Next Article in Journal
Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors
Previous Article in Journal
Fear of Cancer Recurrence in Sarcoma Survivors: Results from the SURVSARC Study
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 14
Issue 24
10.3390/cancers14246100
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Systematic Review

Endocrine Therapy-Based Strategies for Metastatic Breast Cancer with Different Endocrine Sensitivity Statuses: A Systematic Review and Network Meta-Analysis

by
Jiani Wang
1,†,
Yiqun Han
1,†,
Jiayu Wang
1,
Qing Li
1 and
Binghe Xu
1,2,*
1
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2022, 14(24), 6100; https://doi.org/10.3390/cancers14246100
Submission received: 7 November 2022 / Revised: 30 November 2022 / Accepted: 5 December 2022 / Published: 11 December 2022
(This article belongs to the Topic Advances in Anti-Cancer Drugs)
Browse Figures
Versions Notes

Abstract

:

Simple Summary

Over the past few years, a great deal of considerable research has been conducted to develop more effective targeted agents for metastatic breast cancer (mBC) patients. This systematic review and meta-analysis of 47 randomized clinical trials identified CDK4/6i + Fulvestrant 500 as the best treatment option in improving efficacy outcomes in endocrine therapy-sensitive (ETS) patients. Chemotherapy had a higher likelihood of therapeutic success in endocrine therapy-resistant (ETR) patients. In ETR settings, with visceral and bone metastases, CDK4/6i +Fulvestrant 500 was the best regimen, while in ETS patients, CDK4/6i + Fulvestrant 500 was the best for bone metastases and CDK4/6i + aromatase inhibitors (AI) for visceral metastases. This study assessed the relative efficacies and provided a rank order of ET-based regimens in the key endpoints PFS and OS for HR+/HER2- mBC patients with different endocrine sensitivity statuses. Different endocrine sensitivity statuses required various optimal treatment strategies, which may provide guidance for clinical practice.

Abstract

Background: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (mBC). Methods: We performed a systematic search with a predefined search strategy in PubMed, Embase and Cochrane CENTRAL databases to perform a network meta-analysis and evaluate the relative efficacies of ET-based treatment regimens in HR+/HER2- mBC patients with different endocrine sensitivity statuses. The study was registered in the PROSPERO database (CRD42021235570). Results: A total of 47 trials (20,267 patients) were included. Analysis of progression-free survival (PFS) in endocrine therapy-sensitive (ETS) patients revealed cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) + fulvestrant 500 mg (Ful 500) (random effect (RE): hazard ratio (HR), 0.46; 95% credibility interval (CrI), 0.27–0.78; surface under the cumulative ranking curve (SUCRA), 0.93; fixed effect (FE): HR, 0.48; 95% CrI, 0.40–0.58; SUCRA, 0.99) to be the best therapy followed by CDK4/6i + aromatase inhibitors (AIs) (RE: HR, 0.53; 95% CrI, 0.40–0.72; SUCRA, 0.86; FE: HR, 0.54; 95% CrI, 0.48–0.61; SUCRA, 0.91). Chemotherapy followed by CDK4/6i + Ful 500 appears to be the most effective option for the endocrine therapy-resistant (ETR) group. Analysis of overall survival revealed CDK4/6i + Ful 500 (SUCRA: 0.99) and AKTi + Ful 500 (SUCRA: 0.87) to be the first-rank regimen for the ETS group and ETR groups, respectively. Conclusion: Our comprehensive analysis suggests that CDK4/6i combined with ETs may be the best treatment option in terms of PFS for ETS patients and chemotherapy for ETR patients with HR+/HER2- mBC. Different endocrine sensitivity statuses required various optimal treatment strategies, which may provide guidance for clinical practice.

