{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:00:53Z","timestamp":1790863253070,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Palbociclib has shown survival benefits in hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. At present, however, no genetic predictors of palbociclib-related hematological toxicity have been validated for clinical use. The aim of this study was to evaluate whether genetic variants are associated with palbociclib toxicity and patient prognosis. Multicenter study of 113 patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer treated with palbociclib plus endocrine therapy. Genotyping of DNA from blood samples was performed to determine 18 variants in seven target genes (CYP3A4, SULT2A1, ABCB1, ABCG2, NR1I2, POR, and CDKN1B). Association analyses were performed to assess the relationship between the genetic variants and treatment-related toxicity and survival outcomes. Sixty-seven patients (59.3%) developed grade 3\/4 neutropenia, 62 (54.9%) experienced disease progression, and 43 (38.1%) died. Although none of the univariate associations remained significant after Bonferroni correction, the multivariate analysis, adjusted for clinical variables, revealed several nominally significant associations. The NR1I2 gene variants rs6785049 (p = 0.01) and rs3732360 (p = 0.009) were associated with grade 3\/4 neutropenia. The NR1I2 rs6785049 variant was associated with palbociclib treatment interruption (p = 0.03) and with worse progression-free (p = 0.003) and overall survival (p = 0.02). The findings of this exploratory study suggest potential associations between the NR1I2 rs6785049 variant and treatment toxicity and survival outcomes in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer treated with palbociclib. However, these hypothesis-generating findings need to be independently validated.<\/jats:p>","DOI":"10.3390\/ijms27188310","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Variation in NR1I2 and Palbociclib Safety and Prognosis in Advanced Breast Cancer: An Exploratory Multicenter Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Cristina","family":"Arqueros","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Spanish Group for Breast Cancer Research (GEICAM), 08041 Barcelona, Spain"},{"name":"Department of Medicine, Faculty of Medicine, Universitat Aut\u00f2noma de Barcelona, 08035 Barcelona, Spain"},{"name":"Translational Medical Oncology Laboratory, Institut 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Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"S\u00f2nia","family":"Servitja","sequence":"additional","affiliation":[{"name":"Spanish Group for Breast Cancer Research (GEICAM), 08041 Barcelona, Spain"},{"name":"Medical Oncology, Hospital del Mar, 08003 Barcelona, Spain"},{"name":"Hospital del Mar Research Institute, 08003 Barcelona, Spain"},{"name":"Department of Medicine and Life Science, Universitat Pompeu Fabra, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1672-0010","authenticated-orcid":false,"given":"J\u00falia","family":"Giner","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Corporaci\u00f3 Sanit\u00e0ria Parc Taul\u00ed, 08208 Sabadell, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0229-6987","authenticated-orcid":false,"given":"Ariadna","family":"Tibau","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain"},{"name":"Program on Regulation, Therapeutics and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02120, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Maria","family":"Borrell","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron Hospital, 08035 Barcelona, Spain"},{"name":"Breast Cancer Group, Vall d\u2019Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8056-7100","authenticated-orcid":false,"given":"Sergio","family":"Martinez-Recio","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0429-1349","authenticated-orcid":false,"given":"Agust\u00ed","family":"Barnadas","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"},{"name":"Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3581-4499","authenticated-orcid":false,"given":"Juliana","family":"Salazar","sequence":"additional","affiliation":[{"name":"Translational Medical Oncology Laboratory, Institut de Recerca Sant Pau (IR Sant Pau), 08041 Barcelona, 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