Genetic Variation in NR1I2 and Palbociclib Safety and Prognosis in Advanced Breast Cancer: An Exploratory Multicenter Study
Year: 2026
Type: article
Abstract: 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.
DOI: 10.3390/ijms27188310
Institutions: Universitat Autònoma de Barcelona, Hospital de Sant Pau, GEICAM – Spanish Breast Cancer Group, Institut de Recerca Sant Pau, Universitat Pompeu Fabra, Hospital Del Mar, Hospital del Mar Research Institute, Corporació Sanitària Parc Taulí, Brigham and Women's Hospital, Harvard University, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institute of Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7214434266