1. Introduction

Breast cancer is currently the most common malignancy in women worldwide, accounting for approximately 11.7% of all new malignancies [1]. Hormone-receptor-positive (HR+)/HER2-negative (HER2-) breast cancer accounts for approximately 65–70% of mBC. Existing evidence substantiated that the estrogen receptor signaling pathway plays a pivotal role in cancer cell growth and survival in these tumors, and, hence, endocrine-based therapies (ETs) are considered to be one of the most effective systemic treatment cornerstones [2] for these patients, even in visceral metastatic settings. Despite the perceived significant therapeutic effect of ETs, a major therapeutic challenge in treating HR+ breast cancer is to delay or reverse endocrine resistance (ER). A subset of patients (30–40%) eventually acquire resistance to ETs due to prolonged use in the adjuvant setting [3].
Over the past few years, a great deal of considerable research has been made to develop more effective targeted agents. In patients with mBC, the main drivers of resistance include ESR1 gene fusion which may require a combination treatment with targeted agents to overcome the resistance and also to minimize the probability of the emergence of resistance in endocrine-sensitive patients [4,5]. Among the other mechanisms of endocrine resistance, targeting high expression of EGFR or HER2 [6,7], phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) or RAS/RAF/MEK/ERK pathways could also minimize the emergence of ER in patients with mBC [8]. Furthermore, addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has also been shown to extend the duration of progression-free survival (PFS) and overall survival (OS) in comparison to ET alone in patients with mBC. Given the absence of direct head-to-head comparisons for all available treatment regimens, decision-making guidelines are urgently needed for multiple therapeutic options.
Previous meta-analyses have taken into account the efficacy of CDK4/6i and ET combinations but were limited in many aspects, such as discovery of appropriate targeted therapies, use of heterogeneity model, non-inclusion of data related to OS, menopausal women and heterogeneity of disease [9,10]. Furthermore, the studies did not perform an extensive efficacy analysis of all possible subgroups of patients with different endocrine sensitivity statuses. Thus, the objective of this network meta-analysis is to perform an extensive analysis and rank the available ET-based strategies (with/without targeted agents) based on their relative efficacies to guide the clinical decision making for patients with HR+/HER2- mBC with different endocrine sensitivity statuses.

2. Materials and Methods

2.1. Search Strategy and Eligibility Criteria

A systematic search with a predefined search strategy (Supplementary Table S1) consisting of HR status, advanced breast cancer, interested therapeutic regimens and desired endpoints with relevant study design was performed in PubMed, Embase and Cochrane CENTRAL databases. The search was performed from January 2000 till April 2022 and included only studies published in English. We also performed a supplementary search of major conferences in the American Society of Clinical Oncology Annual Meeting, European Society for Medical Oncology Congress and San Antonio Breast Cancer Symposium to retrieve updated survival data from unpublished landmark trials.
Only phase II/III randomized controlled trials (RCTs) evaluating the efficacy of at least one ET-based regimen for the treatment of patients with advanced or metastatic HR+/HER2- breast cancer were considered for this analysis. This systematic review and network meta-analysis was based on the Cochrane Collaboration Handbook (version 6.1, https://training.cochrane.org/handbook, accessed on 5 October 2022) and registered in the PROSPERO database (CRD42021235570). The PRISMA (Preferred Reporting Items for Systematic reviews) and Meta-Analyses extension for network meta-analysis guidelines were followed to report the present study. The information was recorded by one investigator (H. Yiqun) and is concurrently collected by two investigators (X. Binghe and W. Jiani). Three investigators independently extracted data.
The classification criteria used for defining endocrine sensitivity statuses followed the current international consensus guidelines. Characteristics of endocrine therapy-sensitive (ETS) population include: (1) completion of adjuvant ETs and recurrence after one year of drug discontinuation; (2) no ETs background, including those mBC without any ETs and recurrence after surgery without adjuvant ETs. Characteristics of endocrine therapy-resistant (ETR) population include: (1) Primary ETR: relapse after less than 2 years of adjuvant ETs, or disease progression after less than 6 months of advanced first-line ETs; (2) Secondary ETR: patients with adjuvant ETs for more than 2 years and relapsed within 1 year of discontinuation, or progress on late first-line endocrine therapy for more than 6 months. If not explicitly mentioned in the clinical trial, other information, such as enrollment and subgroup analysis, was used to determine endocrine status.

