Standardization of HER2 TestingInconsistency Raises Questions Opinions Sunil S. Badve, MD, FRCPath Clarian Pathology Laboratory, Indiana University School of Medicine An expert in the field of breast pathology, Dr. Badve is Associate Professor in the Department of Pathology and Laboratory Medicine with additional appointment in the Department of Internal Medicine. He serves as the Director of Translational Genomics Core at the Indiana University Cancer Center. He received his MBBS degree from the Bombay University in 1984, and completed a residency in Pathology at Sir JJ Group of Hospitals of Grant Medical College with a year of specialized training at Tata Memorial Hospital for Cancer. He served as Lecturer at Grant medical college for three years. He was in the UK for five years where he completed further training at the St. Georges Medical School and at Royal Marsden Hospital. Following his arrival in USA, he completed a residency in Anatomic and Clinical Pathology at the Albert Einstein School of Medicine, New York. After a year of fellowship in Oncological Pathology at Yale under Professor Darryl Carter, he was recruited to the faculty of the North- western University in 1999. He has been part of the faculty at Indiana University since 2002. Dr. Badves main research and clinical expertise is in breast cancer. He is the main breast Pathologist for the Eastern Co-operative Oncology Group, where he serves as the Pathology Chair for several breast cancer clinical trials, including the TAILORx clinical trial based on the Oncotype Dx assay. He also serves on the NIH-sponsored FFPE Working Group and Datamart Program. He has been a Co-investigator on several NIH, DOD and foundation grants which have resulted in the publication of over 70 peer-reviewed scientific articles in addition to invited reviews and book chapters. Dr. Badve is a regular speaker at national and international pathology meetings and has conducted short courses on breast pathology for the CAP and USCAP. HER2 is a member of the human epidermal growth factor family which consists of four members: Epidermal growth factor receptor (EGFR or HER1), HER2 (also known as neu/c-erb B2), HER3 (or c-erb-B3) and HER4 (c-erb-B4). HER2 was recognized as having an oncogenic influence on the rat model, whereby a single mutation was sufficient to lead to the development of neuroblastoma - hence the term neu HER2 clinical impor. tance in human breast cancer was first reported in 1987 at the UCLA´s Jonsson Comprehensive Cancer Center by Dennis Slamon, MD. These initial studies were based essentially on detection of protein by Western blot or of mRNA by Northern blot. Subsequently, a number of reagents, including polyclonal and monoclonal antibodies as well as probes for in situ hybridization, were developed and used to detect the protein or amplification of the HER2 gene. Studies using these reagents found that HER2 gene amplification and/or protein expression predicted for poor prognosis. Also HER2 was a relatively poor predictive marker in that the predictive potential was often eclipsed by other parameters such as tumor size, grade and lymph node status. The interest in HER2 was revitalized following the development of a humanized monoclonal antibody against HER2 (Herceptin® (trastuzumab-Genentech). Its efficacy in treating aggressive HER2 positive disease was originally shown in a company sponsored metastatic clinical trial often referred to as the pivotal trial. More recently, prospective randomized trials conducted by the National Surgical Adjuvant Breast Project (NSABP) B-31 and the Breast Cancer Intergroup Study (N-9831) in the US and the HERceptin® Adjuvant trial (or HERA trial) in Europe have shown that adjuvant trastuzumab given along with chemotherapy reduces the risk of recurrence in patients with HER2 positive early stage breast cancer. More recent updates of these trials have also shown a reduction in the mortality in these patients. Herceptin® is not just another drug being licensed to treat breast cancer. The degree of benefit seen in patients treated with this agent is significant. The reduction in risk of recur- Connection 2008 | 58 April 2008, VOL 11 Connection IHC STANDARDIZATION AROUND THE WORLD In this issue Q&A with Patho Contents APRIL 2008, VOL 11 2 3 4 Editorial George L. Kumar, PhD Featured Laboratory The Osamura Editorial Immunohistochemistry (IHC) Standardization Around the World George L. Kumar, PhD Managing Featured Laboratory The Osamura Laboratory Laboratory headed by Prof. Robert Yoshiyuki Osamura, MD, Q&A Ask the Experts: On Immunohistochemistry (IHC) Standardization Professor Leong is Medical Di time interval between removal of tissue and immersion in fixative, the temperature of tissue storage Connection: How would you like to standardize IHC in Australia? As discussed above, standardization Connection: Antigen retrieval is essential in immunohistochemistry (IHC) in order to restore epitope Connection: Is a universal image analysis system feasible? No, not until we standardize the all impo Q&A Fernando Soares, MD, PhD University of São Paulo, São Paulo, Brazil Dr. Fernando Soares is F Connection: In your opinion, what is the biggest hurdle for standardization? Probably education in l There are no standards in Latin America. We always follow the manufacturers protocol during our firs Q&A Bryan R. Hewlett, ART, MLT Consultant Technologist to the Anatomic Pathology EQA program of There is no standardization of AR steps circumstances, it would be impossible toand, undera the pre Connection: How would you rate European (UK NEQAS, NordiQC) and US IHC standards to Canadian IHC sta Q&A Prof. Chen