Comparative efficacy & safety of buparlisib plus fulvestrant, fulvestrant plus dalpiciclib, and ribociclib plus letrozole for postmenopausal, hormone receptor-positive, and HER2-negative breast cancer

Highlights • Dalpiciclib + fulvestrant is effective in hormone (+) and HER2 (−) breast cancers.• Dalpiciclib and buparlisib cause neutropenia.• Gastrointestinal tract-related adverse effects while treatment with fulvestrant.• Liver function monitoring is recommended for ribociclib + letrozole treatment.• Women should be under the supervision of a consultant while 100 mg/day of buparlisib.


Introduction
Breast cancer is the most prevalent cancer in Chinese women. 1 In breast cancer, the most common tumor subtype is hormone receptorpositive. 2 Endocrine therapy-based regimens are the preferred treatment for hormone receptor-positive breast cancers. 3Ribociclib is an oral selective inhibitor of cyclin-dependent kinases 4 and 6. 4 Ribociclib plus letrozole combination has high progression-free survival in premenopausal 5 and postmenopausal 6 women with hormone receptor-positive, HER2-negative, breast cancer, but has worse adverse effects, such as neutropenia and leukopenia.Women with hormone receptor-positive HER2-negative breast cancer in China are treated with fulvestrant plus CDK4/6 inhibitors (for example, dalpiciclib). 7In addition, palbociclib, ribociclib, and abemaciclib plus fulvestrant were approved by the United States Food and Drug Administration (USFDA) and the European Medicines Agency. 8The Chinese Society of Clinical Oncology Breast Cancer recommends CDK4/6 inhibitors with endocrine therapy for hormone receptor-positive HER2-negative breast cancer. 9ormone receptor-positive breast cancer has various genomic alterations and is not homogeneous.Therefore, there are opportunities for targeted therapies. 10In hormone receptor-positive breast cancer, PIK3CA mutation activation causes disease progression and resistance to endocrine therapy. 11Therefore, targeting phosphatidylinositol 3-kinase is a potential therapeutic strategy. 10Buparlisib is an oral phosphatidylinositol 3-kinase inhibitor. 12Fulvestrant is a selective estrogen receptor degrader, and the combination of buparlisib with fulvestrant has favorable clinical outcomes with manageable adverse effects in women with metastatic estrogen receptor-positive breast cancer 10,13 ; however, this combination (buparlisib plus fulvestrant) has the highest rate of discontinuation of treatment. 10he objectives of this retrospective study were to compare progression-free survival, overall survival, clinical benefits, and adverse effects in postmenopausal Chinese women with hormone receptor-positive and HER2-receptor-negative breast cancer who received buparlisib plus fulvestrant against those of women who received dalpiciclib plus fulvestrant, considering ribociclib plus letrozole treatment as the reference standard.

Ethics approval and consent to participate
The protocols of the established study were designed by the authors and approved (Approval number: 14Y18 dated 15 January 2019) by the human ethics committee of the Taihe Hospital and the Chinese Society of Clinical Oncology Breast Cancer.The current study followed the law of China and the current version of the Declaration of Helsinki.As this was a retrospective study, informed consent to participate was waived by the human ethics committee of Taihe Hospital.

Inclusion criteria
Postmenopausal women with confirmed (histologically or cytologically confirmed) hormone receptor-positive and HER2-negative breast cancers were included in the analysis.

Exclusion criteria
Women with severe depression were excluded from the study.

Cohorts
One hundred and eight women received 100 mg/day oral buparlisib 10 plus intramuscular 500 mg fulvestrant (BF cohort).One hundred thirty-two women received oral 150 mg/day dalpiciclib 8 plus intramuscular 500 mg fulvestrant (DF cohort).One hundred and fifty women received oral 600 mg/day ribociclib plus oral 2.5 mg/day letrozole 5 (RL cohort).A total of oral 100 mg/day buparlisib, 10 or 150 mg/day dalpiciclib, 8 or 600 mg/day ribociclib 5 was administered once daily for 3-weeks followed by a washout period of one week and with a total treatment period of (cycle) was 4-weeks.Fulvestrant was administered intramuscularly on day one, followed by day 15 of the first cycle.Then, after (after the first cycle) intramuscularly only on day 1 of the 4-week cycle. 8These treatment cycles were continued until unacceptable toxicity was achieved.

