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Beyond Mammography: New Frontiers in Breast Cancer Screening

      Abstract

      Breast cancer screening remains a subject of intense and, at times, passionate debate. Mammography has long been the mainstay of breast cancer detection and is the only screening test proven to reduce mortality. Although it remains the gold standard of breast cancer screening, there is increasing awareness of subpopulations of women for whom mammography has reduced sensitivity. Mammography also has undergone increased scrutiny for false positives and excessive biopsies, which increase radiation dose, cost, and patient anxiety. In response to these challenges, new technologies for breast cancer screening have been developed, including low-dose mammography, contrast-enhanced mammography, tomosynthesis, automated whole breast ultrasound, molecular imaging, and magnetic resonance imaging. Here we examine some of the current controversies and promising new technologies that may improve detection of breast cancer both in the general population and in high-risk groups, such as women with dense breasts. We propose that optimal breast cancer screening will ultimately require a personalized approach based on metrics of cancer risk with selective application of specific screening technologies best suited to the individual's age, risk, and breast density.

      Keywords

      See Related Editorial p. 465
      It is generally accepted that early detection of breast cancer increases the probability of cure, and mammography has been shown to reduce breast cancer mortality in population-based screening programs.
      • Kuhl C.K.
      • Kuhn W.
      • Schild H.
      Management of women at high risk for breast cancer: new imaging beyond mammography.
      However, mammography has limitations, and some investigators propose that the benefits do not always outweigh the risks. The sensitivity of mammography is highly variable, ranging from 98% in women with fatty breast parenchyma to 36% in women with dense breasts.
      • Kolb T.M.
      • Lichy J.
      • Newhouse J.H.
      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.
      • Mandelson M.T.
      • Oestreicher N.
      • Porter P.L.
      • et al.
      Breast density as a predictor of mammographic detection: comparison of interval-and screen-detected cancers.
      Thus, women who undergo annual mammography may still present with cancers found only on physical examination. False-positive rates in breast cancer screening also are a significant limitation, as high callback rates and unnecessary biopsies increase cost, radiation dose, and patient anxiety. Concern for long-term sequelae of radiation exposure remains, as recent studies suggest that mammography may actually contribute to an increased incidence of breast cancer in certain high-risk populations.
      • Pijpe A.
      • Andrieu N.
      • Easton D.F.
      • et al.
      Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK).
      These concerns understandably may decrease compliance with screening recommendations.
      • Aro A.R.
      • de Koning H.J.
      • Absetz P.
      • Schreck M.
      Two distinct groups of non-attenders in an organized mammography screening program.
      • Mammography is the only screening test that reduces breast cancer mortality.
      • Mammography has decreased sensitivity in women with dense breasts.
      • New technologies for breast cancer screening include low-dose mammography, contrast-enhanced mammography, tomosynthesis, automated whole breast ultrasound, and magnetic resonance imaging.
      • Optimal breast cancer screening will require a personalized approach, with selective application of screening technologies best suited to the individual's age, risk, and breast density.
      More successful breast cancer screening requires increased sensitivity and specificity, ideally, limiting both financial cost and radiation burden. Some of this may be obtained through new technological development. However, we propose that optimal patient care will ultimately require a new paradigm, with adoption of patient-specific screening strategies tailored to risk assessment based on family history, age, genetic profiles, and breast density. The goal in this approach is development of personalized imaging algorithms that maximize specificity and sensitivity while minimizing cost and radiation exposure. In this article we discuss both current practices and imaging techniques that may be combined in novel ways to achieve optimal, personalized imaging strategies for detecting breast cancer.

