A qualitative transcriptional signature to reclassify estrogen receptor status of breast cancer patients

Purpose: Immunohistochemistry (IHC) assessment of the estrogen receptor (ER) status has low consensus among pathologists. Quantitative transcriptional signatures are highly sensitive to the measurement variation and sample quality. Here, we developed a robust qualitative signature, based on within-sample relative expression orderings (REOs) of genes, to reclassify ER status. Methods: From the gene pairs with significantly stable REOs in ER+ samples and reversely stable REOs in ER− samples, concordantly identified from four datasets, we extracted a signature to determine a sample’s ER status through evaluating whether the REOs within the sample significantly match with the ER+ REOs or the ER− REOs. Results: A signature with 112 gene pairs was extracted. It was validated through evaluating whether the reclassified ER+ or ER− patients could benefit from tamoxifen therapy or neoadjuvant chemotherapy. In three datasets for IHC-determined ER+ patients treated with post-operative tamoxifen therapy, 11.6–12.4% patients were reclassified as ER− by the signature and, as expected, they had significantly worse recurrence-free survival than the ER+ patients confirmed by the signature. On another hand, in two datasets for IHC-determined ER− patients treated with neoadjuvant chemotherapy, 18.8 and 7.8% patients were reclassified as ER+ and, as expected, their pathological complete response rate was significantly lower than that of the other ER− patients confirmed by the signature. Conclusions: The REO-based signature can provide an objective assessment of ER status of breast cancer patients and effectively reduce misjudgments of ER status by IHC.