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Published: August 2010

Breast Disorders and
Breast Screening

Mark Mayer

Pelin Batur

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Definition

Evaluation of breast complaints and screening for breast cancer account for a significant part of primary care practice and are the dual roles of the primary physician. Complaints most commonly presented include breast pain, breast lumps, and nipple discharge. These symptoms often arise from benign conditions, but accurate evaluation is essential.

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Prevalence

In one study, 16% of women between ages 40 and 69 years came to the doctor with breast complaints over a 10-year period.1 Estimates of the number of insured women between ages 50 and 64 years getting screening mammography at least every 2 years vary from 72% to 81%2 ; uninsured women clearly obtain less preventive care. Breast cancer is diagnosed in about 213,000 women in the United States each year. The breast cancer mortality rate has declined gradually since 1990 to about 41,000 per year.

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Pathophysiology

Most breast lumps and other breast complaints are due to benign conditions. Breast pain can be produced by fibrocystic changes, mastitis, pendulous breasts, or hidradenitis suppurativa. Chest wall pain, which may be felt as breast pain, can have many causes that do not originate in the breast. These include gallbladder disease, ischemic heart disease, trauma, intercostal neuralgia, costochondritis, and thoracic spine arthritis. Many breast lumps are due to fibrocystic changes. Most lumps are benign, but of all complaints, they constitute the greatest percentage of symptoms leading to a diagnosis of cancer. Nipple discharge is usually benign, especially if nonbloody, bilateral, and not spontaneous. Discharge can be due to medications, hormonal factors, prior nursing or pregnancy, or, less commonly, cancer.

Risk factors for the development of breast cancer include increased age, genetic predisposition, and increased exposure to estrogen.3 Breast cancer risk is increased even if the nearest relative with breast cancer is a third-degree relative.4 Among women with a positive family history of breast cancer, having multiple first-degree relatives with premenopausal breast cancer confers the highest risk; a small minority of these are associated with BRCA1 or BRCA2 mutations. A number of models for assessing risk of carrying a mutation have been proposed. All account for early-onset breast cancer in the family, and most give weight to the number of affected relatives.5

Increased exposure to estrogen modestly raises the risk of breast cancer. Early menarche (before age 12 years) and late menopause (after age 55 years), both markers of increased estrogen exposure, confer some increased risk. The role of hormone therapy (HT) is controversial. The Women's Health Initiative, the first large-scale randomized placebo-controlled trial of postmenopausal hormone use, showed a 26% increased risk of breast cancer. However, this was after 5.2 years of use and only in women who used combination estrogen and progestin in the form of Prempro.6 In contrast, women in the estrogen-only arm of this trial, using Premarin, did not have any increased risk of breast cancer. The Million Women Study in the United Kingdom is the largest nonrandomized study of hormone use. This study concluded that all types of hormone use, including estrogen-only forms, increased the risk of breast cancer compared with never users. The risk increased with increasing duration of use.7

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Signs and symptoms

Breast pain, breast lumps, and nipple discharge are the most common complaints presented to the physician. Screening is performed in the absence of symptoms; when symptoms exist, the evaluation may dictate going beyond screening procedures. In addition to a history and examination directed by the complaint, any benign disorders identified may need to be treated. If cancer is considered once the history and physical examination are completed, discussions about diagnostic modalities such as imaging, aspiration, or biopsy may need to be addressed at the time of the office visit. Depending on the clinical evaluation, referral may be suggested even with pending imaging studies.

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Diagnosis

History

History should include the characteristics of symptoms and their timing in relation to menstrual cycles. Breast pain is most commonly caused by fibrocystic changes. Other causes include mastitis, which usually produces sudden pain, with signs of inflammation. Pendulous breasts can cause pain. Hidradenitis suppurativa can manifest as breast nodules and pain; signs of infection and possible concomitant involvement of the axilla should be evaluated. One should be alert for history suggesting thoracic arthritis, chest wall inflammation, breast or axillary infection, cholecystitis, or cardiac ischemia.

