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Here, we review evidence supporting de-escalation in the neoadjuvant setting from docetaxel or paclitaxel, carboplatin, trastuzumab, pertuzumab to docetaxel or paclitaxel, trastuzumab, pertuzumab with weekly paclitaxel and examine biomarker-guided strategies for further de-escalation, including chemotherapy-free approaches. DESTINY-Breast11 and DESTINY-Breast05 have established the use of neoadjuvant and postneoadjuvant fam-trastuzumab deruxtecan-nxki, respectively, as new options for high-risk disease, with both indications recently granted approval from the U S Food and Drug Administration. We propose a framework for risk-adapted treatment optimization, highlighting the potential of circulating tumor DNA monitoring and functional imaging as response-adapted strategies and identifying them as priorities for future investigation. Together, these advances support a more precise, individualized approach to caring for patients with early-stage HER2-positive breast cancer.<\/jats:p>","DOI":"10.1200\/jco-26-01423","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T19:59:26Z","timestamp":1788983966000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Risk-Adapted Optimization of Neoadjuvant Therapy in Human Epidermal Growth Factor Receptor 2\u2013Positive Early-Stage Breast Cancer"],"prefix":"10.1200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1720-8804","authenticated-orcid":false,"given":"Sam O.","family":"Kleeman","sequence":"first","affiliation":[{"name":"Department of Medicine, Weill Cornell Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4018-4708","authenticated-orcid":false,"given":"Vered","family":"Stearns","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medicine, New York, NY"},{"name":"Meyer Cancer Center, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00579-0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3798106"},{"key":"e_1_3_4_4_2","first-page":"1550","article-title":"Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2\/neu gene product","volume":"50","author":"Fendly BM","year":"1990","unstructured":"Fendly BM, Winget M, Hudziak RM, et al: Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2\/neu gene product. 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