Breast cancer (BC) is the cancer with the highest morbidity and mortality in females and seriously jeopardizes women’s physical and mental health (1). BC is highly heterogeneous, and HR+/HER2- is the most common molecular subtype, accounting for approximately 75% of BC cases (2). Endocrine therapy provides several advantages, including low drug toxicity, relatively affordable costs, and convenient administration. As a well-established treatment modality for BC, endocrine therapy is frequently employed to treat hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) BC. However, some patients exhibit primary or secondary resistance to endocrine therapy as a result of the activation of the hormone receptor signaling pathway (3). Abemaciclib is currently the sole CDK4/6 inhibitor approved for the treatment of early-stage BC. It inhibits the activity of CDK4/6 kinase, thereby preventing the transition of the cell cycle from the G1 phase to the S phase and suppressing tumor cell proliferation. Additionally, abemaciclib targets the estrogen receptor signaling pathway, creating a synergistic effect when combined with endocrine therapy (4). Abemaciclib has been shown to significantly improve the survival rate of BC patients and has emerged as a novel treatment option for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) BC patients. Consequently, the introduction of abemaciclib marks a transformative shift from conventional chemotherapy or endocrine monotherapy to innovative targeted combination therapy, heralding a new era in targeted therapy for HR+/HER2- BC (5).

Blood toxicity and diarrhea are the most frequently reported adverse effects (AEs) associated with CDK4/6 inhibitors. Notably, abemaciclib may induce hepatotoxicity and nephrotoxicity, which can compromise patient tolerance and hinder the attainment of maximal therapeutic efficacy. Furthermore, these toxicities may predispose patients to severe infections, thereby posing significant risks to their health and, in extreme cases, threatening their lives (6, 7). Therefore, it is essential to screen patients for risk factors associated with common abemaciclib-related AEs and implement preventive measures and early interventions to mitigate their impact on patients. In this study, comprehensive patient information, including clinical characteristics, laboratory indicators, and medications, was systematically collected. Patients were closely monitored for adverse reactions during treatment, and multivariate logistic regression analysis was conducted on clinical characteristics and laboratory indicators to identify the factors influencing common abemaciclib-related AEs.

During treatment with abemaciclib, gastrointestinal toxicity particularly diarrhea is the most common AE in patients with BC. In the phase II MONARCH1 trial (15), diarrhea occurred in 90.2% of patients, with 19.7% experiencing grade ≥3 severity and 20.5% requiring dose reductions. In phase III MONARCH2 (16) and MONARCH3 (17) trials, the incidences of diarrhea were 85.4% and 81.1%, respectively, while grade ≥3 events occurred in 13.4% and 9.3% of cases. The MONARCH2 and MONARCH3 studies (10) further indicated that diarrhea associated with abemaciclib combined with endocrine therapy peaked during in the first month of treatment and then declined over time. The median duration of the initial episode of diarrhea was 6-8 days;for grade 2, 9–12 days; and for grade 3, 6–8 days. In the MONARCHE study on adjuvant therapy (18), the incidence of diarrhea caused by abemaciclib combined with endocrine therapy was 83.5%, with grade ≥3 events occurring in 7.8% of patients. The median time to onset was 8 days, and the median duration was ≤7 days. In the subsequent multinational phase III MONARCHplus (19) study, 78-80% of patients experienced diarrhea, which was generally mild; only 2-4% developed grade ≥3 events. However, Hamilton E et al. (20) showed that for the abemaciclib treatment, the real-world incidence of diarrhea was reduced to 43%-67%, and fewer than 10% of the patients had grade ≥3 diarrhea. Similarly, Cuyun Carter et al. (21) evaluated the efficacy of abemaciclib in HR+/HER2- advanced BC patients within the first year after the Food and Drug Administration (FDA) approval and found a 67% incidence of diarrhea. These results may be related to the preventive use of antidiarrheal drugs. In this study, the incidence of diarrhea in patients was 67%, and the incidence of grade ≥3 diarrhea was 9.3%; these values are consistent with the findings of these clinical trials.