Outcome measures
Eastern Cooperative Oncology Group (ECOG) performance status.

Survival
Progression-free survival.From the start of treatment(s) to the first documented progression of disease or death due to any reason, progression-free survival was considered. 10verall survival.
From the start of treatment(s) to death due to any reason, it was considered as overall survival. 10

Clinical benefits
Clinical benefits were defined as the sum of complete response, partial response, and no signs of progressive response after treatment(s). 10he Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria 15 were used for the evaluation of complete response, partial response, and no signs of progressive response.

Adverse effects
The Common Terminology Criteria for Adverse Events (CTCAE) v5.0 16 were used to evaluate adverse events during the treatment and follow-up periods.

Statistical analyses
Statistical analyses were performed using 3.01 InSat (GraphPad Software, San Diego, CA, USA).Categorical, continuous linear, and continuous nonlinear variables are depicted as frequencies with percentages in parentheses, mean ± Standard Deviation (SD), and medians with Q3 −Q1 in parentheses, respectively.Fisher's exact test or chi-square test (χ 2 -test, for sample size > 40) was used for statistical analyses of categorical variables.The Kolmogorov−Smirnov method was used to check the linearity of continuous variables.One-way analysis of variance (ANOVA) was used for the statistical analyses of continuous linear variables.All results were considered statistically significant at p < 0.05.

Study population
From March 1, 2017, to January 13, 2019, 405 postmenopausal women with hormone receptor-positive and HER2-negative breast cancer were treated at the Hubei University of Medicine, Shiyan, Hubei, P.R. China, the Taihe Hospital, Shiyan, Hubei, P.R. China, and the People's Hospital of Yunxi County, Yunxi, Hubei, P.R. China.Among 405 women, 15 had severe depression.Therefore, these women were excluded from this study.Survival, clinical benefits, and adverse effects in 390 postmenopausal women with hormone receptor-positive and HER2-negative breast cancer were included in the analyses.A flow chart of the retrospective analysis is shown in Fig. 1.

Demographic and clinical parameters
All the women were approximately 50 years of age.More than 50 % of included women had an ECOG performance status of '0' and more than 90 % of included women had an ECOG performance status of '1' or less.Age, ethnicity, and ECOG performance status of women were comparable among the cohorts (p > 0.05, Table 1).

Progression-free survival
After 42 months of follow-up, a total of 81 (75 %), 114 (88%), and 85 (57 %) women survived without progression in the BF, DF, and RL cohorts, respectively.After 42 months of follow-up, progression-free survived women were higher in the DF cohort than those in the BF (p = 0.0306, Fischer exact test, 95 % CI: 1.003 to 2.131 [using the approximation of Katz]) and RL (p < 0.0001, Fischer exact test, 95 % CI: 1.725 to 4.045 [using the approximation of Katz]).cohorts.After 42 months of follow-up, progression-free survived women were higher in  the BF cohort than the RL cohort (p = 0.0025, Fischer exact test, 95 % CI: 1.168 to 2.367 [using the approximation of Katz]).The details of the progression-free survival of women are presented in Fig. 2. At 26 months, charts of progression-free survival of women in the DF and RL cohorts intercepted each other.However, the line art for the progression-free survival of women in the BF cohort in the progression-free survival of women chart is not intercepted to the line-art of the progression-free survival of women in the DF and RL cohorts.

