Hologic Selenia Dimensions C-View Software Module. October 24, 2012

Transcription

1 Hologic Selenia Dimensions C-View Software Module October 24, 2012

2 Introduction and Agenda Peter Soltani, Ph.D. Senior VP & GM, Breast Health Hologic, Inc.

3 Agenda Technology Overview Clinical Overview Clinical Study Design Clinical Study Results Risk/Benefit Summary 3

4 Presenters Peter Soltani, Ph.D. Senior VP & GM, Breast Health Hologic, Inc. Andrew Smith, Ph.D. VP, Advanced Imaging Science Hologic, Inc. Loren Niklason, Ph.D. Director, Tomosynthesis Programs Hologic, Inc. Elizabeth A. Rafferty, M.D. Director, Breast Imaging Avon Comprehensive Breast Center Massachusetts General Hospital 4

5 Hologic and External Experts Jay A. Stein, Ph.D. Chief Technology Officer Hologic, Inc. Zhenxue Jing, Ph.D. Senior Vice President & Chief Science Officer Hologic, Inc. Arthur Friedman Senior Vice President, RA, QA, Clinical Hologic, Inc. Elkan Halpern, Ph.D. Director of Statistics, Institute of Technology Assessment Statistical Consultant, Radiology, RSNA 5

6 Technology Overview Andrew Smith, Ph.D. Vice President, Imaging Science Hologic, Inc.

7 Nomenclature Shorthand 2D FFDM 3D 2D plus 3D, Combo C-View, Synthesized 2D 3Ds, 3D plus C-View Definition Conventional digital mammography Tomosynthesis 2D digital mammogram and tomosynthesis images are acquired: currently approved tomosynthesis screening indication A projectional 2D image calculated from the 3D dataset. Does not require additional radiation exposure. Only tomosynthesis images are acquired, and a synthesized 2D image is created. Both are read together. This is the proposed new screening indication for use. 7

8 Selenia Dimensions 8

9 Tomosynthesis Screening Imaging 3D Reconstruct Tomo Slices Imaging 2D Review 3D + 2D Current combo mode Imaging 3D Reconstruct Tomo Slices Synthesize C-View Review 3D + C-View Proposed additional optional mode 3D plus C-View 9

10 How does it work? Perform a standard tomosynthesis scan (existing product) 10

11 ~60 Tomosynthesis Slices How does it work? Perform a standard tomosynthesis scan (existing product) Reconstruct tomosynthesis slices (existing product) Reconstruction Algorithm 15 Projection Images 11

12 ~60 Tomosynthesis Slices How does it work? Perform a standard tomosynthesis scan (existing product) Reconstruct tomosynthesis slices (existing product) Synthesize 2D image (C- View) Similar to Maximum Intensity Projection (MIP) as done with MRI images Image Summation C-View 12

13 13

14 Synthesized 2D Image Usage C-View is part of the 3D data set Image is identified, to avoid confusion with true 2D image 14

15 15

16 System Changes The synthesized 2D algorithm is a software module New 3D plus C-View mode is an option Optional mode available along with existing 2D plus 3D modes 16

17 Current Intended Use Statement (The same clinical applications as the commercially available 2D and/or 3D system) The Hologic Selenia Dimensions system generates digital mammographic images that can be used for screening and diagnosis of breast cancer. The Selenia Dimensions (2D or 3D) system is intended for use in the same clinical applications as a 2D mammography system for screening mammograms. Specifically, the Selenia Dimensions system can be used to acquire 2D digital mammograms and 3D mammograms. 17

18 Current Intended Use Statement (cont.) (The same clinical applications as the commercially available 2D and/or 3D system) Each view in a screening examination will consist of: a 2D image set, or a 2D and 3D image set The Selenia Dimensions system may also be used for additional diagnostic workup of the breast. 18

19 Proposed Intended Use Statement (cont.) (The same clinical applications as the commercially available 2D and/or 3D system) Each view in a screening examination will consist of: a 2D image set, or a 2D and 3D image set, or a 3D image set in combination with a synthesized 2D image The Selenia Dimensions system may also be used for additional diagnostic workup of the breast. 19

20 Breast Tomosynthesis: Clinical Benefit Elizabeth A. Rafferty, M.D. Director, Breast Imaging Avon Comprehensive Breast Center Massachusetts General Hospital