      Screening Mammography Recommendations

      Controversies surrounding mammography and breast cancer screening have led to uncertainty about optimal screening strategies. In 2009, the United States Preventive Services Task Force (USPSTF), a panel of health care professionals that reviews published research and makes recommendations about preventive health care, issued revised mammography guidelines. These included the recommendation for screening mammograms every 2 years beginning at age 50 years for women at average risk of breast cancer. They recommended against routine screening mammograms before age 50 years. This recommendation ignited an ongoing, often passionate debate about optimal screening strategies.
      At present, the USPSTF is the only group or consensus panel in the US that recommends screening to begin at age 50 years (Table 1). Most such groups recommend breast cancer screening to begin at age 40 years, and women with a first-degree relative diagnosed with breast cancer should begin annual mammography 10 years before the age of diagnosis of that relative.
      • Dershaw D.D.
      Mammographic screening of the high-risk woman.
      Table 1Screening Mammography Guidelines from Major Consensus Groups and Organizations in the United States
      Begin Screening Age (Years)Interval (Years)
      American Cancer Society401
      National Cancer Institute401 to 2
      American Medical Association40 (discussion)
      Recommends that the patient have a discussion with their medical provider about the risks and benefits prior to undergoing mammography at age 40.
      1 to 2
      American College of Surgeons401
      American College of Physicians40 (discussion)
      Recommends that the patient have a discussion with their medical provider about the risks and benefits prior to undergoing mammography at age 40.
      1 to 2
      American College of Radiology401
      American College of Obstetrics and Gynecology401
      United States Preventive Services Task Force502
      low asterisk Recommends that the patient have a discussion with their medical provider about the risks and benefits prior to undergoing mammography at age 40.

      Limitations of Mammography and the Need for an Adjunctive Screening Tool

      There is clear evidence that mammography detects early breast cancers and that screening large populations reduces mortality. However, mammography is an imperfect screening tool. The sensitivity of mammography is inversely proportional to breast density.
      • Carney P.A.
      • Miglioretti D.L.
      • Yankaskas B.C.
      • et al.
      Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography.
      Among women with heterogeneously dense or extremely dense breast parenchyma, full-field digital mammography (FFDM) has been shown to be more sensitive than film-screen mammography.
      • Nelson H.D.
      • Tyne K.
      • Naik A.
      • et al.
      Screening for breast cancer: an update for the U.S. Preventive Services Task Force.
      Unfortunately, the sensitivity of both digital and analog mammography remains low in women with dense breast parenchyma,
      • Kolb T.M.
      • Lichy J.
      • Newhouse J.H.
      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.
      • Mandelson M.T.
      • Oestreicher N.
      • Porter P.L.
      • et al.
      Breast density as a predictor of mammographic detection: comparison of interval-and screen-detected cancers.
      limiting its usefulness in high-risk younger women.

      Radiation Risks and Low-dose Mammography

      While the absorbed radiation dose received by the breast during mammography represents a relatively small component of the lifetime-accumulated dose from medical imaging and other sources, the popular press and medical literature frequently raise concerns about the radiation risks from mammography. According to the National Research Council of the National Academies Biologic Effects of Ionizing Radiation (BEIR) VII study; the average mean glandular dose (MGD) from digital mammography is 3.7 mGy. This is estimated to have a lifetime attributable risk of fatal breast cancer of 1.3 per 100,000 women aged 40 years at exposure and <1 case per 1,000,000 women aged 80 years at exposure.
      Board on Radiation Effects Research, Division on Earth and Life Sciences, National Research Council of the National Academies
      It also has been estimated that for the same cohort, 292 lives would be saved as a result of annual screening.
      • Feig S.A.
      • Hendrick R.E.
      Radiation risk from screening mammography of women aged 40-49 years.
      While this favorable risk-benefit ratio seems clear, many women and physicians remain concerned.
      Strategies are being investigated to lower radiation dose and alleviate patient fears without compromising cancer detection. Spectral imaging or photon counting is a promising new technology in digital mammography aimed at lowering the MGD to the breast. The image is acquired by a scanning method that utilizes a multislit collimator, eliminating 97% of scattered radiation, significantly lowering the absorbed dose.
      • Aslund M.
      • Cederstrom B.
      • Lundqvist M.
      • Danielsson M.
      Scatter rejection in multislit digital mammography.
      The direct capture of individual X-ray studies occurs without the analog-to-digital conversion steps, increasing efficiency. Recently, the US Food and Drug Administration (FDA) approved a low-dose photon-counting mammography unit in the US, which delivers approximately half the dose of standard FFDM.
      • Baldelli P.
      • McCullagh J.
      • Phelan N.
      • Flanagan F.
      Comprehensive dose survey of breast screening in Ireland.
      This device is popular in Europe, and the image quality has been judged acceptable in preliminary investigations.
      • Cole E.B.
      • Toledano A.Y.
      • Lundqvist M.
      • Pisano E.D.
      Comparison of radiologist performance with photon-counting full-field digital mammography to conventional full-field digital mammography.

