{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:16:57Z","timestamp":1785406617845,"version":"3.56.0"},"reference-count":80,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Project of Shanghai Municipal Health Commission","award":["202140232"],"award-info":[{"award-number":["202140232"]}]},{"name":"Climb Plan of Tongji University Affiliated Yangpu Hospital","award":["Ye2202105"],"award-info":[{"award-number":["Ye2202105"]}]},{"award":["Ye2202105"],"award-info":[{"award-number":["Ye2202105"]}],"id":[{"id":"https:\/\/ror.org\/03rc6as71","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Project of College-level Key Discipline of Yangpu Hospital Affiliated to Tongji University","award":["2023YJXK01"],"award-info":[{"award-number":["2023YJXK01"]}]},{"award":["2023YJXK01"],"award-info":[{"award-number":["2023YJXK01"]}],"id":[{"id":"https:\/\/ror.org\/03rc6as71","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cyclin-dependent kinase 4\/6 inhibitors have fundamentally changed the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. However, these drugs are not interchangeable and the field is moving away from the notion of a uniform \u201cclass effect.\u201d In early breast cancer, adjuvant abemaciclib and ribociclib improve invasive disease-free survival in patients at a high risk of recurrence, whereas palbociclib does not. This difference likely stems from agent-specific pharmacological profiles, differences in trial design, and patient selection, rather than simply dosing nuances. In metastatic breast cancer, all three agents prolong progression-free survival when combined with endocrine therapy, but only ribociclib and potentially abemaciclib have shown an overall survival advantage. In addition, resistance remains a major obstacle in clinical practice. We propose that resistance mechanisms can be meaningfully grouped into two categories: target-driven (e.g., RB1 loss, CDK6 amplification) and bypass-driven (e.g., ESR1 mutations, PI3K\/AKT pathway activation, APOBEC3-mediated mutagenesis). Distinguishing between these classes helps in the design of rational sequencing algorithms and combinatorial regimens. Emerging strategies, such as next-generation protein degraders, oral selective estrogen receptor degraders, antibody\u2013drug conjugates, and inhibition of autophagy, are promising methods for overcoming resistance. Moving forward, the greatest need in breast cancer treatment will be not simply developing additional agents but using current therapies more intelligently by refining biomarker-guided patient selection, tailoring treatment duration, and ensuring broad global access.<\/jats:p>","DOI":"10.3390\/cancers18152376","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:05:42Z","timestamp":1784819142000},"page":"2376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CDK4\/6 Inhibitors in Breast Cancer: Clinical Applications, Translational Insights, and Future Directions"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2302-9930","authenticated-orcid":false,"given":"Mengying","family":"Guan","sequence":"first","affiliation":[{"name":"Department of Breast Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s10549-024-07469-6","article-title":"Trends in HR+ metastatic breast cancer survival before and after CDK4\/6 inhibitor introduction in the United States: A SEER registry analysis of patients with HER2\u2212 and HER2+ metastatic breast cancer","volume":"208","author":"Brufsky","year":"2024","journal-title":"Breast Cancer Res. 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