21 Mammography Prompt annual mammography has shown the ability to reduce the mortality rate from breast cancer in a population by 15% to 50%. 1-3 As many as 20% of breast cancers will be missed by mammography. Approximately 10% of women are recalled for additional workup and a significant portion prove to have no abnormality, resulting in unnecessary anxiety and cost. 1. Smith RA, Duffy SW, Gabe R et al. The randomized trials of breast cancer screening: what have we learned? Radiol Clin N Am 42 (2004) Hendrick RE, Smith RA, Rutledge JH, Smart CR. Benefit of screening mammography in women ages 40-49: a new meta-analysis of randomized controlled trials. Monogr Natl Cancer Inst 1997;22: Tabar L, Vitak B, Chen T H-H, Yen MF, Duffy SW, Smith RA. Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality. Cancer 2001;91:

22 Mammography Limitations A major factor contributing to the limited performance of mammography is the tissue superimposition that is created by the overlap of normal breast structures in a two-dimensional mammographic projection. These overlapping structures can obscure a lesion making it more difficult to perceive or rendering it completely mammographically occult. 22

23 RMLO 2D 23

24 Mammography Limitations A major factor contributing to the limited performance of mammography is the tissue superimposition that is created by the overlap of normal breast structures in a two-dimensional mammographic projection. These overlapping structures can obscure a lesion making it more difficult to perceive or rendering it completely mammographically occult. By mimicking mammographic lesions, overlapping structures can also generate false positive findings at screening, resulting in unnecessary recalls. 24

25 2D 25

26 Anticipated Benefits of 3D Increased breast cancer detection Decreased recall rate for non-cancer cases Improved lesion margin visibility Precise lesion localization 26

27 RMLO 2D 27

28 2D 3D 28

29 RCC RCC 2D 3D 29

30 Slice

31 Benefits of 2D plus 3D Combined digital mammography and breast tomosynthesis approved for clinical use by the FDA on February 11,

32 Benefits of 2D plus 3D Study 1 2D plus 3D Study 1 2D Study 2 2D plus 3D Study 2 2D Radiology. In press. 32

33 Benefits of 2D plus 3D At the 98 th Scientific Assembly and Annual Meeting of the Radiological Society of North America scheduled for November of 2012: 9 abstracts will be presented detailing the positive benefits of combined digital mammography and breast tomosynthesis for both screening and diagnostic applications in the clinical environment. 33

34 2D plus 3D Dose While evidence of the clinical benefits of 3D are accruing, attention has also been drawn to the incremental increase in dose over 2D FFDM. Phantom Dose (mgy) FDA MQSA Dose Limit The imaging community is always striving to minimize dose while maintaining quality D 2D plus 3D MLO 2D plus 3D 34

35 2D plus 3D Dose One strategy for reducing dose is to perform only the 3D MLO in addition to the 2D FFDM Study 1 2D plus 3D Study 1 2D Study 2 2D plus 3D Study 2 2D Study 2 2D plus 3D MLO 35

36 Rationale for 3D plus C-View

37 Rationale for 3D plus C-View The advantage of two-view tomosynthesis suggests an alternative strategy to reducing dose while capitalizing on the benefits of 3D: elimination of the 2D mammogram. In interpreting the 3D study, there is value to having a 2-dimensional summary image available to the radiologist: Assessment of side to side symmetry 37

38 RCC LCC 2D FFDM 38

39 RCC LCC 39

40 RMLO LMLO 2D FFDM 40

41 RMLO LMLO 41

42 Rationale for 3D plus C-View The advantage of two-view tomosynthesis suggests an alternative strategy to reducing dose while capitalizing on the benefits of 3D: elimination of the 2D mammogram. In interpreting the 3D study, there is value to having a 2-dimensional summary image available to the radiologist: Assessment of side to side symmetry Assessment of interval change 42

43 43

44 44

45 Assessment of Interval Change The aesthetic of the C-View image may be different This is commonly encountered in clinical practice Comparing digital mammography with analog prior imaging Comparing digital mammography with prior imaging from a different vendor Comparing digital mammography with prior imaging using different processing algorithms This situation presents itself whenever technology changes 45

