Breast cancer diagnostic solutions Deliver diagnostic confidence

Breast cancer diagnostic solutions Deliver diagnostic confidence

2 Breast cancer diagnostic solutions Roche Tissue Diagnostics is committed to improving outcomes in breast cancer Breast cancer...the most common cancer type and cause of cancer-related deaths in women 1...annually claims more than 500,000 lives worldwide 1...in the US, 1 out of 8 women will develop invasive breast cancer during their lifespan 2 Breast cancer remains a significant scientific, clinical and societal challenge. Everyone s cancer diagnosis is as distinct as the person it affects. Breast cancer is heterogeneous in nature and has distinct biological, pathological and genetic diversity. Biomarkers can help identify patient subgroups most likely to benefit from a specific treatment. Diagnostic and prognostic descriptions of subtypes, guided by biomarker results, have become increasingly more sophisticated over the past decades.

Breast cancer diagnostic solutions 3 Precision medicine: The right test at the right time facilitates differential diagnosis Evidence supports that breast cancer tumors can be grouped into subtypes with distinct clinical profiles and treatment options. 3 Understanding the diversity in breast cancer allows for stratification of patient subgroups. Individual biomarkers (or panels of biomarkers) characterize subtypes, confirm origin of tissue, differentiate primary from metastatic tumor and provide prognostic and predictive information. 4 Biomarkers play an important role in the detection and management of patients 5 Biomarkers are the most precise way of identifying intrinsic subtypes 6 Failure to correctly stratify a patient can lead to unnecessary and costly exposure to therapeutics, prevent the delivery of the most beneficial treatment and may reduce the degree of positive outcomes 7,8,9 Three reasons to choose Roche Tissue Diagnostic s Solutions Our breast cancer diagnostics deliver on three key benefits that are valued by pathology professionals: 1. Clinical utility With proven accuracy 15,21 our breast cancer diagnostic assays help you identify patients other assays can miss 7,9,16,17 so you can deliver the right test, with clinical confidence in the shortest possible time. Our mission is to improve the lives of all patients afflicted with cancer. We are committed to empowering you in your quest to elevate the standard of care. 2. Analytical performance Specific and sensitive rabbit monoclonal antibodies, bestin-class probes, and powerful detection systems help you diagnose precisely and confidently. 3. Testing efficiency Our comprehensive breast cancer workflow solution delivers fully automated assays on market-leading platforms, with digital pathology and workflow solutions that free resources, reduce labor costs, and reduce time to results.

4 Breast cancer diagnostic solutions Biomarker status helps to identify patient groups most likely to respond to a specific treatment HER2 overexpression accounts for 15% to 20% of all breast cancers. Tumors that overexpress the HER2 gene are associated with more rapid growth compared to HER2 negative tumors. 6,10,12 Estrogen Receptor (ER) and Progesterone Receptor (PR) positive tumors account for approximately 74% of all breast cancer tumors. Dual positive hormone receptor tumors are usually slow growing and less aggressive. 5 Luminal A tumors have favorable short-term prognosis and show favorable response to hormonal therapy. 5 Luminal B tends to be more aggressive and higher grade than Luminal A. 5 In early breast cancer, moderate to strong PR expression is an aid to differentiate between Luminal A and B tumors. 12 Classifications of IHC subtypes: St. Gallen Consensus 12 Erb-B2 overexpression (non-luminal) Luminal A Luminal B (Her2 +) Luminal B (Her2 -) Basel like (Ductal, TN) HER2 + Overexpressed or amplified + - - ER - + + + - PR - + Any Negative or low - Ki-67 Low Any High Key + positive - negative This chart is not for diagnostic use. It represents staining patterns that are associated with breast cancers based on St. Gallen Expert Consensus, 2013. 12 TN triple negative

Breast cancer diagnostic solutions 5 Pathology assessments play a critical role in breast cancer management Breast cancer management is complex and biomarkers play an integral role in determining the status of the tumor. IHC and ISH biomarkers help facilitate decision-making for subsequent therapeutic options. 3,6,10 The benefit of chemotherapy is dependant on multiple factors: Tumor size, lymph node involvement and the presence of biomarkers. 5 Multiple tests used to determine treatment 11 HER2 status Treatment decision Hormone receptor status HER2+ Hormone therapy * and targeted therapy ER+ and/or PR+ HER2- HER2- Hormone therapy * Breast cancer histology HER2+ Targeted therapy* ER- and/or PR- Non-targeted therapy* Source: Diagram is developed based on NCCN Guideline for Invasive Breast Cancer 11 * Targeted therapy can include chemotherapy with trastuzumab for HER2 positive patients, hormone therapy is for ER and/or PR positive patients, non-targeted therapy refers to chemotherapy for patients with triple negative status.

