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Screening for Breast Cancer in Women With Dense Breasts
Plain Language Summary
Mammography is the only screening test that reduces death from breast cancer in randomized trials. However, it does not detect all cancers that are present. One of the reasons that mammography misses cancers is that dense areas on the image can obscure cancers. Both breast cancers and breast density show up as white on mammograms so it is more difficult to identify cancer in an area of density. Digital mammography improves the detection of breast cancers in dense breasts, but cancers are still missed. This raises the question about the potential benefits of additional screening with different technology.
Four approaches have been advocated to identify cancers in women with dense breasts and normal screening mammograms: hand-held ultrasound, automated breast ultrasound, breast magnetic resonance imaging (MRI), and digital breast tomosynthesis. All four of these technologies generate multiple images representing slices of the breast that allow the radiologist to visualize the breast with less overlapping tissue. This is particularly useful in dense breasts because overlapping dense tissue may hide breast cancer.
No clinical trials demonstrate that supplemental screening reduces death from breast cancer. Studies do show that all four techniques identify additional cancers in women with normal mammograms. Hand-held ultrasound is the best studied: it identifies an additional two cancers per 1000 women screened, but is time-consuming, dependent on the skill of the operator, and requires more biopsies to find one cancer than other techniques. Automated breast ultrasound was developed to remove the operator dependency, shorten the time of image acquisition, and improve the efficiency of ultrasound, but suffers from the same high number of biopsies performed to find one cancer. MRI finds the most additional cancers, but is very expensive, time-intensive, and requires intravenous contrast. It is only practical for women at the highest risk for breast cancer, such as carriers of mutations in the BRCA genes. Tomosynthesis, on the other hand, finds an additional two cancers per 1000 women screened and requires a similar number of biopsies to find one cancer as traditional digital screening mammography; however, as currently practiced it doubles the radiation dose. It is the most promising technology.
Not all women with dense breasts require additional imaging. Breast density information can be combined with a woman’s risk for breast cancer to target those women at highest risk for missed cancers. Using a risk-based strategy, only about one in four women with dense breasts would be recommended for supplemental screening.
Introduction
This chapter summarizes the evidence on the comparative clinical effectiveness of standard screening mammography and supplemental imaging to screen women with mammographically dense breasts following a negative mammogram. As of 2015, 24 states in the United States have passed legislation requiring mammography facilities to notify women with dense breasts about their density. For example, on April 1, 2013 a law went into effect in California requiring mammography facilities to inform women with dense breasts about the potential for “masking” and the increased risk of breast cancer associated with dense breast tissue. Masking occurs when breast cancers are hidden by dense breast tissue on a mammogram, which, like cancer, appears white. The law requires the following language be included in reports sent to women who have dense breast tissue:
Your mammogram shows that your breast tissue is dense. Dense breast tissue is common and is not abnormal. However, dense breast tissue can make it harder to evaluate the results of your mammogram and may also be associated with an increased risk of breast cancer. This information about the results of your mammogram is given to you to raise your awareness and to inform your conversations with your doctor. Together, you can decide which screening options are right for you. A report of your results was sent to your physician.
The primary motivation for the law is to alert women to the masking effect of dense breast tissue on their mammograms. However, dense breast tissue may also play an important role by identifying women at high enough risk for breast cancer to warrant additional imaging with a different technology. A number of new technologies and new applications of existing technologies have been promoted to enhance screening in women with dense breasts. These include hand-held and automated breast ultrasound, magnetic resonance imaging (MRI), and digital breast tomosynthesis (DBT).
This chapter will summarize the evidence about film and digital screening mammography in women with dense breasts and the harms and benefits of supplemental screening after a normal screening mammography examination. We will also assess ways to estimate the overall risk of breast cancer for women with dense breasts and a negative mammogram to guide the decision about which women are more likely, and which less, to benefit from supplemental screening.
Background
Breast Cancer
Breast cancer is the most common cancer in women worldwide. There were approximately 1.7 million new cases of breast cancer and 552,000 deaths from breast cancer in 2012. In the United States, mortality from breast cancer has declined by about 2.2% per year since 1990, a 28% overall decline. The median values from a series of models estimated that a little more than half of the decline was due to improvements in therapy for breast cancer and that a little less than half (46%) was due to early diagnosis from mammography while a more recent study in Norway found only 33% of the reduction in breast cancer mortality was due to screening. An analysis of 30 years of data from the United States Surveillance, Epidemiology, and End Results (SEER) data also called into question the contributions of screening mammography to decreasing breast cancer mortality. Bleyer and Welch estimated that 31% of breast cancer diagnosed with mammography represents “overdiagnosis” (ie, identification of cancers unlikely to cause significant morbidity or mortality) and concluded that screening mammography has had, at best, only a small effect on breast cancer mortality.