46 Rationale for 3D plus C-View The advantage of two-view tomosynthesis suggests an alternative strategy to reducing dose while capitalizing on the benefits of 3D: elimination of the 2D mammogram. In interpreting the 3D study, there is value to having a 2-dimensional summary image available to the radiologist: Assessment of side to side symmetry Assessment of interval change Detection of calcifications 46

47 Calcification Detection: Case 1

48 LMLO 2D FFDM 48

49 LMLO 49

50 2D FFDM C-View 3D Slices 50

51 Calcification Detection: Case 2

52 MLO CC 2D FFDM C-View 3D Slice 52

53 Calcification Detection: Case 3

54 2D FFDM C-View 3D Slice 54

55 Calcification Detection: Case 4

56 2D FFDM C-View Tomosynthesis 56

57 Rationale for 3D plus C-View The advantage of two-view tomosynthesis suggests an alternative strategy to reducing dose while capitalizing on the benefits of 3D: elimination of the 2D mammogram. In interpreting the 3D study, there is value to having a 2-dimensional summary image available to the radiologist: Assessment of side to side symmetry Assessment of interval change Detection of calcifications Recognition of the distributional aspect of features (particularly calcifications) 57

58 RCC 2D FFDM

59 RCC

60 2D FFDM C-View Tomosynthesis

61 Rationale for 3D plus C-View 3D plus C-View imaging provides another lower dose tomosynthesis imaging option for the radiologist. Our study was designed to compare the diagnostic accuracy of 3D plus C-View to the current standard: 2D FFDM. 61

62 Clinical Study Overview

63 Study Design Image Acquisition Cases were accrued from 22 sites in the United States under IRB approval with written informed consent Subjects presented for either screening or biopsy Subjects underwent investigational 2D and 3D imaging (in a single compression) of both breasts in the MLO and CC views Screening subjects also underwent standard of care 2D FFDM imaging (SOC) on the same day Biopsy subjects were eligible for the study if their SOC imaging had been performed within the past 60 days. SOC imaging and investigational imaging were interpreted by different radiologists at the accruing sites 63

64 Enrollment Exclusion Criteria Women with a prior excisional biopsy Women with an internal breast marker Women with breast implants Breasts too large to be imaged in a single compression 64

65 Enrollment Exclusion Criteria Prior excisional biopsy 65

66 Enrollment Exclusion Criteria Prior excisional biopsy Presence of an internal tissue marker 66

67 Enrollment Exclusion Criteria Prior excisional biopsy Presence of an internal tissue marker Breast implants 67

68 Enrollment Exclusion Criteria Prior excisional biopsy Presence of an internal tissue marker Breast implants 68

69 Enrollment Exclusion Criteria Prior excisional biopsy Presence of an internal tissue marker Breast implants Breasts too large to be imaged in a single compression 69

70 Study Design Case Selection Eligible collected cases were classified into one of 4 categories: 1. Malignant (biopsy-proven) 2. Benign (biopsy-proven) 3. Recalled from screening Based on either the reading of the SOC or investigational imaging 4. Negative Based on a negative interpretation of both the SOC and investigational imaging REFERENCE STANDARD: Malignant cases: pathology Non-malignant cases: one year follow up to confirm non-malignant status 70

71 QC Exclusion Criteria 3521 Subjects imaged 536 Excluded at site level 2985 Eligible cases after site exclusions 590 Excluded at QC 96 Excluded for use in a pilot study and exclusions based on reader study criteria 2299 Eligible Subjects 1997 Not randomized for reader study 302 Randomized into study 71

72 QC Exclusion Criteria Entire case was excluded if any of the 8 images acquired failed to pass QC Acquisition protocol did not allow for repeat imaging Quality Control exclusions Patient motion Positioning Gridlines or artifacts Approximately 3% of images excluded Number of 2D FFDM and 3D exclusions rates ~ equal 19.8% (590/2985) cases excluded Age, breast density and ethnicity of cases excluded were very similar to cases included 72

73 Overview of Reader Study Comparison of 3Ds to 2D FFDM Retrospective enriched reader study (crossed design with one month delay) 302 cases reviewed by 15 radiologists Readers were MQSA qualified with a wide range of experience with 2D and 3D Primary Endpoint: Receiver-operator characteristic (ROC) area under the curve (AUC) performance for 3Ds imaging is non-inferior to that of 2D FFDM Secondary Endpoints: ROC AUC for subjects with dense breasts using 3Ds is non-inferior to that of 2D FFDM The non-cancer recall rate for 3Ds is non-inferior to that of 2D FFDM 73