      Contrast-enhanced Mammography

      A major advantage of MRI in detection of breast cancer is its ability to detect and evaluate blood flow in breast masses. Recent studies have shown that contrast-enhanced digital mammography also can image blood flow using temporal subtraction and dual-energy subtraction.
      • Lewin J.M.
      • Isaacs P.K.
      • Vance V.
      • Larke F.J.
      Dual-energy contrast-enhanced digital subtraction mammography: feasibility.
      • Dromain C.
      • Balleyguier C.
      • Muller S.
      • et al.
      Evaluation of tumor angiogenesis of breast carcinoma using contrast-enhanced digital mammography.
      • Jong R.A.
      • Yaffe M.J.
      • Skarpathiotakis M.
      • et al.
      Contrast-enhanced digital mammography: initial clinical experience.
      This technique requires injection of an iodinated contrast agent, and the sensitivity for tumor detection has ranged from 78%-92%.
      • Lewin J.M.
      • Isaacs P.K.
      • Vance V.
      • Larke F.J.
      Dual-energy contrast-enhanced digital subtraction mammography: feasibility.
      • Dromain C.
      • Balleyguier C.
      • Muller S.
      • et al.
      Evaluation of tumor angiogenesis of breast carcinoma using contrast-enhanced digital mammography.
      • Jong R.A.
      • Yaffe M.J.
      • Skarpathiotakis M.
      • et al.
      Contrast-enhanced digital mammography: initial clinical experience.
      • Dromain C.
      • Thibault F.
      • Diekmann F.
      • et al.
      Dual-energy contrast-enhanced digital mammography: initial clinical results of a multireader, multicase study.
      Recent literature has demonstrated that the addition of contrast-enhanced mammography to standard mammography and ultrasound in a diagnostic setting improves reader sensitivity from 71% to 78% and improved reader performance when compared with mammography and ultrasound alone.
      • Dromain C.
      • Thibault F.
      • Diekmann F.
      • et al.
      Dual-energy contrast-enhanced digital mammography: initial clinical results of a multireader, multicase study.
      In 2011, the FDA approved contrast-enhanced digital mammography in the US as an adjunct to standard mammographic views (Figure 1). This technology is currently under evaluation at several mammography centers in Europe and Japan.
      Figure thumbnail gr1
      Figure 1Images of a 49-year-old female patient with palpable mass, left breast. (A) Craniocaudal (CC) and (B) mediolateral oblique (MLO) low-energy mammographic views demonstrate a focal asymmetry in the left central breast (arrows) with adjacent biopsy clip. Contrast-enhanced mammography in the CC (C) and MLO (D) projections demonstrate multiple enhancing masses in the left lower inner quadrant extending to the nipple (arrows). Ultrasound-guided core biopsy confirmed the presence of multifocal invasive mammary carcinoma with lobular features.
      Images courtesy of Maxine S. Jochelson, MD, Director of Radiology Breast and Imaging Center, Memorial Sloan Kettering Cancer Center and Associate Professor of Radiology, Weill Medical College of Cornell University.