Compared with other CDK4/6 inhibitors, the gastrointestinal toxicity associated with abemaciclib is more pronounced and involves multiple contributing factor. In addition to the inhibition of CDK4 and CDK6, abemaciclib also targets CDK9, a key regulator of intestinal cell proliferation, thereby increasing the incidence of diarrhea. In a preclinical model (22), morphological changes in the gastrointestinal tract, such as severe absence of microvilli, vacuolar degeneration, reduction of goblet cells, shortening of villi, proliferation of crypt cells, enterocyte degeneration, and mucosal inflammation, were observed in abemaciclib-treated rats. Moreover, abemaciclib has been shown to activate the Wnt/β-catenin pathway and upregulate the expression of solute carrier family genes such as SLC28a1,SLC37a2, and SLC5a12, ultimately promoting cell proliferation (23). Abemaciclib also inhibits GSk3β and CAMKII to increase intestinal peristalsis, thus causing diarrhea (24).

Therefore, in this study, age, BMI, comorbid gastrointestinal diseases, and inflammatory factors were included in the investigation of diarrhea-associated risk factors. The analyses revealed that the occurrence of grade ≥2 diarrhea was significantly correlated with age ≥ 70 years (P = 0.007) and comorbid gastrointestinal disease (P = 0.001). If patients are ≥70 years old or have gastrointestinal diseases, the chance of developing grade ≥2 diarrhea greatly increases. To date, few studies have investigated the risk factors associated with abemaciclib treatment. This study revealed that the risk factors for diarrhea were age ≥ 70 years and comorbid gastrointestinal diseases. Modi ND et al. (25) used Cox proportional hazards analysis to study the correlations between pretreatment clinicopathological data and the development of grade ≥3 diarrhea after treatment in the MONARCH1, MONARCH2, and MONARCH3 clinical trials, and the analysis revealed that age ≥70 years was a risk factor for the development of grade ≥3 diarrhea induced by abemaciclib, which is related to decreased gastrointestinal function and disorders caused by ageing (26). Furthermore, polypharmacy and pharmacokinetic/pharmacodynamic changes in the elderly subgroup may lead to an increased risk of abemaciclib-induced grade ≥3 diarrhea (27, 28). In addition, abemaciclib may cause mucosal inflammation, thus inducing diarrhea (22). Findings of other studies (29) have indicated that CDK4/6 inhibitors may attenuate CDK6-dependent inflammatory gene expression. The LMR, NLR and PLR are markers of body inflammation, which can lead to tissue and cell damage and increased vascular permeability, and tumor-associated inflammation, which promotes tumorigenesis, angiogenesis and tumor progression (30). Therefore, inflammatory factors, such as the baseline LMR, NLR, and PLR, were included in this study, but no correlation was found between these factors and grade ≥2 diarrhea, since the diarrhea caused by abemaciclib is considered to be related mainly to the stimulation of a secondary target (31). In addition, Franzoi MA et al. (32) examined the impact BMI on the incidence of diarrhea in the MONARCH2 and MONARCH3 trials and found no statistically significant association consistent with the results of our study. Compared with CDK6, abemaciclib exhibits greater selectivity for CDK4 inhibition (33, 34). CDK6 regulates the expression of cytokines in hematopoiesis (35) and inhibits the expansion of myeloid progenitor cells, thus playing an important role in myeloid differentiation (36). Inhibiting CDK6 can disrupt hematopoietic stem cell differentiation, leading to myelosuppression, which may necessitate dose reductions or even discontinuation of abemaciclib treatment.