74 Reader Study Cohort Calcification Cases Non-Calcification Cases All Cases Benign Cancer Recall (32%) 120 (68%)

75 Reader Study Cohort Calcification Cases Non-Calcification Cases All Cases Benign Cancer Recall Negative 126 Total

76 Study Design Case Selection BIRADS Density 1 BIRADS Density 2 BIRADS Density 3 BIRADS Density 4 Cases were selected to give an approximate 50/50 mix of fatty vs dense parenchymal patterns 76

77 Inherent Case Selection Bias The vast majority of the cancers included in the reader study came from the biopsy cohort (4 came from screening cohort) and had already been diagnosed by conventional methods prior to enrollment. This method of case selection biases the study against demonstrating a gain in sensitivity using 3D plus C-View because nearly all of the cancers were detected with FFDM imaging. Sensitivity was not an endpoint of the study given the case selection bias. 77

78 Study Design Readers 15 readers participated in the study All readers were MQSA qualified Based on their experience, readers were classified into 3 categories: 1. High volume: interprets > 5000 mammograms / year 2. Medium volume: interprets between 3000 and 5000 mammograms / year 3. Low volume: interprets 3000 mammograms / year or less Additionally, readers were asked whether they had prior clinical experience interpreting tomosynthesis imaging. 78

79 Reader Experience Reader # Mammography exams per year Tomosynthesis Experience Y Y N Y N Y N N Y Y N Y Y N N 79

80 Study Design Reader Training Training focused on the interpretation of 3D images: Normal anatomy Resolution of summation artifact Appearance of masses, architectural distortion and calcifications C-View images were presented with each training case reviewed Emphasis was placed on the use of the C-View image functioning as an overview to guide interpretation of the 3D data set Analogous to a MIP image in MRI 80

81 Study Design Reader Training Training focused on the interpretation of 3D images: Normal anatomy Resolution of summation artifact Appearance of masses, architectural distortion and calcifications C-View images were presented with each training case reviewed Readers read 2 assessment sets and performance thresholds were measured for assessment set 2 In total the readers reviewed approximately 150 cases for training purposes No training cases were used in the Reader Study 81

82 Study Design Reader Case Review 302 cases 2D FFDM and 3Ds Session 1 2D FFDM (151) Session 1 3D s (151) 1 month washout Session 2 3D s (151) Session 2 2D FFDM (151) Data Analysis 82

83 Study Design Reader Case Review Scoring was lesion-based Only lesions deemed actionable were marked Up to 3 lesions could be marked per case Lesion location was recorded for each lesion Lesion type (calcification, non-calcification or both) was recorded for each lesion Scoring: Initial BIRADS: 0, 1, or 2 Forced BIRADS: 1 to 5 score for all BIRADS 0 cases Probability of Malignancy: 0% to 100% for all cases 83

84 Data Analysis Loren Niklason, Ph.D. Director, Tomosynthesis Programs Hologic, Inc.

85 Study Design Study Endpoints Primary Endpoint: ROC AUC performance for 3Ds imaging is noninferior to that of 2D FFDM Delta 5% Probability of malignancy (POM) scores used for ROC analysis p < 0.05 considered significant difference, prospectively defined Retrospective enriched ROC study design similar to FDA approval studies for 2D plus 3D and 2D FFDM systems 85

86 Study Design Study Endpoints Primary Endpoint: ROC AUC performance for 3Ds imaging is noninferior to that of 2D FFDM Secondary Endpoints: ROC AUC for subjects with dense breasts using 3Ds is non-inferior to that of 2D FFDM Delta 5% Probability of malignancy (POM) scores used for ROC analysis 86

87 Study Design Study Endpoints Primary Endpoint: ROC AUC performance for 3Ds imaging is noninferior to that of 2D FFDM Secondary Endpoints: ROC AUC for subjects with dense breasts using 3Ds is non-inferior to that of 2D FFDM The non-cancer recall rate for 3Ds is non-inferior to that of 2D FFDM Delta 5%, all non-cancer cases included 87

