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

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

Hologic Proprietary and Confidential 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) Throughout this presentation, acronyms will be used. As you see, the terminology used to describe contrast enhanced 2D mammography is very similar. CEDM is abbreviated for contrast enhanced digital mammography CEM for contrast enhanced spectral CESM is a term found frequently in GE SenoBright literature for contrast enhanced spectral mammography For this presentation, we will use the term CE2D for contrast enhanced 2D mammography. Hologic Proprietary and Confidential

Contrast Enhanced Imaging Detection of increased formation of blood vessels (angiogenesis) associated with tumor development Growing Tumor The technology is designed to detect increased formation of blood vessels (angiogenesis), associated with tumor development (Detection of increased formation of blood vessel that may be an indication of tumor development) Increased vascularity is generally associated with tumor development. New capillary growth is triggered to provide increased supply of oxygen and food needed by cancers to thrive and grow Cancer cells migrate to other parts of the body Source: Time Magazine, May 1998 Hologic Proprietary and Confidential

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 The technology is designed to detect increased formation of blood vessels (angiogenesis), associated with tumor development (Detection of increased formation of blood vessel that may be an indication of tumor development) Increased vascularity is generally associated with tumor development. New capillary growth is triggered to provide increased supply of oxygen and food needed by cancers to thrive and grow

CE2D Potential Clinical Applications 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 Contrast enhanced Digital Mammography is: Viewed as an alternative to Breast MRI to evaluate difficult to interpret mammograms and it is less expensive than MRI Patients contraindicated for MRI such as due to weight, phobia, pacemakers etc. Monitor effectiveness drug therapy such as: anti-angiogenesis Identify potential undetected malignancies* in women already diagnosed with one cancer. 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 Clin Oncol. 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 Hologic Proprietary and Confidential

FDA approved CE systems GE Essential SenoBright CE2D Hologic Dimensions I-View CE2D + Tomo Contrast enhanced Digital Mammography is: Viewed as an alternative to Breast MRI to evaluate difficult to interpret mammograms and it is less expensive than MRI Patients contraindicated for MRI such as due to weight, phobia, pacemakers etc. Monitor effectiveness drug therapy such as: anti-angiogenesis Identify potential undetected malignancies* in women already diagnosed with one cancer. Hologic Proprietary and Confidential

A Typical CE2D Procedure The following slides cover a typical procedure including contrast administration and an imaging sequence used in Hologic’s clinical trials and in published literature. Hologic Proprietary and Confidential

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 This is an example of a typical contrast injection: Step 1: The imaging procedure requires an injection of a standard non-ionized CT contrast agent. A typical dose is 1.5cc per kg of body weight using a power injector with an IV. Injecting approximately 3 cc per second is injected. during the injection the breast is not compressed the imaging begins after a 2 minute delay after the injection Hologic Proprietary and Confidential

Hologic Proprietary and Confidential 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 Let me explain the 2D imaging sequence performed by Hologic: There are 2 exposures made in rapid sequence The first exposure is a low kVp exposure; the technique is what is used to produce a normal mammogram The second exposure has a higher kVp with copper filtration The next step is to subtract the 2 images thus creating the 2D image with contrast displayed if there is contrast in the extracellular space 8 minutes is the average window for imaging due to the wash out of the injected contrast Hologic Proprietary and Confidential

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 kV and subtraction images are stored High kV Subtraction Low kV In order to view the contrast after injection, 2 exposures are acquired. The subtraction image is created when the low kV image is subtracted from the high kV image. The result is an image displaying the contrast if it is absorbed within a lesion. The Dimensions system will send only the low kV image & the subtraction image to the PACS or archive. Hologic Proprietary and Confidential

Hologic Proprietary and Confidential CE2D – Dual Energy 2D Low kV, High kV images acquired for each view Views can be any order s ~ 120 180 Ipsilateral Breast Contralateral Breast inject 240 300 480 E n e r g y MLO CC L H The sequence of breast and view that are acquired are decided by the hospital’s imaging protocol. Here is an example of a bilateral, two-view contrast study. In this example, the ipsilateral MLO view is acquired first. It consists of the low and high energy imaging pairs previously discussed. The breast is repositioned in the four views shown here, and dual energy pairs are taken at each breast position. Each facility will need to determine their own CEDM protocol. For diagnostic evaluation of an affected breast, the protocol may be to perform all the imaging on the important breast in the early phase. Views may be performed in any order. Hologic Proprietary and Confidential

A Typical CE2D Combo Procedure This is a typical procedure of a 2D contrast exam with the addition of a tomosynthesis scan and is used in Hologic’s clinical trials and is in published literature. Hologic Proprietary and Confidential