In the phase III MONARCH2 trial (16), the incidence of neutropenia was 46.0%; the incidence of grade ≥3 neutropenia was 26.5%; and the incidences of neutropenia in cycles 1 and 2 were 11.6% and 15.8%, respectively. In the phase III MONARCH3 trial (17), the incidence of neutropenia was 43.7%; the incidence of grade ≥3 neutropenia was 21.1%; the incidences of neutropenia in cycles 1 and 2 were 6.4% and 11.0%, respectively; and the incidences of neutropenia were ≤10% in all subsequent cycles. Due to neutropenia, 10%-13% of patients required dose reductions, 16%-17% missed doses, and 1%-3% discontinued treatment. A pooled study of the MONARCH2 and MONARCH3 trials (37) revealed that the median duration of grade ≥3 neutropenia was 29-33 days, the median time to remission was 11-15 days, and the incidence of grade ≥3 neutropenia was approximately 25%. In addition, for patients with grade ≥3 neutropenia, comorbid infection often occurred within 1 week, with an incidence ranging from 1.5% to 4.0%. The incidence of febrile neutropenia was 1%. A retrospective study by Takada S et al. (38) involving 365 Japanese patients treated with abemaciclib found a 75% incidence of neutropenia. Consistent with these findings, our study observed neutropenia in 73.6% of the 216 patients treated with abemaciclib higher than previously reported in the clinical trials. Similar findings are observed for other CDK4/6 inhibitors. For example, in a phase I study of palbociclib combined with letrozole in Japanese patients, 83% of patients developed neutropenia (39), and similar results have been reported for ribociclib (40). Roncato R (41) showed that the reported incidence of neutropenia in Asian patients was greater than that in non-Asian patients, and this finding may be related to body size, dietary habits such as soybean intake, the expression of proinflammatory genes in tumors, and drug-metabolizing enzymes. In this study, grade 1-2 neutropenia was dominant, and grade ≥3 neutropenia accounted for 23.1% of neutropenia cases, which was consistent with the clinical trial data.

Our analysis revealed that grade ≥3 neutropenia was significantly associated with the ECOG score (P = 0.008), baseline serum ALB level (P = 0.031), baseline WBC count (P = 0.007), and BMI classification (P = 0.035). First, the ECOG score can reflect a patient’s physical status and tolerance to treatment and is also closely related to AEs in patients after treatment. A pooled clinical study of abemaciclib similarly reported that patients with higher ECOG scores were more likely to develop grade ≥3 neutropenia (42). The results of this study were consistent with those of previous studies, i.e., the higher the ECOG score, the greater the likelihood for the patient having grade ≥3 neutropenia. Other studies have reported that the plasma protein binding rate of abemaciclib is 95% (43), and low levels of ALB lead to a large increase in free drug, resulting in increased drug toxicity (44). Therefore, baseline ALB level was included in this study to explore the relationship with neutropenia. Compared with patients with a baseline ALB level <4.0 g/dL, patients with a baseline ALB level >4.0 g/dL had a lower incidence of neutropenia. Nakatsukasa H (45) reported that among 33 patients with advanced BC treated with abemaciclib, 27.3% developed SAEs, 12.1% of which were hematologic. Notably, no SAEs occurred in patients with baseline ALB level >4.0 g/dL group. Therefore, a baseline ALB level >4.0 g/dL is expected to be a useful AE marker for the selection of patients for abemaciclib treatment. Abemaciclib should be selected for patients with poor physical strength and liver and kidney diseases only after a comprehensive evaluation is performed, and these patients should be closely monitored during treatment.

Emerging studies demonstrated that the outcomes of BC patients in the high NLR and high PLR groups are worse than those of patients in the low NLR and PLR group. A significantly higher incidence of bone marrow toxicity in the high NLR group than in the low NLR group has been revealed; furthermore, this AR occurs earlier during chemotherapy for lung cancer in the high NLR group than in the low NLR group. Moreover, agranulocytosis and thrombocytopenia after chemotherapy for lung cancer are more severe in the high PLR group than in the low PLR group, and agranulocytosis, decreased hemoglobin, and thrombocytopenia are more likely to occur in the low LMR group. In addition, neutrophils constitute the highest percentage of circulating leukocytes and have a key antibacterial function (33). Therefore, baseline LMR, NLR, and PLR were included in this study, but the results were not statistically significant. It is possible that CDK4/6 inhibitors and chemotherapeutic drugs cause different types of blood toxicity, i.e., CDK4/6 inhibitors inhibit only the cell cycle and do not cause inflammation.