6 Breast cancer diagnostic solutions Provide confidence in your lab with Roche Tissue Diagnostics HER2 testing Breast carcinoma HER2 Dual ISH non-amplified, Magnification: 40X INFORM HER2 Dual ISH DNA Probe cocktail INFORM HER2 Dual ISH DNA Probe cocktail is designed to detect amplification of the HER2 gene and is indicated as an aid in the assessment of patients for whom Herceptin treatment is being considered. 13 ISH utilized as a reflex for IHC equivocal (2+) results Patient breast tissue sample Standardized and validated test platforms Adequate (formalin) fixation (6-72h) Results are easily scored using brightfield microscopy in-house with familiar technologies HER2 gene amplification assessment over the entire slide not just a pre-selected area facilitates scoring and identification of heterogeneity Simultaneous morphological assessment independent of H&E stain Archivable results allow for easy maintenance and simplifies consults in difficult cases Enhanced technical support tools including clear, consolidated guidance on best practices and streamlined training H&E stain Primary staining shows morphologic changes IHC Controls passed No significant staining in normal epithelium No faint or partial staining a Weak complete staining a Greater than 10% Intense complete staininga Greater than 10% 0 1+ 2+ 3+ ISH Report as HER2 positive oncologist for HER2-targeted therapies 2 2 a) Membrane staining

7 Breast cancer diagnostic solutions In a recent publication7 assessing the socioeconomic impact of inaccurate HER2 breast cancer testing, laboratory-developed in vitro diagnostic (IVD) were compared to U.S. Food and Drug Administration-approved IVD, found a cost benefit in using an approved IVD test. Breast carcinoma HER2 (4B5) positive, Score: 3+ Magnification: 40X HER2/neu (4B5)* Rabbit Monoclonal Primary Antibody The use of pre-dilutedpathway HER2 (4B5),14 in combination with the fully automated BenchMark IHC/ISH slide staining instrument, standardizes all IHC processes from baking through staining, and reduces the possibility of human error. It also minimizes inherent variability resulting from individual reagent dilution and other processes found in manual and semi-automated IHC methods. The PATHWAY HER2 (4B5) Primary Antibody empowers you to: Achieve consistently high proficiency assessment scores with HER2 (4B5) antibody, compared to other clones15 Employ the most widely adopted and reliable HER2-IHC primary antibody15 High concordance with HER2 FISH16,17 Proportion of sufficient stains (optimal or good) HER2 (4B5): Consistent high performance* competitor 1 concentrate competitor 1 ready-to-use competitor 2 ready-to-use HER2 4B5* (pre-dilute) Assessments *Data refers to PATHWAY and VENTANA products. Based on 5 years of data from a leading external quality assessment scheme. Retrieved from http://www.nordiqc.org/epitopes.htm

8 Breast cancer diagnostic solutions Provide an aide in the management, prognosis and prediction of therapy outcomes of breast cancer Breast carcinoma ER (SP1) positive, Magnification: 40X Breast carcinoma PR (1E2) positive, Magnification: 40X CONFIRM anti-estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody and CONFIRM anti-progeserone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody ER is a powerful predictor of response to hormone therapy (such as Tamoxifen) and clinical outcome of breast cancer patients. PR status can add additional prognostic and predictive value to ER status by providing an independent and significant tool for predicting hormone therapy response and clinical outcome. 18 Indicated as an aid in patient management, prognosis, and the prediction of therapy outcomes in breast cancer 19,20 Rapid and consistent results delivered through fully automated platforms and digital pathology solutions ER (SP1) is a significant predictor of disease-specific survival 9,21 Achieve consistently high proficiency assessment scores with ER (SP1) antibody, compared the other clones 15 PR (1E2) antibody provides significant value as a prognostic factor and response prediction of hormone therapy, even in ER negative patients 18 ER (SP1): Consistent high performance* competitor 1 Proportion of sufficient stains (optimal or good) competitor 2 competitor 3 competitor 4 competitor 5 competitor 6 ER2 (SP1) (pre-dilute) Assessments *Based on 5 years of data from a leading external quality assessment scheme. Retrieved from http://www.nordiqc.org/epitopes.htm

