Roche Virtuoso Používateľská príručka

Companion Algorithm HER2 (4B5) Image Analysis Software User Manual, v. 5.1

HER2 (4B5) Handbuch zur Bildanalyse-Software-Anwendung, v. 5.1

Manuel d’utilisation de l’application logicielle d’analyse d’images de l’HER2

(4B5), v. 5.1

Manuale dell’utente del software per l’analisi delle immagini -

HER2 (4B5), v. 5.1

Manual de usuario de la aplicación del software de análisis de imagen de HER2

(4B5), v. 5.1

Uživatelská pøíruèka softwaru pro analýzu obrazu HER2 (4B5), v. 5.1

Brugervejledning for Software til HER2 (4B5)-billedanalyse, v. 5.1

Εγχειρίδιο χρήσης του λογισμικού ανάλυσης εικόνας του HER2 (4B5), v. 5.1

HER2 (4B5) képelemző szoftver használati útmutató, v. 5.1

Gebruikershandleiding voor de HER2 (4B5) beeldanalysesoftware, v. 5.1

Brukerhåndbok for HER2 (4B5) bildeanalyseprogram, v. 5.1

Podręcznik użytkownika oprogramowania do analizy obrazu

HER2 (4B5), v. 5.1

Manual do utilizador para o software para análise de imagem

do HER2 (4B5), v. 5.1

Priročnik za uporabo programske opreme za analizo slik HER2 (4B5), v. 5.1

Användarhandbok för programmet för bildanalys av HER2 (4B5), v. 5.1

Not for distribution in the US

PS-001314/06449000001

Ventana Medical Systems, Inc. Part No.: 101406900 Rev. A

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Companion Algorithm HER2 (4B5) Image Analysis

Software User Manual, v. 5.1

Ventana Medical Systems, Inc. Part No.: 101406900 Rev. A

Companion Algorithm HER2 (4B5) Image Analysis Software User Manual

Copyright

Trademarks

BENCHMARK, PATHWAY, COMPANION ALGORITHM, VENTANA ISCAN HT, ISCAN, VIRTUOSO,

VENTANA, and the VENTANA logo are trademarks of Roche. All other trademarks are the property of their respective

owners.

Companion Algorithm HER2 (4B5) image analysis software is licensed for use between Ventana Medical Systems, Inc.

and a licensee, and only users authorized there under are permitted to access and use the software. Unauthorized use and

distribution may result in civil and criminal penalties.

Open Source and Commercial Software

Refer to the Virtuoso Reference Guide for information on Open Source and Commercial Software programs.

Contact Information:

Ventana Medical Systems, Inc.

1910 E. Innovation Park Drive

Tucson, AZ 85755

USA

+1 520 887 2155

www.ventana.com

Ventana Medical Systems, Inc.

203 Ravendale Drive

Mountain View, CA 94043

USA

Roche Diagnostics GmbH

Sandhofer Strasse 116

D-68305 Mannheim

Germany

+49 621 7590

Part No.: 101406900 Rev. A iii

Table of Contents

About the HER2 (4B5) Image Analysis Software . . . . . . . . . . . . . . . . . . . . . . . . .1

Topics Covered in this Chapter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Who Should Read this Guide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Related Document . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Technical Support. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Connection Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Cyber Security . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

User Authorization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Securing Networks and Servers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Protecting Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Chapter 1: Intended Use and Indications for Use . . . . . . . . . . . . . . . . . . . . . . . .5

Intended Use and Indications for Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Summary and Explanation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Test Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Warnings and Precautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Required Materials Not Provided. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Performance Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Chapter 2: HER2 Comparison and Reproducibility Studies . . . . . . . . . . . . . . . . . .9

HER2 Marker Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Study Devices and Samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Staining Procedure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

HER2 Concordance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Intra-System and Inter-System Studies

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Appendix A: Reagents (Antibody) Package Inserts. . . . . . . . . . . . . . . . . . . . . . .13

Reagents (Antibody) Package Inserts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15

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Table of Contents HER2 (4B5) Image Analysis Software User Manual

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Part No.: 101406900 Rev. A 1

About the Companion Algorithm HER2 (4B5) image analysis

software

Welcome to the Companion Algorithm HER2 (4B5) Image Analysis Software User Manual.

