Abstract P4-08-05: Delineation of HER2 Gene Status in Korean Breast Cancers by Standardized Immunohistochemistry (IHC) and Silver In Situ Hybridization (SISH): Comparison of Local IHC Result with Central IHC and SISH Results
Authors: Bae YK , Gong G , Kang J , Lee A , Cho EY , Lee JS , Suh K-S , Lee DW. 
Published: April 2011

Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene and concomitant protein overexpression are present in 20-25% of breast cancers. HER2 overexpression and/or gene amplification is associated with a worse clinical outcome and an important predictive marker for sensitivity to anthracycline-based chemotherapy and HER2- targeted therapy. In Korea, the HER2 status has usually been assessed by immunohistochemistry (IHC) in the laboratories. To verify the preanalytic, analytic, and postanalytic factors of IHC in multi-institutions, we assessed the interlaboratory variability of HER2 IHC by comparing the local IHC with the central IHC and SISH results, as a first step toward building a nationwide quality assurance program.

Methods: The Breast Pathology Study Group of Korean Society of Pathologists collected 1,198 breast carcinoma samples from 7 university-based hospitals and constructed 56 tissue microarray (TMA) blocks with triplicate of 1 mm cores. Local IHC results for HER2 were obtained from 1,130 patients. We performed IHC (PATHWAY anti-HER2/neu (4B5) rabbit monoclonal antibody, Ventana Medical Systems) and SISH (INFORM HER2 DNA Probe Kit, Ventana Medical Systems) for HER2 on the TMA sections using the automated Benchmark platform (Ventana Medical Systems). We interpreted the results according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Results from local IHC were compared with central IHC and SISH. The concordant rates between central IHC and SISH results were also calculated.

Results: The total percentage of cases in each category of local IHC score was: 0/1+, 70.4%; 2+, 8.8% (range among hospitals, 0-36%); and 3+, 20.8% (10.8-28.8%). The percentage of central IHC results (1,110 patients) in each category was: 0/1+, 79.7%; 2+, 3.6% (1.1-8.3%); and 3+, 16.7% (13.1-18.8%). SISH results were obtained from 1,033 patients: negative, 79.5%; equivocal, 0.2% (0-1.6%); and positive, 20.3% (19.2-22.6%). SISH amplifications in each local IHC category were observed as follows: 0/1+, 4.3% (0.6-10%); 2+, 18.8% (5.6-66.7%); and 3+, 71.2% (50-97.3%). When considering the central SISH as gold standard, 3% of cases (30/995) were false negative and 6.3% (63/995) were false positive in local IHC. In central lab, the concordance rates between IHC 3+ and SISH-positive, and IHC 0/1+ and SISH-negative were 95.5% and 98%, respectively.

Conclusions: The results of central IHC and SISH markedly decreased the interlaboratory variability of HER2 status. The measurement of HER2 gene amplification by SISH was less affected by the preanalytic factors than the measurement of overexpression of HER2 protein by IHC. Because the rate of false positivity is higher than that of false negativity in the local IHC, the quality assurance program needs to be focused on decreasing not only the false negativity, but also the false positivity of HER2 IHC in local laboratories

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-05.