 (9198): 129-34, 2000.|
|2.||Gøtzsche PC, Nielsen M: Screening for breast cancer with mammography. Cochrane Database Syst Rev (4): CD001877, 2006.|
|3.||Nyström L, Andersson I, Bjurstam N, et al.: Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 359 (9310): 909-19, 2002.|
|4.||Shapiro S, Venet W, Strax P, et al.: Ten- to fourteen-year effect of screening on breast cancer mortality. J Natl Cancer Inst 69 (2): 349-55, 1982.|
|5.||Shapiro S: Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, Md: Johns Hopkins University Press, 1988.|
|6.||Andersson I, Aspegren K, Janzon L, et al.: Mammographic screening and mortality from breast cancer: the Malmö mammographic screening trial. BMJ 297 (6654): 943-8, 1988.|
|7.||Nyström L, Rutqvist LE, Wall S, et al.: Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 341 (8851): 973-8, 1993.|
|8.||Tabár L, Fagerberg CJ, Gad A, et al.: Reduction in mortality from breast cancer after mass screening with mammography. Randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1 (8433): 829-32, 1985.|
|9.||Tabàr L, Fagerberg G, Duffy SW, et al.: Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 30 (1): 187-210, 1992.|
|10.||Tabar L, Fagerberg G, Duffy SW, et al.: The Swedish two county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Community Health 43 (2): 107-14, 1989.|
|11.||Holmberg L, Duffy SW, Yen AM, et al.: Differences in endpoints between the Swedish W-E (two county) trial of mammographic screening and the Swedish overview: methodological consequences. J Med Screen 16 (2): 73-80, 2009.|
|12.||Roberts MM, Alexander FE, Anderson TJ, et al.: Edinburgh trial of screening for breast cancer: mortality at seven years. Lancet 335 (8684): 241-6, 1990.|
|13.||Miller AB, To T, Baines CJ, et al.: The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age 40 to 49 years. Ann Intern Med 137 (5 Part 1): 305-12, 2002.|
|14.||Bailar JC 3rd, MacMahon B: Randomization in the Canadian National Breast Screening Study: a review for evidence of subversion. CMAJ 156 (2): 193-9, 1997.|
|15.||Baines CJ, Miller AB, Kopans DB, et al.: Canadian National Breast Screening Study: assessment of technical quality by external review. AJR Am J Roentgenol 155 (4): 743-7; discussion 748-9, 1990.|
|16.||Fletcher SW, Black W, Harris R, et al.: Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst 85 (20): 1644-56, 1993.|
|17.||Miller AB, Baines CJ, To T, et al.: Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ 147 (10): 1477-88, 1992.|
|18.||Frisell J, Eklund G, Hellström L, et al.: Randomized study of mammography screening--preliminary report on mortality in the Stockholm trial. Breast Cancer Res Treat 18 (1): 49-56, 1991.|
|19.||Moss SM, Cuckle H, Evans A, et al.: Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial. Lancet 368 (9552): 2053-60, 2006.|
|20.||Kerlikowske K: Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. J Natl Cancer Inst Monogr (22): 79-86, 1997.|
|21.||Glasziou PP, Woodward AJ, Mahon CM: Mammographic screening trials for women aged under 50. A quality assessment and meta-analysis. Med J Aust 162 (12): 625-9, 1995.|
|22.||Harris R, Leininger L: Clinical strategies for breast cancer screening: weighing and using the evidence. Ann Intern Med 122 (7): 539-47, 1995.|
|23.||Nelson HD, Tyne K, Naik A, et al.: Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med 151 (10): 727-37, W237-42, 2009.|
|24.||Mandelblatt JS, Cronin KA, Bailey S, et al.: Effects of mammography screening under different screening schedules: model estimates of potential benefits and harms. Ann Intern Med 151 (10): 738-47, 2009.|
|25.||Duffy SW, Tabár L, Chen HH, et al.: The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties. Cancer 95 (3): 458-69, 2002.|
|26.||Jonsson H, Nyström L, Törnberg S, et al.: Service screening with mammography of women aged 50-69 years in Sweden: effects on mortality from breast cancer. J Med Screen 8 (3): 152-60, 2001.|
|27.||Broeders MJ, Peer PG, Straatman H, et al.: Diverging breast cancer mortality rates in relation to screening? A comparison of Nijmegen to Arnhem and the Netherlands, 1969-1997. Int J Cancer 92 (2): 303-8, 2001.|
|28.||Verbeek AL, Hendriks JH, Holland R, et al.: Reduction of breast cancer mortality through mass screening with modern mammography. First results of the Nijmegen project, 1975-1981. Lancet 1 (8388): 1222-4, 1984.|
|29.||Elmore JG, Reisch LM, Barton MB, et al.: Efficacy of breast cancer screening in the community according to risk level. J Natl Cancer Inst 97 (14): 1035-43, 2005.|
|30.||Berry DA, Cronin KA, Plevritis SK, et al.: Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353 (17): 1784-92, 2005.|