Topics Covered in this Chapter

• Who Should Read this Manual (page 1)

• Introduction (page 1)

• Related Document (page 1)

• Technical Support (page 1)

• Connection Requirements (page 1)

• Cyber Security (page 2)

Who Should Read this Manual

System Administrators should read this user manual and use it for reference while operating the Virtuoso software.

Introduction

The Companion Algorithm HER2 (4B5) image analysis software assists the pathologist in the semi-quantitative measurement of

HER2 in tissues stained with Ventana Medical Systems, Inc. PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary

Antibody (PATHWAY HER2 (4B5)). This application generates an HER2 score that can be reviewed and accepted by the

pathologist, or if necessary, overridden by the pathologist. The image analysis application is an assist to the pathologist in the scoring

and interpretation of PATHWAY HER2 (4B5) staining on breast cancer tissues.

The Virtuoso HER2 Digital Read Application allows the pathologist to view PATHWAY HER2 (4B5) stained slides as images on a

computer monitor, similar to what can be viewed under a microscope. While reviewing the image, the pathologist may change

magnification and move freely about the image.

Related Document

For additional information on the Virtuoso software, see the following document:

• Virtuoso Reference Guide (PL-000123-EN)

Technical Support

Connection Requirements

Refer to the Virtuoso Reference Guide information on connection requirements.

Ventana Medical Systems, Inc.

1910 E. Innovation Park Drive

Tucson, AZ 85755

USA

Tel: +1 520 887 2155; for Technical Support, press 1

2 Part No.: 101406900 Rev. A

About the Companion Algorithm HER2 (4B5) image analysis software HER2 (4B5) Image Analysis Software User Manual

Cyber Security

Any device that is connected to a network (internally or externally) has the potential to be compromised by unauthorized access or

viruses. As with most devices, the software is designed to run on a computer utilizing Microsoft Windows and virus protection

software which requires the validation and implementation of the appropriate patches.

Some of the potential cyber security hazards are:

• Malicious software that alters the device software (such as viruses)

• Unauthorized access to the system that could compromise data safety

• Security of data transmitted over the Internet

Cyber security involves protecting data by preventing, detecting, and responding to malicious cyber attacks. Cyber attacks could

involve computer viruses which can completely erase data or hackers who alter files or even use the device as a host to attack other

devices. As serious as these hazards are, steps can be taken to maximize cyber security.

User Authorization

All software users must login with a valid user name and password. The user name and password are securely transmitted in

encrypted form over the Internet or Intranet. Once a user has logged in, the user remains active in the application until the user

explicitly logs out, closes the browser, or because the application closes after a period of inactivity.

Securing Networks and Servers

Network security consists of the provisions made in the computer network infrastructure, policies adopted by the network

administrator to protect the network, and the network resources that prevent unauthorized access.

The following are critical steps for securing a network server:

• Physical security (servers and network infrastructure behind locked doors)

• Use of robust passwords

• System and data backups (at regular intervals)

• Data protection

• Terminating unused services

• Restricting access to used services

The following are critical steps and methodologies used to secure network and servers:

• Data protection

• Data backups (at regular intervals)

• Refusal of automatic updates from off-the-shelf software

• Antivirus software for computers and servers

HER2 (4B5) Image Analysis Software User Manual About the Companion Algorithm HER2 (4B5) image analysis software

Part No.: 101406900 Rev. A 3

Protecting Data

Establishment of a network firewall and protection of the network against viruses using anti-virus software are effective methods

to protect data. Virus definitions should be kept up to date and regular scans of computers for spyware should be performed using

a legitimate anti-spyware application. If viruses or spyware are found, remove them immediately.