2.2. Study Objectives and Endpoints

The primary objective of the study was to compare the relative efficacies of the available therapeutic options including monotherapy and combination therapy for the treatment of HR+/HER2- mBC. The primary efficacy endpoint was PFS, defined as the time from randomization to progressive disease or death, and the secondary endpoint was OS, defined as the time from randomization until death with any cause. The efficacy analysis was performed based on endocrine status (ETS and ETR). Subgroup analysis based on specific targeted regimens, site of metastasis (visceral and bone-only) and menopausal status was also performed. Multiple reports collection and data extraction were performed by one author and verified by a second author. A third author resolved disagreements.

2.3. Statistical Analysis

Evaluation of quality of the selected RCTs was performed by the investigators using Cochrane Collaboration’s risk-of-bias tool. For each study, the hazard ratio (HR) for PFS and OS along with their 95% credibility intervals (CrI) were extracted from baseline demographics. A Bayesian network meta-analysis was performed using the “Gemtc” 4.2.1 package from R software (version 4.0.4). Within the framework, heterogeneity across studies was tested by I2 and the Q statistics along with a forest plot; statistically significant heterogeneity was defined as a p-value < 0.1 or an I2 statistic > 50%. A random effect (RE) model was performed when I2 ≥ 50%; otherwise, a fixed effect (FE) model was applied to quantitate effect size. The surface under the cumulative ranking curve (SUCRA) value was used to rank the effective treatment regimens. Thus, treatments were ranked in a table from best to worst along the leading diagonal [11] with high odds in SUCRA suggesting better ranking [12]. PFS and OS, as defined above for efficacy analysis of treatments based on endocrine status, will be ranked based on the SUCRA value to suggest the most efficacious treatment group.

2.4. Network Geometry

Based on the availability of evidence, networks were constructed for ETS and ETR patients separately. Since the purpose of the network meta-analysis is to provide the relative efficacies of all the available regimens, more than one evidence network was provided for some of the evaluated endpoints and subgroups. In case of two regimens not being accommodated within the major network of evidence, those regimens were excluded from the analyses. For the construction of the evidence networks, comparison was made at the level of drug class. However, additional subgroup analyses at the level of individual drugs were performed for specific drugs as stated above.

2.5. Risk Bias in Individual Studies

The quality of each RCT included was evaluated by two independent authors using a Cochrane Risk of Bias 2 (RoB 2.0) tool [13,14]. The tool includes (1) randomization process, (2) deviations from intended interventions, (3) missing outcome data, (4) measurement of the outcome and (5) selection of the reported result [13]. Biases are assessed either as “Low” or “High” risk of bias, or can express “Some concerns”.

2.6. Publication Bias and Sensitivity Analysis

Egger’s test and Begg’s test were used to assess the potential publication bias. Sensitivity analysis was performed for those which showed publication bias by step-wise removal of single studies (Supplementary Figures S1–S3).

3. Results

3.1. Systematic Review and Characteristics

A total of 1032 publications and 152 abstract reviews were retrieved through the initial literature and conference search, and 1083 studies remained after duplications were excluded. A total of 47 studies with a cumulative population of 20,267 patients were identified for the detailed analysis. Among the 47 studies, 35 studies were included for the analysis of ETR and 34 studies were included for the analysis of ETS patients (Figure 1). Since the widespread standardized testing of HER2 status was implemented in 2007, articles published from 2009 to 2022 were screened based on the eligibility criteria of this study. The baseline factors of the included studies are provided in Table 1.

3.2. Quality of the Evidence

The overall risk of bias of included studies is presented in Supplementary Figure S4. Of the 47 trials included, 33 studies (70%) presented an overall low risk in the five areas of potential bias. A high risk of bias was present in seven (15%) trials while the remaining trials (15%) had “some concerns”, mainly due to open label design and assessment of outcomes by the investigator. The risk of bias was frequently high/unclear in trials with results published only in the form of meeting abstracts (n = 3).
The methodological quality showed high risk of bias in three trials [29,53,56]. The final results of the ETR OS and ETR of CDK4/6i in combination with other drugs were not affected by the presence of these trials. After removing studies by Jeresaleum et al. [53] and Martin et al. [56], treatment regimens remained the same, confirming that the results were reliable. Similarly, in cases of CDK4/6i in combination with other drugs in ETR and ETS patients, the best treatment regimens remained unchanged after removal of studies [29,56]. There was, however, a noticeable change in the treatment regimens in cases of ETR-PFS and post-menopausal status in ETR patients after exclusion of the trials [53,56].