Breast cancer diagnostic solutions 9 Supporting breast cancer diagnostics Breast carcinoma Ki-67 (30-9) stained Magnification: Low Breast carcinoma E-cadherin (36) stained Magnification: 40X CONFIRM anti-ki-67 (30-9) Rabbit Monoclonal Primary Antibody CONFIRM Ki-67 (30-9) Antibody is directed against C-terminal portion of Ki-67 antigen. Staining for Ki-67 can be used to aid in assessing the proliferative activity of normal and neoplastic tissue. With intense nuclear staining and no adipose (K2) or cell membrane staining (MIB-1), CONFIRM Ki-67 (30-9) rabbit monoclonal antibody can help deliver a confident assessment of tumor aggressiveness. 22,23 Uncontrolled proliferation is a hallmark of malignancy. The 2013, St Gallen Expert Concensus 12 found that the degree of proliferative activity in breast cancer helped differentiate Luminal A from Luminal B tumors. VENTANA anti-e-cadherin (36) Mouse Monoclonal Primary Antibody Ventana E-cadherin (36) antibody is directed against the cytoplasmic domain of the human transmembrane protein E-cadherin expressed as a part of the cell-cell adhesion complex in epithelial tissues. 24 Reduction or loss of expression is associated with invasive carcinoma and possibly metastasis in a variety of carcinomas. This antibody may be used to aid in the differentiation of in-situ and/or invasive lobular carcinoma from in situ and/or invasive ductal carcinoma of the breast. CONFIRM p53 (DO-7) Primary Antibody CONFIRM p53 (DO-7) is used in conjunction with VENTANA Companion Algorithm p53 (DO-7) image analysis application using the VENTANA iscan Coreo Au scanner and VIRTUOSO software. 25 GATA3 (L50-823) Mouse Monoclonal Primary Antibody Use of this antibody is indicated as an aid in the identification of breast carcinomas within the context of an antibody panel, clinical history and a qualified pathologist. 26 GATA3 expression is primarily seen in breast carcinoma and urothelial carcinoma and only rarely found in tumors from other organs. 26 Mammaglobin (31A5) Rabbit Monoclonal Antibody Use of this antibody is indicated as an aid in the identification of metastatic breast carcinomas within the context of an antibody panel, clinical history and a qualified pathologist. 27 When combined with other breast-restricted markers such as GCDFP-15, an overall sensitivity for breast carcinoma of 84% has been achieved. 27

10 Breast cancer diagnostic solutions Digital pathology: Virtual consultation, image analysis and education Roche Digital Pathology is transforming the practice of pathology by developing innovative technologies that deliver medical value, inform decision making and improve cancer care. The integrated solution consists of high-quality scanners, image analysis software, image and workflow management software and education applications, all working together globally to optimize laboratories. Digital pathology enables more efficient and informed treatment decisions for patients enchanting care by eliminating the boundaries of time and distance. Your benefit Virtual consultation Maximize pathologist time Enable flexibility for tumor boards, case sharing and collaboration Enable fast turnaround time for expert opinions Provide access to sub-specialists Image analysis Build clinical confidence with US and CE-IVD validated Companion Algorithm image analysis software Facilitate consistent, objective interpretations for breast IHC verified by a pathologist for every patient Education Enrich and accelerate learning in a collaborative environment Allow students to review material anywhere, anytime, from the device of their choice Product features VENTANA Virtuoso image and workflow management software Anytime, anywhere access to slide images Optimize digital workflow and decision-making environment Web-based application to support remote consults and image analysis VENTANA Companion Algorithm image analysis software US and CE-IVD validated image analysis algorithms for the full breast panel: HER2, ER, PR, Ki-67 and p53 Semi-quantitative scores for markers requiring cell counts Fully validated as part of a systems approach includes reagents, staining platforms, scanners and software VENTANA iscan Coreo slide scanner Intended for low- to mid- volume scanning sites Brightfield scanning capability (160 slide capacity) at various magnifications 4x, 10x, 20x, 40x Live mode (remotely controlled microscope) VENTANA iscan HT slide scanner Intended for high-volume scanning sites Brightfield scanning capability (360 slide capacity) at various magnifications 20x, 40x Continuous random access and STAT processing with no workflow interruption VENTANA Vector education and collaboration software Support education and collaboration with digital images Standardize content and eliminate sharing resources (slides or microscopes) Allow students to review material anywhere, anytime, from the device of their choice (mobile-capable on ios and Android devices)

