Quantitative immunohistochemistry of estrogen receptor in breast cancer - "Much Ado About Nothing!"

The value of a clinical test should be assessed in the overall context of disease management. The ultimate goal of an assay for detection of estrogen receptor (ER) content in breast cancer tissue is to identify patients who will or will not benefit from endocrine therapy. In the past 2 decades, scenarios for ER testing of patient samples have shifted from tissue homogenate-based, biochemical ligand-binding assays to the more practical and clinically relevant slide-based immunohistochemical methods. Although the superiority of the predictive value of ER-immunohistochemistry (ER-IHC) over ligand-binding techniques has been established to everyone's satisfaction, there remains the controversial issue of quantitation of immunohistochemical results. The assumption that ER-IHC should be quantitative stems largely from the fact that the old biochemical assay results were numerical. Seasoned immunohistochemists, nevertheless, know that IHC of routinely fixed and processed tissue does not yield itself to accurate quantitation of results, even when performed by well-qualified laboratories. Furthermore, in the case of ER, immunohistochemical methods only identify a segment or epitope of ER protein that is immunologically reactive with the used antibody. Hence, as it is, an immunohistochemical technique gives no information about the functional status of ER molecule, and/or that of the complex downstream ER pathways. This may be one of the reasons why one-third of patients with ER-positive breast cancers initially, and another one-third eventually, do not respond to endocrine treatment modalities. In this review, I attempt to present an argument that is based on our current information; quantitation of ER-IHC is neither technically reliable nor clinically relevant.