Contrast Enhanced 2D Mammography This presentation is a description of the theory of contrast enhanced 2D mammographic imaging. Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Agenda Definition of contrast enhanced digital mammography The importance in identifying breast cancer An understanding of the 2D procedure: contrast agent and imaging sequence Sharing of example cases It will include Definition of Contrast enhanced digital 2D mammography The importance of this modality in identifying breast cancer An understanding of the 2D procedure: contrast agent and imaging sequence Sharing of example cases Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

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 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Contrast Enhanced 2D Mammography (CE2D) Detection of increased formation of blood vessels (angiogenesis) associated with tumor development 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 Source: www.thinkstockphotos.com/legal/license-information Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Potential Clinical Applications Alternative to Breast MRI Evaluate difficult to interpret mammograms1 Patients contraindicated for MRI2 Monitor effectiveness of drug therapy3 Identify potential undetected malignancies1 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Regulatory Status Product FDA Clearance CE Mark Hologic CE2D GE SenoBright Currently, commercially available approvals have been obtained by Hologic & GE The FDA approval stated the indications for use: This imaging technique can be used as an adjunct following mammography and/or ultrasound exams to localize a known or suspected lesion. This imaging technique can be used as an adjunct following mammography and/or ultrasound exams to localize a known or suspected lesion Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

1. Contrast Agent Administration Standard non-ionized CT contrast agent IV injection 1.5 cc/kg body weight 3 cc/sec via Power Injector 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

2. Dual Energy 2D Imaging Two exposures are made in rapid sequence: Low kV (normal mammogram) High kV (~45-49 kVp, Cu filter) Subtraction gives a 2D contrast image Repeat as desired Imaging window ends after ~8 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472 10

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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

A Typical CE2D Combo Mode 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D + Combo Mode Procedure The CE2D images can also be part of a combo mode acquisition, giving 2D + 3D™ exam information Provides co-registered physiological and morphological data Compared to the contrast image alone, the co-registered image set may allow improved visibility of the radiographic margins of the lesion If you can correlate the CE2D lesion to a tomo lesion, a 3D™ guided biopsy can be performed 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 & tomo slices. Compared to the contrast image alone, the co-registered image set may allow improved visibility of the radiographic margins of the lesion. If you can correlate the CE2D lesion to a tomo lesion, a tomo guided biopsy can be performed Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

1. Contrast Agent Administration Follow the steps as previously explained for 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

2. Dual Energy 2D Combo Mode Imaging Three exposures are made in rapid sequence: Low kV tomosynthesis scan Low kV (normal mammogram) High kV (~45-49 kVp, Cu filter) Subtraction gives a 2D contrast image Repeat as desired Imaging window ends after ~8 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Combo Mode CE2D: Dual Energy 2D + 3D™ scan 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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Example Images Courtesy of Andrea Woodroof, MD Kentucky Breast Care Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Case 1 CE2D procedure for Discordant Findings 52 year old female, presented for screening 0.8 cm spiculated mass in the left axillary tail noted on both 2D and tomo slice Focal area of possible distortion noted on tomo slice Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for Discordant Findings Using CE2D to resolve discordant findings Left breast – 2 areas found on tomo Screening exam –0.8 cm spiculated mass in left axillary tail noted on both 2D and 3D Focal area of possible distortion noted on 3D Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for Discordant Findings Area of distortion could not definitively be correlated on ultrasound for ultrasound guided biopsy Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for Discordant Findings Couldn’t be definitively correlated on U/S for biopsy Mass enhanced on CE2D and distortion localized with tomo Tomo guided biopsy ensued Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for Discordant Findings Area of distortion could not definitively be correlated on ultrasound for U/S biopsy The enhancing mass on CE2D was correlated with the tomo distortion 3D™ guided biopsy ensued Mass enhanced on CE2D and distortion localized with tomo Tomo guided biopsy ensued Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for Discordant Findings Mass enhanced on CE2D and distortion localized with tomo Tomo guided biopsy ensued Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Case 2 CE2D procedure for MRI Contraindications Patients with pacemakers Body habitus Claustrophobia Lack of insurance or deductible cost issues Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for MRI Contraindications 50 year old female with pacemaker and 6-month history of irritation underlying skin of left breast Patient assumed irritation due to the pacemaker, but the skin irritation did not resolve Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for MRI Contraindications Using CE2D for MRI-contraindicated patients Patient had 2D/3D exam revealing a 4 cm spiculated mass in the left breast U/S guided bioposy: IDC CE2D performed before & after neoadjuvant therapy – Prior to neoadjuvant therapy showed 3.4 x 3.4 mass in LMLO view Following neoadjuvant therapy, CE2D shows an interval decrease in size of mass to 1.7 x 1.7 cm Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for MRI Contraindications Imaging demonstrated 4 cm spiculated mass U/S guided biopsy Pathology: Invasive ductal carcinoma Patient referred to oncology and neoadjuvant chemotherapy Pre and post-treatment MRI not possible PET scan declined by insurance CE2D exam performed U/S guided bioposy: IDC CE2D performed before & after neoadjuvant therapy – Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for MRI Contraindications U/S guided bioposy: IDC CE2D performed before & after neoadjuvant therapy – Prior to neoadjuvant therapy showed 3.4 x 3.4 mass in LMLO view Following neoadjuvant therapy, CE2D shows an interval decrease in size of mass to 1.7 x 1.7 cm Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

