Molecular-Based Imaging

Molecular-based imaging technology uses a physiological approach to identify lesions in the breast and can detect mammographically occult cancers.57,58 Gamma detectors are used to image the breast after injection of a radiotracer, technetium sestamibi, which has preferential uptake in highly proliferating tumor cells, thereby identifying functional differences in tumors from normal breast tissue.58-60 Breast-specific γ imaging uses a dedicated, single-head, scintillating sodium iodide detector. Molecular breast imaging is the latest generation of systems and uses cadmium zinc telluride detectors in a dual-head configuration. Although the technologies differ between these 2 systems, the terms are often interchangeably used.58,59 Compared with breast-specific γ imaging, molecular breast imaging has improved rates of count sensitivity, energy resolution, spatial resolution, and lesion detection. In addition, molecular breast imaging requires fewer amounts of injected radiotracer.58 Positron emission mammography is another nuclear medicine system in practice; however, radiotracer uptake increases with breast density, resulting in background parenchymal activity that could obscure underlying malignancies.61

Rechtman et al57 investigated the sensitivity of breast-specific γ imaging for the detection of breast cancer in women with dense vs nondense breasts in 347 biopsy-proven breast cancers, and they determined that the sensitivity rate was similar in women with dense (94.7%) and nondense breasts (96.5%). In addition, mammographically occult breast cancers were equally detected in both groups. The authors concluded that breast-specific γ imaging detected breast cancer regardless of the pathological subtype, nuclear grade, or tumor size.57

Shermis et al59 retrospectively assessed the clinical performance of molecular breast imaging as a supplementary screening tool for dense breasts in 1,696 women not at high risk and detected 13 mammographically occult malignancies, 11 of which were invasive. The authors reported that the incremental cancer detection rate (7.7%) and positive predictive value for biopsy (19.4%) were higher than that seen with screening ultrasonography.59 They concluded that molecular breast imaging is an acceptable alternative for supplemental screening in women with dense breasts.59 These findings are in line with earlier prospective studies: Data have shown that molecular breast imaging can detect mammographically occult cancers that are primarily invasive and range in size from 2 mm to 5.1 cm.58

Although studies have shown that molecular-based imaging has a high rate of sensitivity for detecting cance in dense breasts, as well as a high positive predictive value, its availability and use as a supplemental imaging tool has been limited secondary to concerns of radiation exposure.58,62 The injected radiotracer delivers radiation throughout the body, including radiosensitive organs beyond the breast. The radiation dose for breast-specific γ imaging has been reported to be more than 5 times that of standard mammography and twice that of standard mammography plus tomosynthesis.62 The radiation dose of molecular-based imaging is 2 to 5 times greater than the dose of mammography, but research has shown promising results using lower doses of radiotracer, which may be more acceptable.58 However, future studies are needed to ensure adequate image quality at this dose.

The total dose of mammography and molecularbased imaging is low (< 10 mSv) compared with the dose associated with adverse-event risk (> 50 mSv), so the benefit may outweigh the risk for some women.58 The only commercially available, FDA-approved biopsy unit is a breast-specific γ imaging system.58 However, biopsy units guided by molecular breast imaging are in development.58,60 Advantages of molecular-based imaging over MRI include its lower cost and fewer contraindications.58,63

Automated Breast Density

Reporting of breast density has implications on the assessment of patient care and risk of breast cancer. However, intraobserver and interobserver variability exist in the visual assessment of the BI-RADS density category selected by the clinician on mammography.1 In response to this challenge, several automated software programs have been developed that measure volumetric breast density. However, quartiles of breast density have been eliminated in the BI-RADS criteria, so the assessment is no longer quantitative and brings into question the utility of quantitative software in the BI-RADS reporting.1 In a retrospective study of 1,185 mammography examinations, Youk et al64 compared the visual assessment of breast density based on the BI-RADS criteria with that of 2 commercially available software programs. They found that more findings on mammography were classified as being nondense with one program and as dense with another program when compared with the findings from the visual assessment.64 By contrast, Ekpo et al65 evaluated one of the programs previously determined to be underestimating. In their study, they compared automated vs visual breast density assessment in 234 women undergoing digital breast tomosynthesis. The authors found a moderate to substantial agreement in breast density assessment between the BI-RADS criteria and the automated software.65 Active research is being conducted to incorporate both automated and visual density assessments into patient risk models, and volumetric breast density measurements may prove to be beneficial in developing algorithms for automated risk assessment.64