|31.||Autier P, Boniol M, Gavin A, et al.: Breast cancer mortality in neighbouring European countries with different levels of screening but similar access to treatment: trend analysis of WHO mortality database. BMJ 343: d4411, 2011.|
|32.||Harris R, Yeatts J, Kinsinger L: Breast cancer screening for women ages 50 to 69 years a systematic review of observational evidence. Prev Med 53 (3): 108-14, 2011.|
Mammography screening may be effective in reducing breast cancer mortality in certain populations. As with any medical intervention, it has limitations, which can pose potential harm to women who participate. These limitations are best described as false-negatives (related to the sensitivity of the test), false-positives (related to the specificity), overdiagnosis (true positives that will not become clinically significant), and radiation risk.
The specificity of mammography (refer to the Mammography section of this summary for more information) affects the number of "unnecessary" interventions due to false-positive results. Even though breast cancer is the most common noncutaneous cancer in women, only a very small fraction (0.1%–0.5%, depending on age) actually have the disease when they are screened. Therefore, even though the specificity of mammography is approximately 90%, most abnormal tests are false-positives. Women with abnormal screening test results have additional procedures performed to determine whether the mammographic finding is cancer. These procedures include additional mammographic imaging (e.g., magnification of the area of concern), ultrasound, and tissue sampling (by fine-needle aspiration, core biopsy, or excisional biopsy). A study of breast cancer screening in 2,400 women enrolled in a health maintenance organization found that over a 10-year period, 88 cancers were diagnosed, 58 of which were identified on mammography. During that period, one-third of the women had an abnormal mammogram result that required additional testing, including 539 additional mammograms, 186 ultrasound examinations, and 188 biopsies. The actuarial cumulative biopsy rate (the rate of true positives) due to mammographic findings was approximately 1 in 4 (23.6%). The positive predictive value (PPV) of an abnormal screening mammogram in this population was 6.3% for women aged 40 to 49 years, 6.6% for women aged 50 to 59 years, and 7.8% for women aged 60 to 69 years. A subsequent analysis and modeling of data from the same cohort of women, all of whom were continuously enrolled in the Harvard Pilgrim Health Care plan from July 1983 through June 1995, estimated that the risk of having at least one false-positive mammogram was 7.4% (95% confidence interval [CI], 6.4%–8.5%) at the first mammogram, 26.0% (95% CI, 24.0%–28.2%) by the fifth mammogram, and 43.1% (95% CI, 36.6%–53.6%) by the ninth mammogram. Cumulative risk of at least one false-positive by the ninth mammogram varied from 5% to 100%, depending on four patient variables and three radiologic variables. Patient variables independently associated with increased chance of a false-positive result included younger age, higher number of previous breast biopsies, family history of breast cancer, and current estrogen use. Radiologic variables included longer time between screenings, failure to compare the current and previous mammograms, and the individual radiologist's tendency to interpret mammograms as abnormal, which ranged from 2.6% to 24.4% across 93 radiologists in the study. Overall, the largest risk factor for having a false-positive mammogram was the individual radiologist's tendency to read mammograms as abnormal. The authors noted that CIs for estimates of false-positives beyond five mammograms were wide because of the relatively small numbers of women in the analysis with more than five mammograms.
By reviewing Medicare claims following mammographic screening in 23,172 women older than 65 years, one study  found that 85 per 1,000 had follow-up testing and 23 per 1,000 had biopsies. The cancer detection rate was 7 per 1,000, so the PPV for an abnormal mammogram was 8%. For women older than 70 years, the PPV was 14%. An audit of mammograms done in 1998 at a single institution revealed that 14.7% of examinations resulted in a recommendation for additional testing (Breast Imaging Reporting and Data System category 0), 1.8% resulted in a recommendation for biopsy (categories 4 and 5), and 5.7% resulted in a recommendation for short-term interval mammography (category 3). Cancer was diagnosed in 1 out of 30 of the cases referred for additional testing.
