ABCG2 genetic variant as risk factor for neutropenia in patients with metastatic or advanced hormone receptor -positive, HER2-negative breast cancer treated with palbociclib

Background Palbociclib, combined with endocrine therapy (ET), is widely used for hormone receptor (HR)-positive, HER2-negative advanced breast cancer, but severe neutropenia is common, particularly in Asian populations. Pharmacogenetic determinants beyond ABCB1 remain insufficiently characterized, and real-world data in Japanese patients are scarce. Methods A total of 84 patients were investigated for their absolute neutrophil count (ANC) within the first cycle of Palbociclib plus ET at the National Cancer Center (NCC) Hospital East (2017-2023). DNA samples obtained from the NCC Biobank Registry were used for the analysis of seven genetic (ABCB1, ABCG2, CYP3A4, CYP3A5) polymorphisms related to Palbociclib pharmacokinetics. These genotypes were evaluated for their association with Grade 3/4 neutropenia, and further their risk factors were examined using a multivariate logistic regression. Results Severe neutropenia occurred in 71.4% of patients. In multivariate analysis, low baseline ANC (≤4510/μL) independently predicted severe neutropenia (odds ratio [OR] 16.249, p < 0.001). Notably, the ABCG2 rs2231142 AA genotype was also an independent risk factor (OR 19.198, p = 0.019). Variants in ABCB1, CYP3A4, and CYP3A5 showed no significant associations. The findings align with the concentration-dependent nature of palbociclib-induced neutropenia and the reduced transport activity conferred by the ABCG2 421A allele, which may increase systemic exposure. Conclusions ABCG2 rs2231142 and low baseline ANC independently predict Grade 3/4 neutropenia in Japanese patients receiving palbociclib.