Current Trends and New Developments in Breast Cancer Imaging

Lilian C. Wang,* Paula Grabler, Mariana Solari, Sandra S. Rao, and Patricia J. Karstaedt

Northwestern University, Chicago, IL

 ABSTRACT

Breast imaging is utilized for the detection, diagnosis, and clinical management of breast cancer. In this article, current standard imaging modalities are discussed as well as emerging technologies at various stages of research and development. Mammography, ultrasound, and magnetic resonance imaging (MRI) are commonly used breast imaging studies. Mammography is currently the only modality that has been proven in large randomized controlled trials to reduce mortality due to breast cancer. The controversy regarding recent United States Preventive Services Task Force recommendations for screening mammography will be addressed. Ultrasound and MRI are increasingly important adjuncts to standard mammography, particularly in patients with increased breast density and those at increased risk for breast cancer. In addition to diagnostic imaging modalities, percutaneous breast biopsy methods will be reviewed. New technologies, including tomosynthesis, dedicated breast computed tomography, elastography, breast-specific gamma imaging, positron emission mammography, and MR spectroscopy, show promise in improving early detection, accurate diagnosis, and assessment of therapeutic response of breast cancer.

Keywords: mammography, breast ultrasound, breast MRI, screening

 INTRODUCTION

Breast cancer is the most frequently diagnosed noncutaneous cancer and the second leading cause of mortality from cancer in women in the United States (1). As demonstrated in randomized controlled trials, the widespread use of screening mammography has significantly reduced breast cancer mortality (2). Recent advances in treatment have contributed to this reduction, as well (3). Given that mammography can detect breast cancer before it is symptomatic, it is considered the standard of care in early detection with a sensitivity of 77% to 95% and specificity of 94% to 97% (4).

Major organizations including the American Cancer Society (ACS) (5), the American Medical Association (6), and the American College of Radiology (ACR) (7) have recommended annual screening mammography for women beginning at the age of 40. High-risk women, including those with genetic mutations (BRCA1 and 2) as well as those who have received radiation to the chest at an earlier age, are recommended to begin screening mammography prior to age 40.

The screening recommendations are based on the results from multiple international, randomized controlled trials which evaluated screening mammography and its impact on breast cancer mortality. Meta-analyses have reported an approximately 30% reduction in mortality from breast cancer for women between the ages of 50 and 74 screened with mammography (8,9). The limitations of the randomized controlled studies for evaluating mortality reduction for women aged 40 to 49 is based on individual studies that included too few women in this age group to detect significant differences, variable screening intervals, and exclusion of newer technologies, for example, digital mammography which is more sensitive for detecting breast cancers in younger women (21).

Support for the screening of women beginning at the age of 40 comes from research conducted in two Swedish counties where deaths from breast cancer diagnosed 20 years before the introduction of screening were compared with deaths during the 20 years after the introduction of screening. A significant reduction in breast cancer mortality was demonstrated and included the 40 to 49 age group (10). Although the randomized controlled trials did not evaluate the relative advantages of a 1-year versus a 2-year screening interval, an observational study demonstrated that the longer interval was associated with an increase in the number of women in their forties diagnosed with later stage disease, and, for older women, the longer interval was associated with a greater likelihood of being diagnosed with invasive disease compared with ductal carcinoma in situ (DCIS), resulting in more extensive therapy (11).

Although controversies regarding annual screening mammography for women beginning at the age of 40 have existed for many years, the recent recommendations by the United States Preventive Services Task Force (USPSTF) have again called the recommendations into question. Although the task force acknowledges that the decrease in mortality from breast cancer is due to both screening and treatment (with women aged 40–50 benefiting as well), given the lower incidence of breast cancer in younger women and the resultant increase in the number needed to screen to save one life, the task force recommends against routine screening mammography in women aged 40 to 49. It instead focuses on recommendations for this age group based on individual harms and benefits from screening with women at higher risk of breast cancer benefiting more. Additionally, biennial screening mammography, rather than annual, is recommended for women aged 50 to 74. The lack of screening recommendations for women at ages beyond 74 is based on the fact that this age group has not been studied in multiple randomized clinical trials (12).