Overall survival
After 42 months of follow-up, a total of 95 (88 %), 121 (92 %), and 110 (73 %) women survived in the BF, DF, and RL cohorts, respectively.Survival of women in the DF cohort was higher than that in the RL cohort (p < 0.0001, Fischer exact test, 95 % CI: 1.418 to 4.158 [using the approximation of Katz]).Survival of women in the DF cohort was higher than the BF cohort but was statistically not significant than that of women in the BF cohort (p = 0.3906, Fischer exact test, 95 % CI 0.7787 to 1.918 [using the approximation of Katz]).Survival of women in the BF cohort was higher than that in the RL cohort (p = 0.0047, Fisher's exact test, 95 % CI: 0.5824 to 0.8679 [using the approximation of Katz]).The details of the overall survival of women are presented in Fig. 3.At 33 months, overall survivals of women in the DF and RL cohorts intercepted each other.However, line art for the overall survival of women in the BF cohort in the overall survival of women chart is not intercepting to line art of the overall survival of women in the DF and RL cohorts.

Clinical benefits
After treatment, 117 (89 %), 80 (74 %), and 84 (56 %) women from the BF, DF, and RL cohorts, respectively had clinical benefits.The clinical benefits for women in the DF cohort were greater than those in the BF and RL cohorts.The clinical benefits for women in the BF cohort were greater than those in the RL cohort.Women in the DF cohort had the highest clinical benefit, followed by women in the BF cohort, and women in the RL cohort had the least clinical benefit.Details of the clinical benefits to women after treatment(s) are presented in Table 2.

Adverse effects
Patients in the DF, BF, and RL cohorts reported neutropenia, leukopenia, anemia, thrombocytopenia, and lymphopenia hematological adverse effects during treatment(s) and in the follow-up period.Neutropenia was more frequent in women of the DF and the BF cohorts than women in the RL cohort.Leukopenia was reported to be higher in women in the RL cohort than in those in the DF and BF cohorts.The details of the hematological adverse effects during treatment(s) and the follow-up period are reported in Table 3.
Patients in the DF, BF, and RL cohorts reported anorexia, headache, nausea, vomiting, hyperglycemia, skin rash, and fatigue as non-hematological adverse effects during treatment(s) and in the follow-up period.Vomiting, constipation, nausea, diarrhea, and anorexia were higher in women in the DF and BF cohorts than in women in the RL cohort.Increased levels of alanine aminotransferase and aspartate aminotransferase were reported to be higher in women in the RL cohort than in women in the DF and BF cohorts (p < 0.05, Fisher's exact test for both).
Depression and anxiety were reported to be higher in women in the BF cohort than in those in the DF and RL cohorts (p < 0.05, Fisher's exact test for all).The details of non-hematological adverse effects during treatment(s) and in the follow-up period are reported in Table 4.

Discussion
The study reported that postmenopausal women with hormone receptor-positive and HER2-negative breast cancer who received dalpiciclib plus fulvestrant had higher progression-free survival, overall survival, and clinical benefits than postmenopausal women with hormone receptor-positive and HER2-negative breast cancer who received buparlisib plus fulvestrant or ribociclib plus letrozole.Dalpiciclib provides extended benefits of cure from diseases (breast cancer) compared to buparlisib or ribociclib plus letrozole, 8 because dalpiciclib has dosedependent plasma exposure in Chinese women with hormone receptorpositive and HER2-negative breast cancer. 17The results of this study suggest that dalpiciclib plus fulvestrant is effective in postmenopausal Chinese women with hormone receptor-positive and HER2-negative breast cancer.
Women who received dalpiciclib or buparlisib reported neutropenia during treatment and follow-up periods.The results of the hematological adverse effects of the current study are consistent with those of a phase 3 trial 8 and a phase 1 trial. 17CDK4/6 inhibitors have adverse effects on neutropenia in Chinese women. 18Dalpiciclib and buparlisib cause neutropenia.
Women who received dalpiciclib or buparlisib plus fulvestrant reported non-hematological adverse effects related to the gastrointestinal tract during the treatment and follow-up periods.Fulvestrant is responsible for adverse effects in the gastrointestinal tract. 19It is necessary to manage adverse effects related to the gastrointestinal tract during treatment with fulvestrant.
Increased aspartate aminotransferase levels were reported to be higher in women in the RL cohort during the treatment and follow-up periods.The results of the hepatological adverse effects of the current study are consistent with those of a phase 3 trial 5 and a MONALEESA-2 trial. 6Liver function monitoring is recommended for ribociclib plus   Clinical benefits: The sum of women with complete response, partial response, and no signs of progressive response.Variables are depicted as the frequencies with percentages in parenthesis.
a Concerning the DF value.Fischer exact test was used for statistical analyses.RECIST version 1.1 criteria was used for evaluation of clinical benefits.All results were significant if p < 0.05.95 % CI, 95 % Confidence Interval (using the approximation of Katz.).

