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July 21, 2004

HER-2 and Fluorescent In Situ Hybridization to Evaluate Breast Cancer—Reply

Author Affiliations

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2004;292(3):328. doi:10.1001/jama.292.3.328-b

In Reply: Dr Tanvetyanon is concerned that some 3+ IHC test results would be found to be false-positives if evaluated with FISH. It is not clear whether this is true. First, the mechanism underlying protein overexpression is not limited to gene amplification. In 2 large studies (561 and 690 invasive breast cancers, respectively),1,2 chromosome 17 polysomy was found in almost half of the tumors with 3+ IHC with negative FISH results, suggesting an increased absolute number of chromosome 17 alleles in these cases led to HER-2 protein overexpression. Second, some studies indicate a response to trastuzumab in patients with 3+ IHC with negative FISH results. In the study by Vogel et al,3 the group of patients with 3+ IHC with negative FISH results composed of 30 patients, 3 of whom (10%) showed response to treatment. Furthermore, in the reanalysis by the Food and Drug Administration of company data to validate FISH testing, that group of patients had the highest response rate, regardless of FISH results.4 Thus, a 3+ IHC with negative FISH test result may not reflect a deficiency in IHC but rather an alternate mechanism of protein overexpression that may well respond to treatment, as it is the HER-2 protein that is targeted, not the gene. Therefore, FISH is most useful in confirming more uncertain 2+ score test results. In the case of chromosome 17 aneuploidy, FISH retesting of tumors with reliable 3+ score are not only unnecessary but could be misleading if the test results are negative.