{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:12:09Z","timestamp":1787703129773,"version":"build-2784847793"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Estrogen receptor (ER)-low human epidermal growth factor receptor 2 (HER2)-negative breast cancer shares similar pathological and molecular features with triple-negative breast cancer, yet the utility of the 21-gene assay in this population remains uncertain. This study aimed to evaluate the distribution and molecular drivers of the 21-gene recurrence score (RS) in early breast cancer with low, intermediate, and high ER expression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ER-positive, HER2-negative early breast cancer patients with 21-gene testing results from Shanghai Jiao Tong University Breast Cancer Database (2009-2022) were included. Eligible patients were categorized into three groups: ER-low (1-9%), ER-intermediate (10-50%), and ER-high (&amp;gt;50%). Chi-square and Kruskal-Wallis tests were conducted to compare the 21-gene RS and expression profiles among these groups. Spearman correlation and linear variance decomposition were performed to assess the associations between RS and its constituent gene modules.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 4754 patients were included (ER\u2011low: 70, 1.5%; ER\u2011intermediate: 129, 2.7%; ER\u2011high: 4555, 95.8%). Mean RS values were 39, 32, and 24 in the three groups, with RS &amp;gt;25 observed in 72.9%, 62.8%, and 42.5% of patients, respectively (P &amp;lt; 0.001).. Among patients with ER-low tumors, the rates of RS &amp;gt;25 were 62.5% and 81.6% for those \u226450 or &amp;gt;50 years, 66.7% and 83.3% for those with low or high clinical risk, and 61.6% and 87.1% for those with PR-positive or PR-negative diseases, respectively. Notably, 90.6% younger patients had RS &amp;gt;15 in the ER-low group. Expression of\n                      <jats:italic>ESR1<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001),\n                      <jats:italic>PGR<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001),\n                      <jats:italic>BCL2<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.035),\n                      <jats:italic>SCUBE2<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001) from the ER module, and\n                      <jats:italic>STMY3<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.001) from the invasion module were significantly lower in ER-low than in ER-high. Only, the proliferation module had a modest correlation with RS among patients with ER-low tumors (R\u00a0=\u00a00.34,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a00.0076). Variance decomposition showed that the four modules explained only 8.83% of RS variance in ER\u2011low tumors (7.38% from proliferation), compared with 48.74% (42.93% from ER module) in ER\u2011high and 28.97% (21.94% from ER module) in ER\u2011intermediate tumors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The 21-gene RS was higher in ER-low breast cancer patients, particularly among those \u226450 years, with high clinical risk or PR-negative diseases. RS was only moderately correlated with proliferation features and minimally determined by any of the four module components in ER-low tumors. These findings are exploratory and require further validation in larger cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1653477","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T05:40:01Z","timestamp":1777527601000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Distribution and molecular drivers of the 21-gene recurrence score in early breast cancer with low, intermediate, and high estrogen receptor expression"],"prefix":"10.3389","volume":"17","author":[{"given":"Shuai","family":"Li","sequence":"first","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifei","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siji","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqi","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ou","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianrong","family":"He","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, 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