Simple SummaryPalbociclib, an oral cyclin-dependent kinase 4/6 inhibitor, in combination with endocrine therapy improved outcomes in the metastatic breast cancer patient. Neutropenia (NP) is the most common adverse event, with palbociclib being more frequent among Asians. To date, there is limited data on the factors that increase the risk of early-onset neutropenia after palbociclib treatment and whether neutropenia affects treatment outcomes. We conducted a retrospective study to investigate the risk factors associated with early-developing neutropenia in patients with HR+/HER2−metastatic breast cancer and evaluate median progression-free survival (PFS). Our study showed that early-developing NP was significantly associated with low baseline BSA, ANC, WBC, and PLT, and baseline ANC < 3700/mm3, WBC < 6.30 × 109/mm3, PLT < 230 × 109/mm3, and BSA < 1.58 m2increased the risk by approximately 4.0-fold, 3.7–4.0-fold, 2.1-fold, and 2.0-fold, respectively. The occurrence of early-onset neutropenia did not affect median PFS (p= 0.710), although patients with neutropenia had more frequent dose reductions or treatment delays.AbstractPurpose: This study aimed to determine the risk factors for palbociclib-induced grade 4 or grade 3 neutropenia (NP) requiring dose reduction or delayed treatment in patients with HR+/HER2−metastatic breast cancer in the first 3 cycles (early grade 3/4 NP) and whether the early developing grade 3/4 NP affects progression-free survival. Methods: A retrospective study using electronic medical records was conducted on patients who received palbociclib for metastatic breast cancer between January 2018 and August 2022. The early grade 3/4 NP risk factors were evaluated with univariate and multivariable logistic regression analyses. In addition, the Kaplan-Meier method was used to estimate the median progression-free survival (PFS) to analyze the effect of early grade 3/4 NP on treatment. Results: Out of the 264 patients included in this study, 173 (65.6%) experienced early grade 3/4 NP. A total of four models were applied for multivariable analysis to identify early grade 3/4 NP-developing factors. Low baseline ANC, WBC, PLT, and BSA were significant risk factors for early grade 3/4 NP; baseline ANC < 3700/mm3, WBC < 6.30 × 109/mm3, PLT < 230 × 109/mm3, and BSA < 1.58 m2increased the risk by approximately 4.0-fold, 3.7–4.0-fold, 2.1-fold, and 2.0-fold, respectively. Early grade 3/4 NP did not affect PFS (p= 0.710), although patients with early grade 3/4 NP had more frequent dose reductions or treatment delays. Conclusions: Based on the results, low baseline ANC, WBC, PLT, and BSA were associated with early grade 3/4 NP. Patients with risk factors require careful monitoring, and this study is expected to help predict NP, which may appear in early treatment.