Evaluate Your Software Settings

The default settings of most software enable all available functionality. However, hackers may be able to take advantage of this

functionality to access devices. It is especially important to check the settings for software that connects to the Internet (browsers,

email clients, etc.). Apply the highest level of security available that still provides needed functionality.

Backup and Recovery

In order to develop a successful backup and recovery plan, comprehension of data accessibility needs and the potential impact of

data loss is essential. Automatic backup procedures need to be adopted using a data backup utility.

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About the Companion Algorithm HER2 (4B5) image analysis software HER2 (4B5) Image Analysis Software User Manual

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Part No.: 101406900 Rev. A 5

Chapter 1: Intended Use and Indications for Use

This chapter shows comparison and reproducibility studies for the HER2 marker.

Intended Use and Indications for Use

The Virtuoso system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro

diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical

interest based on particular morphology, color, intensity, size, pattern and shape.

The IHC HER2 4B5 Digital Read and Image Analysis applications are intended for use as an aid to the pathologist in the detection

and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. HER2

results are indicated for use as an aid in the management, prognosis and prediction of therapy outcomes in breast cancer. When used

with Ventana Medical Systems, Inc. PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody, it is indicated for use

as an aid in the assessment of breast cancer patients for whom HERCEPTIN (Trastuzumab) treatment is being considered.

Note: The IHC HER2 4B5 Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the

qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens

stained for the presence of HER-2/neu receptor protein. The pathologist should verify agreement with the Image Analysis

software application score. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is

the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the

instructions for the anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay used to assure the validity of the iScan

System for IHC HER2 Digital Read and Image Analysis scores. The actual correlation of anti-HER-2/neu (4B5) to clinical outcome

has not been established.

Summary and Explanation

The Virtuoso system for HER2 4B5 is an instrument and software system designed to assist the qualified pathologist in the

consistent quantitative assessment of protein expression in immunohistochemically (IHC) stained histologic sections from

formalin-fixed, paraffin-embedded (FFPE) normal and neoplastic tissues. The Virtuoso system can be used for review of digitized

images of histologic sections with image analysis algorithms (Companion Algorithm Virtuoso image analysis applications), or

without Companion Algorithm image analysis algorithms (Virtuoso Digital Read applications).

Digital Read applications present images on the computer screen in the same manner as one would see with a manual microscope,

inclusive of the pathologist's ability to select any areas of interest and the option of various magnification levels. For the Companion

Algorithm Virtuoso image analysis applications, the pathologist may use the system software to select and outline one or several field

of views, (FOVs), and each FOV may be viewed at various magnifications and then analyzed by the software (analysis at 20x

magnification); a count of the total number of target cells and the number interpreted by the algorithm as positive and negative is

generated. The HER2 algorithm analysis also reports the HER2 score (0, 1+, 2+ or 3+) for a particular FOV, or an aggregate score

for all selected FOVs for that slide. The pathologist can accept the score provided by the algorithm, or may override the score with

a different score. The system requires competent human intervention at all steps in the analysis process, and the software makes no

independent interpretations of the data.

The Virtuoso system consists of a slide scanner, computer, monitor, keyboard, mouse, Companion Algorithm image analysis

algorithms, and software with a user interface. Virtuoso is an end-to-end digital pathology software solution that allows pathology

laboratories to acquire, manage, view, analyze, share, and report on digital images of pathology specimens. Using the Virtuoso

software, the pathologist can view digital images at various magnifications (as previously stated), add annotations, make tissue section

measurements, perform image analysis, and generate reports.

For in vitro diagnostic (IVD) use.

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Chapter 1: Intended Use and Indications for Use HER2 (4B5) Image Analysis Software User Manual

Test Principles

The Companion Algorithm HER2 (4B5) image analysis software employs image analysis techniques to obtain HER2 scores.