The presence or absence of lumps should be ascertained, and whether they wax and wane with the menstrual cycle (suggesting fibrocystic changes). Lumps associated with nipple discharge, particularly unilateral bloody discharge, are worrisome.

Symptoms of nipple discharge should be elicited. The overall rate of malignancy is low (probably around 1%). If the discharge is nonbloody, the risk of cancer is lower. Purulent discharge may be caused by mastitis or a breast abscess. Milky discharge may persist after childbearing and can occur with some medications (see “Treatment”). An endocrine workup (for prolactin excess) may be needed if symptoms are sustained or are associated with menstrual problems. Prior biopsies, prior treatments, and use of hormones should be ascertained.

Risk factors for cancer should be assessed whether symptoms are present or the visit is for screening only. These include age, menarche before age 12 years, menopause after age 55 years, and first live birth at age 30 years or older. Information should be obtained about previous biopsies (whether ductal hyperplasia and, if so, whether atypical), and the number of first-degree relatives with breast cancer (and at what age their cancer was detected). The Gail Model Risk Assessment Tool may be used to help calculate risk from these history questions.8 A computer disk for use of the Gail model is available from the National Cancer Institute to use in calculating this. Such estimates can aid in decision making, particularly about chemoprevention.

Physical Examination

There is an overall consensus that clinical breast examination (CBE) is useful in screening as well as in evaluation of a lump, although there has been debate on this issue. Four screening clinical trials included both mammography and CBE, four others evaluated mammography only, but no trial studied CBE alone without mammography. In a comparison of studies including both screening modalities, the range of cancers detected by CBE but not by mammography was 3% to 45%. Although the sensitivity of mammography is greater than that of CBE, there is a residual diagnostic value of CBE that favors its continued use in screening.9

Careful, systematic palpation has been shown to increase detection of breast lumps. Patient position, palpation of breast boundaries, and examination pattern and technique are important variables in CBE.9

The physical examination should include inspection and palpation. Inspection of the breasts can be done with the woman sitting with hands on her hips; some advocate inspection also with the patient sitting with her hands on top of her head, pushing downward. The examiner looks for lumps, asymmetry, or skin dimpling.

The breasts should be palpated for evaluation of texture and detection of masses. The supine patient position is preferable because CBE requires flattening breast tissue against the patient's chest, and the distance from skin to chest wall is minimized with the patient supine. The patient's ipsilateral hand should be brought up to head level for examination of the lateral aspect of the breast; the elbow should be at shoulder level for examination of the medial part of the breast.

The examination pattern should be systematic. It is important to include the area bordering the clavicle, and laterally toward the axilla, so as to ensure examination of all breast tissue. One preferred method is to start at the axilla in the midaxillary line and then cover the breast by palpating in parallel lines, in vertical strips to the sternum. A rectangular area bordered by the clavicle, the midsternum, the midaxillary line, and the bra line should be covered (Figure 1). Small circular motions should be made at each step using the pads of the index, third, and fourth fingers, with gradated pressure (Figure 2).

Examination of the axillae for lymph nodes should follow breast examination. Examination along the chest wall is especially important. The position and size of any nodes should be recorded. The presence of lymphadenopathy should prompt referral to a breast specialist, although the significance of shotty nodes is unclear.

The character of breast lumps is particularly important. Characteristics that suggest cancer include a hard or gritty texture, immobility, an irregular border, and a size greater than 2 cm. A new dominant mass or a gritty or growing lump deserves evaluation by a breast specialist. Unfortunately, likelihood ratios for these signs indicating cancer are not very large, except for the presence of fixed lesions and lump size greater than 2 cm.9

After the history and physical examination, further assessment of breast lumps may include careful clinical follow-up, ultrasound, mammography, and biopsy. Guidelines for screening mammography are reviewed in the “National Guidelines” section.

Mammography

Mammography may be performed as an adjunct to the physical examination in evaluating breast lumps or as a screening tool. Mammography is not generally useful in women younger than 35 years who present with a lump.10 Ultrasonography may be useful in evaluating lumps in these younger women, although it is important to refer to a breast specialist for any lesion in doubt.

