Contrast Enhanced Mammography Andy Smith, Ph.D. Vice President, Image Research

1. Contrast Enhanced MammographyAndy Smith, Ph.D.Vice President, Image Research

2. Learning Objectives on Contrast Mammo • What it is • How it works • When to use it • Its benefits • Comparison to alternate modalities • Required hardware • Implementation challenges • Reimbursement considerations

3. Terminology Several names mean the same thing: • CEDM is Contrast Enhanced Digital Mammography • CEM is Contrast Enhanced Mammography • CESM is Contrast Enhanced Spectral Mammography • CE2D is Contrast Enhanced 2D Mammography They are all 2D contrast images (at this time) Hologic Proprietary and Confidential

4. Contrast Enhanced Imaging Growing Tumor Cancer cells migrate to other parts of the body Source: Time Magazine, May 1998 Detection of increased formation of blood vessels (angiogenesis) associated with tumor development Hologic Proprietary and Confidential

5. Contrast Enhanced Imaging • Breast MRI – uses Gd contrast agent with MRI • CE2D – uses Iodine contrast agent with mammo • Same basic physiologic principle • Images lesions with higher neovascularity and extracellular leakage of contrast agent • Same basic advantages/disadvantages • High sensitivity for cancer detection • False positives: some benign lesions enhance • Both involve injection • Imaging not affected by breast density

6. CE2D Potential Clinical Applications 1 Lewin et al. Contrast Mammography Reveals Hard-to-Find Cancers. RSNA Press Release. 30th September 2003. 2 Weinstein SP, Localio AR, Conant EF, Rosen M, Thomas KM, Schnall MD. Multimodality screening of high-risk women: a prospective cohort study. J ClinOncol. 2009 Dec 20;27(36):6124-8. doi: 10.1200/JCO.2009.24.4277. Epub 2009 Nov 2. 3 http://www.acr.org/~/media/2a0eb28eb59041e2825179afb72ef624.pdf • Alternative to Breast MRI • Evaluate difficult to interpret mammograms1 • Monitor effectiveness of drug therapy3 • Identify potential undetected malignancies1 • High risk screening (not FDA approved) • Patients contraindicated for MRI2 Hologic Proprietary and Confidential

7. FDA approved CE systems • GE Essential SenoBright • CE2D • Hologic Dimensions I-View • CE2D • CE2D + Tomo Hologic Proprietary and Confidential

8. A Typical CE2D Procedure Hologic Proprietary and Confidential

9. 1. Contrast Agent Administration • Standard non-ionized CT contrast agent • IV injection • 1.5 cc/kg body weight • 3 cc/sec via Power Injector • Saline flush after injection • Need to assess for renal sufficiency • Breast is uncompressed during injection • Wait ~2 minutes post injection before imaging Hologic Proprietary and Confidential

10. 2. Dual Energy 2D Imaging • Two exposures are made in rapid sequence: • Low kV (normal mammogram) • High kV (~45-49 kV, Cu filter) • Subtraction gives a 2D contrast image • Repeat as desired • Imaging window ends after ~6 minutes due to contrast redistribution Hologic Proprietary and Confidential

11. Dual-Energy Subtraction • You cannot see the contrast in high or low kV images • But you can if we subtract the images: Subtraction = high kV - low kV • Only the low kVand subtractionimages are stored Low kV Subtraction High kV Hologic Proprietary and Confidential

12. Ipsilateral Breast Contralateral Breast MLO CC CC MLO H H H H y g r L L L L e n E inject 0 s ~ 120 s ~ 180 s ~ 240 s ~ 300 s ~ 480 s CE2D – Dual Energy 2D Hologic Proprietary and Confidential Low kV, High kV images acquired for each view Views can be any order

13. A Typical CE2D Combo Procedure Hologic Proprietary and Confidential

14. CE2D + Tomosynthesis Acquisition The CE2D images can also be part of a combo acquisition, giving 3-D tomosynthesis information Provides co-registered physiological and morphological data If you can correlate the CE2D lesion to a tomo lesion, can perform tomo biopsy Hologic Proprietary and Confidential

15. 1. Contrast Agent Administration Identical steps as in the CE2D procedure Hologic Proprietary and Confidential

16. 2. Dual Energy 2D Combo Imaging • Three exposures are made in rapid sequence: • Low kV tomosynthesis scan • Low kV (normal mammogram) • High kV (~45-49 kV, Cu filter) • Subtraction gives a 2D contrast image • Repeat as desired • Imaging window ends after ~6 minutes due to contrast redistribution Hologic Proprietary and Confidential

17. Combo CE2D – Dual Energy 2D with Tomosynthesis Tomo, Low kV, High kV images acquired for each view Views can be any order Hologic Proprietary and Confidential

18. Patient Work Flow From Palmieri et al, 2016 ARRS Annual Meeting Hologic Proprietary and Confidential

19. Example Images Courtesy of Andrea Woodroof, Kentucky Breast Care Hologic Proprietary and Confidential

20. Case 1 Hologic Proprietary and Confidential

21. CE2D for Discordant Findings 52 y.o. female, presented for screening 0.8 cm spiculated mass in the left axillary tail noted on both 2D and 3D Focal area of possible distortion noted on 3D Hologic Proprietary and Confidential

22. CE2D for Discordant Findings Hologic Proprietary and Confidential

23. CE2D for Discordant Findings Area of distortion couldn’t definitively be correlated on ultrasound for US biopsy Hologic Proprietary and Confidential