False Sense of Security
The sensitivity of mammography (refer to the Mammography section of this summary for more information) ranges from 70% to 90%, depending on a woman's age and the density of her breasts, which is affected by her genetic predisposition, hormone status, and diet. Assuming an average sensitivity of 80%, mammograms will miss approximately 20% of the breast cancers that are present at the time of screening (false-negatives). If a woman does not seek medical attention for a breast symptom or if her physician is reluctant to evaluate that symptom because she has a "normal" mammogram, she may suffer adverse consequences. Whereas the medical community has been carefully educated that a negative diagnostic mammogram should not deter work-up of a palpable lump, the medical and lay communities should be made aware that a negative screening mammogram misses one in five cancers.
Because radiation exposure is a known risk factor for the development of breast cancer, it is ironic that ionizing radiation is our best screening tool. The major predictors of risk are young age at the time of radiation exposure and the radiation dose. For women older than 40 years, the benefits of annual mammograms may outweigh any potential risk of radiation exposure due to mammography. It is speculated that certain subpopulations of women may have an inherited susceptibility to ionizing radiation damage,[7,8] but mammography has never been shown to be harmful in these, or any, subgroups. In the United States, the mean glandular dose for screening mammography is 1 mGy to 2 mGy (100–200 mrad) per view or 2 mGy to 4 mGy (200–400 mrad) per standard two-view exam.[9,10]
Because large numbers of women have false-positive tests, the issue of psychological distress—which may be provoked by the additional testing—has been studied. A telephone survey of 308 women performed 3 months after screening mammography revealed that about one-fourth of the 68 women with a "suspicious" result were still experiencing worry that affected their mood or functioning, even though subsequent testing had ruled out a cancer diagnosis. Several studies,[12,13,14] however, show that the anxiety following evaluation of a false-positive test leads to increased participation in future screening examinations.
Overdiagnosed disease is a neoplasm that would never become clinically apparent prior to a patient's death without screening. An example is a tumor that is found by mammographic screening that would never be evident otherwise.
Autopsy studies have found tumors in people who died of causes unrelated to the tumors. The studies indicate that lesions exist that fulfill the histologic criteria of cancer but that were not clinically apparent in the woman's lifetime. An overview of seven autopsy studies documents a median prevalence of 1.3% for undiagnosed invasive breast cancer (range, 0%–1.8%) and 8.9% for undiagnosed ductal carcinoma in situ (range, 0%–14.7%).[16,17] Finding such cancers by mammography would be overdiagnosis. Because cancers that will progress cannot be distinguished with certainty from those that will not, these tumors are often treated (with surgery and possibly with radiation, chemotherapy, and hormonal therapy). This treatment would constitute overtreatment because it would not confer a benefit to the woman.
It is difficult to determine the proportion of screen-detected cancers that are overdiagnosed. A widely accepted estimation method is to compare breast cancer incidence over time in a screened population with that of an unscreened population. Randomized screening trials are the most credible, but the period of screening versus control is limited in all the trials. If a woman complies with not being screened during the study period but gets screened afterwards, then a breast cancer that would have been found had the woman been assigned to screening would likely be found shortly thereafter. (Most of the women in the control group in the Swedish trials were assigned to receive a control mammogram at the end of the study period.) Such delayed screening will also find overdiagnosed cancers; the cumulative incidence of cancers will be similar in the two groups, irrespective of the magnitude of overdiagnosis.
