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However, the efficacy of T-DM1 for patients after failure of pyrotinib and\/or trastuzumab plus pertuzumab has not been clear. Additionally, no biomarker has been reported to predict the effect of T-DM1. In this multicenter phase II trial (NCT06125834), 36 participants with HER2-positive metastatic breast cancer were enrolled to receive T-DM1 therapy on a 21-day cycle until progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints included the disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and toxicity. The primary endpoint was an ORR of 47.2% (17\/36, 95% CI 30.4\u201364.5). The treatment exhibited a manageable toxicity profile. The DCR was 66.7% (24\/36, 95% CI 49.0\u201381.4), and the CBR was 50.0% (18\/36, 95% CI 32.9\u201367.1). The median PFS was 6.6 (95% CI 5.2-NA) months. Single-cell RNA sequencing revealed that the low cell cycle activity of cancer cells, activated macrophages and CD8+ T cells was associated with the good efficacy of T-DM1, which was validated in a neoadjuvant cohort. This study suggests that T-DM1 is effective with a measurable safety profile in patients with metastatic HER2-positive breast cancer after failure of pyrotinib and\/or trastuzumab plus pertuzumab. Our preliminary findings suggest potential biomarkers that may help predict T-DM1 efficacy, generating hypotheses for novel therapeutic targets that may address T-DM1 resistance.<\/jats:p>","DOI":"10.1038\/s41392-025-02409-2","type":"journal-article","created":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T23:02:50Z","timestamp":1759100570000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tumor microenvironment delineates differential responders to trastuzumab emtansine in HER2-positive metastatic breast cancer patients previously treated with pyrotinib: an exploratory biomarker analysis of a phase II study (NJMU-BC02)"],"prefix":"10.1038","volume":"10","author":[{"given":"Hong","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanfan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingduo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrui","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1220-6797","authenticated-orcid":false,"given":"Wenbin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"2409_CR1","doi-asserted-by":"publisher","first-page":"3997","DOI":"10.1200\/JCO.2013.50.9984","volume":"31","author":"AC Wolff","year":"2013","unstructured":"Wolff, A. 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