      Digital Breast Tomosynthesis

      Overlapping breast tissue in standard mammography can conceal important features of malignancy and is a frequent cause of false-positive findings. Digital breast tomosynthesis is an imaging technique designed to eliminate the pitfalls of overlapping tissue (Figure 2). It has the potential to lower recall rates on screening mammography and reduce false-negative examinations due to dense breast tissue. Tomosynthesis produces tomographic “slices” of an entire tissue volume, similar to a computed tomography (CT) scan, using a single acquisition. The radiation exposure for tomosynthesis remains a potential limitation as the MGD varies from approximately 1.5-4 mGy per acquisition.
      • Dobbins 3rd, J.T.
      Tomosynthesis imaging: at a translational crossroads.
      • Dobbins 3rd, J.T.
      • Godfrey D.J.
      Digital x-ray tomosynthesis: current state of the art and clinical potential.
      • Poplack S.P.
      • Tosteson T.D.
      • Kogel C.A.
      • Nagy H.M.
      Digital breast tomosynthesis: initial experience in 98 women with abnormal digital screening mammography.
      The entire radiation dose for the examination depends on whether the examination is a 1-view or 2-view technique and whether or not it is combined with a standard mammogram. Although there are conflicting reports, the “average breast” that undergoes tomosynthesis is reported to receive an MGD approximately 8% higher than standard digital mammography.
      • Feng S.S.
      • Sechopoulos I.
      Clinical digital breast tomosynthesis system: dosimetric characterization.
      Figure thumbnail gr2
      Figure 2Images of a 35-year-old female patient with a palpable mass above the left nipple. (A) CC and (B) MLO mammographic views show heterogeneously dense breasts and subtle architectural distortion in the left upper outer quadrant (arrows). Tomographic slices in the CC (C) and MLO (D) projections demonstrate a 1.6-cm spiculated mass in the left upper outer quadrant (arrows). Subsequent mastectomy showed grade III invasive ductal carcinoma (IDC).
      Images reprinted with permission. Courtesy of Linda R.N. Greer, MD, Medical Director and Radiologist, Breast Health & Research Center, John C. Lincoln, Health Network in Phoenix, Ariz.
      A potential limitation of tomosynthesis is decreased sensitivity for detection of microcalcifications. Tomosynthesis is currently FDA approved as an adjunct to standard mammography, and does not replace it. There is promise that, in this adjunct capacity, tomosynthesis can increase the specificity of mammography.

      Automated Breast Density

      A number of studies have demonstrated that women with dense breast tissue have a 4- to 6-fold increased risk of breast cancer.
      • Harvey J.A.
      • Bovbjerg V.E.
      Quantitative assessment of mammographic breast density: relationship with breast cancer risk.
      • McCormack V.A.
      • dos Santos Silva I.
      Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis.
      • Boyd N.F.
      • Guo H.
      • Martin L.J.
      • et al.
      Mammographic density and the risk and detection of breast cancer.
      Increased breast density also decreases the sensitivity of the mammogram and may limit the potential for early detection.
      • van Gils C.H.
      • Otten J.D.
      • Verbeek A.L.
      • Hendriks J.H.
      Mammographic breast density and risk of breast cancer: masking bias or causality?.
      • Whitehead J.
      • Carlile T.
      • Kopecky K.J.
      • et al.
      Wolfe mammographic parenchymal patterns A study of the masking hypothesis of Egan and Mosteller.
      • Sala E.
      • Warren R.
      • McCann J.
      • et al.
      Mammographic parenchymal patterns and mode of detection: implications for the breast screening programme.
      The American College of Radiology Breast Imaging Reporting and Data System classification describes 4 categories of breast tissue density and instructs radiologists to include this density information in the medical report. At the present time, this classification is a primarily subjective estimate of quartiles from almost entirely fat to extremely dense. There is marked interobserver variability among radiologists,
      • Berg W.A.
      • Campassi C.
      • Langenberg P.
      • Sexton M.J.
      Breast Imaging Reporting and Data System: inter- and intraobserver variability in feature analysis and final assessment.
      • Ooms E.A.
      • Zonderland H.M.
      • Eijkemans M.J.
      • et al.
      Mammography: interobserver variability in breast density assessment.
      raising concern for integrating this information into clinical use.
      Automated, objective, volumetric density measurements may have the potential to provide reproducible risk metrics that can be integrated into personalized breast cancer risk assessments.
      • Heine J.J.
      • Fowler E.E.
      • Flowers C.I.
      Full field digital mammography and breast density: comparison of calibrated and noncalibrated measurements.
      There are several commercially available software solutions that can be incorporated seamlessly into the mammography work flow and “automate” the calculation of breast density through an algorithm that utilizes volumetric parameters. If automated breast density measurements are determined to be accurate and reproducible, baseline and serial breast cancer risk estimates could potentially be used to advise individual patients on optimal frequency and type of screening studies.

