In recent years, novel drugs for metastatic and recurrent breast cancer have been approved, and treatment options are increasing. However, as there is no clear consensus on which drug to use and in what order, there has been much debate regarding the choice of treatment. Cyclin-dependent kinase (CDK)4/6 inhibitors selectively inhibit CDK4 and CDK6, arrest cell cycle progression and suppress tumor growth (1). To date, 3 types of CDK4/6 inhibitors have been developed, and in Japan, 2 drugs, palbociclib and abemaciclib, have been approved. Palbociclib is a newly launched molecular-targeted therapeutic agent for use in inoperable or recurrent breast cancer and was the first selective CDK4/6 inhibitor to be introduced worldwide (2-5). In the PALOMA 3 trial, the median progression-free survival (PFS) times were shown to be 9.2 months in the palbociclib combination group and 3.8 months in the placebo group, with significantly better results in the palbociclib combination group [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.32-0.56) (6). Its efficacy and safety have been confirmed in Japan, and the drug was approved in December, 2017 in combination with endocrine therapy for hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer (7,8). The efficacy and safety of abemaciclib were subsequently validated, and abemaciclib was then approved in Japan in 2018 (9-11). In the MONARCH 2 trial, the median PFS times were 16.4 months for the abemaciclib combination group and 9.3 months for the placebo group, with significantly better results in the abemaciclib combination group (HR, 0.553; 95% CI, 0.449-0.681) (10). The side-effects associated with the use of CDK4/6 inhibitors are primarily blood toxicity and digestive complications, such as nausea, vomiting and diarrhea. However, the side-effect profiles are somewhat different; palbociclib has been reported to induce a high frequency of hematologic toxicity, and abemaciclib has been reported to induce a high frequency of diarrhea (2-6,9-11). Thus, the appropriate applications for the use of these 2 CDK4/6 inhibitors have not yet been determined.

In this study, we analyzed the efficacy and side-effects associated with the use of palbociclib in patients at our hospital and examined the suitability of palbociclib or abemaciclib based on adverse events.

Currently, there are no clear guidelines regarding the use of palbociclib and abemaciclib. In this study, in cases in which the number of neutrophils prior to the introduction of a CDK4/6 inhibitor was <3,000 or less, neutropenia of grade 3 or higher was observed in all cases owing to palbociclib. We believe that abemaciclib may be selected in cases in which the number of neutrophils prior to introduction of the CDK4/6 inhibitor is <3,000.

CDK4/6 inhibitors are agents that block the cell cycle and lead to similar side-effects as cytotoxic preparations (1). The use of palbociclib frequently leads to side-effects associated with the blood system. In the PALOMA-3 trial, neutropenia, anemia and thrombocytopenia were detected in 79, 26 and 19% of cases when palbociclib was used in combination with fulvestrant (6); in particular, neutropenia of grade 3 or higher was as high as 62%, and the incidence of adverse events of febrile neutopenia was 0.9%. Although not frequent, we experienced 1 case of febrile neutropenia, in which hospitalization was required; thus, the occurrence of febrile neutopenia should be avoided. Moreover, in the PALOMA-3 trial, the proportion of patients experiencing withdrawal of palbociclib for neutropenia was 59.7%, and the proportion of patients experiencing dose reduction was 27%. By contrast, in the MONARCH 2 test, when administered a combination of fulvestrant and abemaciclib, the incidences of neutropenia, anemia, thrombocytopenia and neutropenia of grade 3 or higher were 46, 29, 15 and 26%, respectively (10).

The side-effect of cytopenia was lower for abemaciclib compared with that of palbociclib. Palbociclib has not been reported to result in differences in PFS between those who had dose reductions of 1 or more levels (n=100) and those who did not have dose reductions (n=245) (12). However, no analysis has been conducted for patients who had dose reductions in 1 or 2 stages. In the current study, the initial dose of palbociclib was 125 mg for 29 patients (83%) and 100 mg for 6 patients (17%). Patients who were reduced to 100 mg were patients 74 years of age or older, or patients with brain metastases and PS2 or greater. PFS was significantly improved in patients who did not have a dose reduction. In addition, there were 6 cases in which a 2-stage dose reduction was required, indicating a relatively high frequency. The current study differs from previous clinical trials. However, blood levels [maximum blood concentration, Cmax and the area under the blood concentration-time curve (AUC)] are proportional to the dose (13). When the relative dose intensity (RDI) decreases, the clinical effect may not be sufficient. However, since the sample size was small in this study, verification with a larger sample size is also necessary. Thus, in order to maintain the RDI, it is better to avoid drug withdrawal and dose reduction as much as possible in most cases. In order to avoid the appearance of neutropenia of grade 3 or higher and to maintain RDI, it is suggested that abemaciclib should be considered for cases with neutrophils of <3,000 prior to the introduction of a CDK4/6 inhibitor.

In conclusion, the results revealed that palbociclib administration was extremely likely to cause neutropenia of grade 3 or higher in cases in which the number of neutrophils was <3,000 prior to induction. Therefore, such cases should be treated with neutropenia in mind.