{"doi":"10.1002/ijc.33969","title":"Clinical and molecular characteristics of estrogen receptor‐positive ultralow risk breast cancer tumors identified by the 70‐gene signature","abstract":"The metastatic potential of estrogen receptor (ER)-positive breast cancers is heterogeneous and distant recurrences occur months to decades after primary diagnosis. We have previously shown that patients with tumors classified as ultralow risk by the 70-gene signature have a minimal long-term risk of fatal breast cancer. Here, we evaluate the previously unexplored underlying clinical and molecular characteristics of ultralow risk tumors in 538 ER-positive patients from the Stockholm tamoxifen randomized trial (STO-3). Out of the 98 ultralow risk tumors, 89% were luminal A molecular subtype, whereas 26% of luminal A tumors were of ultralow risk. Compared to other ER-positive tumors, ultralow risk tumors were significantly (Fisher's test, P < .05) more likely to be of smaller tumor size, lower grade, progesterone receptor (PR)-positive, human epidermal growth factor 2 (HER2)-negative and have low Ki-67 levels (proliferation-marker). Moreover, ultralow risk tumors showed significantly lower expression scores of multi-gene modules associated with the AKT/mTOR-pathway, proliferation (AURKA), HER2/ERBB2-signaling, IGF1-pathway, PTEN-loss and immune response (IMMUNE1 and IMMUNE2) and higher expression scores of the PIK3CA-mutation-associated module. Furthermore, 706 genes were significantly (FDR < 0.001) differentially expressed in ultralow risk tumors, including lower expression of genes involved in immune response, PI3K/Akt/mTOR-pathway, histones, cell cycle, DNA repair, apoptosis and higher expression of genes coding for epithelial-to-mesenchymal transition and homeobox proteins, among others. In conclusion, ultralow risk tumors, associated with minimal long-term risk of fatal disease, differ from other ER-positive tumors, including luminal A molecular subtype tumors. Identification of these characteristics is important to improve our prediction of nonfatal vs fatal breast cancer.","journal":"International Journal of Cancer","year":2022,"id":256158,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9573,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":385635,"name":"Nancy Yu","orcid":"0000-0001-8321-8141","position":1,"is_corresponding":false},{"id":711477,"name":"Adina Iftimi","orcid":"0000-0001-8117-3461","position":2,"is_corresponding":false},{"id":797292,"name":"Nicholas P. Tobin","orcid":"0000-0003-2343-9772","position":3,"is_corresponding":false},{"id":905479,"name":"Laura van 't Veer","orcid":null,"position":4,"is_corresponding":false},{"id":711478,"name":"Bo Nordenskjöld","orcid":"0000-0002-2134-7586","position":5,"is_corresponding":false},{"id":1907,"name":"Christopher C. Benz","orcid":"0000-0001-5479-4641","position":6,"is_corresponding":false},{"id":601443,"name":"Tommy� Fornander","orcid":null,"position":7,"is_corresponding":false},{"id":712332,"name":"Gizeh Pérez‐Tenorio","orcid":null,"position":8,"is_corresponding":false},{"id":600878,"name":"Olle Stål","orcid":"0000-0002-8290-0592","position":9,"is_corresponding":false},{"id":74873,"name":"Laura J. Esserman","orcid":"0000-0001-9202-4568","position":10,"is_corresponding":false},{"id":14257,"name":"Christina Yau","orcid":"0000-0002-1937-0859","position":11,"is_corresponding":false},{"id":666890,"name":"Linda S. Lindström","orcid":"0000-0002-7722-7532","position":12,"is_corresponding":false},{"id":711475,"name":"Annelie Johansson","orcid":"0000-0001-9029-1996","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T00:25:21.336200Z","pmid":"35179782","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}