88 Recall Rate Analysis Non-Cancer Cases Analysis of recall rate was performed for individuals and for all readers using a bootstrapping analysis Bootstrapping analysis allows determination of confidence limits based on randomly selecting new samples of readers and cases from the original sample. 88

89 ROC Curves Higher Recall Rate Higher Cancer Detection Lower Recall Rate Lower Cancer Detection 89

90 ROC Curves AUC Difference System 2 System 1 Area Under Curve System #1 90

91 ROC Curves System 2 System 1 91

92 Clinical Reader Study Results Elizabeth A. Rafferty, M.D. Director, Breast Imaging Avon Comprehensive Breast Center Massachusetts General Hospital

93 Results Reader Inclusion Pre-determined thresholds for reader performance had been determined for 2D FFDM and 3Ds Application of the pre-determined thresholds resulted in several of the radiologists not meeting criteria for inclusion in the data analysis (predominantly based on their interpretation of the 2D FFDM) After discussions with the FDA, it was decided to include all 15 readers in the analysis Subsequent data analysis confirmed nearly identical outcomes regardless of the thresholding standards applied. 93

94 Results Primary Endpoint ROC AUC performance for 3Ds imaging is non-inferior to that of 2D FFDM 94

95 ROC AUC: All Cases, All Readers ROC AUC Difference Reader 2D 3D S 3D S -2D FFDM Mean One Sided 95% CI Lower Limit p-value

96 Mean ROC curves: All Cases, All Readers AUC D = p =

97 Primary Endpoint ROC AUC performance for 3Ds imaging is non-inferior to that of 2D FFDM Using multi-reader, multi-case ROC analysis, 3Ds imaging was non-inferior to 2D FFDM In fact, 3Ds imaging was superior to 2D FFDM 14 out of 15 radiologists demonstrated improved AUC with 3Ds compared to 2D FFDM 97

98 RMLO 2D FFDM 98

99 RMLO 99

100 2D FFDM 6/15 readers recalled 100

101 2D FFDM mean POM: 8.5% 101

102 C-View 3D Slice 15/15 readers recalled 102

103 C-View 3D Slice mean POM: 91.3% 103

104 Primary Endpoint ROC AUC performance for 3Ds imaging is non-inferior to that of 2D FFDM Using multi-reader, multi-case ROC analysis, 3Ds imaging was non-inferior to 2D FFDM In fact, 3Ds imaging was superior to 2D FFDM 14 out of 15 radiologists demonstrated improved AUC with 3Ds compared to 2D FFDM The primary endpoint was met. 104

105 Secondary Endpoints ROC AUC for subjects with dense breasts using 3Ds is non-inferior to that of 2D FFDM 105

106 ROC AUC; Dense Breast Cases, All Readers ROC AUC Difference 3D S Reader 2D 3D S -2D FFDM Mean One Sided 95% CI Lower Limit p-value

107 Mean ROC curves; Dense Breast Cases, All Readers AUC D = p =

108 Secondary Endpoint Dense Breasts ROC AUC for subjects with dense breasts using 3Ds is noninferior to that of 2D FFDM Using multi-reader, multi-case ROC analysis, 3Ds imaging was non-inferior to 2D FFDM 14 out of 15 radiologists demonstrated improved AUC with 3Ds compared to 2D FFDM 108

109 LMLO 2D FFDM

110 LMLO

111 2D FFDM 4/15 readers recalled

112 2D FFDM mean POM: 14.4%

113 C-View 3D Slice 10/15 readers recalled

114 C-View 3D Slice mean POM: 46.1%

115 Secondary Endpoint Dense Breasts ROC AUC for subjects with dense breasts using 3Ds is noninferior to that of 2D FFDM Using multi-reader, multi-case ROC analysis, 3Ds imaging was non-inferior to 2D FFDM 14 out of 15 radiologists demonstrated improved AUC with 3Ds compared to 2D FFDM This secondary endpoint was met. 115

