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We develop a predictive index to identify patients with increased probability of dose reduction, intolerable toxicities, or therapy discontinuation (hereafter: dose reduction) in metastatic breast cancer (MBC) and compare real\u2010world effectiveness of reduced (RSD) versus full starting dose (FSD) using this index. This analysis included 618 patients with HR\u2010positive, HER2\u2010negative MBC from the prospective, observational, multicenter registry OPAL (NCT03417115), receiving first\u2010line palbociclib (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009386) or ribociclib (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009232) plus endocrine therapy. A logistic regression model was employed to derive the predictive index. Inverse probability of treatment weighting was used to emulate a head\u2010to\u2010head comparison of RSD and FSD by analyzing progression\u2010free (PFS) and overall survival (OS). Within 6\u2009months, 215 patients (35%) underwent dose reduction, including 109 (51%) with RSD. Predictors for dose reduction were age \u226565\u2009years and Charlson comorbidity index (CCI) \u22651. Among patients with increased probability of dose reduction (index \u22651: \u226565\u2009years and\/or CCI\u2009\u2265\u20091), median PFS and OS were 30.1 [21.7, 54.0] and 57.6 [40.0, NA] months with RSD vs. 29.3 [24.9, 32.0] and 43.1 [38.8, 50.3] months with FSD. For low\u2010probability patients (index\u2009=\u20090: &lt;65\u2009years and CCI\u2009=\u20090), median PFS and OS were 17.6 [9.1, 29.8] and 32.9 [23.1, 40.9] months with RSD vs. 24.5 [19.8, 32.0] and 54.2 [48.8, NA] months with FSD. In this real\u2010world MBC setting, patients \u226565\u2009years and\/or with CCI\u2009\u2265\u20091 had an increased probability of dose reduction and may benefit from RSD, as this yielded outcomes comparable to FSD. Younger, fitter patients may require full dosing. Future studies, ideally randomized controlled trials, should aim to confirm these findings.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70433","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T03:06:26Z","timestamp":1773889586000},"page":"244-256","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Prediction of dose reductions and impact of reduced starting doses of\n                    <scp>CDK4<\/scp>\n                    \/6i on effectiveness in\n                    <scp>HR<\/scp>\n                    \u2010positive\/\n                    <scp>HER2<\/scp>\n                    \u2010negative metastatic breast cancer: Real\u2010world data from the\n                    <scp>OPAL<\/scp>\n                    registry"],"prefix":"10.1002","volume":"159","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3372-1819","authenticated-orcid":false,"given":"Patrick","family":"Marschner","sequence":"first","affiliation":[{"name":"Praxis f\u00fcr interdisziplin\u00e4re Onkologie &amp; H\u00e4matologie  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5886-6745","authenticated-orcid":false,"given":"Kai","family":"Ringwald","sequence":"additional","affiliation":[{"name":"Biostatistics iOMEDICO  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Thill","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Gyn\u00e4kologie und Gyn\u00e4kologische Onkologie, Brustzentrum, Agaplesion Markus Krankenhaus  Frankfurt am Main Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark\u2010Oliver","family":"Zahn","sequence":"additional","affiliation":[{"name":"MVZ Onkologische Kooperation Harz  Goslar Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0948-4385","authenticated-orcid":false,"given":"Anja","family":"Welt","sequence":"additional","affiliation":[{"name":"Innere Klinik, Tumorforschung Universit\u00e4tsklinikum Essen  Essen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnd","family":"Nusch","sequence":"additional","affiliation":[{"name":"Praxis f\u00fcr H\u00e4matologie und internistische Onkologie  Ratingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Kaltenecker","sequence":"additional","affiliation":[{"name":"Frauenklinik St\u00e4dtisches Klinikum Karlsruhe  Karlsruhe Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Rodemer","sequence":"additional","affiliation":[{"name":"Praxisgemeinschaft f\u00fcr Onkologie und Urologie  Wilhelmshaven Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Hagen","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Innere Medizin II St. Johannes Hospital  Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Schock","sequence":"additional","affiliation":[{"name":"Ambulantes Therapiezentrum f\u00fcr H\u00e4matologie und Onkologie Onkologie Offenburg  Offenburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Kruggel","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology and Health Economics iOMEDICO  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Kaiser\u2010Osterhues","sequence":"additional","affiliation":[{"name":"Medical Department iOMEDICO  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunja","family":"Klein","sequence":"additional","affiliation":[{"name":"Medical Department iOMEDICO  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5130-9193","authenticated-orcid":false,"given":"Nina","family":"Haug","sequence":"additional","affiliation":[{"name":"Biostatistics iOMEDICO  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elmar","family":"Stickeler","sequence":"additional","affiliation":[{"name":"Gyn\u00e4kologie und Geburtsmedizin Uniklinik RWTH Aachen  Aachen Germany"},{"name":"Center of Integrated Oncology Aachen Bonn Cologne D\u00fcsseldorf (CIO ABCD)  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Harbeck","sequence":"additional","affiliation":[{"name":"Brustzentrum, Frauenklinik und CCC M\u00fcnchen LMU Klinikum  M\u00fcnchen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Achim","family":"W\u00f6ckel","sequence":"additional","affiliation":[{"name":"Frauenklinik und Poliklinik Universit\u00e4tsklinikum W\u00fcrzburg  W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6098-1301","authenticated-orcid":false,"given":"Norbert","family":"Marschner","sequence":"additional","affiliation":[{"name":"Med. 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Available from:https:\/\/jhoponline.com\/issue\u2010archive\/latest\u2010issue\/19651\u2010predictive\u2010factors\u2010of\u2010dose\u2010reduction\u2010among\u2010patients\u2010treated\u2010with\u2010palbociclib\u2010for\u2010advanced\u2010or\u2010metastatic\u2010breast\u2010cancer\u2010in\u2010a\u2010real\u2010world\u2010setting"},{"key":"e_1_2_14_18_1","first-page":"544","article-title":"Palbociclib associated with endocrine therapy in patients with metastatic breast cancer: predictive factors of severe early hematological toxicity","volume":"108","author":"Vazquez L","year":"2019","journal-title":"Breast Cancer"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2019-0019"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.2310"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/10781552221144280"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-020-00771-5"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-021-01415-9"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.SABCS22-PD17-12"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.breast.2021.11.013"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.breast.2025.104448"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm324"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwv254"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-023-06882-7"},{"key":"e_1_2_14_30_1","unstructured":"European Medicines Agency.ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials; 2020 [cited 2024 Dec 11]. 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