{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:58:22Z","timestamp":1790751502836,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Estrogen receptor (ER)\u2010positive\/HER2\u2010positive breast cancer demonstrates significantly lower rates of pathological complete response (pCR) to neoadjuvant HER2\u2010targeted therapies compared to ER\u2010negative\/HER2\u2010positive disease. However, the optimal ER positivity cutoff for clinically meaningful patient stratification remains undefined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed a retrospective cohort of 741 HER2\u2010positive breast cancer patients treated with neoadjuvant chemotherapy plus dual HER2 blockade (trastuzumab and pertuzumab) at Sun Yat\u2010sen University Cancer Center. The optimal ER cutoff for predicting pCR was determined by ROC analysis with Youden index and validated by bootstrap resampling (1000 iterations). Transcriptomic data from TCGA and SCAN\u2010B cohorts were analyzed to characterize biological differences between ER subgroups. Drug response was predicted using the oncoPredict algorithm, and cancer dependency was assessed using DepMap CRISPR screening data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ER\u2009\u2265\u200950% positivity was identified as the optimal predictive cutoff (bootstrap 95% CI: 25.0%\u201377.5%) and was an independent predictor of significantly lower pCR rates in multivariate analysis (OR\u2009=\u20090.27; 95% CI: 0.19\u20130.40;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Transcriptomic analysis revealed that ER\u2009\u2265\u200950% tumors are characterized by activated estrogen response signaling, downregulated cell cycle and immune pathways. Predicted resistance to trastuzumab, T\u2010DM1, and T\u2010DXd was consistently enriched in this subgroup, consistent with lower HER2 and CD16A expression observed in ER\u2009\u2265\u200950% tumors. CCND1, a canonical transcriptional target of ESR1, was significantly upregulated in ER\u2009\u2265\u200950% tumors across both cohorts, and ER\u2009+\u2009\/HER2\u2009+\u2009cell lines exhibited significantly higher CCND1 and CDK4 dependency scores in DepMap CRISPR screening (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), supporting activation of the ESR1\u2010CCND1\u2010CDK4\/6 axis in this subgroup.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>ER\u2009\u2265\u200950% positivity defines a clinically and biologically distinct HER2\u2010positive subgroup with poor response to standard neoadjuvant therapy and predicted resistance to ADCs, consistent with lower HER2 and CD16A expression in this subgroup. The convergent transcriptomic and functional evidence for ESR1\u2010CCND1 axis activation provides mechanistic support for combining CDK4\/6 inhibitors with endocrine and anti\u2010HER2 therapies to improve outcomes in this resistant subgroup.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.72331","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:23:13Z","timestamp":1790749393000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing the\n                    <scp>ER<\/scp>\n                    Cutoff in\n                    <scp>HER2<\/scp>\n                    \u2010Positive Breast Cancer:\n                    <scp>ER<\/scp>\n                    \u2009\u2265\u200950% Predicts Low\n                    <scp>pCR<\/scp>\n                    Rates and Resistance to Antibody\u2010Drug Conjugates in the Neoadjuvant Setting"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0841-6484","authenticated-orcid":false,"given":"Tian","family":"Du","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Breast Oncology Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Ultrasound Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gehao","family":"Liang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Breast Oncology Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Breast Oncology Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Breast Oncology Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Breast Oncology Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luhao","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Breast Oncology Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9788-8389","authenticated-orcid":false,"given":"Jun","family":"Tang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"},{"name":"Department of Breast Oncology Sun Yat\u2010Sen University Cancer Center  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.breast.2024.103733","article-title":"Distinct ER and PR Expression Patterns Significantly Affect the Clinical Outcomes of Early HER2\u2010Positive Breast Cancer: A Real\u2010World 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