Trastuzumab Use in Breast Cancer: Clinical Issues

John Horton, MB, ChB


Cancer Control. 2002;9(6) 

In This Article


The test used for determining HER2 protein expression in the trial by Slamon and colleagues[4] is an immunohistochemical (IHC) "clinical trial assay" that is not commercially available. Several other IHC tests are commercially available, such as the HercepTest (Dako Corp, Carpinteria, Calif). These usually report test results as 0, 1+, 2+, or 3+, with 3+ representing positive, 2+ indeterminate, and 0 or 1+ negative for HER2 protein expression. IHC tests performed in laboratories with a low testing volume were recently shown to correlate poorly with results from large-volume reference laboratories, a factor of particular concern to patients being accrued onto adjuvant treatment studies ( Table 1 ).[5,6] More recent follow-up suggests that correlations are now closer (E. Perez, MD, personal communication, September 2002).

Some laboratories now use quantitative image IHC analysis that provide reports of tumor HER2 protein overexpression as follows:

  • Favorable (staining intensity in tumor cells <1.7)

  • Unfavorable (staining intensity >2.4)

  • Indeterminate (staining intensity between 1.7 and 2.3)

Trastuzumab therapy is considered for breast cancer patients with tumors that demonstrate 3+ overexpression or are in the "unfavorable" IHC category.

Fluorescence in situ hybridization (FISH) technology measures the extent of HER2 gene expression. The PathVysion (Vysis Inc, Downers Grove, Ill) HER2 DNA probe is considered positive when the ratio of HER2 to CEP 17 (chromosome enumeration probe) is ≥2 [7] FISH testing is probably the "gold standard" evaluation of HER2 activity and provides the best correlation with clinical response to trastuzumab,[8,9] although results are similar when correlations of outcomes are made with IHC 3+ or IHC "unfavorable" test results. A FISH test is indicated in situations such as when an IHC result is reported as 2+ or indeterminate, or where there is an aggressive clinical picture of breast cancer in the face of an IHC report of 0 or 1+. Trastuzumab appears to be ineffective when the FISH test demonstrates nonamplification.

Thus, trastuzumab should be considered for use only in breast cancer patients with a tumor that is IHC 3+ or in the "unfavorable" IHC category or have a HER2:CEP 17 ratio of ≥2. Those with an IHC HER2 expression of 2+ should be treated with trastuzumab only if a confirmatory FISH test was done and the result was positive.


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