      Breast Density Legislation

      There has been significant legislative activity surrounding the issue of breast density and the limited sensitivity of mammography screening in women with dense breasts. In 2009, Connecticut passed a law requiring radiologists to inform women of their breast density in the plain language report they receive after their mammogram, and advise them of alternate screening options (ie, screening breast ultrasound and MRI).
      Texas, Virginia, New York, and Utah subsequently passed similar laws requiring radiologists to notify patients of their breast density. At the time of this writing, there is legislation pending on this issue in at least 11 more states, and a similar bill has been introduced in the US House of Representatives. This legislation will put important knowledge in the hands of the patient about their breast density, and open the door for conversations between women and their physicians regarding additional screening options.

      Automated Whole-Breast Ultrasound System (AWBUS)

      Sonography is widely available, inexpensive, requires no contrast injection, does not use ionizing radiation, and is well tolerated by patients. However, scanning with hand-held transducers has provided little practical benefit in the detection of cancers due to the poor conspicuity of some cancers and the significant operator time and experience necessary for a high-quality screening breast ultrasound. The variability in technologist skill and experience has made standardization of examinations nearly impossible.
      However, hand-held screening breast ultrasound in high-risk women has been shown to detect more cancers than mammography alone. Unfortunately, it also resulted in more recalled examinations, biopsies, and recommendations for short-interval follow-up than mammography alone. The rate of biopsy following screening ultrasound in the American College of Radiology Imaging Network (ACRIN) 6666 trial was 5%, with a positive predictive value of 11%. Furthermore, generalization of these results is limited because all study participants were at elevated risk, with over half having a personal history of breast cancer.
      • Berg W.A.
      • Zhang Z.
      • Lehrer D.
      • et al.
      Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk.
      Two-dimensional AWBUS is a promising technology that aims to standardize the screening examination and produce a consistently high-quality examination to improve the conspicuity of cancers. Typically, the study is performed with robotic guidance of a standard ultrasound probe over the entirety of both breasts followed by cine presentation of closely spaced images in the axial plane (Figure 3A) or reconstruction of the images to present a series of images in the coronal plane (Figure 3B).
      • Kelly K.M.
      • Richwald G.A.
      Automated whole-breast ultrasound: advancing the performance of breast cancer screening.
      AWBUS as an adjunct to mammography has shown similar malignancy detection rates as those with hand-held ultrasound, 3.6 per 1000, with a higher positive predictive value of 38%.
      • Kelly K.M.
      • Dean J.
      • Comulada W.S.
      • Lee S.J.
      Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts.
      Figure thumbnail gr3
      Figure 3Images of a 55-year-old female patient with dense breast parenchyma and normal screening mammogram who underwent automated whole breast screening ultrasound. (A) Axial sonographic image from the right breast at 12 o'clock shows a 10-mm irregular hypoechoic mass (arrow) with angular margins and posterior acoustic shadowing. (B) Coronal reformatted image from a screening automated whole-breast ultrasound system demonstrates a 10-mm hypoechoic mass at 12 o'clock in the right breast (arrow). Ultrasound-guided core biopsy showed IDC.
      Images courtesy of U-Systems, Inc. Sunnyvale, Calif.