Evaluating Symptoms

Mammography is usually recommended as part of the evaluation in women older than 35 years who have a breast mass, to help evaluate the mass and to search for other lesions. It is an error to rely on negative mammogram results when there is a clinically suspicious lump. In such cases, the mammogram is a diagnostic adjunct to the surgeon, and negative findings should not preclude referral.

Mammographic findings that suggest cancer include increased density, irregular border, spiculation, and clustered irregular microcalcifications. Round, dense lesions on mammography might represent cystic fluid. Ultrasonography can often suggest a cystic lesion, and needle aspiration can confirm this.

Mammography findings are usually negative when mammography is used to evaluate breast pain, although it may be of reassurance value in this setting.

Screening

The age at which to begin mammography for screening is controversial. There have been eight major trials of mammography screening. The observed change in breast cancer mortality has varied widely among these studies. Differences in randomization techniques, quality of the mammograms, duration of follow-up, and evolving treatments for breast cancer during the trials have made it difficult to draw conclusions about mammographic screening. There have been several meta-analyses of the effect of mammographic screening. Differences in these derive from the time they were done, the presence or absence of follow-up data from individual trials, and the exclusion of certain trials in some meta-analyses.

A consensus has emerged that women between 50 and 69 years should be screened by mammography. Results of a meta-analysis11 of breast cancer screening trials found a 26% reduction in breast cancer mortality over 7 to 9 years among women screened at ages 50 to 74 years.

For women first screened in their 40s, the magnitude of breast cancer mortality reduction is at best 18% after 10 to 18 years of follow-up.12 Although some guidelines discuss starting mammographic screening earlier in women with a family history of breast cancer, data on the sensitivity of mammograms show no better cancer detection rates in this group.13 However, due to a higher pretest probability of breast cancer in those with a family history, the positive predictive value of mammograms is higher for those women (and therefore the false-positive rate is lower for them).

The number needed to be screened to prevent one death from breast cancer is estimated at between 1500 and 2500 for women screened in their 40s.14 In addition, nearly one half of women screened starting at age 40 years have at least one abnormal screening mammogram during the subsequent 10-year period, leading to additional mammographic views and biopsies for a significant number. Many of these abnormal screening studies prove to be false positives.

If the patient or physician finds a palpable lump, a diagnostic (four-view) mammogram, with or without ultrasound, may be used to help guide diagnosis. Again, mammography is not sufficient to exclude cancer in the evaluation of a palpable mass (see the discussions of ultrasonography and triple diagnosis).

Ultrasonography

Ultrasonography does not have a role as a single or initial study in screening for breast cancer. However, it is very useful for evaluating breast lumps and in further defining mammographic abnormalities. It is especially useful in women younger than 35 years, when a mass is noted on screening mammography but is not palpable, when a patient declines aspiration of a mass, and if a mass is too small or too deep for aspiration.

The risk of cancer is low if a simple cyst is found on ultrasound. One study found no cancers in 223 cysts.15 However, some experts recommend moving directly to fine-needle aspiration if a simple cyst is found at the site of a palpable mass.16 In our experience, we have found only one cancer in a “simple cyst” noted by ultrasound; the “cyst” was 2 cm in size, new, and palpable by patient and physician, and it warranted aspiration based on its size.

Fine-Needle Aspiration

Fine-needle aspiration can be performed to aspirate a palpable suspected cyst. A 22- or 24-gauge needle is inserted into a cyst that has been stabilized with the other hand. If nonbloody fluid is obtained, it can be discarded, because no cancer was found in nonbloody cyst fluid in a large series.17 A clinical recheck should be performed in 4 to 6 weeks; recurrence of the lump should prompt surgical referral. Bloody fluid should be sent for pathologic analysis. Cancer is found in approximately 1% of bloody aspirates.17 When no fluid is obtained, cells can be obtained for cytologic evaluation with fine-needle aspiration biopsy.