Population-based studies suffer from the same problem as randomized trials, although to a lesser extent. However, the population-based studies have their own problems. Unbiased estimates would only be possible if the screened and nonscreened populations were the same except for screening, but the populations may differ in time, in geography, in culture, and by the use of postmenopausal hormone therapy. In addition, investigators differ in their assessments of overdiagnosis regarding how and whether to adjust for characteristics such as lead-time bias.[18,19] As a consequence, the magnitude of overdiagnosis due to mammographic screening is controversial, with estimates ranging from 7% to 50%.[18,19,20,21]
Several observational population-based comparisons consider breast cancer incidence before and after adoption of screening.[22,23,24,25,26] If there were no overdiagnosis—and other aspects of screening were unchanged—there would be a rise in incidence followed by a decrease to below the prescreening level, and the cumulative incidence would be similar. Such results have not been observed. Breast cancer incidence rates increase at the initiation of screening without a compensatory drop in later years. For example, in Sweden, the age-specific incidence rates doubled between 1986 and 2002 for all age groups participating in screening. Another study in 11 rural Swedish counties showed a persistent increase in breast cancer incidence following the advent of screening. A population-based study from Norway and Sweden showed increases in invasive breast cancer incidence of 54% in Norway and 45% in Sweden in women aged 50 to 69 years, following the introduction of nationwide screening programs. No corresponding decline in incidence in women older than age 69 years was ever seen. Similar findings suggestive of overdiagnosis have been reported from the United Kingdom  and the United States.[25,26]
|1.||Kerlikowske K, Grady D, Barclay J, et al.: Positive predictive value of screening mammography by age and family history of breast cancer. JAMA 270 (20): 2444-50, 1993.|
|2.||Elmore JG, Barton MB, Moceri VM, et al.: Ten-year risk of false positive screening mammograms and clinical breast examinations. N Engl J Med 338 (16): 1089-96, 1998.|
|3.||Christiansen CL, Wang F, Barton MB, et al.: Predicting the cumulative risk of false-positive mammograms. J Natl Cancer Inst 92 (20): 1657-66, 2000.|
|4.||Welch HG, Fisher ES: Diagnostic testing following screening mammography in the elderly. J Natl Cancer Inst 90 (18): 1389-92, 1998.|
|5.||Rosen EL, Baker JA, Soo MS: Malignant lesions initially subjected to short-term mammographic follow-up. Radiology 223 (1): 221-8, 2002.|
|6.||Feig SA, Ehrlich SM: Estimation of radiation risk from screening mammography: recent trends and comparison with expected benefits. Radiology 174 (3 Pt 1): 638-47, 1990.|
|7.||Helzlsouer KJ, Harris EL, Parshad R, et al.: Familial clustering of breast cancer: possible interaction between DNA repair proficiency and radiation exposure in the development of breast cancer. Int J Cancer 64 (1): 14-7, 1995.|
|8.||Swift M, Morrell D, Massey RB, et al.: Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325 (26): 1831-6, 1991.|
|9.||Kopans DB: Mammography and radiation risk. In: Janower ML, Linton OW, eds.: Radiation Risk: a Primer. Reston, Va: American College of Radiology, 1996, pp 21-22.|
|10.||Suleiman OH, Spelic DC, McCrohan JL, et al.: Mammography in the 1990s: the United States and Canada. Radiology 210 (2): 345-51, 1999.|
|11.||Lerman C, Trock B, Rimer BK, et al.: Psychological side effects of breast cancer screening. Health Psychol 10 (4): 259-67, 1991.|
|12.||Gram IT, Lund E, Slenker SE: Quality of life following a false positive mammogram. Br J Cancer 62 (6): 1018-22, 1990.|
|13.||Burman ML, Taplin SH, Herta DF, et al.: Effect of false-positive mammograms on interval breast cancer screening in a health maintenance organization. Ann Intern Med 131 (1): 1-6, 1999.|
|14.||Pisano ED, Earp J, Schell M, et al.: Screening behavior of women after a false-positive mammogram. Radiology 208 (1): 245-9, 1998.|
|15.||Brewer NT, Salz T, Lillie SE: Systematic review: the long-term effects of false-positive mammograms. Ann Intern Med 146 (7): 502-10, 2007.|
|16.||Welch HG, Black WC: Using autopsy series to estimate the disease "reservoir" for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 127 (11): 1023-8, 1997.|
|17.||Black WC, Welch HG: Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. N Engl J Med 328 (17): 1237-43, 1993.|
|18.||Duffy SW, Lynge E, Jonsson H, et al.: Complexities in the estimation of overdiagnosis in breast cancer screening. Br J Cancer 99 (7): 1176-8, 2008.|
|19.||Gøtzsche PC, Jørgensen KJ, Maehlen J, et al.: Estimation of lead time and overdiagnosis in breast cancer screening. Br J Cancer 100 (1): 219; author reply 220, 2009.|
|20.||Gøtzsche PC, Nielsen M: Screening for breast cancer with mammography. Cochrane Database Syst Rev (4): CD001877, 2006.|