      High-risk Screening and Magnetic Resonance Imaging

      Women at high risk for breast cancer may benefit from supplemental screening with MRI, and it is recommended as an adjunct to mammography in selected high-risk patients (Figure 4).
      • Saslow D.
      • Boetes C.
      • Burke W.
      • et al.
      American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
      There are several risk prediction models available for clinical use; such as the Gail model,
      • Gail M.H.
      • Brinton L.A.
      • Byar D.P.
      • et al.
      Projecting individualized probabilities of developing breast cancer for white females who are being examined annually.
      Claus model,
      • Claus E.B.
      • Risch N.
      • Thompson W.D.
      Autosomal dominant inheritance of early-onset breast cancer Implications for risk prediction.
      BRCAPRO,
      • Berry D.A.
      • Iversen Jr, E.S.
      • Gudbjartsson D.F.
      • et al.
      BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
      and Tyrer-Cuzick
      • Tyrer J.
      • Duffy S.W.
      • Cuzick J.
      A breast cancer prediction model incorporating familial and personal risk factors.
      models. An online risk-assessment tool utilizing the Gail model is available on the American Cancer Society website: http://www.cancer.gov/bcrisktool/about-tool.aspx, accessed on November 4, 2012.
      Figure thumbnail gr4
      Figure 4Images of a 33-year-old female patient with known BRCA 2 mutation. (A) CC and (B) MLO mammographic views of the left breast demonstrate heterogeneously dense breast parenchyma and no identifiable masses, calcifications, or other abnormality. (C) Axial contrast-enhanced MRI subtraction sequences with kinetic overlay (D) demonstrate a 1.5-cm rapidly enhancing irregular mass (arrow) with irregular margins and adjacent clumped ductal enhancement measuring up to 8.0 cm in greatest dimension. Ultrasound-guided biopsy and subsequent mastectomy showed multi-centric grade III IDC with high-grade ductal carcinoma in situ (DCIS).
      MRI has superior sensitivity to mammography and ultrasound in the detection of invasive cancer and has been shown to be cost effective in some high-risk groups.
      • Taneja C.
      • Edelsberg J.
      • Weycker D.
      • et al.
      Cost effectiveness of breast cancer screening with contrast-enhanced MRI in high-risk women.
      • Plevritis S.K.
      • Kurian A.W.
      • Sigal B.M.
      • et al.
      Cost-effectiveness of screening BRCA1/2 mutation carriers with breast magnetic resonance imaging.
      • Kriege M.
      • Brekelmans C.T.
      • Boetes C.
      • et al.
      Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition.
      Recent data report an additional 14.7 cancers per 1000 women detected when MRI is used as a supplement to mammography and whole-breast ultrasound.
      • Berg W.A.
      • Zhang Z.
      • Lehrer D.
      • et al.
      Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk.
      However, there are no data to show a reduction in mortality from breast cancer as a result of MRI screening, and it is often criticized for decreased specificity, prompting biopsy or follow-up imaging.
      The American Cancer Society guidelines (Table 2) for MRI as an adjunct to annual screening mammography recommend MRI for women who are first-degree relatives of BRCA carriers but have not undergone BRCA testing themselves, and women with a lifetime risk that is 20%-25% or greater than that of the average woman, as defined by risk-prediction models.
      • Saslow D.
      • Boetes C.
      • Burke W.
      • et al.
      American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
      Some centers offer mammography and breast MRI at the same time, while others advocate staggering these examinations by 6 months, optimizing the time interval between imaging the breasts in one modality or another.
      Table 2American Cancer Society Recommendations for Annual Supplemental MRI Screening
      High risk women for whom annual MRI is recommended
      BRCA1 or BRCA2 gene mutations
       First-degree relative with BRCA1 or BRCA2 mutation who have not been tested
       Lifetime risk of breast cancer of 20%-25%
       History of radiation therapy to the chest between the ages of 10 and 30 years
       Li-Fraumeni, Cowden, or Bannayan-Riley-Ruvalcaba syndrome
      Women at moderately increased risk who should talk to their doctors about the benefits and limitations of MRI screening as an adjunct to mammography
       Lifetime risk of breast cancer of 15%-20%
       Personal history of breast cancer ductal carcinoma in situ
       History of lobular carcinoma in situ, atypical ductal hyperplasia, or atypical lobular hyperplasia at biopsy
       Extremely dense or unevenly dense breasts
      MRI=magnetic resonance imaging.

