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1. Moasser MM. The Oncogene Her2: Its Signaling and Transforming Functions and Its Role in Human Cancer Pathogenesis. Oncogene. 2007;26(45):6469-6487. 2. Hsu JL, Hung MC. The Role of Her2, Egfr, and Other Receptor Tyrosine Kinases in Breast Cancer. Cancer Metastasis Rev. 2016;35(4):575-588. 3. Hudis CA. Trastuzumab--Mechanism of Action and Use in Clinical Practice. N Engl J Med. 2007;357(1):39-51. 4. Cornejo KM, Kandil D, Khan A, et al. Theranostic and Molecular Classification of Breast Cancer. Arch Pathol Lab Med. 2014;138(1):44-56. 5. Cardoso F, Kyriakides S, Ohno S, et al. Early Breast Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann Oncol. 2019. 6. Ferretti G, Felici A, Papaldo P, et al. Her2/Neu Role in Breast Cancer: From a Prognostic Foe to a Predictive Friend. Curr Opin Obstet Gynecol. 2007;19(1):56-62. 7. Moasser MM, Krop IE. The Evolving Landscape of Her2 Targeting in Breast Cancer. JAMA Oncol. 2015;1(8):1154-1161. 8. Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719-726. 9. Baselga J, Carbonell X, Castaneda-Soto NJ, et al. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol. 2005;23:2162-2171. 10. Slamon DJ, Leyland-Jones B, Shak S, et al. Concurrent administration of anti-HER2 monoclonal antibody and first-line chemotherapy for HER2-overexpressing metastatic breast cancer. A phase III, multinational, randomized controlled trial. N Engl J Med. 2001;344:783-792. 11. Marty M, Cognetti F, Maraninichi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatments: The M77001 Study Group. J Clin Oncol. 2005;23:4265-4274. 12. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659-1672. 13. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684. 14. Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018;142(11):1364-1382 15. Bang YJ, Van Cutsem E, Feyereislova A, et al: ToGA Trial Investigators: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010;376: 687-697. 16. Subasinghe D, Acott N, Kumarasinghe MP. A Survival Guide to Her2 Testing in Gastric/Gastroesophageal Junction Carcinoma. Gastrointest Endosc. 2019;90(1):44-54. 17. Smyth EC, Verheij M, Allum W, et al. Gastric Cancer: Esmo Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann Oncol. 2016;27(suppl 5):v38-v49 18. Van Cutsem E, Bang YJ, Feng-Yi F, et al. Her2 Screening Data from Toga: Targeting Her2 in Gastric and Gastroesophageal Junction Cancer. Gastric Cancer. 2015;18(3):476-484. 19. Abrahao-Machado LF, Scapulatempo-Neto C. Her2 Testing in Gastric Cancer: An Update. World J Gastroenterol. 2016;22(19):4619-4625. ",
"Language": "en",
"Country": "XG",
"Code": "Background Information"
},
{
"Name": "Intended Use",
"Value": "The VENTANA HER2 Dual ISH DNA Probe Cocktail is intended to determine HER2 gene status by enumeration of the ratio of the HER2 gene to Chromosome 17 by light microscopy. The HER2 and Chromosome 17 probes are detected using two-color chromogenic in situ hybridization (ISH) in formalin-fixed, paraffin-embedded human breast and gastric carcinoma tissue specimens, including the gastroesophageal junction, following staining on BenchMark IHC/ISH instruments.
The VENTANA HER2 Dual ISH DNA Probe Cocktail is indicated as an aid in the assessment of patients for whom Herceptin (trastuzumab) is being considered. This product should be interpreted by a qualified pathologist in conjunction with histological examination, relevant clinical information, and proper controls.
This product is intended for in vitro diagnostic (IVD) use.",
"Language": "en",
"Country": "XG",
"Code": "Intended Use"
},
{
"Name": "Content",
"Value": "The VENTANA HER2 Dual ISH DNA Probe Cocktail dispenser contains sufficient reagent for 30 tests.
One 6 mL dispenser of VENTANA HER2 Dual ISH DNA Probe Cocktail contains approximately 14 μg/mL of the HER2 probes labeled with dinitrophenyl (DNP) and 0.24 μg/mL of the Chromosome 17 probes labeled with digoxigenin (DIG) formulated in a formamide-based hybridization buffer. Both probes are used to determine HER2 gene status (i.e., ratio of HER2/Chromosome 17). Refer to the appropriate VENTANA detection kit method sheets for detailed descriptions of: Principles of the Procedure, Materials and Methods, Specimen Collection and Preparation for Analysis, Quality Control Procedures, Troubleshooting, Interpretation of Results, and Limitations.",
"Language": "en",
"Country": "XG",
"Code": "Content"
},
{
"Name": "Principle",
"Value": "The VENTANA HER2 Dual ISH DNA Probe Cocktail contains HER2 probes (labeled with the hapten dinitrophenyl or DNP) and Chromosome 17 probes (labeled with the hapten digoxigenin or DIG) formulated in a formamide-based buffer. The probes are designed to detect amplification of the HER2 gene in invasive breast carcinoma and GEA. The HER2 DNA Probe is a mixture of oligo probes that specifically targets the HER2 gene (also known as ERBB2 and NEU), which is located on human Chromosome 17 (17q12). The Chromosome 17 probe is a mixture of oligo probes that target sequences within the centromeric region and serves as a reference for aneusomy. Copy numbers of both probes are enor nuclei and results are reported as a ratio of HER2/Chromosome 17 to determine HER2 amplification status (HER2/Chromosome 17 ratio ≥ 2.0 is amplified, while a ratio < 2.0 is non-amplified). The VENTANA HER2 Dual ISH DNA Probe Cocktail is optimally formulated for use with VENTANA Silver ISH DNP Detection Kit, VENTANA Red ISH DIG Detection Kit, and accessory reagents on a BenchMark IHC/ISH instrument.
