Abstract
Background/Aim: The efficacy of endocrine therapy combined with abemaciclib for hormone receptor–positive, HER2-negative metastatic breast cancer has been established through pivotal clinical trials. However, abemaciclib-induced liver injury (AILI) can be a cause for dose reduction or discontinuation. Therefore, it is critical to understand the risk factors for AILI. Patients and Methods: This retrospective study analyzed data from patients who had received abemaciclib combined with endocrine therapy for metastatic breast cancer as first- or second-line therapy at our hospital between December 2018 and October 2021. Relevant data were extracted from their medical records. Logistic regression analysis was performed to identify characteristics associated with AILI. Results: Of the 52 eligible patients, 12 (23%) received an aromatase inhibitor (AI), and 40 (77%) received fulvestrant, concomitantly with abemaciclib. Fifteen (29%) of the patients developed liver injury after starting abemaciclib. Univariate analysis revealed the following risk factors for AILI: age ≥65 years (p=0.047), fatty liver disease (p=0.047), and concomitant use of an AI (p=0.002). Concomitant use of an AI was identified by multivariate analysis as an independent risk factor for AILI [odds ratio (OR)=10.23, 95% confidence interval (CI)=2.02-51.91, p=0.005]. Conclusion: Concomitant use of an AI could be the most significant factor associated with increased risk of AILI. Future research on the mechanism by which the use of an AI plus abemaciclib can cause liver injury, and prospective studies to validate our findings regarding AILI risk factors, are warranted.
In recent years, remarkable progress has been made in the field of cancer pharmacotherapy. Specifically, the development of molecular targeted therapy has contributed to improving treatment outcomes for breast cancer patients. Cyclin-dependent kinase (CDK) 4/6 inhibitors have been developed as molecular targeted drugs that arrest the cell cycle and inhibit proliferation by regulating the G1/S phase checkpoint (1). CDK4/6 inhibitors have been shown to significantly prolong progression-free survival (PFS) in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer; however, appropriate management of adverse events in patients receiving this treatment is essential (2).
Abemaciclib, like palbociclib and ribociclib, is a CDK4/6 inhibitor that has been shown to have superior clinical efficacy in pivotal clinical trials. The MONARCH 3 and MONARCH 2 trials showed prolonged PFS in HR-positive, HER2-negative metastatic breast cancer patients who had received abemaciclib plus endocrine agents as first- or second-line therapy (3, 4). The monarchE trial also showed that abemaciclib in combination with endocrine therapy prolongs invasive disease–free survival when used as adjuvant therapy in patients with HR-positive, HER2-negative early-stage breast cancer with a high risk of recurrence (5).
The use of abemaciclib in combination with endocrine agents is, however, also associated with increased risk of adverse events (6). Significant adverse events associated with abemaciclib (and their reported incidences) include diarrhea (84.6%), neutropenia (45.1%), elevated alanine aminotransferase (ALT) (15.1%), elevated aspartate aminotransferase (AST) (14.2%), venous thromboembolism (5.3%), and intestinal lung disease (3.4%) (7). Notably, the recently reported results of Japanese subpopulation analyses showed that elevation of hepatic transaminases occurred in 30.2%-34.9% of patients in MONARCH 2 (8) and 50.0% in MONARCH 3 (9), thus indicating a higher incidence compared with the overall population (7).
Abemaciclib-induced liver injury (AILI) is a critical issue in clinical practice, not only because it can lead to dose reduction or discontinuation of abemaciclib, but because it can also affect subsequent treatment (10). In the Japanese cohort of MONARCH 3, the most common adverse events leading to dose reduction of abemaciclib were ALT elevation (15.8%), neutropenia (13.2%), and diarrhea (13.2%), indicating that AILI was the most frequent cause (9). Likewise, the most common reasons for discontinuation of abemaciclib were related to AILI, such as ALT elevation (10.5%) and AST elevation (5.3%) (9). Therefore, to avoid the risk of dose reduction and discontinuation, it is worth investigating characteristics associated with the development of AILI, which have not been reported previously. In this study, we attempted to identify risk factors for the development of AILI by analyzing real-world data.
Patients and Methods
Patients. We assessed data from all 140 patients treated with abemaciclib combined with endocrine therapy for HR-positive, HER2-negative metastatic breast cancer at the Osaka International Cancer Institute between December 2018 and October 2021. Of these patients, the present study included the 52 who received abemaciclib combined with endocrine therapy as first- or second-line treatment for metastatic breast cancer. To exclude the effects of other drugs regarding liver injury, patients who received third-line treatment were not included.
The study was approved by the Ethical Review Board for Clinical Research of the Osaka International Cancer Institute (approval no. 22026). Because the study was retrospective in design, informed consent was obtained using the opt-out method.