|21.||Zackrisson S, Andersson I, Janzon L, et al.: Rate of over-diagnosis of breast cancer 15 years after end of Malmö mammographic screening trial: follow-up study. BMJ 332 (7543): 689-92, 2006.|
|22.||Hemminki K, Rawal R, Bermejo JL: Mammographic screening is dramatically changing age-incidence data for breast cancer. J Clin Oncol 22 (22): 4652-3, 2004.|
|23.||Jonsson H, Johansson R, Lenner P: Increased incidence of invasive breast cancer after the introduction of service screening with mammography in Sweden. Int J Cancer 117 (5): 842-7, 2005.|
|24.||Johnson A, Shekhdar J: Breast cancer incidence: what do the figures mean? J Eval Clin Pract 11 (1): 27-31, 2005.|
|25.||White E, Lee CY, Kristal AR: Evaluation of the increase in breast cancer incidence in relation to mammography use. J Natl Cancer Inst 82 (19): 1546-52, 1990.|
|26.||Feuer EJ, Wun LM: How much of the recent rise in breast cancer incidence can be explained by increases in mammography utilization? A dynamic population model approach. Am J Epidemiol 136 (12): 1423-36, 1992.|
|27.||Zahl PH, Strand BH, Maehlen J: Incidence of breast cancer in Norway and Sweden during introduction of nationwide screening: prospective cohort study. BMJ 328 (7445): 921-4, 2004.|
Women With Limited Life Expectancy
Achieving balance between the benefits and harms of screening is especially important for women with a life expectancy of no longer than 5 years. Such women might have end-stage renal disease, severe dementia, terminal cancer, or severe functional dependencies in activities of daily living. Early cancer detection and prompt treatment are unlikely to reduce morbidity or mortality within the woman's 5 years of expected survival, but the negative consequences of screening will occur immediately. Abnormal screening may trigger additional testing with attendant anxiety. In particular, the detection of low-risk malignancy would probably result in a recommendation for treatment, which could impair rather than improve quality of life, without improving survival. Despite these considerations, many women with poor life expectancy due to age or health status often undergo screening mammography.
Screening mammography in women older than 65 years often results in additional diagnostic testing in 85 per 1,000 women, with cancer diagnosed in nine. The testing is often accomplished over many months, which may cause anxiety due to diagnostic uncertainty. While screening mammography may yield cancer diagnoses in approximately 1% of elderly women, many of these cancers are low risk. A study of California Medicare beneficiaries aged 65 to 79 years demonstrated this clearly. The relative risk (RR) of detecting local breast cancer was 3.3 (95% confidence interval, 3.1–3.5) among screened women. Diagnosis of metastatic cancer was reduced among screened women (RR = 0.57), suggesting there may be benefit of mammography screening in elderly women, though it comes with an increased risk of overdiagnosis.
There is no evidence for starting mammography in women younger than age 40 years.
Women With Thoracic Radiation
Screening has been recommended for women exposed to therapeutic radiation, especially if exposed at a young age. One systematic review of observational studies of women exposed to large doses (≥20 Gy) of chest radiation before age 30 years found standardized incidence ratios of 13.3 to 55.5 for breast cancer with no plateau with increasing age. Screening mammography and magnetic resonance imaging can identify early-stage cancers, but the benefits and risks have not been clearly defined.
Although age-adjusted breast cancer incidence rates are higher in white women than in black women, mortality rates are higher in black women. Among breast cancer cases diagnosed from 1995 to 2001, 64% of white women and only 53% of black women had localized disease. The 5-year relative survival rate for localized disease was 98.5% for white women and 92.2% for black women; for regional disease, it was 82.9% for white women and 68.3% for black women; and for distant disease, it was 27.7% for white women and 16.3% for black women. Both breast cancer incidence and mortality are lower among Hispanic and Asian/Pacific Islander women than among white and black women.
Several explanations for these findings have been proposed, including lower socioeconomic status, lower level of education, and less access to screening and treatment services. Population-based studies demonstrate that, compared with other groups, Medicaid recipients and uninsured patients of all races have later-stage breast cancer diagnosis, and survival from the time of diagnosis is shorter. This difference is associated with socioeconomic status and may reflect lack of participation in screening activities.[6,7] Black women older than 65 years are less likely to undergo mammogram screening. Among regular users of mammography, however, cancer was diagnosed in black and white women at similar stages.