Approximately 50% of women have breasts that are at least heterogeneously dense — a figure that amounts to 27.6 million women aged 40 to 75 years in the United States.11 The American College of Radiology identifies breast density as a controversial risk factor for breast cancer with no consensus that it confers sufficient risk to warrant supplemental screening.10 In a position statement from the American Congress of Obstetricians and Gynecologists, dense breasts are identified as a modest risk factor for breast cancer.66 The organization does not recommend routine use of adjunctive studies to screening mammography in asymptomatic women with dense breasts who are without additional risk factors.66

Understanding breast cancer risk conferred by density in the setting of a patient’s history, as well as an appreciation of the imaging tools available, will help aid clinicians in developing the most appropriate screening plan for each of their patients. Mammography remains the most appropriate modality for population-based screening.2,66 One suggested approach for screening women with dense breasts is to use tomosynthesis for all levels of risk, supplemental whole-breast ultrasonography for women with average risk, and supplemental magnetic resonance imaging for women with intermediate and high risk (Figure 6).67 For women who are at high risk and also have a contraindication to magnetic resonance imaging, wholebreast ultrasonography or molecular breast imaging, if available, may be an appropriate alternative. Additional studies are warranted to evaluate optimal supplemental screening strategies, although we suspect that the strategy will likely require a personalized approach based on risk assessment. 

(To view a larger version of Figure 6, click here.)

Shannon Falcon, MD, Angela Williams, MD, R. Jared Weinfurtner, MD, and Jennifer S. Drukteinis, MD 

From the Department of Radiology, H. Lee Mof tt Cancer Center & Research Institute, Tampa, Florida.

Submitted November 29, 2015; accepted February 14, 2016.

Address correspondence to Shannon Falcon, MD, Mof tt Cancer Center, 10920 North McKinley Drive, MKC Third Floor, Room 3002, Tampa, FL 33612. E-mail: Shannon.Falcon@Mof

No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. 

From the Department of Radiology, H. Lee Mof tt Cancer Center & Research Institute, Tampa, Florida.

Submitted November 29, 2015; accepted February 14, 2016.

No significant relationships exist between the authors and the companies/organizations whose products or services may be referenced in this article. 


1. D’Orsi CJ SE, Mendelson EB, Morris EA, et al. ACR BI-RADS Atlas: Breast Imaging Reporting and Data System. 5th ed. Reston, VA: American College of Radiology; 2013.

2. Price ER, Hargreaves J, Lipson JA, et al. The California Breast Density Information Group: a collaborative response to the issues of breast density, breast cancer risk, and breast density notification legislation. Radiology. 2013;269(3):887-892.

3. Checka CM, Chun JE, Schnabel FR, et al. The relationship of mammographic density and age: implications for breast cancer screening. AJR Am J Roentgenol. 2012;198(3):W292-W295.

4. Wolfe JN. Breast patterns as an index of risk for developing breast cancer. AJR Am J Roentgenol. 1976;126(6):1130-1139.

5. McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15(6):1159-1169.

6. Boyd NF, Martin LJ, Yaffe MJ, et al. Mammographic density and breast cancer risk: current understanding and future prospects. Breast Cancer Res. 2011;13(6):223.

7. Sobotka J, Hinrichs C. Breast density legislation: discussion of patient utilization and subsequent direct financial ramifications for insurance providers. J Am Coll Radiol. 2015;12(10):1011-1015.

8. DenseBreast-info website. Legislation and regulations – what is required? Revised February 13, 2017. Accessed February 15, 2017.

9. Yeh VM, Schnur JB, Margolies L, Montgomery GH. Dense breast tissue notification: impact on women’s perceived risk, anxiety, and intentions for future breast cancer screening. J Am Coll Radiol. 2015;12(3):261-266.

10. American College of Radiology. ACR statement on reporting breast density in mammography reports and patient summaries. Published April 24, 2012. Accessed February 1, 2017.

11. Lee CH, Dershaw DD, Kopans D, et al. Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer. J Am Coll Radiol. 2010;7(1):18-27.

12. Smith RA, Duffy SW, Gabe R, et al. The randomized trials of breast cancer screening: what have we learned? Radiol Clin North Am. 2004;42(5):793-806, v.

13. Kerlikowske K. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. J Natl Cancer Inst Monogr. 1997(22):79-86.

14. Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med. 2003;138(3):168-175.

15. Roubidoux MA, Bailey JE, Wray LA, Helvie MA. Invasive cancers detected after breast cancer screening yielded a negative result: relationship of mammographic density to tumor prognostic factors. Radiology. 2004;230(1):42-48.

16. Nelson HD, Tyne K, Naik A, et al. Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151(10):727-737, W237-742.

17. Kolb TM, Lichy J, Newhouse JH. Comparison of the performance of screening mammography, physical examination, and breast US and evaluation of factors that influence them: an analysis of 27,825 patient evaluations. Radiology. 2002;225(1):165-175.