Breast cancer diagnostic solutions 11 World-class antibodies to stratify breast cancer Product Name Catalog no. Ordering code Tests CA-125 (OC125) Mouse Monoclonal Antibody 760-2610 05267269001 50 Calponin-1 (EP798Y) Rabbit Monoclonal Antibody 760-4376 05435684001 50 E-cadherin (36) Mouse Monoclonal Primary Antibody, VENTANA 790-4497 05905290001 50 E-cadherin (EP700Y) Antibody 760-4440 05973872001 50 Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody, CONFIRM 760-4324 05278406001 50 Estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody, CONFIRM 790-4325 05278414001 250 FOXA1(2F83) Mouse Monoclonal Primary Antibody 760-4937 07292848001 50 GATA3 (L50-823) Mouse Monoclonal Primary Antibody 760-4897 07107749001 50 GCDFP-15 (EP1582Y) Rabbit Monoclonal Antibody 760-4386 05463530001 50 GLIAL Fibrillary Acidic Protein (EP672Y) Rabbit Monoclonal Antibody 760-4345 05269784001 50 Growth Hormone (polyclonal) 760-2804 05268257001 50 Human Placental Lactogen (hpl) (polyclonal) 760-4443 05973830001 50 HER2 Dual ISH DNA Probe Cocktail, INFORM 780-4422 05586640001 HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody, PATHWAY 790-2991 05278368001 50 Her-2/neu (4B5) Rabbit Monoclonal Primary Antibody, VENTANA 790-4493 05999570001 50 Ki-67 (30-9) Rabbit Monoclonal Primary Antibody, CONFIRM 790-4286 05278384001 50 Mammaglobin (31A5) Rabbit Monoclonal Antibody 760-4263 05269253001 50 P53 (BP53-11) Primary Antibody 760-2542 05267102001 50 P53 (DO-7) Primary Antibody, CONFIRM 800-2912 05278775001 50 P57 (Kp10) Mouse Monocloncal Primary Antibody 760-4617 06523897001 50 p63 (4A4) Mouse Monoclonal Primary Antibody, VENTANA 790-4509 05867061001 50 P120 CATENIN (98) Mouse Monoclonal Primary Antibody, VENTANA 790-4517 05867088001 50 PAX8 (MRQ-50) Mouse Monoclonal Primary Antibody 760-4618 06523927001 50 PLAP (NB10) 760-2664 05267757001 50 Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody 790-2223 05277990001 50 Progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody 790-4296 05278392001 250 PTEN (SP218) Rabbit Monoclonal Primary Antibody 790-5097 07970200001 50 Topoisomerase IIα (JS5B4) Rabbit Monoclonal Primary Antibody 790-4371 0547933900 50 Experience the power and confidence that comes from bringing VENTANA breast cancer diagnostics to your practice and patients today. For more information, contact your local Account Manager or visit us at www.ventana.com/breast