Screening for Breast Cancer
The primary method worldwide used to screen for breast cancer is mammography. Nine large clinical trials established the efficacy of screening mammography by randomizing over 600,000 women and following them for 10–20 years. The results have been summarized in many systematic reviews and meta-analyses. There is general consensus that, for women between the ages of 50 and 69 years, screening mammography reduces breast cancer mortality by approximately 20% to 25% after 15 years of follow-up. For average-risk women between the ages of 40 and 49 years, there remains controversy about whether the benefits of routine mammography outweigh the harms, such that most countries that offer mammography do not offer routine screening to women aged 40–49 years and some recommend a discussion of the benefits and harms of mammography allowing women to decide on screening based on their personal preference.
Digital Mammography
Mammography was traditionally performed with film. It was one of the last radiographic procedures to transition from film to digital imaging because mammography requires extremely high resolution to be effective. Digital image acquisition improves the signal to noise ratio of X-ray detection over a wider contrast range than film. Digital enhancement of the images at computer workstations may also improve the accuracy of mammographic interpretation. In particular, increased contrast resolution improves the detection of low contrast lesions in radiographically dense breasts. Digital mammography has become the standard across the United States. As of October 1, 2015, 97.5% (14,769/15,153) of all US mammography machines accredited by the Food and Drug Administration (FDA) are full-field digital.
Mammographic Breast Density
Mammographic density refers to areas within the breast that absorb significant amounts of X-ray energy and show up as relatively white areas on the mammogram. These correspond to regions in the breast that are rich in epithelial and stromal tissue while the nondense (darker gray areas) correspond to regions that are predominantly fat.
In the United States, the Breast Imaging Reporting and Data System (BI-RADS) of the American College of Radiology classifies density in the following four breast composition categories:
- a.
The breasts are almost entirely fatty.
- b.
There are scattered areas of fibroglandular density.
- c.
The breasts are heterogeneously dense, which may obscure small masses.
- d.
The breasts are extremely dense, which lowers the sensitivity of mammography.
The prevalence of high breast density (BD; heterogeneous or extremely dense tissue) is 43% in women 40–74 years old, which represents almost 28 million women in the United States. The prevalence varies by age declining from 57% for women between the ages of 40 and 44 years to 28% for women ages 85 years and older. High BD using the BI-RADS categories is also more common in Asian women.
It has been known for years that the sensitivity of film mammography is lower in women with dense breasts than in women with fatty breasts. There is a masking effect due to mammographic density. In the Breast Cancer Surveillance Consortium (BCSC), a US collaboration of breast imaging registries, the sensitivity of film mammography decreased markedly with increasing density (see Table 10.1 ). This study evaluated the results from 463,372 screening film mammograms performed between 1996 and 1998. Among women in the low density categories, the sensitivity of mammography was 88% and 82% for density categories a and b, respectively, but this decreased to 69% for women with heterogeneously dense breasts and to 62% for women with extremely dense breasts.
Table 10.1
Sensitivity of Film and Digital Mammography by Breast Density
| Study | Type | BI-RADS Density Category | |||
|---|---|---|---|---|---|
| Almost Entirely Fatty (a) | Scattered Fibroglandular Densities (b) | Heterogeneously Dense (c) | Extremely Dense (d) | ||
| BCSC (Carney 2003) | Film | 88.2 | 82.1 | 68.9 | 62.2 |
| DMIST (Pisano 2005) | Film | 55 a | |||
| Digital | 70 a | ||||
| BCSC (Kerlikowske 2011) | Film | 85.7 | 85.1 | 79.3 | 68.1 |
| Digital | 78.3 | 86.6 | 82.1 | 83.6 | |
a The DMIST study reported results for the combined high-density categories only.
BD and Digital Mammography
As described above, the increased contrast resolution of digital mammography improves the detection of low contrast lesions in radiographically dense breasts. Thus digital mammography should improve the sensitivity of mammography in women with dense breast tissue compared to film.