      Molecular Imaging

      Positron emission mammography (PEM) and breast-specific gamma imaging (BSGI) use molecular imaging to increase specificity in cancer detection by demonstrating increased metabolic activity. Both of these techniques have high positive predictive values and low negative predictive values. BSGI uses a gamma radiation detector under the breast with mild compression to acquire images after intravenous administration of technetium 99m (99mTc) sestamibi (Figure 5). PEM uses paired radiation detectors to detect coincident gamma rays after the intravenous administration of fluorine 18 fluorodeoxyglucose (FDG). These modalities are not currently suitable for screening, because each study results in whole-body radiation equivalent to 20-30 mammograms.
      • Hendrick R.E.
      Radiation doses and cancer risks from breast imaging studies.
      Their application is primarily in staging women with a diagnosis of cancer. Increasingly, however, FDG positron emission tomography (PET) is used to evaluate response to therapy, or detect post-treatment recurrence.
      Figure thumbnail gr5
      Figure 5Images of a 78-year-old female patient with history of right lumpectomy and radiation therapy for invasive lobular carcinoma 4 years prior presents with increasing heaviness to the right breast after recent trauma. (A) CC and (B) MLO mammographic views of the right breast demonstrate postlumpectomy changes with stable skin thickening, unchanged since the prior study. BSGI in the CC (C) and (D) MLO views demonstrate multiple areas of increased radiotracer uptake (presented as white on black) consistent with multifocal metabolically active disease. Subsequent mastectomy confirmed multi-centric invasive lobular carcinoma.
      Images courtesy of Michael Portillo, MD, Susan Cheek Needler Breast Centers, Morton Plant Mease Healthcare, Clearwater, Fla.

      Personalized Screening Strategies

      Current screening strategies are clearly limited by the intrapopulation heterogeneity of breast cancer appearance, normal breast densities, and individual risk factors. Additional concerns include the financial cost of screening, the potential hazards of radiation exposure, and the medical, psychological, and financial burden of both false-positive and false-negative studies. We propose that new technologies in both imaging and risk assessment require re-thinking of the typical screening paradigm in which a single strategy is applied to all individuals in a population.
      In other words, it seems clear that optimal breast cancer screening must be increasingly tailored to an individual's risk and optimized through strategic, patient-specific application of available technology. Advances in breast imaging modalities, breast cancer risk assessment, breast density, and a patient's own views about the risks and benefits of screening should be carefully integrated into a personalized screening strategy. This paradigm differs from traditional guidelines in which all women are screened similarly with either annual or biennial mammograms, beginning at the age of 40 or 50 years.
      Risk-stratification tools are improving as our knowledge of the pathogenesis of breast cancer deepens. Commercially available risk-stratification kits combine traditional risk models, such as the Gail Model, with DNA analysis; evaluating genetic mutations associated with breast cancer, separate from BRCA1 and BRCA2 mutations. This type of technology may aid in the evolution of personalized screening strategies as women obtain a more accurate estimate of their individual risk through risk assessment tools, genetic testing, and clinical characteristics such as breast density.
      These risk assessment tools along with the patient's age, breast density, and personal preferences could then be integrated to develop an optimal screening program. For example, a 52-year-old woman with heterogeneously dense breasts, highly concerned about radiation dose, may benefit from annual low-dose mammography and automated whole-breast ultrasound. A 65-year-old woman with dense breasts concerned about false positives and excessive biopsies may prefer annual mammography combined with tomosynthesis. A 43-year-old woman with heterogeneously dense breasts who has undergone DNA risk stratification and been found to be “high risk,” may choose annual mammography and tomosynthesis alternating with breast MRI every 6 months.
      Personalized screening strategies are not an entirely novel concept. Women with BRCA1 or BRCA2 mutations already participate in a form of personalized screening, with many women opting for annual mammography and breast MRI, often alternating at 6-month intervals. As technology further evolves and we are able to more accurately identify high-risk women, we will likely see evolution of personalized approaches to breast cancer screening, ranging from highly intricate to annual or perhaps biennial screening in low-risk groups.

