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Diagnostic Technologies and Molecular and Cellular Profiling: Biomarker Assay Development, Validation, and Qualification

Assessment of hormone receptor status in breast cancer by immunohistochemical and gene expression assays

Celera Diagnostics, Alameda, CA, University of California, San Francisco, CA, Laboratory Corporation of America, Research Triangle Park, NC, California Pacific Medical Center, San Francisco, CA

Abstract

A10

Accurate measurement of hormone receptor expression is critical for the care of breast cancer patients. Immunohistochemical (IHC) assays are currently the most widely used method for hormone receptor determination. While IHC assays have broad utilization there are concerns regarding standardization of methods and interpretation. We assessed hormone receptor status using contemporary estrogen (ER) and progesterone (PR) receptor IHC assays as well as real-time quantitative RT-PCR assays to measure gene expression (GE) levels of ER, PR and additional mRNAs involved in receptor expression.Tumor specimens from 315 well-characterized, early-stage, node-negative breast cancer patients were examined. Although the patients were diagnosed between 1975 and 1986, IHC assays for ER and PR were performed using current methods in a single laboratory. Tumors with an Allred score >3 were classified as positive; those <3 were classified as negative. For GE assays, a procedure that permits analysis of routinely-collected and processed, formalin-fixed, paraffin-embedded sections was used. Positive and negative receptor status was assigned according to cut points determined by a 2-mean clustering algorithm. The concordance rate between these two methods and the degree of agreement by kappa statistics with 95% confidence intervals (CI) were calculated.There was a significant correlation between IHC and GE assays. For ER status, the concordance rate was 88% while the kappa statistic (95% CI) was 0.64 (0.53 - 0.75). For IHC ER-positive and ER-negative patients, the ER GE assay scored 87% as positive and 91% as negative, respectively. For PR status, the concordance rate was 87% while the kappa statistic was 0.7 (0.6-0.79). For IHC PR-positive and PR-negative patients, the PR GE assay scored 86% as positive and 89% as negative, respectively. A multi-gene expression signature was also developed for hormone receptor status and will be discussed.These results demonstrate a high concordance for scoring ER and PR status between IHC and GE assays. A multi-gene signature shows promise to capture information from a combination of mRNAs that may provide a more complete assessment of hormone receptor status. The approximately 10% of samples discordant between IHC and GE merit further investigation to determine if the results can provide valuable complementary information for optimal breast cancer treatment selection. Since GE assays are sensitive, quantitative and can be readily standardized, they may complement existing laboratory IHC methods.