The USPSTF based its recommendations on a new review of randomized controlled trials (2), which estimated that the number needed to invite to screen to extend 1 life was 1904 for women aged 40 to 49 versus 1339 for women aged 50 to 59. The task force also based its recommendations on modeling studies (13) which used statistical methods to predict mortality outcomes. Although all of the models demonstrated reductions in breast cancer mortality with strategies beginning screening at 40 or 50, the USPSTF emphasized reducing mortality with the greatest efficiency, thus capitalizing on the potential benefits and limiting the potential harms. Those programs with screening beginning at the age of 50 were deemed most efficient. When the goal was to efficiently maximize the number of life years gained, beginning screening at age 40 was the preferred strategy.

The USPSTF elucidated the harms of screening resulting from false-positive tests as well as overdiagnosis and treatment. The harms from the false-positive examinations include psychological stress, unnecessary additional imaging, the consequent increase in radiation exposure, and inconvenience to patients. Overdiagnosis and treatment occur when breast cancer is treated, but would not have become clinically apparent during an individual’s lifetime and when the cancer would have become clinically apparent but would not have resulted in mortality from breast cancer (12).

Critics of the USPSTF have challenged the recommendations. First, selecting the age of 50 to begin screening is arbitrary (14), given that the rate of breast cancer for women aged 45 to 49 is essentially the same as for women aged 50 to 54. Second, the recommendation to base screening on a patient’s risk to develop breast cancer is not supported by randomized controlled trials, which did not stratify by risk, and, in fact, would miss at least 75% of the breast cancers that occur in women of low risk (15). Third, the calculations of the task force were based on the results of randomized controlled trials, all of which have been reported to have significant limitations. A low estimate in the reduction of breast cancer deaths (15%) was used by the task force in forming their recommendations. Contributing to this underestimation was that in the randomized controlled trials women who were invited to screen but declined and subsequently died of breast cancer were included in the screening group. Conversely, those who were assigned to the control group, whose lives were extended by the early detection of breast cancer from mammo-grams which they received outside of the trial, were included in the control group (16). Observational studies demonstrating reductions in mortality of 30% to 40% for women in their forties were not included (10,17,18). Given the potential of a 30% decrease in deaths from breast cancer for women in their forties screened with mammography, recalculating the results, the number needed to screen to save one life is significantly reduced and is well below the task force threshold (16). Fourth, regarding false-positive mammograms, although they are problematic, additional testing typically involves only a few additional mammographic images and most biopsies are CNBs and do not involve surgery. Studies have demonstrated that the vast majority of women are willing to accept the anxiety, additional testing, and core biopsies related to false-positive mammograms rather than risk breast cancer detection at a later stage (19). Fifth, the task force indicated that, based on randomized trials, although a large proportion of the screening benefit is maintained with biennial screening, some lives will be lost by increasing the interval to 2 years (12). Screening biennially maintained an average of 81% (67–99%) of the benefit of annual screening. As breast cancer in younger women tends to be more aggressive compared with older women, prolonging the screening interval is especially concerning for those aged 40 to 50 (20). Sixth, the supporting data for the task force’s recommendations were based on fi lm mammography without the benefit of digital technology, which has been demonstrated to be more beneficial for younger women (21). Seventh, basing recommendations on the potential years of life lost rather than mortality alone is especially important in the younger age group. Eighth, the morbidity related to later stage cancers requiring mastectomy and adjuvant therapy compared with early detected localized cancers amenable to lumpectomy was not addressed. Finally, recommendations for women older than 74 years should be made in the context of a woman’s overall health and life expectancy (22). Because of all of these limitations, there is not a compelling reason to limit routine screening mammograms to women between the ages of 50 to 74 and to extend the screening interval to 2 years.

Mammogram

Asymptomatic women presenting for mammography obtain a screening examination with either film or digital technology. Two views are obtained of each breast. For patients for whom an abnormality was detected on a screening mammogram or who have clinical symptoms such as a palpable lump or thickening, spontaneous and/or bloody nipple discharge, erythema, or nipple changes, a diagnostic examination is performed. Patients with a personal history of breast cancer may also obtain a diagnostic examination. This may include routine images as well as specialized views. For patients younger than 30 years, only ultrasound may be performed. Screening mammograms are typically read in batches with patients receiving their results by mail. Diagnostic examinations are supervised by the radiologist often with immediate recommendations directly given to the patient.