      Conclusion

      For many years, mammography has been the sole imaging test recommended for breast cancer screening, and remains the only test proven to reduce breast cancer-related mortality.
      • Kuhl C.K.
      • Kuhn W.
      • Schild H.
      Management of women at high risk for breast cancer: new imaging beyond mammography.
      However, the widespread application of mammography in population-based screening remains controversial, owing to decreased sensitivity in women with dense breast parenchyma, radiation concerns, and a high rate of false-positive studies.
      Breast imagers are adapting to these challenges with the development of new technologies. Low-dose mammography can reduce radiation risk to the breast. Contrast-enhanced mammography can evaluate blood flow in the breast, similar to MRI. Tomosynthesis produces multiple mammographic slices through the breast, similar to CT, and has significant potential to lower recall rates and increase specificity.
      Both whole-breast ultrasound and MRI have been shown to detect additional cancers in certain high-risk populations and will likely be increasingly used in screening women with dense breasts. However, a decrease in mortality has not been proven.
      • Berg W.A.
      • Zhang Z.
      • Lehrer D.
      • et al.
      Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk.
      Molecular imaging in the form of BSGI and PEM of the breast is widely available, although due to relatively large whole-body radiation doses, not currently suitable for annual screening.
      While these advances are encouraging, it is improbable that any of the new technologies will replace mammography for population-based screening programs, because all have significant limitations (Table 3). Furthermore, given the heterogeneity of the human population, a “perfect” imaging technology for breast cancer screening will likely never be found. In fact, because of this heterogeneity, the very concept of “one strategy fits all” population-based screening may be outmoded. The increasing ability to perform molecular, clinical, and tissue-based risk assessments for an individual patient has opened new opportunities for patient-based screening strategies. Ultimately, optimal breast cancer screening will likely require a personalized approach that integrates patient-specific and age-dependent metrics of cancer risk with selective application of specific screening technologies best suited to the individual's age, risk, and breast density.
      Table 3Strengths and Limitations of Breast Imaging Modalities
      ModalityStrengthsLimitationsScreening
      Spectral or photon counting low-dose mammographyApproximate 40% ↓ in doseLimited literatureYes
      CE mammographyOutlines vascularity in the breastLimited data in screening contrast injectionAdjunct
      Tomosynthesis↑Specificity↑RadiationAdjunct
      AWBUS↑Sensitivity↓SpecificityAdjunct
      ↑False positives
      MRI↑Sensitivity↓SpecificityAdjunct
      ↑False positives
      ↑Cost
      Contrast injection
      BSGI↑Specificity↑RadiationNo
      PEM↑Specificity↑RadiationNo
      AWBUS=automated whole-breast ultrasound system; BSGI=breast-specific gamma imaging; CE=contrast-enhanced; MRI=magnetic resonance imaging; PEM=positron emission mammography.

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