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. Prior to neoadjuvant therapy showed 3.4 x 3.4 mass in LMLO view Following neoadjuvant therapy, CE2D shows an interval decrease in size of mass to 1.7 x 1.7 cm Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

CE2D for MRI Contraindications Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Case 3 Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response 49 year old female with palpable mass 2D/3D imaging revealed spiculated mass Pathology: Invasive Ductal Carcinoma Extent of disease difficult to measure with either 2D or tomosynthesis imaging due to dense parenchymal tissue Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response CE2D for measuring extent of disease in very dense breasts and for evaluation of response to therapy 2D/tomo exam for palpable mass revealed spiculated mass in dense tissue U/S biopsy: IDC CE2D imaging prior to and after neoadjuvant therapy demonstrated an interval decrease in the size of the mass Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Prior to initiation of neoadjuvant chemotherapy, CE2D exam was performed 1.5 x 1.3 cm enhancing spiculated mass CE2D for measuring extent of disease in very dense breasts and for evaluation of response to therapy 2D/3D exam for palpable mass revealed spiculated mass in dense tissue U/S biopsy: IDC CE2D imaging prior to and after neoadjuvant therapy demonstrated an interval decrease in the size of the mass Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response Prior to initiation of neoadjuvant chemotherapy, CE2D exam was performed 1.5 x 1.3 cm enhancing spiculated mass CE2D exam after 3 months, demonstrates partial response to chemotherapy CE2D for measuring extent of disease in very dense breasts and for evaluation of response to therapy 2D/3D exam for palpable mass revealed spiculated mass in dense tissue U/S biopsy: IDC CE2D imaging prior to and after neoadjuvant therapy demonstrated an interval decrease in the size of the mass Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Evaluating Extent of Disease in Dense Breasts and Neoadjuvant Chemotherapy Response CE2D for measuring extent of disease in very dense breasts and for evaluation of response to therapy 2D/3D exam for palpable mass revealed spiculated mass in dense tissue U/S biopsy: IDC CE2D imaging prior to and after neoadjuvant therapy demonstrated an interval decrease in the size of the mass Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Future Directions* Contrast-guided biopsy Tomo contrast mammography both 2D (stereo) and 3D™ guided procedures Tomo contrast mammography * Not commercially available Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

Clinical Performance Hologic Proprietary - For Educational Purposes Only - November 2015 - rev004 PRE-00472

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 - For Educational Purposes Only - November 2015 - rev004 PRE-00472