Analysis of the mammogram includes an assessment of breast density, categorized as almost entirely fat, scattered fibroglandular densities, heterogeneously dense, and extremely dense. The density of the breasts is significant, as the latter categories may obscure lesions and decrease the sensitivity of mammography. In addition, density has been associated with an increased risk for breast cancer (23). Although both film and digital technologies have both been found effective in diagnosing breast cancer, research has demonstrated that for women younger than 50 or who have dense breast tissue, detection is higher with digital mammography (21). There has been a continual shift to digital mammography throughout the United States in recent years.

Findings on a mammogram include masses, asymmetries, architectural distortion, and calcifications. Circumscribed masses are more likely benign, whereas masses with margins that are indistinct or spiculated are suspicious. Asymmetries in breast parenchyma are common and are often benign, whereas new or developing asymmetries are concerning. Architectural distortion may be a sign of cancer but can also be a result of benign etiologies such as prior surgery. Calcifications occur in the majority of women’s breasts and are commonly benign. Calcifications suspicious for DCIS with or without an invasive component may be pleomorphic, clustered, and/or linearly or segmentally distributed.

To assist radiologists in the interpretation of mammograms, computer-aided detection systems are commonly used. They incorporate software to search for abnormalities that may indicate the presence of breast cancer. The system highlights the findings on the mammogram, alerting the radiologist who makes the final assessment as to whether the abnormality is of concern.

The Mammography Quality Standards Act requires mammography practice auditing. Important national guidelines for screening mammography are as follows (24): (a) cancer detection rates per 1000: 2 to 10, with 2 to 4 expected for patients screened annually, reflecting incident cancers, and 6 to 10 for first-time screening reflecting prevalent cancers; (b) stage 0 and 1: >50%; (c) minimal cancers including invasive cancers ≤ 1 cm and DCIS: >30%; (d) node positivity: <25%; (e) recall rates (screening mammograms for which additional imaging is requested): <10%; (f) positive predictive value (PPV) based on an abnormal screening examination: 5% to 10%; and (g) PPV when biopsy is recommended: 25% to 40%.

An ultrasound image is created real-time from the reflections of the high-frequency sound waves that are produced and received by the ultrasound transducer. Historically, breast ultrasound was used to differentiate solid from cystic lesions. Fluid will appear black on the image because it contains no reflecting surfaces, whereas solid masses will appear varying shades of gray because of numerous reflecting surfaces. With the technical advances of the last 20 years, ultrasound image resolution has dramatically improved. It is now frequently possible to distinguish malignant from benign solid lesions, and simple from complicated fluid collections. As a result, the role of ultrasound has expanded dramatically. In addition to numerous diagnostic applications, there are also therapeutic and interventional applications. Guidelines for the use of breast ultrasound have been developed by the ACR (25). These include the following:

1.  Evaluation and characterization of palpable masses in the breast and axilla, and other breast related signs and/or symptoms. When a palpable abnormality is detected on the physical breast examination, it is important that the precise location of the abnormality be communicated to both the patient and the radiologist, to ensure that the area of concern is fully evaluated.

2.  Evaluation of abnormalities detected on other imaging studies, such as mammography or MRI. To accurately correlate the findings of different examinations, and to determine the significance, the radiologist must have direct access to all current and previous examinations. When patients change from one imaging center to another, it is essential that they are instructed to bring all their previous examinations and examination reports to the new facility.

3.  The initial imaging evaluation of palpable masses in women younger than 30 years and in lactating and pregnant women. Ultrasound does not utilize ionizing radiation, so there are no adverse effects. Unless there is a suspicious ultrasound finding, mammography may not be performed as these patients usually have very dense breast tissue which requires more radiation to penetrate, radiation in women younger than 30 years is proportionally more carcinogenic, and the yield is very low (26).