18. Mendelson G, Aronow WS. Underutilization of measurement of serum low-density lipoprotein cholesterol levels and of lipid-lowering therapy in older patients with manifest atherosclerotic disease. J Am Geriatr Soc. 1998;46(9):1128-1131.

19. US Food and Drug Administration. Radiation-emitting products: digital accreditation. Updates January 27, 2017. Accessed February 15, 2017.

20. Helvie MA. Digital mammography imaging: breast tomosynthesis and advanced applications. Radiol Clin North Am. 2010;48(5):917-929.

21. Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA. 2014;311(24):2499-2507.

22. Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology. 2013;267(1):47-56.

23. Ciatto S, Houssami N, Bernardi D, et al. Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study. Lancet Oncol. 2013;14(7):583-589.

24. Rose SL, Tidwell AL, Bujnoch LJ, et al. Implementation of breast tomosynthesis in a routine screening practice: an observational study. AJR. Am J Roentgenol. 2013;200(6):1401-1408.

25. Haas BM, Kalra V, Geisel J, et al. Comparison of tomosynthesis plus digital mammography and digital mammography alone for breast cancer screening. Radiology. 2013;269(3):694-700.

26. Lee CI, Cevik M, Alagoz O, et al. Comparative effectiveness of combined digital mammography and tomosynthesis screening for women with dense breasts. Radiology. 2015;274(3):772-780.

27. Berg WA, Blume JD, Cormack JB, et al. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299(18):2151-2163.

28. Berg WA, 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. JAMA. 2012;307(13):1394-1404.

29. Hooley RJ, Greenberg KL, Stackhouse RM, et al. Screening US in patients with mammographically dense breasts: initial experience with Connecticut Public Act 09-41. Radiology. 2012;265(1):59-69.

30. Weigert J, Steenbergen S. The Connecticut experiment: the role of ultrasound in the screening of women with dense breasts. Breast J. 2012;18(6):517-522.

31. Tagliafico AS, Calabrese M, Mariscotti G, et al. Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial. J Clin Oncol. 2016;34(16):1882-1888.

32. US Food and Drug Administration. Automated breast ultrasound system [premarket approval {PMA}]. cdrh/cfdocs/cfpma/pma.cfm?id=p110006.

33. Brem RF, Tabar L, Duffy SW, et al. Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight Study. Radiology. 2015;274(3):663-673.

34. Kelly KM, Dean J, Comulada WS, et al. Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol. 2010;20(3):734-742.

35. Gold LS, Klein G, Carr L, et al. The emergence of diagnostic imaging technologies in breast cancer: discovery, regulatory approval, reimbursement, and adoption in clinical guidelines. Cancer Imaging. 2012;12:13-24.

36. Heywang-Kobrunner SH, Hacker A, Sedlacek S. Magnetic resonance imaging: the evolution of breast imaging. Breast. 2013;22(suppl 2):S77-S82.

37. DeMartini WB, Liu F, Peacock S, et al. Background parenchymal enhancement on breast MRI: impact on diagnostic performance. AJR Am J Roentgenol. 2012;198(4):W373-W380.

38. Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75-89.

39. Emaus MJ, Bakker MF, Peeters PH, et al. MR imaging as an additional screening modality for the detection of breast cancer in women aged 50-75 years with extremely dense breasts: the DENSE trial study design. Radiology. 2015;277(2):527-537.

40. Lehman CD, Blume JD, Weatherall P, et al. Screening women at high risk for breast cancer with mammography and magnetic resonance imaging. Cancer. 2005;103(9):1898-1905.

41. Kam JK, Naidu P, Rose AK, Mann GB. Five-year analysis of magnetic resonance imaging as a screening tool in women at hereditary risk of breast cancer. J Med Imag Radiat Oncol. 2013;57(4):400-406.

42. Chiarelli AM, Prummel MV, Muradali D, et al. Effectiveness of screening with annual magnetic resonance imaging and mammography: results of the initial screen from the Ontario high risk breast screening program. J Clin Oncol. 2014;32(21):2224-2230.

43. Le-Petross HT, Whitman GJ, Atchley DP, et al. Effectiveness of alternating mammography and magnetic resonance imaging for screening women with deleterious BRCA mutations at high risk of breast cancer. Cancer. 2011;117(17):3900-3907.

44. Sardanelli F, Podo F, Santoro F, et al. Multicenter surveillance of women at high genetic breast cancer risk using mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (the high breast cancer risk italian 1 study): final results. Invest Radiol. 2011;46(2):94-105.