116 Secondary Endpoint Non-cancer recall rate The non-cancer recall rate for 3Ds is non-inferior to that of 2D FFDM 116

117 Recall Rates: Non-Cancer Cases (Recalls, Negatives, Benign) Reader 2D FFDM Recalls 3D S Recalls Number Cases 2D FFDM Recall rate 3D S Recall rate Difference 3DS-2DFFDM % 36.4% -7.2% % 37.3% -31.6% % 23.6% -11.5% % 17.8% -9.3% % 23.6% -7.5% % 30.7% -19.1% % 36.9% -18.2% % 27.6% -9.3% % 33.8% -17.3% % 42.2% -9.4% % 38.7% -14.2% % 33.3% -14.3% % 22.2% -16.0% % 42.7% -10.2% % 35.1% -12.5% Total/Mean 1551/ / % 32.1% -13.9% On average, readers reduced the number of cases recalled using 3Ds compared to 2D FFDM by 31 cases Relative reduction in recall rate was 30% 117

118 Recall Rates: Screening Cases (Recalls, Negatives) 2D FFDM Number 2D FFDM 3D S Recall Difference Reader Recalls 3D S Recalls Cases Recall rate rate 3DS-2DFFDM % 26.0% -6.0% % 22.7% -38.0% % 10.0% -14.0% % 8.0% -11.3% % 13.3% -9.4% % 19.3% -18.0% % 24.0% -19.3% % 15.3% -10.0% % 22.7% -16.6% % 28.7% -10.0% % 27.3% -14.0% % 22.7% -16.0% % 12.7% -16.6% % 34.0% -8.0% % 25.3% -11.4% Total/Mean 796/53 468/ % 20.8% -14.6% On average, readers reduced the number of cases recalled using 3Ds compared to 2D FFDM by 22 cases Relative reduction in recall rate was 41% 118

119 Secondary Endpoint Non-cancer recall rate The non-cancer recall rate for 3Ds is non-inferior to that of 2D FFDM Using bootstrapping analysis, this secondary endpoint was met and 3Ds was non-inferior to 2D FFDM In fact, 3Ds was superior to 2D FFDM 15 of 15 radiologists had a statistically significant reduction in non-cancer recall rate 119

120 RCC 2D FFDM

121 RCC

122 2D FFDM 11/15 readers recalled

123 Tomosynthesis C-View 2/15 readers recalled Tomosynthesis

124 Secondary Endpoint Non-cancer recall rate The non-cancer recall rate for 3Ds is non-inferior to that of 2D FFDM Using bootstrapping analysis, this secondary endpoint was met and 3Ds was non-inferior to 2D FFDM In fact, 3Ds was superior to 2D FFDM 15 of 15 radiologists had a statistically significant reduction in non-cancer recall rate This secondary endpoint was met. 124

125 Summary of Endpoints The primary endpoint was met 3Ds was shown to be superior to 2D FFDM for the primary endpoint: diagnostic accuracy for all cases The secondary endpoints were met 3Ds was shown to be non-inferior to 2D FFDM for the secondary endpoint of diagnostic accuracy in dense breast cases 3Ds was shown to be superior to 2D FFDM for the secondary endpoint of non-cancer recall rate 125

126 Risk Benefit Analysis

127 Benefits of Mammography Clinical Trials have demonstrated that screening mammography reduces breast cancer mortality by 15% to 50% 1-3 These numbers are conservative 1-view vs. 2-view mammography Annual vs. biennial screening Compliance and contamination Limited number of screening rounds Advances in technology 1. Smith RA, Duffy SW, Gabe R et al. The randomized trials of breast cancer screening: what have we learned? Radiol Clin N Am 42 (2004) Hendrick RE, Smith RA, Rutledge JH, Smart CR. Benefit of screening mammography in women ages 40-49: a new meta-analysis of randomized controlled trials. Monogr Natl Cancer Inst 1997;22: Tabar L, Vitak B, Chen T H-H, Yen MF, Duffy SW, Smith RA. Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality. Cancer 2001;91:

128 Summary of Screening Benefits Likely mortality reduction is at least 30% - 50%* * EUROSCREEN Working Group. Summary of the evidence of breast cancer service screening outcomes in Europe and first estimate of the benefit and harm balance sheet. Med Screen, September 2012, Vol. 19 [Suppl 1], pp

129 Risk Analysis Estimates of the lifetime mortality risk from annual mammography from age 40-80: 2D FFDM: D plus C-View: Hendrick RE. Radiation Doses and Cancer Risks from Breast Imaging Studies, Radiology 257: ,