Core Needle Biopsy

A larger needle (14- to 18-gauge) is used for core needle biopsy. It is mostly used for evaluating nonpalpable breast masses (those found on mammography only), with ultrasound or mammographic guidance. Agreement between core needle biopsy and surgical biopsy was 94% in seven studies.18

Triple Diagnosis

The combination of the physical examination, mammography, and fine-needle aspiration biopsy for diagnosing palpable lumps is referred to as triple diagnosis. There is excellent sensitivity (99%) and specificity (99%) with this approach.19 If any of these three modalities suggests cancer, excisional biopsy is warranted.

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Treatment

Breast Pain

Treatment for breast pain depends on an accurate diagnosis. Antibiotics may be required for some infections; abscesses or hidradenitis can require surgical drainage. Breast reduction surgery may be helpful for those with pendulous breasts and resultant pain.

Treatment of fibrocystic disease is aimed at relieving pain. Wearing a soft brassiere with good support may be helpful. Acetaminophen or a nonsteroidal anti-inflammatory drug can also help. Some patients note relief of pain with avoidance of caffeine, but this has not been proved by controlled studies. Use of vitamin E (400 U) is supported by some studies. Other possibly helpful remedies include evening primrose oil (1500-3000 mg/day) or vitamin B6. Optimal doses of vitamin B6 are unclear, although it is prudent to avoid doses greater than 50 mg/day, due to risk of neuropathy. Oral contraceptives have shown some promise, and those containing progestins with androgenic properties (e.g., 19-norprogestins) may be more beneficial. Danazol inhibits estrogen secretion and can behelpful; side effects include weight gain, acne, hirsutism, and amenorrhea.

Lumps and Discharge

Treatment of a breast lump or nipple discharge depends on the results of history, physical examination, and sometimes diagnostic studies. Characteristics of lumps suggesting malignancy include size (>2 cm), firmness, immobility, and irregularity. The triple diagnosis protocol outlined in the previous section is helpful in sorting out whether lumps are benign or malignant. Benign lumps should be followed up clinically.

Nipple discharge can be caused by several factors. Some medications (e.g., phenothiazines) can cause increased prolactin levels and thus nipple discharge; change in medication may be needed. Pituitary adenomas can lead to increased prolactin. Endocrine studies, starting with a prolactin level, should be obtained if discharge is persistent. Medical or surgical therapy may be warranted if a prolactinoma is identified. Nipple stimulation can sometimes cause discharge, and cessation may be required to stop symptoms. Cytology of suspect nipple discharge (especially bloody discharge) can be obtained, and galactography can also be performed. Fiberoptic ductography is available in some centers and should improve our ability to find papillary lesions. If nipple discharge is associated with a palpable mass, referral to a breast surgeon is mandatory.

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Guidelines

National Guidelines

There are a number of breast cancer screening guidelines in North America. Each organization making recommendations has a publication or website with its guidelines. A comparison of the guidelines can be found at http://www.guidelines.gov.

The American Cancer Society (ACS) recommends CBE every 3 years between ages 20 and 39 years. The National Cancer Institute recommends against screening mammography in women younger than 40 years, because there are no data showing benefit in this age group. The recommendation for a baseline mammogram has likewise disappeared from the American Cancer Society recommendations.

The ACS and the American College of Radiology recommend yearly screening with mammography and CBE starting at age 40 years. The Canadian Task Force recommends screening with CBE and mammography from ages 50 to 69 years and recommends against screening from ages 40 to 49 years. The U.S. Preventive Services Task Force (USPSTF) recommends screening with mammography with or without CBE every 1 to 2 years from age 40 years. They note that the age at which screening should be stopped is unclear, although women with a comorbidity limiting life expectancy have less benefit. The National Cancer Institute of the National Institutes of Health notes that screening mammography in women ages 40 to 70 years decreases breast cancer mortality and that screening by CBE reduces breast cancer mortality. These statements are tempered by a discussion of the harms of screening (Table 1).