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 CE2D can also utilize tomosynthesis. Performing the 2 images (low kV & high kV acquisition) within a combo mode acquisition, produces the tomosynthesis data along side the 2D data. The radiologist has the to evaluate the co-registered physiological & morphological data from both the 2D & 3D images. Compared to the contrast image alone, the co-registered image set may allow improved visibility of the radiographic margins of the lesion. From Andy Hologic Proprietary and Confidential

1. Contrast Agent Administration Identical steps as in the CE2D procedure Follow the steps as previously explained for CE2D procedure. This is an example of a typical contrast injection: Step 1: The imaging procedure requires an injection of a standard non-ionized CT contrast agent. A typical dose is 1.5cc per kg of body weight using a power injector with an IV. Injecting approximately 3 cc per second is injected. during the injection the breast is not compressed the imaging begins after a 2 minute delay after the injection Hologic Proprietary and Confidential

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 Let me explain the Dual energy 2D combo imaging sequence performed by Hologic: there are 3 exposures made in rapid sequence The first exposure is a low kVp exposure; the technique is what is used to produce a normal mammogram The second exposure has a higher kVp with copper filtration The next step is to subtract the 2 images thus creating the 2D image with contrast displayed if there is contrast in the extracellular space ~8 minutes is the average window for imaging due to redistribution of the injected contrast Hologic Proprietary and Confidential

Combo CE2D – Dual Energy 2D with Tomosynthesis Tomo, Low kV, High kV images acquired for each view Views can be any order If the procedure is performed with tomosynthesis acquisition, within the combo mode, the tomosynthesis scan is acquired first (click) and then the 2D images; both the low kV & high kV images. Hologic Proprietary and Confidential

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

Hologic Proprietary and Confidential Example Images Courtesy of Andrea Woodroof, Kentucky Breast Care I will share 4 example cases with you. These studies were provided by the following: John Lewin, MD, Denver, CO Kaohsiung Veterans General Hospital, Taiwan Hologic Proprietary and Confidential

Hologic Proprietary and Confidential Case 1 Hologic Proprietary and Confidential

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

CE2D for Discordant Findings Hologic Proprietary and Confidential

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

CE2D for Discordant Findings Hologic Proprietary and Confidential

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

CE2D for Discordant Findings Hologic Proprietary and Confidential

Hologic Proprietary and Confidential Case 2 Hologic Proprietary and Confidential

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

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

CE2D for MRI Contraindications Hologic Proprietary and Confidential

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

CE2D for MRI Contraindications Hologic Proprietary and Confidential

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

CE2D for MRI Contraindications Hologic Proprietary and Confidential

Hologic Proprietary and Confidential Case 3 Hologic Proprietary and Confidential

Hologic Proprietary and Confidential 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

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

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

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

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

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

Hologic Proprietary and Confidential Clinical Performance Hologic Proprietary and Confidential

Hologic Proprietary and Confidential Clinical Performance Hologic Proprietary and Confidential

Diagnostic Clinical Performance 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 In summary, CE2D Alternative to Breast MRI Evaluate difficult to interpret mammograms Patients contraindicated for MRI Monitor effectiveness of drug therapy Identify potential undetected malignancies* 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 Radiat Oncol. 2015 Jun;59(3):300-5. [Epub 2015 Apr 21]. Hologic Proprietary and Confidential

Hologic Proprietary and Confidential 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 In summary, CE2D Alternative to Breast MRI Evaluate difficult to interpret mammograms Patients contraindicated for MRI Monitor effectiveness of drug therapy Identify potential undetected malignancies* Hologic Proprietary and Confidential

Hologic Proprietary and Confidential Required Hardware Mainly a software upgrade Also includes additional x-ray filter (copper) May require detector upgrade for older systems In summary, CE2D Alternative to Breast MRI Evaluate difficult to interpret mammograms Patients contraindicated for MRI Monitor effectiveness of drug therapy Identify potential undetected malignancies* Hologic Proprietary and Confidential

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 In summary, CE2D Alternative to Breast MRI Evaluate difficult to interpret mammograms Patients contraindicated for MRI Monitor effectiveness of drug therapy Identify potential undetected malignancies* Hologic Proprietary and Confidential

Hologic Proprietary and Confidential Reimbursement In summary, CE2D Alternative to Breast MRI Evaluate difficult to interpret mammograms Patients contraindicated for MRI Monitor effectiveness of drug therapy Identify potential undetected malignancies* Hologic Proprietary and Confidential

Hologic Proprietary and Confidential Summary Potential Clinical Applications Viable alternative to MRI Evaluating patients contraindicated for MRI Monitoring effectiveness of drug therapy Identify potential undetected malignancies In summary, CE2D Alternative to Breast MRI Evaluate difficult to interpret mammograms Patients contraindicated for MRI Monitor effectiveness of drug therapy Identify potential undetected malignancies* Hologic Proprietary and Confidential

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