130 ACR Phantom Dose FDA MQSA dose limit D FFDM 2D FFDM 2D FFDM 2D FFDM 3D + (Hologic) (MQSA*) + 3D-MLO + 3D C-View *Mourad WG. Average Glandular Dose in FDA-approved FFDM Systems (2005) 130

131 Additional Analyses

132 Additional Analyses Calcification cases versus non-calcification cases ROC analysis 132

133 Mean ROC curves All Readers Calcification vs Non-Calcification Cases Non-Calcification Cases AUC D = p = /15 readers improved with 3Ds 133

134 Mean ROC curves All Readers Calcification vs Non-Calcification Cases Non-Calcification Cases Calcification Cases AUC D = p =.011 AUC D = p = /15 readers improved with 3Ds 134

135 2D FFDM 13/15 readers recalled 135

136 2D FFDM C-View 3D Slice 15/15 readers recalled 136

137 Additional Analyses Calcification cases versus non-calcification cases ROC analysis Fatty breasts - ROC analysis 137

138 Mean ROC curves All Readers Fatty Breast Cases AUC D = p = /15 readers improved with 3Ds 138

139 139

140 140

141 RCC 2D FFDM 141

142 RCC 142

143 2D FFDM 8/15 readers recalled 143

144 2D FFDM mean POM: 14.4% 144

145 2D FFDM C-View Tomosynthesis 13/15 readers recalled 145

146 2D FFDM C-View Tomosynthesis mean POM: 60.1% 146

147 Additional Analyses Calcification cases versus non-calcification cases ROC analysis Fatty breasts - ROC analysis Cancer recall analysis 147

148 Cancer Recalls with Correct Location and Lesion Type Reader 2D FFDM Recalls 3D S Recalls Number Cases 2D FFDM Recall rate 3D S Recall rate Difference 3Ds-2D FFDM % 79.2% -2.6% % 90.9% 0.0% % 84.4% 0.0% % 80.5% 7.8% % 80.5% 1.3% % 87.0% 2.6% % 85.7% -2.6% % 85.7% 7.8% % 84.4% 0.0% % 84.4% 0.0% % 90.9% 10.4% % 88.3% 5.2% % 80.5% 3.9% % 89.6% 5.2% % 87.0% 5.2% Total/Mean 951/ / % 85.3% 3.0% 148

149 Additional Analyses Calcification cases versus non-calcification cases ROC analysis Fatty breasts - ROC analysis Cancer recall analysis Distribution of cases potential for bias based on types of cases included 149

150 Distribution of Cases FDA questioned the impact of case mix on the outcome of this study The 3Ds study has more negatives and more cancer cases than our previous 2D plus 3D PMA study 150

151 Distribution of Cases 2D plus 3D Cancer Benign Recall Negatives 3Ds Cancer Benign Recall Negatives 151

152 Distribution of Cases FDA questioned the impact of case mix on the outcome of this study The 3Ds study has more negatives and more cancer cases than our previous 2D plus 3D PMA study Analyses were done to determine if results change as a function of case distribution: All Cases Cancer + recall Cancer + negative Cancer + benign + negative Cancer + benign + recall (more similar to 2D plus 3D case mix) 152

153 Analyses of Results with Different Case Distributions Case Distribution 2D FFDM AUC 3Ds AUC Difference 3Ds -2D FFDM Number Cases One sided 95% CI Lower Limit p-value All Cancer + recalls Cancer + negatives Cancer + benign + recall Cancer + benign + negatives All differences in AUC ~.04 regardless of case distribution and all are significant. 153

154 Summary

155 Summary All primary and secondary endpoints were met or exceeded. 3D plus C-View is a two-view tomosynthesis imaging option that is superior to 2D FFDM at a comparable dose. 155

156 LMLO 2D FFDM 156

157 LMLO 157

158 2D FFDM 5/15 readers recalled 158

159 2D FFDM mean POM: 4.9% 159

160 C-View 3D Slice 15/15 readers recalled 160

161 C-View 3D Slice mean POM: 94.9% 161

162 Conclusion The data from our reader study has demonstrated that 3D plus C-View is effective for clinical use. The analysis of benefits and risk for 3D plus C-View support that it is safe for clinical use. 3D plus C-View provides a lower dose two-view option for tomosynthesis imaging that will help radiologists reduce recall rates and find cancers, translating to reduced patient anxiety and lives saved. 162

163 THANK YOU 163