Table 1: Recommendations for Breast Cancer Screening
Age (years) American Cancer Society U.S. Preventive Services Task Force National Cancer Institute Canadian Task Force on Preventive Health Care American College of Radiology
20-39 Clinical breast exam every 3 yr No data for benefit or for performing baseline mammogram
40-49 Clinical breast exam and mammogram yearly Mammogram with or without clinical breast exam every 1-2 yr Screening mammogram and clinical breast exam decrease breast cancer mortality Recommend against screening Mammogram and clinical breast exam yearly
50-69 Clinical breast exam and mammogram yearly Mammogram with or without clinical breast exam every 1-2 yr Screening mammogram and clinical breast exam decrease breast cancer mortality Clinical breast exam and mammogram during periodic health examination Mammogram and clinical breast exam yearly
70+ Cessation of screening is not age related but due to comorbidity When to discontinue mammogram is unclear; those with comorbidities are less likely to benefit Screening might or might not be helpful

© 2002 The Cleveland Clinic Foundation.

As noted in the diagnosis section, it is estimated that the number of women needed to be screened with mammography to avoid one breast cancer death would be 1500 to 2500 for women screened in their 40s. Because of the high false-positive rate in this population, with a lower pretest probability of disease, about one half of women screened annually starting at age 40 years would require a follow-up diagnostic mammogram during the subsequent 10-year period.

Common-Sense Approach

In the absence of consensus in national guidelines, we favor the following approach to screening. In women younger than 40 years who are concerned because of a family history of breast cancer, we review with them the data for apparent lack of efficacy of mammography.10 The sensitivity of mammograms is known to be less for young women, and to gradually rise with age.13 The relative contribution of the physical examination to diagnosis is probably greater in young women, so careful CBE on a yearly basis is probably useful. We also offer to calculate breast cancer diagnosis percentage risk using the Gail model.8 If there is a family history of more than one first-degree relative with breast cancer or a family history of bilateral premenopausal breast cancer, it is reasonable to discuss genetic testing.

For women in their 40s, we briefly review the data from clinical trials and the recommendations of the ACS and USPSTF. The public tends to be most familiar with the ACS guidelines. Many women want a straightforward recommendation. If a woman seeks more information, we try to inform her about some of the subtle issues.

We offer mammograms to women who are 40 years or older, but we emphasize that, due to the lower sensitivity of mammography in younger women, in our opinion CBE is especially important.

The approach to women 50 to 69 years old is easier because of the consensus among guidelines. We recommend CBE and mammography annually. Of course, risk assessment may be important at any age. It is sometimes sought due to a new family history or a benign biopsy.

In women older than 70 years, although the incidence of breast cancer mortality is high, it represents a stable portion of all deaths because other causes of mortality are also rising. Screening mammography trials that have included older women have not reported significant breast cancer mortality reduction in this group, although there are fewer women in this age range studied overall.

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Summary

  • The reduction in breast cancer mortality since 1990 has probably been multifactorial, with screening, prompt evaluation of palpable lumps, chemotherapy, and hormonal therapy all contributing.
  • Risk factors for developing breast cancer include increased age, genetic predisposition, and increased exposure to estrogen.
  • The Gail Model Risk Assessment Tool may be used to help calculate breast cancer risk from a patient's history and is available from the National Cancer Institute (NCI).
  • There are a number of breast cancer screening guidelines in North America but most recommend screening yearly starting at age 40 years. A comparison of the guidelines can be found at http://www.guidelines.gov .
  • Due to the lower sensitivity of mammography in younger women, the clinical breast examination is especially important.
  • Characteristics of breast lumps that suggest cancer include a hard or gritty texture, immobility, an irregular border, and a size greater than 2 cm.
  • The combination of the physical examination, mammography, and fine-needle aspiration biopsy for diagnosing palpable lumps is referred to as triple diagnosis; there are excellent sensitivity and specificity with this approach. If any of these three modalities suggests cancer, excisional biopsy is warranted.
  • There have been attempts to identify women with the most to gain from continuing mammography. One suggestion is to target women with higher bone mineral density for biennial screening from ages 70 to 79 years, because case finding is more fruitful in this group.24 Others have suggested that the overall health of the woman be assessed, and those with greater residual life expectancy be targeted for screening. The latter is the basic approach we take. If the woman is in good health, we continue to offer CBE and mammography.