45. Riedl CC, Luft N, Bernhart C, et al. Triple-modality screening trial for familial breast cancer underlines the importance of magnetic resonance imaging and questions the role of mammography and ultrasound regardless of patient mutation status, age, and breast density. J Clin Oncol. 2015;33(10):1128-1135.

46. Warner E, Messersmith H, Causer P, et al. Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer. Ann Intern Med. 2008;148(9):671-679.

47. Raikhlin A, Curpen B, Warner E, et al. Breast MRI as an adjunct to mammography for breast cancer screening in high-risk patients: retrospective review. AJR Am J Roentgenol. 2015;204(4):889-897.

48. Port ER, Park A, Borgen PI, et al. Results of MRI screening for breast cancer in high-risk patients with LCIS and atypical hyperplasia. Ann Surg Oncol. 2007;14(3):1051-1057.

49. Friedlander LC, Roth SO, Gavenonis SC. Results of MR imaging screening for breast cancer in high-risk patients with lobular carcinoma in situ. Radiology. 2011;261(2):421-427.

50. Brennan S, Liberman L, Dershaw DD, et al. Breast MRI screening of women with a personal history of breast cancer. AJR Am J Roentgenol. 2010;195(2):510-516.

51. Saadatmand S, Tilanus-Linthorst MM, Rutgers EJ, et al. Cost-effectiveness of screening women with familial risk for breast cancer with magnetic resonance imaging. J Natl Cancer Inst. 2013;105(17):1314-1321.

52. Kuhl CK, Schrading S, Strobel K, et al. Abbreviated breast magnetic resonance imaging (MRI): first postcontrast subtracted images and maximumintensity projection-a novel approach to breast cancer screening with MRI. J Clin Oncol. 2014;32(22):2304-2310.

53. Harvey SC, Di Carlo PA, Lee B, et al. An abbreviated protocol for high-risk screening breast MRI saves time and resources. J Am Coll Radiol. 2016;13(4):374-380.

54. Grimm LJ, Soo MS, Yoon S, et al. Abbreviated screening protocol for breast MRI: a feasibility study. Acad Radiol. 2015;22(9):1157-1162.

55. Moschetta M, Telegrafo M, Rella L, et al. Abbreviated combined MR protocol: a new faster strategy for characterizing breast lesions. Clin Breast Cancer. 2016;16(3):207-211.

56. Schwartz T, Cyr A, Margenthaler J. Screening breast magnetic resonance imaging in women with atypia or lobular carcinoma in situ. J Surg Res. 2015;193(2):519-522.

57. Rechtman LR, Lenihan MJ, Lieberman JH, et al. Breast-specific gamma imaging for the detection of breast cancer in dense versus nondense breasts. AJR Am J Roentgenol. 2014;202(2):293-298.

58. Hruska CB. Molecular breast imaging for screening in dense breasts: state of the art and future directions. AJR Am J Roentgenol 2017;208(2):275-283.

59. Shermis RB, Wilson KD, Doyle MT, et al. Supplemental breast cancer screening with molecular breast imaging for women with dense breast tissue. AJR Am J Roentgenol. 2016;207(2):450-457.

60. Wang AT, Vachon CM, Brandt KR, et al. Breast density and breast cancer risk: a practical review. Mayo Clin Proc. 2014;89(4):548-557.

61. Koo HR, Moon WK, Chun IK, et al. Background (1)(8)F-FDG uptake in positron emission mammography (PEM): correlation with mammographic density and background parenchymal enhancement in breast MRI. Eur J Radiol. 2013;82(10):1738-1742.

62. Fowler AM. Molecular imaging approaches for supplemental screening in women at increased breast cancer risk. J Nucl Med. 2016;57(5):661-662.

63. Linver MN. Molecular breast imaging: where does it fit in? Presented at ARRS Breast Imaging Symposium; February 4, 2017; San Diego, CA.

64. Youk JH, Gweon HM, Son EJ, Kim JA. Automated volumetric breast density measurements in the era of the BI-RADS fifth edition: a comparison with visual assessment. AJR Am J Roentgenol. 2016;206(5):1056-1062.

65. Ekpo EU, Mello-Thoms C, Rickard M, et al. Breast density (BD) assessment with digital breast tomosynthesis (DBT): agreement between Quantra and 5th edition BI-RADS. Breast. 2016;30:185-190.

66. American College of Obstetricians and Gynecologists. Committee opinion no. 625: management of women with dense breasts diagnosed by mammography. Obstet Gynecol. 2015;125(3):750-751.

67. Lee C. Breast density notification. Paper presented at: Society of Breast Imaging/American College of Radiology Breast Imaging Symposium; April 26, 2015; Orlando, FL.

Source: Cancer Control.
Originally published April, 2017.