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A significant proportion of intraductal breast carcinomas (DCIS) demonstrate Her-2/neu amplification/overexpression, suggesting that this oncogene is activated early in the progression of malignant breast disease.
Clinical studies in thousands of patients with breast cancer over the last decade have convincingly demonstrated that amplification/overexpression of Her-2/neu is associated with a poor prognosis. Additional solid tumors with amplification/overexpression of Her-2/neu include gynecologic malignancies (ovary and endometrium), and prostatic, pancreatic and hepatocellular adenocarcinomas; most studies in these malignancies also support the notion that increased Her-2/neu levels are associated with an adverse prognosis.
One of the reasons why the association between Her-2/neu status and prognosis is not unanimous in all series may relate to the method of detecting Her-2/neu levels. Before the advent of fluorescence in situ hybridization (FISH), investigators relied solely on immunohistochemistry (IHC) to determine Her-2/neu status. In archival tissues, Her-2/neu overexpression by IHC does not always correlate with increase in copy numbers of the Her-2/neu gene by FISH. The latter has been found to be more reliable and reproducible than IHC in demonstrating Her-2/neu status. FISH circumvents antigenic changes that may occur in formalin-fixed paraffin tissues, a major limitation of IHC. Measurement of Her-2/neu alteration in archival breast cancers by FISH has been shown to have comparable specificity and sensitivity to Northern and Western blot analyses in fresh tissues. Recent data from large retrospective studies in breast cancer patients has revealed that survival results for women with Her-2/neu overexpression in the absence of Her-2/neu gene amplification is statistically indistinguishable from patients who are negative with both techniques, while a positive FISH result by itself, with or without IHC corroboration, is a significantly better discriminator of adverse prognosis.
Veripath OncoDiagnostics has extensive experience with the assessment of Her-2/neu status in solid tumors. In keeping with the current consensus guidelines, we have adopted a two-pronged strategy to analyze Her-2/neu in archival tissues. At the initial step, all cases are examined by IHC using the primary polyclonal Her-2/neu antibody, A0485 (Dako Corp., Carpenteria, CA). All cases are evaluated with an automated image analysis system and scored at a predetermined cut off value. All cases that are positive for Her-2/neu by IHC are automatically subjected to FISH analysis using the Food and Drug Administration-approved PathVysion™ assay (Vysis Inc.) Due to occasional false negative results with Her-2/neu IHC assay (approx. 8%) all cases with clinically suspicious parameters (i.e. ER/PR negative, increased Ki-67 and Her-2/neu negative are also subjected to FISH assay. In order to preserve absolute stringency of the FISH assay, the results are analyzed using the Quips genetic software and verified by a staff pathologist. The detailed methodologies for the Her-2/neu IHC and the PathVysion™ FISH assay have been previously published by our laboratory (see Reference #4 below). The evaluation of Her-2/neu status is currently offered as part of the breast, ovarian, endometrial, pancreatic, prostate and hepatocellular carcinoma panels, but it can also be ordered individually. Phospho-Specific Her-2/neu is also available for all Breast carcinoma cases. For more information contact Dr Raheela Ashfaq at Veripath OncoDiagnostics at 214.645.7053 or Raheela.Ashfaq@UTSouthwestern.edu.
Selected references:
1. Pauletti G et al. Assessment of the methods for tissue-based detection of the Her-2/neu alteration in human breast cancer: a direct comparison of fluorescence in situ hybridization and immunohistochemistry. J Clin Oncol 18:3651; 2000
2. Press MF et al. Her-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol 15:2894; 1997
3. Ross JS et al. The Her-2/neu oncogene: prognostic factor, predictive factor and target for therapy. Sem Cancer Biol 9:125; 1999
4. Wang S et al. Laboratory assessment of the status of Her-2/neu protein and oncogene in breast cancer specimens: comparison of immunohistochemistry assay with fluorescence in situ hybridization assays. J Clin Pathol 53:374; 2000
5. Wang S, Hossein Saboorian M, Frenkel EP, Haley BB, Siddiqui MT, Gokaslan S, Hynan L, Ashfaq R. Aneusomy 17 in breast cancer: its role in HER-2/neu protein expression and implication for clinical assessment of HER-2/neu status. Mod Pathol. 2002 Feb;15(2):137-45
6. Wang S, Saboorian MH, Frenkel EP, Haley BB, Siddiqui MT, Gokaslan S, Wians FH Jr, Hynan L, Ashfaq R. Assessment of HER-2/neu status in breast cancer. Automated Cellular Imaging System (ACIS)-assisted quantitation of immunohistochemical assay achieves high accuracy in comparison with fluorescence in situ hybridization assay as the standard. Am J Clin Pathol. 2001 Oct;116(4):495-503
7. Maitra A, Wanzer D, Weinberg AG, Ashfaq R. Amplification of the HER-2/neu oncogene is uncommon in pediatric osteosarcomas. Cancer. 2001 Aug 1;92(3):677-83
8. Wang S, Saboorian MH, Frenkel E, Hynan L, Gokaslan ST, Ashfaq R. Laboratory assessment of the status of Her-2/neu protein and oncogene in breast cancer specimens: comparison of immunohistochemistry assay with fluorescence in situ hybridization assays. J Clin Pathol. 2000 May;53(5):374-81 |
