Global Transcriptional Complexity of Estrogen Receptor–Low Positive Breast Cancers in the Prospective Swedish Population–Based SCAN-B Cohort

Abstract

Purpose: There is uncertainty whether estrogen receptor (ER)– low tumors with 1% to 10% IHC staining of nuclei represent a distinct molecular biological entity of breast cancer, posing significant challenges for their clinical management and the development of novel therapies. We aimed to elucidate ER-low tumor biology. Experimental Design: We analyzed primary breast tumors included in the Swedish population–based Sweden Cancerome Analysis Network-Breast (SCAN-B) cohort, 2% (n ¼ 174) of which were classified as 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 nonluminal PAM50 subtypes and downregulated ER signaling. All triple-negative breast cancer (TNBC) molecular subtypes were represented within ER-low/HER2-negative breast cancer. Unsupervised clustering algorithms failed to segregate ER-low/HER2-negative from TNBC tumors, and only two genes showed significant differential expression above a 1.5-fold difference between the groups. However, borderline ER-low tumors (with exactly 10% 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-postumors. Within ER-low/HER2-negative disease, hormone receptor positivity and low/intermediate PAM50 risk of recurrence score inferred from RNA sequencing data and lymphocyte fraction ≥30% were respectively associated with a better prognosis. Conclusions: ER-low/HER2-negative is not a distinct breast cancer 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 endocrine therapies. Hormone receptor–related signatures and tumor-infiltrating lymphocytes may stratify ER-low/HER2-negative tumors according to the risk of recurrence. The true benefit of endocrine therapies in ER-low breast cancer requires prospective investigation.