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The Need for a Quality Control of the Whole Process of Immunohistochemistry Human Epidermal Growth Factor Receptor 2/neu Determination: A United Kingdom National External Quality Assessment Service/Italian Network for Quality Assessment of Tumor Biomarkers Pilot Experience

Italian Network for Quality Assessment of Tumor Biomarkers-Coordinating Unit, National Cancer Institute, Bari, Italy

Keith Miller

United Kingdom National External Quality Assessment Service Immunocitochemistry and Fluorescence In Situ Hybridization Histopathology, University College London, London, United Kingdom

Ettore Marubini

Italian Network for Quality Assessment of Tumor Biomarkers-Biostatistics Unit, Institute of Medical Statistics and Biometry, University of Milan, Milan, Italy

Sara Pizzamiglio

Italian Network for Quality Assessment of Tumor Biomarkers-Biostatistics Unit, Istituto Nazionale dei Tumori, Milan, Italy

Paolo Verderio

Italian Network for Quality Assessment of Tumor Biomarkers-Biostatistics Unit, Istituto Nazionale dei Tumori, Milan, Italy

To the Editor:

The clinical interest in human epidermal growth factor receptor 2 (HER-2)/neu is related to trastuzumab, a drug used to treat patients with invasive breast carcinoma overexpressing the HER-2/neu protein.¹ As suggested by the US Food and Drug Administration guidelines,² the eligibility of breast cancer patients for treatment with trastuzumab is based on the accuracy of the assessment of the HER-2/neu status of the tumor. The quality of the assessment of the HER-2/neu status has been stressed as a crucial point to correctly identify patients who may benefit from trastuzumab.³

In the July 1, 2006, issue of the Journal of Clinical Oncology, Perez et al⁴ investigated the concordance of HER-2/neu testing from local, central, and reference laboratories, concluding that for both fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) assays there is the need for rigorous application of standardized procedures in HER-2/neu testing. However, some aspects remain unexplored, and first of all, it is not clear if this discordance is related to the preanalytic or analytic phase of the assay.

The results of several quality control (QC) programs for IHC determination of HER-2/neu have been published,^5-8 and among them the programs of United Kingdom National External Quality Assessment Service (UK NEQAS) are perhaps the longest lasting and involving the largest number of laboratories. In particular, the UK NEQAS program focused its attention on preanalytic aspects of the IHC assay.^6,7

In 2003, the Italian Network for Quality Assessment of Tumor Biomarkers (INQAT) developed a QC program concerning the analytic phase of HER-2/neu determination in Italy.⁸ The INQAT program investigated inter- and intralaboratory reproducibility of the optical microscope analysis on a set of IHC slides (Table 1, footnote).

In regards to the UK NEQAS results, the performances of each laboratory was judged jointly by four assessors (Table 1, footnote) as making an appropriate, inappropriate, or uninterpretable HER-2/neu determination. In regards to the INQAT program, the performance of each laboratory operator in terms of intralab reproducibility and reproducibility of IHC evaluation at optical microscope versus the reference was considered. Both of these reproducibility aspects were evaluated by the computation of the weighted kappa statistic (k_w).⁹ Values of k_w 0.80 indicate a satisfactory level of reproducibility.

According to the performances of each laboratory in the two QC programs (UK NEQAS and INQAT), five groups of laboratories showing different performance patterns were obtained (Table 1). It should be noted that, although no laboratory can be fully classified as appropriate performer by considering the whole process, for one laboratory (PA01, Group E) the observed level of reproducibility versus the reference value (k_w = 0.79) is closed to the satisfactory threshold (k_w 0.80). Similar consideration can be made for both laboratories belonging to Group B. Moreover, for three (Group C) and two laboratories (Group D) the critical point of the process seem to be related to the preanalytic and analytic phase only, respectively. Finally, for three laboratories (Group A) the whole process of HER-2/neu determination should be revised.

Our results permit two comments. The first one concerns the possibility for each laboratory to have an overall picture of the quality of the whole process of the biomarker determination and a better understanding of the possible reasons for its questionable performance during the different phases of the biomarker determination. The second comment concerns the need to implement QC programs focused on the whole process of biomarker determination moving from standardization of reagents and techniques to reproducibility of biomarker analysis at optical microscope. New QC programs using new standards and operating procedures are in advanced phase of realization by UK NEQAS and other national networks.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Slamon D, Pegram M: Rationale for trasuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 28:38-44, 2001[Medline]

2. Birner P, Oberhuber G, Stani J, et al: Evaluation of the USA FDA-approved scoring and test system of HER-2 protein expression in breast cancer. Clin Cancer Res 7:1669-1675, 2001[Abstract/Free Full Text]

3. Bartlett J, Mallon E, Cooke T: The clinical evaluation of HER-2 status: Which test to use? J Pathol 199:411-417, 2003[CrossRef][Medline]

4. Perez EA, Suman VJ, Davidson NE, et al: HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol 24:3032-3038, 2006[Abstract/Free Full Text]

5. INQAT Group: Interobserver reproducibility of immunohistochemical her-2/neu evaluation in human breast cancer: The real-world experience. Int J Biol Markers 19:147-154, 2004[Medline]

6. Rhodes A, Jesani B, Anderson E, et al: Evaluation of HER-2/neu immunohistochemical assay sensitivity and scoring on formalin-fixed and paraffin-processed cell lines and breast tumors: A comparative study involving results from laboratories in 21 countries. Am J Clin Pathol 118:408-417, 2002[Abstract/Free Full Text]

7. Rhodes A, Jasani B, Couturier J, et al: A formalin-fixed, paraffin-processed cell line standard for quality control of immunohistochemical assay of HER-2/neu expression in breast cancer. Am J Clin Pathol 117:81-89, 2002[Abstract/Free Full Text]

8. NQAT Group: Interobserver reproducibility of immunohistochemical HER-2/neu evaluation in human breast cancer: An update from INQAT-Round III. Int J Biol Markers 20:189-194, 2005[Medline]

9. Fleiss JL: Statistical Methods for Rates and Proportions (ed 2). New York, NY, Wiley and Sons, 1981, pp 212-236

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Paradiso, A. Articles by Verderio, P. Search for Related Content PubMed PubMed Citation Articles by Paradiso, A. Articles by Verderio, P. Social Bookmarking                            What's this?