4.  Evaluation of problems associated with breast implants, such as implant rupture and infection. Peri-implant fluid collections and leakage of silicone are easily recognized with ultrasound. If infection is suspected, fluid can be aspirated and submitted for Gram stain and culture.

5.  Evaluation of the axilla for adenopathy in patients with suspected or newly diagnosed breast cancer.

6.  Guidance for breast biopsies and other interventional procedures such as cyst aspirations, fluid and abscess drainages, and planning for MammoSite eligibility (27).

The role of breast ultrasound in screening for breast cancer is controversial. The American College of Radiology Imaging Network (ACRIN) is a national cancer research organization sponsored and funded by the National Cancer Institute. ACRIN 6666 was a screening study of breast ultrasound and mammography in women at high risk for breast cancer (28). From April 2004 to February 2006, 2809 women, with at least moderately dense breast tissue (≥50% glandular tissuein ≥1 quadrant), were recruited from 21 sites to undergo mammographic and physician-performed ultrasonographic examinations. The results, published in 2008, demonstrated that a single screening ultrasound examination yielded an additional 1.1 to 7.2 cancers per 1000 high-risk women. However, the number of false positives was substantially increased (29). In response, the ACR and the Society of Breast Imaging issued the following joint statement: “ACRIN 6666 established standardized technique and interpretive criteria as well as experience requirements for physicians performing these examinations. At centers which follow similar practice, ultrasound may improve detection of early breast cancer in women at increased risk of breast cancer who are not currently recommended for MRI. These results do not justify the recommendation for screening ultrasound for the general public or in lieu of or in addition to MRI for very high-risk women” (30).

Anticipating a need for screening bilateral whole breast ultrasound has prompted manufacturers to develop automated breast ultrasound systems. Three Food and Drug Administration (FDA)-approved products are commercially available, two of which are fully automated whereas the third requires a technologist to acquire the images. Numerous images are rapidly acquired and can then be reviewed on dedicated workstations, some with 3D reconstruction capability. By automating image acquisition, operator dependence and variability can be minimized. Several studies are currently underway evaluating these systems.

Ultrasound is convenient, is widely available, is relatively inexpensive, and does not require compression or intravenous contrast. Some patients believe it to be an attractive alternative to mammography. However, it must be stressed that ultrasound is not a substitute for mammography. Handheld ultra-sound is very operator dependent, does not reliably detect microcalcifications in the absence of a mass, and has a limited field of view. When used appropriately with optimal technique, breast ultrasound is a powerful adjunctive tool in the detection and treatment of breast abnormalities.

 BREAST MRI

Among all breast imaging modalities, MRI has the highest sensitivity for the detection of invasive breast carcinoma, with sensitivity of 89% to 100% (31,32). The detection rate for DCIS varies in different trials from 43% to nearly 100% (31,33,34). Although mammography is currently the only modality that has been proven in large randomized controlled trials to reduce mortality due to breast cancer, it is limited in that 10% of cancers can be mammographically occult. The sensitivity of mammography is especially decreased in patients with dense breasts, with occult malignancies as high as 50%. Because of these limitations and the high sensitivity of MRI, breast MRI has become an important adjunct to standard breast imaging with mammography. However, given its variable specificity, guidelines have been established for the clinical use of breast MRI.

Clinical Indications

1.  High-risk screening. Based on evidence from nonrandomized screening trials and observational studies, the ACS and ACR currently recommend annual screening breast MRI as an adjunct to mammography in patients who are BRCA1 or BRCA2 mutation carriers, an untested first-degree relative of a BRCA carrier, and those with a lifetime risk of 20% to 25% or greater, based on BRCAPRO or other risk assessment models (35,36). Based on expert consensus opinion, annual screening MRI is also recommended in those with radiation to the chest between 10 and 30 years, Li–Fraumeni syndrome and first-degree relatives, and Cowden and Bannayan– Riley–Ruvalcaba syndromes and first-degree relatives (35). In general, when screening MRI is used in high-risk populations, 3% to 17% will require a biopsy based on MRI findings and approximately 20% to 40% of these patients will be diagnosed with cancer (35–38).

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