3.3. Analysis of PFS/OS in Patients with ETS

A total of 34 trials were included for the PFS analysis including 13 different regimens for the major network and two regimens for the minor network. Among the 13 regimens, CDK4/6i + Fulvestrant (Ful 500, structural representation in Supplementary Figure S5) (RE: HR, 0.46; 95% CrI, 0.27–0.78; FE: HR, 0.48; 95% CrI, 0.40–0.58) was the best regimen and significantly better than aromatase inhibitor (AI), with a SUCRA value of 0.93 in the RE model and 0.99 in the FE model, followed by CDK4/6i + AI (RE: HR, 0.53; 95% CrI, 0.40–0.72; SUCRA, 0.86; FE: HR, 0.54; 95% CrI, 0.48–0.61; SUCRA, 0.91) and Ful 500 + PI3Ki (RE: HR, 0.66; 95% CrI, 0.48–0.89; SUCRA, 0.69; FE: HR, 0.66; 95% CrI, 0.48–0.89; SUCRA, 0.76) (Figure 2A and Figure 3A). The minor network revealed that Tyrosine kinase inhibitors (TKI) + Ful 500 was a better treatment regimen (HR, 0.88; 95% CrI, 0.45–1.7; SUCRA, 0.65) than Ful 250.
A total of eight studies reported OS in patients with ETS and a network of seven regimens was constructed (Figure 3B). CDK4/6i + Ful 500 (HR, 0.50; 95% CrI, 0.34–0.74) ranked the highest, with a SUCRA value of 0.99, without statistical significance among the top three regimens (Figure 2B).

3.3.1. Bone-Only and Visceral Metastasis

A total of eight studies reported PFS based on visceral metastasis and a network of seven regimens was constructed. The SUCRA value was highest for CDK4/6i + AI (HR, 0.56; 95% CrI, 0.44–0.70; SUCRA, 0.92), followed by CDK4/6i + Ful 500 (HR, 0.60; 95% CrI, 0.46–0.79; SUCRA, 0.78), Tam (HR, 0.66; 95% CrI, 0.54–0.80; SUCRA, 0.67) and AI + monoclonal antibody (MAB) (HR, 0.69; 95% CrI, 0.53–0.90; SUCRA, 0.62).
In patients with bone metastasis, among six treatment regimens reported in six studies, CDK4/6i + Ful 500 (HR, 0.43; 95% CrI, 0.24–0.76) was the most favorable with the highest SUCRA value of 0.90, followed by CDK4/6i + AI (HR, 0.44; 95% CrI, 0.28–0.69; SUCRA, 0.87) and Ful (HR, 0.71; 95% CrI, 0.34–1.5; SUCRA, 0.45).

3.3.2. Relative Efficacy of Targeted-Based Regimens

Among the 10 studies reporting the efficacy of CDK4/6i-based regimens, a network with seven regimens was constructed. Sensitivity analysis revealed high risk of bias for the PALOMA-1/TRIO 18 [12] study and hence this was removed from the analysis. Abemaciclib (Abe) + AI (HR, 0.52; 95% CrI, 0.42–0.66) was the most effective regimen, with a SUCRA value of 0.94, followed by Palbociclib (Pal) + AI (HR, 0.64; 95% CrI, 0.53–0.78; SUCRA, 0.72), Ribociclib (Rib) + AI (HR, 0.65; 95% CrI, 0.47–0.89; SUCRA, 0.68), Pal + Ful (HR, 0.70; 95% CrI, 0.51–0.98; SUCRA, 0.59), Rib + Ful (HR, 0.87; 95% CrI, 0.54–1.4; SUCRA, 0.36) and Ful (HR, 1.6; 95% CrI, 1.1–2.3; SUCRA, 0.002) compared with AI with statistically significant differences observed among the top three regimens.
A network of three regimens was constructed among two studies with HDACi. Tucidinostat (Tuc) + AI (HR, 0.68; 95% CrI, 0.50–0.93) demonstrated statistically significant efficacy, with a SUCRA value of 0.89, followed by entinostat (Ent) + AI (HR, 0.85; 95% CrI, 0.54–1.3; SUCRA, 0.49) and AI (SUCRA, 0.12).
Among the two studies with PI3Ki, a network of three regimens was constructed and, among them, buparlisib (Bup) + Ful (HR, 0.87; 95% CrI, 0.35–2.2) was the best, with a SUCRA value of 0.80, followed by alpelisib (Alp) + Ful (HR, 0.75; 95% CrI, 0.57–0.99; SUCRA, 0.50) compared with Ful (SUCRA, 0.20) with no statistically significant difference observed among the three regimens.

