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NCI/PDQ® Health professionals: Breast Cancer Screening (PDQ®)
National Cancer Institute
Last Modified: March 30, 2012

TABLE OF CONTENTS


Summary of Evidence

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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

  • Study Design: Meta-analysis of individual data from four randomized controlled trials (RCTs) 1 and three additional RCTs. 2 3 4
  • Internal Validity: Validity of RCTs varies from poor to good. Internal validity of meta-analysis is good.
  • Consistency: Fair.
  • Magnitude of Effects on Health Outcomes: Relative breast cancerspecific mortality is decreased by 15% for follow-up analysis and 20% for evaluation analysis.[1] Absolute mortality benefit for women screened annually starting at age 40 years is 4 per 10,000 at 10.7 years. 5 The comparable number for women screened annually starting at age 50 years is approximately 5 per 1,000. Absolute benefit is approximately 1% overall but depends on inherent breast cancer risk, which rises with age.
  • External Validity: Good.


Statement of harms

Based on solid evidence, screening mammography may lead to the following harms:


Table 1. Harms of Screening Mammography

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, 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.   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

  • Study Design: RCT, with inference.
  • Internal Validity: Good.
  • Consistency: Poor.
  • Magnitude of Effects on Health Outcomes: Breast cancer mortality was the same for women aged 50 to 59 years undergoing screening clinical breast examinations with or without mammograms. 4
  • External Validity: Poor.


Statement of harms

Based on solid evidence, screening by clinical breast examination may lead to the following harms:


Table 2. Harms of Screening Clinical Breast Examination

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%.  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

  • Study Design: One RCT, case-control trials, and cohort evidence.
  • Internal Validity: Good.
  • Consistency: Fair.
  • Magnitude of Effects on Health Outcomes: No difference in breast cancer mortality was seen after 10 years in Shanghai factory workers randomly assigned to receive breast self-examination instruction and reinforcement, compared with the control group. Forty percent of the women enrolled, however, were younger than 40 years. 15
  • External Validity: Poor.


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

  • Study Design: One RCT.
  • Internal Validity: Good.
  • Consistency: Fair.
  • Magnitude of Effects on Health Outcomes: Biopsy rate is 1.8% among the study population compared with 1.0% among the control group. 15
  • External Validity: Poor.

References:

  1. Nystrím 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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  11. Ronckers CM, Erdmann CA, Land CE: Radiation and breast cancer: a review of current evidence. Breast Cancer Res 7 (1): 21-32, 2005. [PUBMED Abstract]
  12. Goss PE, Sierra S: Current perspectives on radiation-induced breast cancer. J Clin Oncol 16 (1): 338-47, 1998. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]


Significance

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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. 1 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 2 and the United Kingdom 3 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. 4 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 overdiagnosisscreening 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). 2


Table 3. Probability of Developing Invasive Breast Cancer Among Womena

aBased on an analysis of data from the Surveillance, Epidemiology, and End Results registry for 20052007. bWomen who are free from invasive breast cancer at their current age.cNumber of women in 1,000 who would develop invasive breast cancer in the next period of time.
Current Age in Yearsb   Risk per 1,000 Womenc 
  in 10 years   in 20 years  in 30 years   Lifetime 
30  4   17  41   123 
40  14  37   68   120 
50  24  56  86  109 
60  34   67  86  91 
70  37  58    65 
2 
 
 

In 2012, an estimated 39,510 women will die of breast cancer, compared with about 72,590 women who will die of lung cancer. 1 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. 5


Table 4. Mortality Risk According to Age: Breast Cancer and All Causesa

aAdapted from Schwartz, Woloshin, and Welch.
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 
4044   3  21 
4549   4  33 
5054   6  51 
5559   7  81 
6064  8  120 
6569   10  180 
7074   11   270 
7579  12  410 
8084  12  670 
85+  11  790 
6 


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). 9 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. 13

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. 14

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).

References:

  1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
  2. Altekruse SF, Kosary CL, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2007. Bethesda, Md: National Cancer Institute, 2010. Also available online [PUBMED Abstract]
  3. Johnson A, Shekhdar J: Breast cancer incidence: what do the figures mean? J Eval Clin Pract 11 (1): 27-31, 2005. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  14. Goss PE, Sierra S: Current perspectives on radiation-induced breast cancer. J Clin Oncol 16 (1): 338-47, 1998. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  17. Fajardo LL, Hillman BJ, Frey C: Correlation between breast parenchymal patterns and mammographers' certainty of diagnosis. Invest Radiol 23 (7): 505-8, 1988. [PUBMED Abstract]


Breast Cancer Diagnosis

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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. 1 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. 2

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 Carcinoma In 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. 6 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. 7 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. 8 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. 9 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. 12 (Refer to the PDQ® summary on Breast Cancer Treatment for more information.)

References:

  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  3. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]
  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. [PUBMED Abstract]


Breast Cancer Screening Modalities

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Mammography

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. 1

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. 2 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 3 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. 4 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. 5

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. 9

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. 10

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], 1.153.11) for women whose cancers were detected outside screening, even though they were more likely to get adjuvant systemic therapy. 11 Similarly, an examination of the breast cancers found in three randomized screening trials (Health Insurance Plan, National Breast Screening Study [NBSS]-1, and NBSS-2see 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, 1.172.00) for interval and incident cancers in comparison with screen-detected cancers and 1.36 (95% CI, 1.101.68) for cancers in the control group in comparison with screen-detected cancers. 12 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, 0.630.99). 13 Thus, method of cancer detection is a powerful predictor of patient outcome, 11 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. 26 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. 7 HT, which increases breast density, is associated with both lower sensitivity and an increased rate of interval cancers. 27 High breast density is an inherent trait, which can be familial 28 29 but also may be affected by age, endogenous 30 and exogenous 31 32 hormones, 33 selective estrogen receptor modulators such as tamoxifen, 34 and diet. 35 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. 36

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. 37 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. 38

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. 39 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. 41 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. 42

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. 43 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, 1.011.81). A 2-year interval was not associated with late-stage disease for women in their 50s or 60s. 44

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, 0.591.27). 45

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. 46 (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. 47 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. 49 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. 50

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 dif

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