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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. 1999, 130: 651-657.
  2. Bloom SA, Harris JR, Thompson BL, et al: Tracking clinical preventive service use: A comparison of the health plan employer data and information set with the behavioral risk factor surveillance system. Med Care. 2000, 38: 187-194.
  3. Armstrong K, Eisen A, Weber B. Assessing the risk of breast cancer. N Engl J Med. 2000, 342: 564-571.
  4. Slattery ML, Kerber RA. A comprehensive evaluation of family history and breast cancer risk. The Utah population database. JAMA. 1993, 270: 1563-1568.
  5. Ang P, Garber JE. Genetic susceptibility for breast cancer—risk assessment and counseling. Semin Oncol. 2001, 28: 419-433.
  6. Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002, 288: 321-333.
  7. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003, 362: 419-427.
  8. 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. 1989, 81: 1879-1886.
  9. Barton MB, Harris R, Fletcher SW. Does this patient have breast cancer? The screening clinical breast examination: Should it be done? How?. JAMA. 1999, 282: 1270-1280.
  10. Hindle WH, Davis L, Wright D. Clinical value of mammography for symptomatic women 35 years of age and younger. Am J Obstet Gynecol. 1999, 180: (Pt 1): 1484-1490.
  11. Kerlikowske K, Grady D, Rubin SM, et al: Efficacy of screening mammography. A meta-analysis. JAMA. 1995, 273: 149-154.
  12. Berry DA. Benefits and risks of screening mammography for women in their forties: A statistical appraisal. J Natl Cancer Inst. 1998, 90: 1431-1439.
  13. Kerlikowske K. Performance of screening mammography among women with and without a first-degree relative with breast cancer. Ann Intern Med. 2000, 133: 855-863.
  14. Rajkumar SV, Hartmann LC. Screening mammography in women aged 40-49 years. Medicine. 1999, 78: 410-416.
  15. Sickles EA, Filly RA, Callen PW. Benign breast lesions: Ultrasound detection and diagnosis. Radiology. 1984, 151: 467-470.
  16. Donegan WL. Evaluation of a palpable breast mass. N Engl J Med. 1992, 327: 937-942.
  17. Ciatto S, Cariaggi P, Bulgaresi P. The value of routine cytologic examination of breast cyst fluids. Acta Cytol. 1987, 31: 301-304.
  18. Evans WP III. Stereotactic core breast biopsy. In: Harris JR, Lippman ME, Morrow M, Hellman S (eds): Diseases of the Breast. Philadelphia: Lippincott-Raven, 1996, pp 144-151.
  19. Layfield LJ, Glasgow BJ, Cramer H. Fine-needle aspiration in the management of breast masses. Pathol Annu. 1989, 24: (Pt 2): 23-62.
  20. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin. 2001, 51: 15-36.
  21. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet. 1998, 351: 1451-1467.
  22. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet. 1998, 352: 930-942.
  23. Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet. 2000, 355: 1822.
  24. 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. 1999, 282: 2156-2163.

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Suggested Readings

  • American Cancer Society. Breast Cancer Facts & Figures 2009. PDF available for download at http://www.cancer.org/docroot/stt/stt_0.asp (accessed March 20, 2009)
  • Armstrong K, Eisen A, Weber B. Assessing the risk of breast cancer. N Engl J Med. 2000, 342: 564-571.
  • Barton MB, Harris R, Fletcher SW. Does this patient have breast cancer? The screening clinical breast examination: Should it be done? How? JAMA. 1999, 282: 1270-1280.
  • Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003, 362: 419-427.
  • Berry DA. Benefits and risks of screening mammography for women in their forties: A statistical appraisal. J Natl Cancer Inst. 1998, 90: 1431-1439.
  • Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: An overview of the randomised trials. Lancet. 1998, 351: 1451-1467.
  • 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. 1989, 81: 1879-1886.
  • Kerlikowske K, Grady D, Rubin SM, et al: Efficacy of screening mammography. A meta-analysis. JAMA. 1995, 273: 149-154.
  • 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. 1999, 282: 2156-2163.
  • Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet. 2000, 355: 1822.
  • Rossouw JE, Anderson GL, Prentice RL, et al: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002, 288: 321-333.

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