Estrogen and HER-2 receptor discordance between primary breast cancer and metastasis

Abstract

Discordance in estrogen receptor and human epidermal growth factor receptor 2 receptor status between the primary tumor and recurrence is frequently reported in the literature. This is frequently interpreted as evidence for a change in the biology of breast cancer during the course of the disease. This commentary discusses some of the caveats of this interpretation. Discordant receptor results can be caused by any of 3 factors: (a) a genuine switch in the biology of the disease, (b) sampling error in focally receptor-positive cancers, and (c) limited accuracy and reproducibility of receptor assays. The relative contribution of each of these factors to discordant results is unknown. A switch in molecular class between primary and recurrent cancer (or residual cancer after therapy) appears to be a rare event based on the available limited molecular profiling data. Small pockets of strongly focally receptor-positive tumor nests in a larger receptor-negative cancer are also relatively infrequently seen. Discordance resulting from inherent limitations in assay reproducibility is evident from the frequently discordant receptor results even when the same samples are assessed in different laboratories (e.g., central versus local laboratory). A repeat tumor biopsy is clearly justified when it is suspected, on clinical grounds, that the original receptor results may have been false negative or when the diagnosis of metastatic disease is in question. However, routine repeat biopsy for receptor re-evaluation does not necessarily improve diagnostic accuracy and have a potential to harm through a false-negative result. For patients with clinical courses consistent with hormone responsiveness, or with prior positive hormone receptor results, a course of endocrine therapy is reasonable regardless of the most recent hormone receptor assay result.

Figure 1.

Expected concordance rate when the same assay is repeated on the same patient cohort. In this example, the test has 90% sensitivity and specificity (overall accuracy of 90%), the measurement error is random, and the test is applied to 160 tumors. Cases in the boxes represent discordant results between two measurements: 9 + 9 + 5 + 5 = 28, corresponding to a 17.5% discordance rate. After the second test, the same number of cases remain false negative or false positive as after the first test, n = 10 (cases underlined), resulting in no overall improvement in diagnostic accuracy. If repeat testing is limited only to the false-negative cases of the first test, the discordance rate would be high (90%) but the overall diagnostic accuracy would improve substantially. Abbreviation: ER, estrogen receptor.