Table 3
Hematological adverse effects during treatment(s) and in the followed-up period.letrozole treatment in postmenopausal women with hormone receptorpositive and HER2-negative breast cancers.
In the women in the BF cohort, skin rashes, diarrhea, and increased levels of alanine aminotransferase and aspartate aminotransferase were reported.The adverse effects of buparlisib in the current study were consistent with those in a phase I trial. 13Daily buparlisib (100 mg) was responsible for the adverse effects.
Women in the BF cohort had higher levels of depression and anxiety during treatment and follow-up periods.The results of the psychiatric adverse effects in the current study are consistent with those of a phase 3 trial. 10The highly penetrating properties of the blood-brain barrier of buparlisib are responsible for anxiety and depression. 11During treatment with buparlisib, women should be under the supervision of a consultant.
The current study has several limitations, for example, it is a retrospective study and lacks randomized trials.The study was preliminary, and the discriminating criteria of the treatment were not introduced.More demographic and clinical parameters should be considered and be well-balanced.The statistical analysis for Cox regression of the primary outcomes in the manuscript, treatment options, ECOG status, and safety and efficacy of treatment was not performed.

Conclusions
Dalpiciclib plus fulvestrant is more effective and comparatively safe (than fulvestrant plus buparlisib treatment and ribociclib plus letrozole treatment) in postmenopausal women with hormone receptor-positive and HER2-negative breast cancers.Dalpiciclib and buparlisib caused neutropenia during the treatment and follow-up periods.It is necessary to manage the adverse effects related to the gastrointestinal tract during treatment with fulvestrant and follow-up periods.Liver function monitoring is recommended for ribociclib plus letrozole treatment during treatment and follow-up periods in postmenopausal women with hormone receptor-positive and HER2-negative breast cancer.Daily buparlisib (100 mg) was responsible for the adverse effects.

Fig. 1 .
Fig. 1.The flow chart of the retrospective analyses.

Fig. 3 .
Fig. 3. Survival of women.Survival: From the start of treatment(s) to death due to any reason.

Fig. 2 .
Fig. 2. Progression-free survival of women.Progression-free survival: From the start of treatment(s) to the first documented progression of disease or death due to any reason.

Table 1
Demographic and clinical parameters of women before treatment(s).
Continuous linear variables are depicted as mean ± Standard Deviation (SD).Categorial variables are depicted as the frequencies with percentages in parenthesis.a 0: Fully active, 1: Restricted in strenuous activity, and ≥ 2: Increasing disability.All results were significant if p < 0.05.ECOG, Eastern Cooperative Oncology Group; ANOVA, Analysis of variance; χ 2 -test, Chi-Square test for independence; df, Degree of freedom.Test value (F-value for ANOVA; χ 2 -value for χ 2 -test).
a b Significant difference concerning the DF value.c Significant difference concerning the BF value.

Table 4
Non-hematological adverse effects during treatment(s) and in the followed-up period.
CTCAE v5.0 was used for the evaluation of adverse events.Women have one or more hematological adverse effect.Variables are depicted as the frequencies with percentages in parenthesis.aConcerningthe DF value.Fischer exact test was used for statistical analyses.All results were significant if p < 0.05.95 % CI, 95 % Confidence Interval (using the approximation of Katz.).bSignificant difference concerning the DF value.c Significant difference concerning the BF value.