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Cyclin\u2010dependent kinase 4 and 6 inhibitors, initially established as a standard component of first\u2010line therapy in the metastatic setting based on improvements in progression\u2010free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease\u2010free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high\u2010risk, early\u2010stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment\u2010related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin\u2010dependent kinase 4 and 6 inhibition is modest, especially among the favorable\u2010risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision\u2010making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.<\/jats:p>","DOI":"10.1002\/cncr.70587","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T13:56:07Z","timestamp":1788011767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adjuvant CDK4\/6 inhibitors in early\u2010stage breast cancer: Clinical evidence and considerations for risk stratification and treatment selection"],"prefix":"10.1002","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2299-3061","authenticated-orcid":false,"given":"Austin D.","family":"Williams","sequence":"first","affiliation":[{"name":"Division of Breast Surgery Department of Surgery Fox Chase Cancer Center  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5671-959X","authenticated-orcid":false,"given":"Anna","family":"Weiss","sequence":"additional","affiliation":[{"name":"Pluta Cancer Center University of Rochester  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"issue":"8","key":"e_1_2_11_2_1","first-page":"688","article-title":"The natural history of hormone receptor\u2010positive breast cancer","volume":"26","author":"Lim E","year":"2012","journal-title":"Oncology (Williston Park)"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21777"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1804710"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1602253"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(12)61963\u20101"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMOA1803164;WGROUP:STRING:MMS"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2108873"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1557\u20103265.SABCS25\u2010GS1\u201010"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2026.44.16_SUPPL.502"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1701830"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(24)01745\u20108"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.BREAST.2025.104437"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/S41568\u2010023\u201000604\u20103"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco\u201025\u201000099"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2207586"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prro.2023.11.001"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(21)00539\u20108"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.02514"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2025.10.005"},{"key":"e_1_2_11_21_1","unstructured":"SlamonDJ StroyakovskiyD YardleyDA et\u00a0al.Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+\/HER2\u2212 early breast cancer: primary results from the phase III NATALEE trial. 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