Pre-defined parameters are used to obtain HER2 scores. The identification of the nuclei and membrane are carried out automatically

by the image analysis algorithms. The steps involved in the analysis algorithms are:

1. Enhancing the image. This process increases the contrast to make the image more suitable for analysis.

2. Identifying the epithelial area. The epithelial area is the region of the image where there is the possibility of epithelial cells

being present.

3. Identifying the nucleus.

4. Identifying the cell membrane.

5. Classifying the cells based on extent, intensity and thickness of membrane staining.

6. Computing the score

Warnings and Precautions

It is important that glass slides with acceptable staining quality be used.

Pre-Analytical Variables

Tissue preparation and staining should follow the recommendations provided in the PATHWAY HER2 (4B5) assay package insert.

For optimal image capture using the Virtuoso software, it is recommended that the tissue be free of folds and be placed on the slide

with a minimum of 2 mm boundary from the edge on all sides. The cover slip and slide label (if present) should not overhang the

edges of the slide. For further information on scanning, please refer to the appropriate iScan slide scanner reference guide.

Procedure

Refer to Virtuoso Reference Guide.

It is recommended that at least three fields of view be selected for analysis when using the Companion Algorithm HER2 (4B5) image

analysis software.

Required Materials Not Provided

The Virtuoso System for HER2 4B5 requires use of PATHWAY HER2 (4B5), and any additional material or supplies listed in the

Ventana package insert, to stain tissues prior to analysis.

The iScan Coreo slide scanner or the VENTANA iScan HT slide scanner is required for scanning of the slides.

Results

The Companion Algorithm HER2 4B5 image analysis software produces images and a staining score. The pathologist views the

image and the instrument score, makes an assessment, and reports a score which may not be the same as the instrument score. Refer

to Virtuoso Reference Guide for an example of a report.

Limitations

The algorithms are designed to work for HER2 staining. The test results are only as good as the quality and accuracy of the

immunohistochemistry slide that is imaged, and the subsequent image that is analyzed. The pathologist must validate the HER2

HER2 (4B5) Image Analysis Software User Manual Chapter 1: Intended Use and Indications for Use

Part No.: 101406900 Rev. A 7

staining run by examination of the HER2 control images to verify that the expected results have been obtained before images from

patient slides are analyzed by the Virtuoso program. The pathologist must follow the manufacturer's recommendations for

PATHWAY HER2 (4B5) including using all the positive and negative quality control materials for each staining run. If the control

slides are not acceptable, the patient tissues need to be re-stained with acceptable results. (See the PATHWAY HER2 (4B5) package

insert for details about quality control recommendations.) The pathologist must follow the recommendations for HER2

interpretation as recommended in the PATHWAY HER2 (4B5) package insert (available at www.ventana.com). If the images

captured have different staining (nuclear, cytoplasm, etc.), incorrect results will be generated. Incorrect results will also be generated

if the image quality cannot be analyzed. The software algorithms determine whether the quality of an image can be analyzed, based

on pre-defined parameters. Refer to the Virtuoso Reference Guide for more information.

The HER2 4B5 image analysis algorithm will reject nuclei that are elongated regardless of the overall shape of the cell. For this

reason, tumors containing large numbers of cells with elongated nuclei may need to be evaluated manually. In addition, performance

of the Virtuoso system for HER2 4B5 algorithm with the following types of breast cancers has not been evaluated: carcinoma in

situ, carcinosarcoma, comedo carcinoma, cysto sarcoma phylloides, lobular carcinoma, medullary carcinoma of the breast, mucinous

variants of breast cancer and spindle cell carcinoma.

Performance Characteristics

Performance of the staining agent is described in the package insert for the PATHWAY HER2 (4B5) staining process. See

Comparison and Reproducibility Studies in Chapter 2 for a description of the performance of the software.

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Part No.: 101406900 Rev. A 9

Chapter 2: HER2 Comparison and Reproducibility Studies

This chapter shows comparison and reproducibility studies for the HER2 marker.

