Biomarker discordance: Why it occurs and why it is important

Abstract

Although the analysis of hormone receptors and HER-2/neu has usually been performed on primary tumors only, a growing body of evidence suggests that substantial discordance exists between primary and metastatic disease for estrogen receptors (30-40%) and HER-2/neu (10-30%). This discordance may reflect alterations in pathologic assessment techniques, changes between primary and metastatic breast cancer, differences within a heterogenous tumor, or the effect of treatment. The etiology of discordance is poorly understood and frequently may reflect tumor heterogeneity along with lack of standardized preanalytic and analytic variables. Standardization of diagnostic variables can improve diagnostic reproducibility. Because of the emergence of targeted hormonal and HER-2/neu therapies, tumor biomarkers assume a pivotal role in treatment decisions. The loss of sensitivity to hormones or HER-2/neu may suggest tumor resistance; whereas, the acquisition of hormone receptors and HER-2/neu provides potential new treatment targets which can improve overall patient outcomes.

Discordance of the estrogen receptor and HER-2/neu in breast cancer from primary lesion to first and second metastatic site

“…Because most targeted treatment decisions are recommended on the basis of biomarkers for hormone receptors and HER-2/neu, a change in biomarkers could have a dramatic impact on systemic treatment recommendations. 5 – 7 Certainly, patients whose primary hormone receptor or HER-2/neu tumor biomarkers are negative and subsequent tumors are rendered positive provide great opportunity for additional targeted systemic management with hormone manipulation or HER-2/neu-targeted treatments. We and others have previously shown a substantial discordance rate between primary tumor and metastatic disease, with studies reporting hormone receptor discordance rates between 30% and 40% and HER-2/neu discordance rates between 10% and 30%.…”

“…As with ER discordance, the etiology of HER-2/neu change is probably multifactorial and includes pre-analytical as well as analytical factors. 5 , 22 Tumor heterogeneity makes tissue sampling very problematic. Small case series suggest that HER-2/neu discordance occurs in some patients who have received neoadjuvant trastuzumab for HER-2/neu-positive primary cancers.…”

“…However, today, with a growing body of data suggesting that discordance occurs both for hormone receptors and HER-2/neu, treatment recommendations may change based upon the prevalence of hormone receptors and HER-2/neu in metastatic disease. 5 …”

“…Although the etiology of primary metastatic discordance can include tumor sampling, processing, and analysis as well as intrinsic tumor heterogeneity, 5 the actual cause of discordance can be quite elusive. To date, discordance between estrogen receptors (ER) and HER-2/neu has analyzed primary and metastatic tissue from patients with breast cancer.…”