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However, current measurements using immunohistochemistry (IHC) are limited by interobserver variability and lack of standardized cutoffs. To address this, we investigated the association of Ki67 gene (\n                      <jats:italic>MKI67<\/jats:italic>\n                      ) expression with biological features and treatment response in estrogen receptor-positive (ER+) breast cancer (BC), the most common subtype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Patients and Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed 5036 patients with ER+\/HER2\u2212 BC across 11 independent cohorts with tumor transcriptomes and clinical data. Patients with\n                      <jats:italic>MKI67<\/jats:italic>\n                      expression in the top 20% were defined as the high-expression group on the basis of prior IHC-based thresholds.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>MKI67<\/jats:italic>\n                      expression correlated with Nottingham histologic grade and proliferation score, and consistently enriched all the hallmark cell proliferation-related gene sets across TCGA, METABRIC, and SCAN-B cohorts. High\n                      <jats:italic>MKI67<\/jats:italic>\n                      expression trended toward worse survival but achieved statistical significance only in the METABRIC cohort.\n                      <jats:italic>MKI67<\/jats:italic>\n                      high ER+\/HER2\u2212 BC was associated with increased mutation rates, fraction altered, homologous recombination deficiency and intratumoral genomic heterogeneity.\n                      <jats:italic>MKI67<\/jats:italic>\n                      expression was associated with infiltration of Th1 and Th2 cells as well as M1 and M2 macrophages across three cohorts. Conversely,\n                      <jats:italic>MKI67<\/jats:italic>\n                      low ER+\/HER2\u2212 BC was enriched for Hypoxia, Coagulation, Epithelial-to-Mesenchymal Transition, NOTCH, Hedgehog, TGF-beta, and KRAS-signaling gene sets.\n                      <jats:italic>MKI67<\/jats:italic>\n                      high ER+\/HER2\u2212 BC was associated with a higher pathological complete response (pCR) rate in four of the eight neoadjuvant chemotherapy cohorts.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      High\n                      <jats:italic>MKI67<\/jats:italic>\n                      expression identifies highly proliferative tumors that are associated with genomic instability and immune activity and is associated with higher pCR rates following neoadjuvant chemotherapy in ER+\/HER2\u2212 BC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1245\/s10434-026-19620-2","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T18:42:00Z","timestamp":1775846520000},"page":"6422-6432","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ki67 Gene Expression is Associated with Immune Cell Infiltration and Neoadjuvant Chemotherapy Response in ER+\/HER2\u2212 Breast Cancer"],"prefix":"10.1245","volume":"33","author":[{"given":"Kohei","family":"Chida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongrong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Kawashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Grapes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itaru","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Hakamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6435-4241","authenticated-orcid":false,"given":"Kazuaki","family":"Takabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"issue":"5","key":"19620_CR1","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan D, Weinberg RA. 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