HER2 Marker Studies

Staining Procedure

Refer to the PATHWAY HER2 (4B5) package insert for BenchMark XT, ULTRA and GX instruments and ultraView, and iView

detection.

Study Devices and Samples for the BenchMark XT Instrument and iScan Coreo Slide Scanner

The HER2 comparison and reproducibility studies for the Virtuoso Digital Read and Companion Algorithm image analysis software

consisted of 120 de-identified archived breast carcinoma sections immunohistochemically stained with PATHWAY anti-HER2/neu

(4B5) Rabbit Monoclonal Primary Antibody. Study test samples spanned a range of positivity from 0 to 3+, and were interpreted at

three different sites by three different pathologists. All test images were scanned at 20X magnification and were bif file format. For

the image analysis evaluation, a minimum of three fields of view were selected by each pathologist independently for each image.

HER2 Concordance with BenchMark XT Instrument and iScan Coreo Slide Scanner

The following table shows the concordance results for PATHWAY HER2 (4B5) staining interpretation among three different sites:

1. Digital Read vs. Manual Method.

Table 2-1 Agreement - Digital Read vs. Manual (manual = true score).

Confusion Matrix

Digital

Site 1 Site 2 Site 3

(n = 119) (n = 120) (n = 118)

Neg Pos Neg Pos Neg Pos

Manual

Neg (0, 1+) 64 4 51 1 54 4

Pos (2+, 3+) 4 47 20 48 7 53

% Agreement 93% 83% 91%

(95% CI) (87% - 97%) (75% - 88%) (84% - 95%)

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Chapter 2: HER2 Comparison and Reproducibility Studies HER2 (4B5) Image Analysis Software User Manual

2. Image Analysis vs. Manual Method.

Intra-System and Inter-System Studies

The study was designed to demonstrate inter- and intra-Virtuoso system reproducibility for Virtuoso Digital Read and Virtuoso

Image Analysis applications. A randomly selected subset of 40 cases that span the range of the HER2 scoring categories (0, 1+, 2+,

3+) in roughly equal numbers were used.

1. Intra-pathologist/Inter-Day (pair-wise comparisons, Session1 vs. Session 2, Session1 vs. Session 3, Session 2 vs. Session 3)..

Table 2-2 Agreement - Image Analysis vs. Manual (manual = true score).

Confusion Matrix

Image Analysis

Site 1 Site 2 Site 3

(n = 117) (n = 120) (n = 120)

Neg Pos Neg Pos Neg Pos

Manual

Neg (0, 1+) 67 0 52 0 59 1

Pos (2+, 3+) 9 41 22 46 14 46

% Agreement 92% 82% 88%

(95% CI) (86% - 96%) (74% - 88%) (80% - 92%)

Table 2-3 Intra- Pathologist Digital Read.

Confusion Matrix

Intra-Pathologist Digital

Session2 Session 3 Session 3

Neg Pos Neg Pos Neg Pos

19 21 22 18 22 18

Session 1

Neg 17 17 0 17 0

Pos 22 2 20 4 18

Session 2

Neg 19 19 0

Pos 21 318

% Agreement 95% 90% 93%

(95% CI) (83% - 99%) (76% - 96%) (80% - 97%)

HER2 (4B5) Image Analysis Software User Manual Chapter 2: HER2 Comparison and Reproducibility Studies

Part No.: 101406900 Rev. A 11

2. For Intra-Pathologist Image Analysis.

3. Inter-pathologist (pair-wise comparisons, Pathologist 1 vs. Pathologist 2, Pathologist 1 vs. Pathologist 3, Pathologist 2 vs.

Pathologist 3).

4. Inter-Pathologist Image Analysis.

Table 2-4 Intra-Pathologist Image Analysis.

Confusion Matrix

Intra-Pathologist Image Analysis

Session2 Session 3 Session 3

Neg Pos Neg Pos Neg Pos

24 16 23 16 23 16

Session 1

Neg 24 24 0 23 0

Pos 16 0 16 0 16

Session 2

Neg 24 23 0

Pos 16 016

% Agreement 100% 100% 100%

(95% CI) (91% - 100%) (91% - 100%) (91% - 100%)

Table 2-5 Inter-Pathologist Digital Read.