Similar studies of Hispanic populations have been done. Breast cancer stage at diagnosis in San Diego County, California, was more advanced for Hispanic than for white women, especially for those younger than 50 years. Low-income whites were more likely to have late-stage diagnosis than high-income whites. Among Hispanic women, there was no difference according to income, but all the Hispanic groups were at or below the lowest white income level. In New Mexico, a population-based case-control study examined reproductive histories of 719 Hispanic and 836 white breast cancer patients, with half of each group having breast cancer. The Hispanic women had higher body mass index, higher parity, and earlier pregnancies. Whereas reproductive factors such as age at first full-term birth, parity, and duration of lactation accounted for some of the ethnic differences in postmenopausal women, there was no evidence that these factors played a role in the differences in premenopausal patients. A study of mammography screening in a health maintenance organization in Albuquerque found that Hispanic women had consistently lower rates of screening than whites (50.6% vs. 65.5% in 1989, and 62.7% vs. 71.6% in 1996). Predictors of more advanced stage at diagnosis included Hispanic race (odds ratio, 2.12) and younger age.
Approximately 1% of all breast cancers occur in males. Most cases are diagnosed during the evaluation of palpable lesions and treatment consists of surgery, radiation, and systemic adjuvant hormone therapy or chemotherapy. There are no data on the benefits or risks of screening.
|1.||Walter LC, Lindquist K, Covinsky KE: Relationship between health status and use of screening mammography and Papanicolaou smears among women older than 70 years of age. Ann Intern Med 140 (9): 681-8, 2004.|
|2.||Welch HG, Fisher ES: Diagnostic testing following screening mammography in the elderly. J Natl Cancer Inst 90 (18): 1389-92, 1998.|
|3.||Smith-Bindman R, Kerlikowske K, Gebretsadik T, et al.: Is screening mammography effective in elderly women? Am J Med 108 (2): 112-9, 2000.|
|4.||Henderson TO, Amsterdam A, Bhatia S, et al.: Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med 152 (7): 444-55; W144-54, 2010.|
|5.||Ries LAG, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005. Also available online. Last accessed January 23, 2012.|
|6.||Roetzheim RG, Pal N, Tennant C, et al.: Effects of health insurance and race on early detection of cancer. J Natl Cancer Inst 91 (16): 1409-15, 1999.|
|7.||Bradley CJ, Given CW, Roberts C: Race, socioeconomic status, and breast cancer treatment and survival. J Natl Cancer Inst 94 (7): 490-6, 2002.|
|8.||McCarthy EP, Burns RB, Coughlin SS, et al.: Mammography use helps to explain differences in breast cancer stage at diagnosis between older black and white women. Ann Intern Med 128 (9): 729-36, 1998.|
|9.||Bentley JR, Delfino RJ, Taylor TH, et al.: Differences in breast cancer stage at diagnosis between non-Hispanic white and Hispanic populations, San Diego County 1988-1993. Breast Cancer Res Treat 50 (1): 1-9, 1998.|
|10.||Gilliland FD, Hunt WC, Baumgartner KB, et al.: Reproductive risk factors for breast cancer in Hispanic and non-Hispanic white women: the New Mexico Women's Health Study. Am J Epidemiol 148 (7): 683-92, 1998.|
|11.||Frost FJ, Tollestrup K, Trinkaus KM, et al.: Mammography screening and breast cancer tumor size in female members of a managed care organization. Cancer Epidemiol Biomarkers Prev 7 (7): 585-9, 1998.|
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Effect of Screening on Breast Cancer Mortality
Added text about an ecologic study that compared three pairs of neighboring European countries and found that each country had a reduction in breast cancer mortality, with no difference between matched pairs that could be attributed to screening (cited Autier et al. as reference 31).
Added text about a systematic review that examined ecologic and large cohort studies of women aged 50 to 69 years and found that any relative reduction in breast cancer mortality due to screening in this age group would likely be no greater than 10% (cited Harris et al. as reference 32).
If you have questions or comments about this summary, please send them to Cancer.gov through the Web site's Contact Form. We can respond only to email messages written in English.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about breast cancer screening. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
National Cancer Institute: PDQ® Breast Cancer Screening. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/screening/breast/healthprofessional. Accessed <MM/DD/YYYY>.
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page page.
More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site's Contact Form.
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.
The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.
Write to us
For more information from the NCI, please write to this address:
|NCI Public Inquiries Office|
|6116 Executive Boulevard, MSC8322|
|Bethesda, MD 20892-8322|
Search the NCI Web site
The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.
There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.
The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).
Last Revised: 2012-03-30
Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.