Treatment. An aromatase inhibitor (AI) or fulvestrant was the endocrine agent used in combination with abemaciclib. Each AI was administered orally and once daily continuously: letrozole at a dose of 2.5 mg, and anastrozole at a dose of 1.0 mg. Fulvestrant was administered at 500 mg intramuscularly on day 1 of each 28-day cycle, with an additional dose on day 15 of cycle 1. Abemaciclib was administered orally at a dose of 150 mg (reduced to 100 mg as needed) twice daily, and treatment was continued until discontinuation due to progressive disease, adverse events, or withdrawal due to intolerance.
Data collection. Data on age, history of alcohol consumption, body mass index, history of hepatitis, fatty liver disease, diabetes, menopausal status, type of recurrence (de novo or postoperative), HR status, liver metastasis status (presence or absence), treatment line (first or second), concomitant endocrine agent (AI or fulvestrant), duration of abemaciclib treatment, and type and duration of subsequent treatment were extracted from the patients’ electronic medical records. The use of dietary supplements, which can be a cause of drug-induced liver injury (DILI), was not investigated, because in many cases the relevant details were unclear.
Diagnostic criteria and definitions of liver injury grade were in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (Japanese Clinical Oncology Group edition) (11). In patients who developed liver injury, data were collected on time of onset, including grade, AST, ALT, γ-glutamyl transpeptidase, and total-bilirubin levels; the duration of treatment for liver injury was also recorded.
Statistical analyses. Differences in the characteristics of patients who developed AILI and those who did not were analyzed using Fisher’s exact probability test. Univariate logistic regression analysis was performed to identify candidate risk factors for the development of liver injury among the characteristics in both groups. Using data for these candidate risk factors, multivariate logistic regression analysis was performed to identify independent risk factors for AILI. Kaplan–Meier curves were used to determine the time to recovery of liver function and to compare the duration of subsequent treatment in the groups with and without liver injury.
Analyses were performed using JMP statistical software (version 16.1.0, SAS Institute Inc., Cary, NC, USA). In the analyses, 2-tailed p-Values were used, with p<0.05 indicating a significant difference.
Results
Characteristics of eligible patients and comparison of groups with and without AILI. The characteristics of the 52 eligible patients are shown in Table I. Mean age was 60.6 years (range=37-87 years). The treatment was first line in 34 (65%) of the patients, and second line in 18 (35%). The concomitant endocrine agents were AIs in 12 (23%) of the patients and fulvestrant in 40 (77%). Based on the CTCAE version 4.0 criteria, 15 (29%) of the 52 patients had AILI.
Characteristics of the 52 patients eligible for the present study.
Comparison of the groups with and without AILI showed a tendency for liver injury to be more likely in patients with the characteristics of age ≥65 years (p=0.06), fatty liver disease (p=0.05), diabetes (p=0.07), and concomitant use of an AI (p=0.002) (Table II).
Comparison of characteristics in patients with and without abemaciclib-induced liver injury (AILI).
Univariate and multivariate logistic regression analyses. Possible risk factors for AILI were investigated by comparing characteristics in the groups with and without liver injury (Table III). Univariate logistic analysis revealed that age ≥65 years [odds ratio (OR)=3.55, 95% confidence interval (CI)=1.01-12.38, p=0.047], fatty liver disease (OR=6.36, 95% CI=1.02-39.57, p=0.047), and concomitant use of an AI (OR=9.43, 95% CI=2.21-40.24, p=0.002) are associated with liver injury. Of these, concomitant use of an AI was identified as an independent risk factor for AILI based on the results of multivariate logistic regression analysis (OR=10.23, 95% CI=2.02-51.91, p=0.005).
Results of univariate and multivariate logistic regression analyses to identify risk factors for abemaciclib-induced liver injury.
Timing of onset of and recovery from liver injury. Figure 1 shows the timing of onset of liver injury. Of the 15 patients who developed liver injury, 12 (80%) developed it within 3 months of starting abemaciclib, and 3 (20%) developed it after 4 months (p=0.02). Regarding the severity of liver injury, grade 1 was reported for 8 (53%) of the patients, grade 2 for 3 (20%), and grade 3 for 4 (27%); no cases of grade 4 liver injury were recorded. There were no deaths directly related to abemaciclib administration, and no patients met the criteria for Hy’s law (12).
Cases of abemaciclib-induced liver injury (AILI) every 3 months from the start of abemaciclib treatment. A two-sided Fisher’s exact test was used to determine the p-Value for the difference between the two groups (i.e., for developing liver injury at 1-3 months vs. ≥4 months after the start of abemaciclib treatment). The black bar represents the number of patients with onset of liver injury in the first 3 months of treatment. The gray bars represent the numbers of patients with onset of liver injury from month 4 onwards.