Confusion Matrix

Inter-Pathologist Digital

Site 2 Site 3 Site 3

Neg Pos Neg Pos Neg Pos

71 49 61 57 61 57

Site 1

Neg 68 65 3 58 8

Pos 51 6 45 3 48

Site 2

Neg 71 59 10

Pos 49 247

% Agreement 92% 91% 90%

(95% CI) (86% - 96%) (84% - 95%) (83% - 94%)

Table 2-6 Inter-Pathologist Image Analysis.

Confusion Matrix

Inter-Pathologist Image Analysis

Site 2 Site 3 Site 3

Neg Pos Neg Pos Neg Pos

74 46 73 47 73 47

Site 1

Neg 76 71 5 71 5

Pos 42 2 40 1 41

Site 2

Neg 74 69 5

Pos 46 442

% Agreement 94% 95% 93%

(95% CI) (88% - 97%) (89% - 98%) (86% - 96%)

12 Part No.: 101406900 Rev. A

Chapter 2: HER2 Comparison and Reproducibility Studies HER2 (4B5) Image Analysis Software User Manual

HER2 Concordance with BenchMark ULTRA Instrument and iScan Coreo Slide Scanner

Study Devices and Samples for BenchMark ULTRA Instrument and iScan Coreo Slide Scanner

These HER2 (4B5) comparison studies for the Virtuoso Digital Read and Companion Algorithm Image Analysis software consisted

of 120 de-identified archived breast carcinoma sections immunohistochemically stained with PATHWAY anti-HER2/neu (4B5)

Rabbit Monoclonal Primary Antibody on the BenchMark ULTRA instrument. Study test samples spanned a range of positivity from

0 to 3+, and were interpreted by one pathologist at one site. All test slides were scanned at 20X magnification and all images were

output in bif file format. For the image analysis evaluation, a minimum of three fields of view were selected by each pathologist

independently for each image.

The tables below shows the concordance results for PATHWAY HER2 (4B5) assay stained on the BenchMark ULTRA instrument.

Digital Read vs. Manual Microscopic Read

Image Analysis vs. Manual Microscopic Read

Table 2-7 Agreement (ULTRA Instrument) - Digital Read vs. Manual Microscope Read

Manual Microscope Read

Digital Read

Positive Negative Total

Positive (2+, 3+) 50 3 53

Negative (0, 1+) 1 52 53

Total 51 55 106

Positive Percent Agreement (PPA) n/N (%) (95% CI) 50/51 (98.0%) (89.7-99.7%)

Negative Percent Agreement (NPA) n/N (%) (95% CI) 52/55 (94.5%) (85.1-98.1%)

Overall Percent Agreement (OPA) n/N (%) (95% CI) 102/106 (96.2%) (90.7-98.5%)

Table 2-8 Agreement (ULTRA Instrument) - Image Analysis vs. Manual Microscope Read

Manual Microscope Read

Image Analysis Read

Positive Negative Total

Positive (2+, 3+) 52 4 56

Negative (0, 1+) 2 62 64

Total 54 66 120

Positive Percent Agreement (PPA) n/N (%) (95% CI) 52/54 (96.3%) (87.5-99.0%)

Negative Percent Agreement (NPA) n/N (%) (95% CI) 62/66 (93.9%) (85.4-97.6%)

Overall Percent Agreement (OPA) n/N (%) (95% CI) 114/120 (95.0%) (89.5-97.7%)

HER2 (4B5) Image Analysis Software User Manual Chapter 2: HER2 Comparison and Reproducibility Studies

Part No.: 101406900 Rev. A 13

HER2 Concordance with BenchMark XT/ULTRA Instruments and VENTANA iScan HT Slide

Scanner

Study Devices and Samples for BenchMark XT/ULTRA Instruments and iScan HT Slide Scanner