The Digital Mammography Imaging Screening Trial (DMIST) study is the largest trial directly comparing digital mammography to plain film mammography ( n = 42,760). All women were screened with both film and digital mammography on the same visit. Mammograms were read independently by radiologists blinded to the results of the other mammogram. In DMIST, digital mammography had the same recall and biopsy rates as film mammography. Digital mammography was more sensitive than film for younger women with denser breasts (59.1% vs 27.3%, p = 0. 0013). Among women of all ages with either heterogeneously dense or extremely dense breasts, digital mammography was also more sensitive than film mammography (70% vs 55%, p = 0.02, Table 10.2 ). Similarly, in women with dense breast tissue there was a trend towards greater specificity with digital mammography (91% vs 90%, p = 0.09) and the overall accuracy of digital mammography, as measured by the area under the receiver operator curve, was greater than that of film mammography (0.78 vs 0.68, p = 0.003).
Table 10.2
Cancer Detection, Sensitivity, and Specificity of Digital Mammography by Breast Density
| Study | Type | BI-RADS Density Category | |||
|---|---|---|---|---|---|
| Almost Entirely Fatty (a) | Scattered Fibroglandular Densities (b) | Heterogeneously Dense (c) | Extremely Dense (d) | ||
| BCSC (Kerlikowske 2011) | Rate a | 1.8 | 3.3 | 4.8 | 5.1 |
| Sens | 78 | 87 | 82 | 84 | |
| Spec | 95 | 91 | 87 | 89 | |
a Rate =breast cancer detection rate per 1000 women screened.
The BCSC has reported on the accuracy of screening mammography based on a comparison of 231,034 digital mammograms and 638,252 film mammograms performed between January 1, 2000 and December 31, 2006. Similar to the prior study, the sensitivity of film mammography decreased from 86% to 68% across the four BD categories (see Table 10.2 ). However, for digital mammography, the sensitivity of digital mammography remained greater than 80% for the highest density categories and did not appear to decrease with increasing density (see Table 10.2 ). As in the DMIST trial, digital mammography was significantly more sensitive than film mammography in women with dense breasts, but had lower specificity.
Table 10.2 shows the cancer detection rate and specificity in addition to the sensitivity of digital mammography by BI-RADS density category in the BCSC study. Despite concerns about the test performance of mammography in dense breasts, more breast cancers are found per 1000 digital screening mammograms in the dense breast categories than in the nondense categories. This highlights the general principle that the yield of screening tests is greater as the underlying risk of the population screened goes up. Women with dense breasts are at higher risk, so the cancer detection rate is higher. These data also suggest that the masking effect of BD is reduced when digital mammography is used.
Table 10.3 summarizes important outcomes with film and digital mammograms in the three largest studies that report data on both digital and film mammography. These are useful benchmarks to use when evaluating the potential yield of additional imaging compared to no additional imaging. The biopsy rate and cancer detection rate did not differ between women screened with digital or film mammography in any of these studies, although the recall rate for digital was higher in the BCSC (100 vs 93 per 1000, p < 0.001). When cancer detection was stratified by BD in the BCSC, no statistical differences were found between digital and film mammography. However, there was a nominal trend toward higher cancer detection in women with extremely dense breasts (5.1 vs 3.8 per 1000, p = 0.17); the authors concluded that this was primarily due to better detection in women aged 40–49 with extremely dense breasts.
Table 10.3
Recall Rates and Cancer Detection Using Film and Digital Mammography in Large Studies of Screening Irrespective of Density
| Study | Type | Mammograms, n | Recall Rate per 1000 | Biopsy Rate per 1000 | Cancer Detection per 1000 | PPV3 |
|---|---|---|---|---|---|---|
| DMIST (Pisano 2005) | Film | 42,555 | 86 | 16.0 | 4.1 | 24.4 |
| Digital | 42,555 | 86 | 15.9 | 4.4 | 26.0 | |
| Vestfold (Vigeland 2008) | Film | 324,763 | 42 | NR | 6.5 | 15.1 |
| Digital | 18,239 | 41 | NR | 7.7 | 18.5 | |
| BCSC (Kerlikowske 2011) | Film | 638,252 | 93 | 10.6 | 3.8 | 24.7 |
| Digital | 231,034 | 100 | 11.0 | 3.8 | 25.3 |
Note: PPV3, the positive predictive value for biopsies performed.
It is worth noting in Table 10.3 that in Europe, the recall rate for mammography is generally about half that observed in the United States. Thus, one of the harms of mammography, recalls for false-positive imaging results, is less common in Europe. It is important to keep this in mind when evaluating how to apply the results from studies of supplemental screening performed in Europe versus the United States to different countries performing mammography.
In summary, the findings from both the DMIST and BCSC studies, along with the results from other high-quality studies, highlight a critical difference between digital and film mammography in women with dense breasts. The studies find that digital mammography is more sensitive than film mammography in women with dense breasts. Therefore, the masking effect of BD observed with film mammography is reduced, but not eliminated with digital mammography.
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