References 1. International Agency for Research on Cancer (IARC) and World Health Organization (WHO). GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr/pages/fact_sheets_cancer.aspx, 2016. Accessed August 29, 2016. 2. U.S. breast cancer statistics http://www.breastcancer.org/symptoms/understand_bc/statistics Accessed August 29, 2016. 3. Parker JS, Mullins M, Cheang M. et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160-1167. 4. Zaha, DC. Significance of immunohistochemistry. World J Clin Oncol. 2014;5(3):382-392. 5. American Cancer Society: Breast cancer: Facts and figures 2015-2016. Web site. http://www.cancer.org/acs/groups/content/@research/documents/document/ acspc-046381.pdf Assessed September 19, 2016. 6. Purrington KS, Visscher DW, Wang C. Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes. Breast Cancer Res Treat. 2016. [Epub ahead of print] doi: 10.1007/s10549-016-3775-2. 7. Vyberg M, Nielsen S, Røge R, et al. Immunohistochemical expression of HER2 in breast cancer: Socioeconomic impact of inaccurate tests. BMC Health Services Research. 2015;15:352. 8. Luo D, Smith JA, Meadows NA. et al. A Quantitative Assessment of Factors Affecting the Technological Development and Adoption of Companion Diagnostics. Frontiers in Genetics;6 Atricle357:1-12. 9. Welsh AW, Harigopal M, Wimberly H, et al. Quantitative analysis of estrogen receptor expression shows SP1 antibody is more sensitive than 1D5. Appl Immunohistochem Mol Morphol. 2013;2:139-147. 10. Wolff AC, Hicks D, Hammond E. Recommendations for Human Epidermal Growth Factor Receptor 2 testing in breast cancer: American Society of Clinical Oncology/ College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol. 2013;31(31):3997-4013. 11. NCCN Clinical Practice Guidelines in Oncology. Breast cancer. Version 3, 2015. www.nccn.org/patients Accessed September 19, 2016. 12. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Annals of Oncology. 2013;24:2206-2223. 13. INFORM HER2 Dual ISH DNA Probe Cocktail Assay Package Insert. 15. NordiQC Assessments. http://www.nordiqc.org/epitopes.htm Accessed September 19, 2016. 16. Mayr D, et al. Comprehensive immunohistochemical analysis of Her-2/neu oncoprotein overexpression in breast cancer: HercepTest (Dako) for manual testing and Her-2/neuTest 4B5 (VENTANA) for VENTANA BenchMark automatic staining system with correlation to results of BenchMark automatic staining system with correlation to results of fluorescence in situ hybridization (FISH). Virchows Archiv. 2009; 454(3):241 248. 17. Brügmann A, Lelkaitis G, Nielsen S, et al. Testing HER2 in breast cancer: a comparative study on BRISH, FISH, and IHC. Appl Immunohistochem Mol Morphol. 2011;19(3):203-211. 18. Liu, S, Cchia SK, Mehl, E, et al. Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients. Breast Cancer Res Treat. 2010;119:53-61. 19. CONFIRM anti-estrogen Receptor (ER) (SP1) Rabbit Monoclonal Primary Antibody [package insert]. Tucson, AZ: VENTANA Medical. 20. CONFIRM anti-progesterone Receptor (PR) (1E2) Rabbit Monoclonal Primary Antibody [package insert]. Tucson, AZ: VENTANA Medical Systems, Inc.; 2008. 21. Yamamoto-Ibusuki M, Yamamoto Y, Yamamoto S, et al. Comparison of prognostic values between combined immunohistochemical score of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, Ki-67 and the corresponding gene expression score in breast cancer. Mod Patholo 2013: 26):79 86. 22. Leonardo E, Volante M, Barbareschi. et al. Cell membrane reactivity of MIB-1antibody to Ki-67 in human tumors: Fact or artifact? Appl Immunohistochem Mol Morphol. 2007;15(2):220-223. 23. Miller R. Ki-67 clone K-2: A useful marker of fat cells and lipoblasts ProPath The Focus-Immunochistochemistry. http://www.ihnworld.com/-newsletter/2005/2005-02-ki-67clone_k-2.pdf. Published February 2005. 24. VENTANA anti-e-cadherin (36) Mouse Monoclonal Primary Antibody [package insert]. Tucson, AZ: VENTANA Medical Systems, Inc.; 2014. 25. CONFIRM p53 (DO-7) Primary Antibody. [package insert]. Tucson, AZ: VENTANA Medical Systems, Inc.; 2008. 26. GATA3 (L50-823) Mouse Monoclonal Primary Antibody. [package insert]. EN Rev. 0.1 v1. 27. Mammaglobin (31A5) Rabbit Monoclonal Antibody. [package insert]. EN Rev. 4.2. 14. VENTANA anti-her-2/neu (4B5) Rabbit Monoclonal Primary Antibody Package Insert. Ventana Medical Systems, Inc. 1910 E. Innovation Park Drive Tucson, AZ 85755 USA 1 520 887 2155 1 800 227 2155 www.roche.com www.ventana.com 2017 Ventana Medical Systems, Inc. All trademarks mentioned enjoy legal protection. VENTANA, BENCHMARK, COMPANION ALGORITHM, CONFIRM, ISCAN COREO, VENTANA ISCAN, VENTANA VECTOR and VIRTUOSO are trademarks of Roche. All other trademarks are the property of their respective owners. 6073B 0217 RTDPC-ASFASA-0105