24. CE2D for Discordant Findings Hologic Proprietary and Confidential

25. CE2D for Discordant Findings Area of distortion couldn’t definitively be correlated on ultrasound for US biopsy The enhancing mass on CE2D was correlated with the tomo distortion Tomo-guided biopsy ensued Hologic Proprietary and Confidential

26. CE2D for Discordant Findings Hologic Proprietary and Confidential

27. Case 2 Hologic Proprietary and Confidential

28. CE2D for MRI Contraindications Patients with pacemakers Body habitus Claustrophobia Lack of insurance or deductible cost issues Hologic Proprietary and Confidential

29. CE2D for MRI Contraindications 50 y.o. female with pacemaker and 6-month history of irritation underlying skin of left breast Patient assumed irritation due to the pacemaker, but it didn’t resolve Hologic Proprietary and Confidential

30. CE2D for MRI Contraindications Hologic Proprietary and Confidential

31. CE2D for MRI Contraindications Imaging demonstrated 4 cm spiculated mass US biopsy Pathology: Invasive ductal carcinoma Patient referred to oncology and neoadjuvant chemotherapy Pre and post-treatment MRI not possible; PET declined by insurance CE2D performed Hologic Proprietary and Confidential

32. CE2D for MRI Contraindications Hologic Proprietary and Confidential

33. CE2D for MRI Contraindications Prior to therapy, 3.4 cm mass showed strong enhancement 3 month interval showed decrease of size of mass to 1.7 cm. Hologic Proprietary and Confidential

34. CE2D for MRI Contraindications Hologic Proprietary and Confidential

35. Case 3 Hologic Proprietary and Confidential

36. Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response 49 y.o. female with palpable mass 2D/Tomo imaging revealed spiculated mass Pathology IDC Extent of disease difficult to measure with either 2D or Tomo due to dense parenchymal tissue Hologic Proprietary and Confidential

37. Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Hologic Proprietary and Confidential

38. Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Hologic Proprietary and Confidential Prior to initiation of neoadjuvant chemotherapy, CE2D was performed 1.5 x 1.3 cm enhancing spiculated mass

39. Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Hologic Proprietary and Confidential

40. Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Hologic Proprietary and Confidential Prior to initiation of neoadjuvant chemotherapy, CE2D was performed 1.5 x 1.3 cm enhancing spiculated mass CE2D image after 3 months demonstrates partial response to chemotherapy

41. Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Hologic Proprietary and Confidential

42. Clinical Performance Hologic Proprietary and Confidential

43. Clinical Performance Hologic Proprietary and Confidential

44. Diagnostic Clinical Performance Fallenberg E, Dromain C, Diekmann F, et al. Contrast-enhanced spectral mammography versus MRI: Initial results in the detection of breast cancer and assessment of tumour size, Eur. Radiol. 24 (1) (2013) 256–264. Chou C, Lewin J, Chiang C et al. "Clinical Evaluation of Contrast-Enhanced Digital Mammography and Contrast Enhanced Tomosynthesis-Comparison to Contrast-Enhanced Breast MRI" Eur J Radiol. 2015 Dec; 84(12):2501-8. [Epub 2015 Oct 1]. ochelson M, Dershaw D, Sung J, et al., Bilateral contrast-enhanced dual-energy digital mammography: feasibility and comparison with conventional digital mammography and MR imaging in women with known breast carcinoma, Radiology 266 (3) (2013) 743–751. Lobbes MB, Lalji UC, Nelemans PJ, et al. The quality of tumor size assessment by contrast-enhanced spectral mammography and the benefit of additional breast MRI. J Cancer. 2015;6(2):144-150. Hobbes M, Taylor D, Buzynski S et al. “Contrast-enhanced spectral mammography (CESM) and contrast enhanced MRI (CEMRI): Patient preference and tolerance” J Med Imaging RadiatOncol. 2015 Jun;59(3):300-5. [Epub 2015 Apr 21]. CE2D higher sensitivity than 2D or tomo CE2D and bMRI show comparable performance CE2D and bRMI have comparable accuracy in tumor sizing Patients prefer CE2D over bMRI Hologic Proprietary and Confidential

45. Comparison to MRI • Advantages of CE2D • Lower cost procedure • Faster procedure (7-10 min vs 30-60 min for bMRI) • Fast readings • Good imaging of microcalcifications (low energy image) • Disadvantages of CE2D • Don’t get both breasts at same time • Hard to get time-activity information • Involves radiation, but FFDM usually ordered with bMRI • Iodine contrast agent adverse reactions Hologic Proprietary and Confidential

46. Required Hardware Mainly a software upgrade Also includes additional x-ray filter (copper) May require detector upgrade for older systems Hologic Proprietary and Confidential

47. Implementation Considerations Power injector Who will place the IV line and perform injection? Crash cart Review risk mitigation policies regarding contrast agents Menstruation cycle. Same as MRI. 7-14 days after last period Tube heating. Need to wait ~10 minutes after procedure Hologic Proprietary and Confidential

48. Reimbursement Hologic Proprietary and Confidential

49. Summary • Potential Clinical Applications • Viable alternative to MRI • Evaluating patients contraindicated for MRI • Monitoring effectiveness of drug therapy • Identify potential undetected malignancies Hologic Proprietary and Confidential

50. Thank you!Email:andrew.smith@hologic.com