Baseline blood parameters have been identified as important risk factors for the development of neutropenia following treatment with various chemotherapeutic drugs (46, 47). In a pooled clinical study of abemaciclib, Modi ND (25) divided the prebaseline WBC count into four levels: <4.0×109/L, 4.0-4.99×109/L, 5.0-6.5×109/L, and ≥6.5×109/L, and the results revealed that the lower the WBC count in patients before treatment, the greater the incidence of neutropenia. Nakatsukasa H (45) also revealed that the incidence of SAEs in the abemaciclib group with a WBC count >5700/µL was significantly lower than that in the group with a WBC count ≤5700/µL. Iwata H et al. (14) in their analysis of PALOMA-2 and PALOMA-3 clinical trials of palbociclib in Asian populations, also found that patients with lower baseline neutrophil (NEUT) or WBC counts were more likely to develop grade ≥3 neutropenia early during treatment, identifying a NEUT count <3680/mm³ as a predictive risk factor. Baseline blood parameters were also included in this study, and the results showed that the incidence of neutropenia in patients with the low baseline WBC count was high.

It have been shown that anticancer drugs can be dissolved in adipose tissue, thus delaying excretion (48, 49). Other studies also demonstrated that the effect of anticancer drugs is weakened in obese patients (50–52). Therefore, patients BMI was included in this study, and its relationship with grade ≥3 neutropenia was evaluated. Compared with lean and normal body weight patients, overweight and obese patients had a lower incidence of grade ≥3 neutropenia, and the differences were statistically significant. For the MONARCH2 (16) and MONARCH3 (17) clinical trials, Franzoi MA et al. (32) explored the effects of BMI on treatment efficacy and ARs, and their exploration revealed that, compared with patients who were underweight and/or normal weight, overweight and/or obese patients had a statistically significantly lower incidence of any grade of neutropenia and a significantly lower incidence of grade ≥3 neutropenia (14, 50). One possible explanation is that elevated NEUT counts may be serve as inflammatory biomarker in overweight or obese individuals, thereby reflecting a different immunologic baseline (53–55).

Currently, more discussion around potential interventions or clinical actions for high-risk patients has been documented. Diarrhea associated with abemaciclib typically occurs during the early phase of treatment. As the duration of therapy increases, patients generally develop better tolerance, leading to a significant reduction in both the severity and incidence of diarrhea. Therefore, it is advisable to instruct patients to closely monitor and document changes in bowel movement frequency and stool characteristics during the initial weeks of treatment. At present, primary prevention of diarrhea is not recommended (9). For patients at higher risk of such as those with inflammatory bowel disease or irritable bowel syndrome, the dose-escalation strategy of tyrosine kinase inhibitors in the CONTROL study can be referred to, which can effectively reduce the frequency and severity of diarrhea (56). Emerging evidence suggests that biologic agents may increase fecal IgA levels and support the stable longitudinal development of gut microbiota, thereby safeguarding the mucosal surface against pathogenic infections and mitigating inflammatory responses. Mileti E et al. (57) discovered that combining probiotics with loperamide can effectively relieve abemaciclib-induced diarrhea. Furthermore, Masuda H et al. (58) demonstrated that Bifidobacterium, regardless of whether it is combined with trimebutine maleate, can reduce both the duration of diarrhea caused by abemaciclib and the incidence of grade 3 or higher diarrhea, ultimately decreasing the likelihood of drug dose reduction or interruption.

Neutropenia induced by abemaciclib can generally be managed through dose interruptions and appropriate dose adjustment, while endocrine therapy may continue uninterrupted. From a nutritional standpoint, ensuring adequate intake of protein-rich foods such as milk, meat, and eggs is recommended to support neutrophil recovery. To prevent patients from developing febrile neutropenia, it is advisable for all patients to receive pneumococcal vaccination before initiating treatment, along with annual influenza vaccination (59). According to the guidelines of the American Society of Clinical Oncology, all cancer patients undergoing conventional chemotherapy or targeted therapy should be screened for HBV. For individuals infected with HBV, different treatment strategies should be adopted based on their serological characteristics, including measures for treating or preventing viral reactivation (60).

The incidence of diarrhea and neutropenia associated with abemaciclib is relatively high. Factors such as patient age, comorbidities, ECOG performance status, and baseline indicators may correlate with the occurrence of these two common adverse reactions. This study aims to establish a model based on the aforementioned adverse reaction-related factors, thereby enabling more personalized medication monitoring for patients. Consequently, this approach is expected to enhance patients’ quality of life and potentially extend their survival duration.