Breast Cancer Screening Modalities

Mammography
Clinical Breast Examination
Breast Self-Examination
Ultrasonography
Magnetic Resonance Imaging
Scintimammography
Tissue Sampling (Fine-Needle Aspiration, Nipple Aspirate, Ductal Lavage)
Thermography

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).[6-8] 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], 1.15–3.11) 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-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.[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, 0.63–0.99).[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.[14-23] 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, 1.01–1.81). 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, 0.59–1.27).[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 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.[36]

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).[51]

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.[52]

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.[53]

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.[54]

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.[55] The use of CAD systems increases sensitivity but decreases specificity.[56] 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.[58] 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.[58]

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.[59] 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]).[60] 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%.[61] Among community clinicians, screening CBE has higher specificity (97%–99%) [62] and lower sensitivity (22%–36%) compared with examiners in clinical trials of breast cancer screening.[63-66] 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.[67] 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%).[68] 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.[71]

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.[72] 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).[73]

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.[74]

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.[75]

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.[78]

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.[82] 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.

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.[83] 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.[84] 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.[85] 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]

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