Of the patients who developed liver injury, 11 (73%) subsequently recovered to grade 1 or lower. The recovery rates to grade 1 or lower at 3 and 6 months were 63.3%±12.9% and 86.3%±11.6%, respectively (Figure 2). Twelve of the 15 patients with AILI required discontinuation of abemaciclib; of these, 5 were able to restart abemaciclib following improvement of liver function after discontinuation. The management of liver injury consisted primarily of pharmacotherapy, most frequently with glycyrrhizic or ursodeoxycholic acid.
Recovery rate after the onset of abemaciclib-induced liver injury (AILI).
Effect of AILI on subsequent treatment. The duration of subsequent treatment was compared between patients who developed AILI and those who did not (Figure 3). Nine patients in the group with liver injury and 20 in the group without it started subsequent treatment after developing progressive disease during treatment with abemaciclib. Analysis of data for the time to failure of subsequent treatment in each group showed no significant difference between the two groups (p=0.98).
Time to failure of subsequent treatment. To investigate whether abemaciclib-induced liver injury (AILI) affects the duration of subsequent treatment, patients who developed AILI and received a subsequent treatment were compared with those who did not develop AILI and received a subsequent treatment. The solid line represents patients who developed AILI and the dotted line patients who did not develop AILI.
Discussion
In clinical practice, AILI is a critical issue for breast cancer patients treated with abemaciclib (10). Adverse events associated with abemaciclib have been reported to have no adverse effect on PFS, when managed effectively through supportive care and dose adjustment (7). However, although the incidence of AILI is low compared with diarrhea or neutropenia, it cannot be assumed that dose reduction or discontinuation due to AILI will not adversely affect outcomes. To avoid the development of AILI, and to enable appropriate drug selection and early risk management, it is important to understand the risk factors for it. To the best of our knowledge, the present study is the first to investigate potential risk factors for AILI.
In the present study, we found that concomitant use of an AI was the most significant risk factor for the development of AILI. In the MONARCH 2 study, in which fulvestrant was used concomitantly with abemaciclib, elevated ALT and AST were observed in 13.4% and 12.2% of patients, respectively (7). Similarly, in the MONARCH 3 study, in which an AI was the concomitant agent, elevated ALT and AST were observed in 15.6% and 14.7% of patients, respectively (7). In the Japanese cohort of MONARCH 2, elevated ALT and AST were observed in 34.9% and 30.2% of patients, respectively (8), and elevated ALT and AST were each reported to affect 50.0% of Japanese patients in MONARCH 3 (9, 13). These results from previous clinical trials implicate AIs as more likely than fulvestrant to cause AILI, which is consistent with our findings.
There have also been several reports regarding the association between host factors (e.g., older age, fatty liver disease, diabetes) and DILI. Older age is considered a risk factor for DILI because elderly patients are more likely than younger patients to present with cholestatic liver injury, due to decreased cytochrome-mediated hepatic metabolism (14, 15). Although it remains controversial as to whether pre-existing liver disease increases susceptibility to DILI, about 10% of DILI patients have been reported as having pre-existing liver disease, mostly due to hepatitis C and non-alcoholic fatty liver disease (NAFLD) (16, 17). Moreover, there is growing evidence that diabetes and NAFLD can increase the risk of DILI (18, 19).
It is necessary to consider what treatment strategies are appropriate for patients at high risk of developing AILI (e.g., older patients and patients with fatty liver disease or diabetes). One option would be to change the endocrine agent used in combination with abemaciclib from an AI to fulvestrant. Although there are no data allowing direct comparison of the efficacy of fulvestrant versus an AI in combination therapy with abemaciclib, it is helpful to refer to the results of the PARSIFAL trial, which was carried out to determine whether fulvestrant is superior to letrozole when combined with palbociclib as first-line therapy (20). Although this trial failed to demonstrate the non-inferiority of fulvestrant compared with letrozole in terms of PFS (27.9 months vs. 32.8 months, respectively), 3-year overall survival was not significantly different (79.4% vs. 77.1%, respectively); this latter finding suggests that fulvestrant could be used as an alternative to the AI. Another option for patients at high risk of liver injury could be use of AI plus palbociclib as first-line treatment, followed by abemaciclib after disease progression on palbociclib. This strategy has been reported to be safe and well tolerated and may contribute to prolonged time to chemotherapy without affecting the benefits of subsequent chemotherapy regimens (21).