The HER2 comparison and reproducibility studies for the Virtuoso Digital Read and Companion Algorithm image analysis software

consisted of 30 de-identified archived breast carcinoma sections immunohistochemically stained with PATHWAY anti-HER2/neu

(4B5) Rabbit Monoclonal Primary Antibody. Study test samples spanned a range of positivity from 0 to 3+, and were interpreted

by one pathologist. All test slides were scanned at 20X magnification and all images were output in bif file format. For the image

analysis evaluation, a minimum of three fields of view were selected by each pathologist independently for each image.

Digital Read vs. Manual Microscopic Read

Image Analysis vs. Manual Microscopic Read

Table 2-9 Agreement - Digital Read vs. Manual Microscope Read

Digital Read

Manual Microscope Read

Negative Positive Total

Negative 16 1 17

Positive 2 11 13

Total 18 12 30

Positive Percent Agreement (PPA) n/N (%) (95% CI) 11/13 (85%) (58-96%)

Negative Percent Agreement (NPA) n/N (%) (95% CI) 16/17 (94%) (73-99%)

Overall Percent Agreement (OPA) n/N (%) (95% CI) 27/30 (90%) (74-97%)

Table 2-10 Agreement - Image Analysis vs. Manual Microscope Read

Image Analysis Read

Manual Microscope Read

Negative Positive Total

Negative 17 0 17

Positive 2 11 13

Total 19 11 30

Positive Percent Agreement (PPA) n/N (%) (95% CI) 11/13 (85%) (58-96%)

Negative Percent Agreement (NPA) n/N (%) (95% CI) 17/17 (100%) (82-100%)

Overall Percent Agreement (OPA) n/N (%) (95% CI) 28/30 (93%) (79-98%)

14 Part No.: 101406900 Rev. A

Chapter 2: HER2 Comparison and Reproducibility Studies HER2 (4B5) Image Analysis Software User Manual

HER2 Concordance with BenchMark GX Instrument, iScan Coreo, and iScan HT Slide Scanners

Study Devices and Samples for BenchMark GX Instrument, iScan Coreo, and iScan HT Slide Scanners

The HER2 comparison and reproducibility studies for the Virtuoso Digital Read and Companion Algorithm image analysis software

consisted of 30 de-identified archived breast carcinoma sections immunohistochemically stained with PATHWAY anti-HER2/neu

(4B5) Rabbit Monoclonal Primary Antibody. Study test samples spanned a range of positivity from 0 to 3+,, and were interpreted

by two pathologists. All test slides were scanned at 20X magnification and all images were output in bif file format. For the image

analysis evaluation, a minimum of three fields of view were selected by each pathologist independently for each image.

The results were analyzed for each pathologist individually and also averaged across the two pathologists. The average overall

percent agreement (OPA) was determined as the weighted average for the two pathologists who independently scored the same

cases, where the weight of a pathologist's individual OPA rate was determined by the number of cases considered evaluable by that

pathologist.

Digital Read vs. Manual Microscopic Read, iScan Coreo Slide Scanner

The average OPA for Digital Read vs. Manual Microscopic Read for iScan Coreo slide scanner was 95.0%.

Table 2-11 Pathologist #1 Agreement - Digital Read vs. Manual, iScan Coreo Slide Scanner

Digital Read

Manual Microscope Read

Negative Positive Total

Negative 15 1 16

Positive 1 13 14

Total 16 14 30

Overall Percent Agreement (OPA) n/N (%) (95% CI) 93.3%

Table 2-12 Pathologist #2 Agreement - Digital Read vs Manual Microscopic Read,

iScan Coreo Slide Scanner

Digital Read

Manual Microscope Read

Negative Positive Total

Negative 18 0 18

Positive 1 11 12

Total 19 11 30

Overall Percent Agreement (OPA) n/N (%) (95% CI) 96.7%

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