Breast Cancer Screening Modalities—Beyond Mammography
Clinical Breast Examination
No randomized trials of clinical breast examination (CBE) as a sole screening modality have yet been reported. The Canadian National Breast Screening Study (NBSS) compared high-quality CBE plus mammography to CBE alone in women aged 50 to 59 years (refer to the Clinical Breast Examination section in the Overview section of this summary for more information). CBE, lasting 5 to 10 minutes per breast, 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, perhaps because of 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% confidence interval [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; specificity ranged between 88% and 96%. Positive predictive value (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 was 84%, and PPV was 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.[5-8] A study of screening in women with a positive family history of breast cancer showed that, after a normal initial evaluation, the patient herself or her clinician performing a 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 for mammography was 78%, and combined mammography-CBE sensitivity was 82%. Specificity was lower for women undergoing both screening modalities than it was for women undergoing mammography alone (97% vs. 99%). Two international trials of CBE are under way in India and Egypt.
Monthly breast self-examination (BSE) has been promoted, but there is no solid evidence that it is effective in reducing breast cancer mortality.[11,12] The only large, well-conducted, randomized clinical trial of BSE randomly assigned 266,064 women factory workers in Shanghai to receive either BSE instruction with reinforcement and encouragement, or instruction on the prevention of lower back pain. Neither group received any other breast cancer screening. After 10 to 11 years of follow-up, 135 breast cancer deaths occurred in the instruction group, and 131 cancer deaths occurred 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.
Other research on BSE is limited. First, Leningrad investigators cluster-randomized more than 100,000 women to BSE training or control. The group that received BSE training had more breast biopsies but no improvements in breast cancer mortality. Second, 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 breast cancer mortality rates compared to those in women from centers without organized BSE education (RR, 1.07; 95% CI, 0.93–1.22). Third, and last, a case-control study nested within the Canadian NBSS compared self-reported BSE frequency before enrollment 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 rates.
The primary role of ultrasound is the diagnostic evaluation of palpable or mammographically identified masses, rather than serving as a primary screening modality. 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.” In the setting of normal mammography and ultrasonography, less than 3% of women who have a lump will ultimately be found to have breast cancer.[18-21]
Magnetic Resonance Imaging
Breast magnetic resonance imaging (MRI) may be used in women for diagnostic evaluation, including evaluating the integrity of silicone breast implants, assessing palpable masses following surgery or radiation therapy, detecting mammographically and sonographically occult breast cancer in patients with axillary nodal metastasis, and preoperative planning for some patients with known breast cancer. There is no ionizing radiation exposure with this procedure. It has been promoted 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.[22-24] Breast MRI is more sensitive but less specific than screening mammography [25,26] and is more expensive.
Direct comparisons of breast MRI and mammography in young high-risk women report MRI sensitivities of 71% to100% versus mammography sensitivities of 20% to 50%. Contrast-enhancing foci are seen frequently in healthy breasts, so false-positive results are common.[27,28] In these studies, MRI specificities range from 37% to 97%, with threefold to fivefold higher recall rates and substantially lower PPVs. Thus, women who are screened with MRI have more negative surgical biopsies.
Because all studies of MRI screening are observational, none can assess morbidity, survival, or mortality, compared with other screening modalities, though it is likely that MRI screening results in overdiagnosis (refer to the Overdiagnosis section in the Harms of Screening Mammography section of this summary for more information).
Using infrared imaging techniques, thermography of the breast identifies temperature changes in the skin as an indicator of an underlying tumor, displaying 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.[30,31]
Tissue Sampling (Fine-Needle Aspiration, Nipple Aspirate, Ductal Lavage)
Various methods to analyze breast tissue for malignancy have been proposed as screening methods for breast cancer.
Random periareolar fine-needle aspirates were performed in 480 women at high risk for breast cancer, and the women were monitored for a median of 45 months. Twenty women developed breast neoplasms (13 invasive and 7 ductal carcinoma in situ [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 DCIS and invasive breast cancer.
Nipple aspirate fluid cytology was studied in 2,701 women who were monitored 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 cases 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. A total of 383 ductal lavage samples were evaluated, 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%). Discomfort with the ductal lavage procedure was judged by participants to be comparable to mammography. Because ductal lavage screening has not been compared to mammography and there is no evidence of efficacy or mortality reduction, its use as a screening or diagnostic tool remains investigational.
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- 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]
- 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]
- 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]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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. [PUBMED Abstract]
- 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]
- Semiglazov VF, Moiseyenko VM, Bavli JL, et al.: The role of breast self-examination in early breast cancer detection (results of the 5-years USSR/WHO randomized study in Leningrad). Eur J Epidemiol 8 (4): 498-502, 1992. [PUBMED Abstract]
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- Moy L, Slanetz PJ, Moore R, et al.: Specificity of mammography and US in the evaluation of a palpable abnormality: retrospective review. Radiology 225 (1): 176-81, 2002. [PUBMED Abstract]
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