Generally, there are three DILI phenotypes: direct hepatotoxicity, idiosyncratic hepatotoxicity, and indirect hepatotoxicity (22). However, the pathogenesis of AILI remains unclear. Regarding AILI, the hypothesis that immune cells reacting to the metabolite may induce hepatotoxicity when abemaciclib is metabolized in the liver via cytochrome P450 3A4 has been suggested (10). Regarding liver injury due to the CDK4/6 inhibitor ribociclib, it has been suggested that this may be due to its inhibition of the bile salt export pump (BSEP), a transporter involved in bile excretion, or due to ribociclib-induced autoimmune-mediated liver damage (23). Considering that BSEP inhibition and autoimmune-mediated liver damage are both associated with idiosyncratic DILI (24, 25), AILI, like ribociclib-induced liver injury (RILI), might be classified as idiosyncratic hepatotoxicity.
The mechanism by which AIs may contribute to the development of AILI is also unclear. A previous clinical trial of combination therapy with tegafur-uracil and AIs had to be discontinued due to high incidence of liver injury of grade 3 or higher (26); therefore, it is possible that combination therapies with AIs may be more likely to induce liver injury. Anastrozole and letrozole are non-steroidal inhibitors of aromatase, the enzyme responsible for the conversion of testosterone to estrone and of androstenedione to estradiol (27, 28). Because estrogen plays an anti-inflammatory, protective role by inhibiting T-cell autoimmunity, it has been suggested that depletion of estrogen by AIs may induce autoimmunity (29, 30). Moreover, preclinical and clinical studies have shown that CDK4/6 inhibitors exert anticancer effects not only by cell cycle inhibition but also through various immunostimulatory effects, such as enhancing antigen presentation, activating effector T cells, and suppressing regulatory T cells; abemaciclib seems to have stronger immunostimulatory effects than palbociclib (31). Therefore, it has been speculated that the immune cells implicated in AILI could be also induced by combination therapy with AIs and abemaciclib, and that this may be responsible for the onset of AILI.
In the present study, there were no significant differences between patients with and without AILI in terms of time to failure of subsequent treatment. This may be due to most patients with liver injury having mild disease (i.e., grade 1 or 2), and because withdrawal of abemaciclib and use of hepatoprotective drugs and steroids before the liver injury became more severe resulted in early improvement in liver function. It has previously been reported that in some cases of RILI, time to failure of subsequent treatment was adequate after the hepatotoxicity had been addressed (32), suggesting that CDK4/6 inhibitor–induced liver injury may be sufficiently controlled through early detection and appropriate management.
There are a few limitations to the present study. First, although we defined AILI as deterioration of liver function after the start of abemaciclib administration, according to CTCAE version 4.0 criteria, the number of patients who developed AILI remained small and the observation period was short. Therefore, we were unable to evaluate the impact of dose reduction and discontinuation of abemaciclib on overall survival in patients who developed AILI. Data arising from the continued accumulation of cases of AILI are needed, and detailed prognostic data should be verified in the future. Second, due to the retrospective nature of this analysis of real-world data, for some patients, no information was found in their medical records about their history of taking dietary supplements or their alcohol consumption, which are well-known causes of liver injury (33, 34). Therefore, the possibility of liver injury due to supplement use or alcohol consumption could not be completely ruled out. Third, in the present study, liver biopsies were performed for only two patients, both of whom had a histological diagnosis of liver injury. Liver histological findings may help clarify the diagnosis of DILI and have been reported to be particularly useful in cases of biliary stasis or unclear DILI (35). In the future, liver biopsy may be considered to increase certainty in cases of a DILI diagnosis, while also bearing in mind the risks of biopsy.
Conclusion
In conclusion, the results of the present study show that concomitant use of an AI is likely a significant risk factor for AILI. It is especially important to be cautious when treating patients who also have host risk factors for AILI. However, if a patient develops AILI, appropriate countermeasures could be used to minimize its negative effects on subsequent treatment. Although further research is needed to determine the mechanism by which the combination of an AI and abemaciclib causes liver injury, we believe that consideration of risk factors when selecting treatment strategies can lead to appropriate drug selection and early risk management for AILI.
Acknowledgements
We would like to thank all the patients who participated in our study and Medical Translation Service (MTS) (http://medicaltrans.info/) for English language editing.
Footnotes
Authors’ Contributions
NK contributed to the study conceptualization. AT, HK (Kanaoka), SN, YO, YS, AS, HK (Kusama), NW, SM, MN and FF contributed to data analysis and interpretation. TN supervised the conduct of the study. AT drafted the manuscript. All Authors critically reviewed the manuscript draft for intellectual content, approved the final version for submission, and agreed to be accountable for all aspects of the work.
Conflicts of Interest
The Authors declare that they have no potential conflicts of interest and have not received financial support from any funding agency related to this work.
- Received October 26, 2022.
- Revision received November 5, 2022.
- Accepted November 8, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