Jie Prof. Cui Quancai Peking Union Mediacl College Hospital, Beijing, China Prof. Connection: According to Goldstein et al. Appl Immunohistochem Mol Morphol 2007;15:124­133 Immunohis Connection: Is it true that a particular histology feature may be better demonstrated by other fixat Connection: What constitutes standardization of image analysis as applied to immunohistochemistry (I Q&A Dr. Tanuja Manjanath Shet Dr. Vani Parmar Tata Memorial Hospital, Mumbai, India Tanuja Manj ... the biggest hurdle in India is suboptimal fixation and processing of tissues. Though I agree th Connection: Is it true that a particular histology feature may be better demonstrated by other fixat Connection: Can you comment on the internal and external quality control (EQC) procedures followed i Q&A Prof. Robert Yoshiyuki Osamura Department of Pathology, Tokai University School of Medicine Connection: In your opinion, what is the biggest hurdle for standardization? The biggest hurdle for the standardization of image ... appropriate for pre-screeninganalysis is of the staining quality. Connection: Why is standardization of image analysis in diagnostic pathology important? Because the Q&A James F. Happel, DLM (ASCP), HTL Technical Director of Surgical Pathology, Research and Deve Connection: United Kingdom National External Quality Assessment Service (UK NEQAS) helps to ensure t Connection: The American Society of Clinical Oncology (ASCO) and the College of American Pathologist would recommend that standardization Ibegin with identifying a reliable and trustworthy source ... Interview Immunohistochemistry for Oestrogen and Progesterone Receptors Dr. Andrew Lee Consultant H Connection: What is the difference between the H score and the Allred score? Which is better? What d Connection: Can you comment on the burden in the laboratory, if one changes from a current ER/PR ass Opinion & Interview IHC Standardization: A Dako Perspective Dr. Ole Rasmussen R&D Director, Connection: Dako has developed Readyto-Use Antibodies for in vitro diagnostic applications. How is t Articles UK NEQAS-ICC & ISH: Historical perspective, current role, future directions Andy Dodso UK NEQAS-ICC in the 1990s In his first year as Scheme Organiser, Keith oversaw the transition to sub The application could be argued to represent a field change in terms of the rigour with which the an Assessment teams consist of four assessors, who view slides around a multi-headed microscope and sco The archive which UK NEQAS holds, both in terms of stained slides and methodological data, must sure For Immunocytochemistry and FISH RESULT: RUN 80L SLIDE: NEQAS Laboratory No: XXX Mr. A. Scientist De Figure 6. Feedback on results has always been given high priority, and for many years this has been a b c d Figure 7. The antigen chosen by Gerry Reynolds for his very first assessment run was kap Bibliography Selected UK NEQAS-ICC & ISH papers. Ibrahim M, Dodson AR, Barnett S, Fish D, Jasani Articles Nordic Immunohistochemical Quality Control (NordiQC) An Organization for External Quality A parameters (i.e. results interpretation and reporting) (4, 5). In an EQA setting, by circulating ser CD79a (Fig. 2) Among 112 laboratories submitting stains in the latest run, most used mAb clone JCB11 References 1. Rhodes A, Jasani B, Barnes DM, Bobrow LG, Miller KD. Reliability of immuno-histochemic Fig. 2. CD79a A. Optimal CD79a staining of the tonsil using the monoclonal antibody (mAb) clone JCB Standardization of Ki-67 Immunohistochemical Staining for Diagnosing Grade of Gastrointestinal Strom was conducted in 49 GIST cases. The concordance rate for the evaluation results at three laboratorie CB pH6 a b c d TE pH9 e f g h Autoclave 121° C/10 min Water bath 95° C/40 min Microwave 50 Table 1. Correlation between NCC and STD methods R2=0.9483 Categories of proportion NCC Method 3 Opinions Importance of Standardization for Predictive Prognosis David J. Dabbs, MD Chief of Pathol is documented and serves as a surrogate marker for the initial exposure to formalin. Since the first Opinions The New Era for ER and PRIts time to Standardize! Dr. Ian Ellis, B.Med.Sci. BM, MS, FRCpa et al 2001). The main reason for false-negative results is due to inefficient heat-induced epitope ( Standardization of HER2 TestingInconsistency Raises Questions Opinions Sunil S. Badve, MD, FRCPath rence seen in these trials is in the order of 50%. This is the major reason for all the excitement a which now requires expression of HER2 by at least 30% of tumor cells (instead of 10%). It has also r IHC CONSENSUS MEETING, JANUARY 27 2008, SANTA BARBARA, CA, USA , IHC CONSENSUS MEETING, JANUARY 27, Richard Cartun, PhD, Sunil Badve, MD Jon Askaa, PhD Søren Nielsen, HT, CT, Mogens Vyberg, MD Elizab Dako Abstracts Abstracts presented at the 30th Annual San Antonio Breast Cancer Symposium December Dako Abstracts Amplification of ESR1 may predict resistance to adjuvant tamoxifen in postmenopausal Dako Abstracts Abstracts presented at the United States and Canadian Academy of Pathology (USCAP) A Dako Abstracts Metastatic Pancreatic Endocrine Tumors in the Liver Express KOC Briones AJ, Bourne P Dako Abstracts Merkel Cell Carcinomas Express K Homology Domain Containing Protein Overexpressed in Dako Abstracts Immunohistochemical Analysis of KOC/IMP3 in Malignant Pleural Mesothelioma Xu H, Sim Dako Abstracts KOC, TTF-1 and CDX2 Discriminate Small-Cell Carcinoma from Carcinoid and Pancreatic Dako Publications Publications Co-authored by Dako: In Press Li L, Xu H, Spaulding B, Cheng L, Si Dako Meetings 2007 - National Society for Histotechnology Meeting. 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