The detection kit contains a primary antibody and an enzyme-labeled secondary antibody conjugated to horseradish peroxidase (HRP) or alkaline phosphatase (AP) which is used as the chromogenic enzyme. During the Dual in situ hybridization (Dual ISH) staining process, DNP and DIG labeled probes are co-hybridized to their respective specific target DNA sequences within the cell nuclei. Detection of the DNP-labeled HER2 probe occurs first, using the VENTANA Silver ISH (SISH) DNP Detection Kit, which contains the following dispensers: mouse anti-DNP primary antibody labeled with hydroxyquinoxaline (HQ), mouse anti-HQ secondary antibody conjugated to horseradish peroxidase (HRP), Chromogen A (Silver A), Chromogen B (Silver B) and Chromogen C (Silver C). Following incubation with the HQ-labeled mouse anti-DNP primary antibody and then mouse anti-HQ HRP secondary antibody conjugate, the SISH reaction occurs. Briefly described, this reaction is driven by the sequential addition of Chromogens A (silver acetate), B (hydroquinone) and C (H2O2). Here, the silver ions (Ag+) are reduced by hydroquinone to metallic silver atoms (Ag0). This reaction is fueled by the substrate for HRP, hydrogen peroxide (Chromogen C). The silver precipitate is deposited in the nuclei and a single copy of the HER2 gene is visualized as a black dot. Figure 2 illustrates the SISH reaction.Figure 2. VENTANA Silver ISH DNP Detection for HER
Following SISH detection for HER2, the DIG-labeled Chromosome 17 probe is detected with the VENTANA Red ISH DIG Detection Kit. This kit includes the following dispensers: mouse anti-DIG primary antibody labeled with nitropyrazole (NP), mouse anti-NP secondary antibody conjugated to Alkaline Phosphatase (AP), pH Enhancer, Naphthol, and Fast Red. Following development of the SISH signal, the slide is incubated with the NP-labeled mouse anti-DIG primary antibody, which binds to the DIG hapten on the Chromosome 17 probe. The anti-hapten primary antibody is detected with the mouse anti-NP conjugated to AP enzyme. The slide is incubated with the pH Enhancer solution, which provides the proper salt components and concentrations and buffered pH for optimal AP enzyme performance. Next, naphthol phosphate is applied, which serves as the substrate for the AP enzyme (AP dephosphorylates naphthol). Fast Red, added to the slide next, combines with the dephosphorylated naphthol to form a red precipitate, which is readily visualized by light microscopy. Figure 3 illustrates the Red ISH reaction. The specimen is then counterstained with Hematoxylin II for interpretation by light microscopy.
The staining protocol consists of numerous steps in which reagents are incubated for predetermined times at specific temperatures. At the end of each incubation step, the BenchMark IHC/ISH instrument washes the sections to remove unbound material and applies a liquid coverslip which minimizes the evaporation of the aqueous reagents from the slide. Results are interpreted using a light microscope using 20x, 40x, and/or 60x keyives. Figure 3. VENTANA Red ISH DIG Detection for Chromosome 17 ",
"Language": "en",
"Country": "XG",
"Code": "Principle"
},
{
"Name": "Product Purpose",
"Value": "The VENTANA HER2 Dual ISH DNA Probe Cocktail is intended to determine HER2 gene status by enumeration of the ratio of the HER2 gene to Chromosome 17 by light microscopy. The HER2 and Chromosome 17 probes are detected using two-color chromogenic in situ hybridization (ISH) in formalin-fixed, paraffin-embedded human breast and gastric carcinoma tissue specimens, including the gastroesophageal junction, following staining on BenchMark IHC/ISH instruments.
The VENTANA HER2 Dual ISH DNA Probe Cocktail is indicated as an aid in the assessment of patients for whom Herceptin (trastuzumab) is being considered. This product should be interpreted by a qualified pathologist in conjunction with histological examination, relevant clinical information, and proper controls.
This product is intended for in vitro diagnostic (IVD) use.",
"Language": "en",
"Country": "XG",
"Code": "Product Purpose"
}
]
}
}
]
}
Figure 2. VENTANA Silver ISH DNP Detection for HER
