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Originally published as JCO Early Release 10.1200/JCO.2009.22.0269 on April 20 2009 © 2009 American Society of Clinical Oncology.
Is Immunohistochemistry Less Sensitive Than Quantitative Reverse Transcriptase Polymerase Chain Reaction for Hormone Receptor Status Determination in Breast Cancer?Department of Biology and Pathology of Tumors, Centre G-F Leclerc, Cancer Institute of Burgundy, Dijon, France
Department of Clinical Oncology, Centre G-F Leclerc, Cancer Institute of Burgundy, Dijon, France To the Editor: The recent article by Badve et al1 reported a comparison between immunohistochemistry (IHC) and a biologic method (reverse transcriptase polymerase chain reaction [RT-PCR]) for hormone receptor assays. The characteristics of each method (products, technique, and interpretation) must be optimized to ensure the best sensitivity and to allow meaningful comparisons. IHC, the older of the two techniques, has seen many innovations since its inception, improving both its sensitivity and its reproducibility. It is now the subject of various recommendations with respect to the reagents and the technique. Further details of the authors' technical choices are needed to show that these recommendations were followed. First is the primary antibody that recognizes the target. Many products are available on the market, first for primary antibodies, with gradually improving specificity and sensitivity, explaining the large number of products available.1,2 A new generation of primary antibodies for hormone receptor studies is now available and seems to give better results than older antibodies,3,4 but these monoclonal antibodies were not used in this work, even though a previous presentation showed a better correlation.5 Second is the system used to amplify and visualize the signal. The last generation of products, composed of small polymers (not used here), improves the sensitivity of the technique: it is often necessary to reduce the primary antibody concentration, which can be useful in difficult cases. The biggest improvements involve the automatic devices that now perform the most important steps, from unmasking to revelation, while controlling all the technical parameters—something important for quality and reproducibility. The article does not mention the use of such a device. The use of a control block with different tumors showing different expression levels is strongly recommended, as it validates the technique and ensures its sensitivity. UKNeqas, the British Quality Control Institute, requires the use of this type of sample for its quarterly controls. Participation in an external quality assurance program is very common in Europe and is obligatory in some countries. Two readers performed the analysis, but the article does not mention whether this double reading was done independently or by consensus, whether it was systematic or limited to a few cases, and which result was used (average or consensus). The comparison with RT-PCR for estrogen receptor shows that almost all the conflicts involved samples that were negative by IHC and positive by RT-PCR, implying that the IHC technique may have been inadequately sensitive. It is regrettable that the characteristics of conflicting cases were not analyzed (or reported), as this would have provided new information—for example whether conflicting cases involved particular tumors (poorly cellular, or with a large ductal component), an expression level close to the cutoff, or heterogeneous expression. In the case of RT-PCR, one important factor is the cutoff determination. In the literature on the same technique, cutoffs (relative to ref genes, log2) range from 7.0,6,7 to 6.58–10 and for progesterone receptor from 6.06,7 to 5.5,8–10 with no justification as to the methodology used to determine the cutoff, or the repeated changes. We do not also know if these cutoffs were clinically validated. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Badve SS, Baehner FL, Gray RP, et al: Estrogen- and progesterone-receptor status in ECOG 2197: Comparison of immunohistochemistry by local and central laboratories and quantitative reverse transcription polymerase chain reaction by central laboratory. J Clin Oncol 26:2473–2481, 2008. 2. Allred DC: Problems and solutions in the evaluation of hormone receptors in breast cancer. J Clin Oncol 26:2433–2435, 2008. 3. Cheang MC, Treaba DO, Speers CH, et al: Immunohistochemical detection using the new rabbit monoclonal antibody SP1 of estrogen receptor in breast cancer is superior to mouse monoclonal antibody 1D5 in predicting survival. J Clin Oncol 24:5637–5644, 2006. 4. Rocha R, Nunes C, Rocha G, Oliveira F, et al: Rabbit monoclonal antibodies show higher sensitivity than mouse monoclonals for estrogen and progesterone receptor evaluation in breast cancer by immunohistochemistry. Pathol Res Pract 204:655–662, 2008.[CrossRef][Medline] 5. Baehner FL, Habel LA, Quesenberry CP. Quantitative RT-PCR analysis of ER and PR with oncotype DX indicates distinct and different associations with prognosis and prediction of tamoxifen benefit 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 14, 2006. 6. Esteva FJ, Sahin AA, Cristofanilli M, et al: Prognostic role of a multigene reverse transcriptase-PCR assay in patients with node-negative breast cancer not receiving adjuvant systemic therapy. Clin Cancer Res 11:3315–3319, 2005. 7. Cronin M, Pho M, Dutta D, et al: Measurement of gene expression in archival paraffin-embedded tissues: Development and performance of a 92-gene reverse transcriptase-polymerase chain reaction assay. Am J Pathol 164:35–42, 2004. 8. Cobleigh MA, Tabesh B, Bitterman P, et al: Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res 11:8623–8631, 2005. 9. Chang JC, Makris A, Gutierrez MC, et al: Gene expression patterns in formalin-fixed, paraffin-embedded core biopsies predict docetaxel chemosensitivity in breast cancer patients. Breast Cancer Res Treat 108:233–240, 2008.[CrossRef][Medline] 10. Mina L, Soule SE, Badve S, et al: Predicting response to primary chemotherapy: Gene expression profiling of paraffin-embedded core biopsy tissue. Breast Cancer Res Treat 103:197–208, 2007.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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