Letters Section Editor: Stephen J. Lurie,
MD, PhD, Senior Editor.
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.
Yaziji H. HER-2 and Fluorescent In Situ Hybridization to Evaluate Breast Cancer—Reply. JAMA. 2004;292(3):328. doi:10.1001/jama.292.3.328-b