Global Transcriptional Complexity of Estrogen Receptor Low Positive Breast Cancers in a Prospective Swedish Population-based SCAN-B Cohort

Abstract Purpose: There is uncertainty whether ER-low tumors with a 1-10% immunohistochemical staining of nuclei represent a distinct molecular biological entity of BC, posing significant challenges for their clinical management and developing novel therapies. We aimed to elucidate ER-low tumor biology. Experimental Design: We analyzed primary tumors included in a Swedish population-based SCAN-B BC cohort, 2% (n=174) of which were classified ER-low. Transcriptional patterns, tumor inflammatory infiltration and prognosis were compared between ER-low versus ER-negative (ER-neg; 0%) and ER-positive (ER-pos; >10%) tumors. Results: The transcriptomes of ER-low and ER-neg tumors remarkably overlapped; displaying predominantly non-luminal PAM50 subtypes and down-regulated ER signaling. All TNBC molecular subtypes were represented within ER-low/HER2-negative BC. Unsupervised clustering algorithms failed to segregate ER-low/HER2-negative from TNBC tumors and only 2 genes were significantly differentially expressed above 1.5 fold-difference between the groups. However, borderline ER-low tumors (with exactly10% ER) were mostly assigned labels associated with luminal disease biology suggesting possible endocrine responsiveness. Lymphocyte infiltration was comparable between ER-low and ER-neg but was significantly higher relative to ER-pos tumors. Within ER-low/HER2-negative disease, HR-positivity and low/intermediate PAM50 ROR score inferred from RNAseq data and lymphocyte fraction ≥30%, were respectively associated with better prognosis. Conclusions: ER-low/HER2-negative is not a distinct BC molecular biological entity but an integral part of TNBC deserving similar treatments. Nonetheless, a few borderline cases with moderately active ER-signaling can potentially respond to ET. HR-related signatures and TILs may stratify ER-low/HER2-negative tumors according to risk for recurrence. The true benefit of ET in ER-low BC requires prospective investigation.