3.4. Analysis of PFS/OS in Patients with ETR

Out of the total studies, a major network with 31 studies including 17 regimens and a minor network with two studies and three regimens were constructed. Among the regimens considered in the major evidence network, chemotherapy (HR, 0.37; 95% CrI, 0.27–0.51) demonstrated statistically significant benefits, with a SUCRA value of 0.96, followed by CDK4/6i + Ful 500 (HR, 0.42; 95% CrI, 0.28–0.65; SUCRA, 0.88) and mTOR + AI (HR, 0.47; 95% CrI, 0.41–0.55; SUCRA, 0.80). The other regimens considered in the major network were provided in Figure 2C–E and Figure 4A,C. Three regimens were considered for the minor network, among which mTOR + tamoxifen (Tam) had a higher SUCRA (FE: 0.99, RE: 0.93), followed by Tam (FE: 0.41, RE: 0.41), with a statistically significant HR for mTOR + Tam vs. Tam (HR, 0.54; 95% CrI, 0.36–0.81) (Figure 4C).
The evaluation of OS included a total of 19 studies and two different evidence networks were constructed. Network 1 consisted of 14 regimens (Figure 2C andFigure 4B), out of which AKT + Ful 500 (HR, 0.53; 95% CrI, 0.24–1.1) ranked the highest, with a SUCRA value of 0.87, followed by mTOR + Ful500 (HR, 0.64; 95% CrI, 0.35–1.19; SUCRA, 0.78) and chemotherapy (HR, 0.67; 95% CrI, 0.47–0.95; SUCRA, 0.79), without statistically significant difference among them. In network 2, mTOR + Tam (HR, 0.45; 95% CrI, 0.14–1.4) was a better regimen than Tam with SUCRA value of 0.93.

3.4.1. Bone-Only and Visceral Metastasis

Among patients with visceral metastasis, five studies with three regimens were considered. CDK4/6i + Ful 500 was the most beneficial treatment regimen, with a SUCRA value of 0.99, followed by PI3Ki + Ful 500 (SUCRA, 0.49), with statistically significant improvement in PFS observed for CDK4/6i + Ful500 in comparison to Ful 500 (HR, 0.47; 95% CrI, 0.39–0.58) and PI3Ki + Ful 500 (HR, 0.76; 95% CrI, 0.64–0.90). The minor network with one study and two regimens revealed that mTOR was a better regimen than AI (HR, 0.47; 95% CrI, 0.37–0.60, SUCRA, 0.95)
Five studies reporting HRs stratified by patients with bone metastasis along with three regimens were included for the major network evidence analysis. CDK4/6i + Ful 500 (HR, 0.52; 95% CrI, 0.37–0.73) ranked the highest, with a SUCRA value of 0.94 followed by PI3Ki + Ful 500 (HR, 0.68; 95% CrI, 0.50–0.92; SUCRA, 0.56) in comparison with Ful 500 (SUCRA: 0.003) with significant differences observed. The minor network with one study and two regimens showed that mTOR + Ful was a better treatment than AI (HR, 0.33; 95% CrI, 0.078–1.4; SUCRA, 0.95).

3.4.2. Relative Efficacy of Targeted-Based Regimens

A total of six studies with six regimens reported the efficacy of the available CDK4/6i in combination with other drugs. Among the Ful-containing regimens, dalpiciclib + Ful 500 (HR, 0.42; 95% CrI, 0.31–0.57) was significantly better than Ful 500, with a SUCRA value of 0.90, followed by Abe + Ful 500 (HR, 0.52; 95% CrI, 0.43–0.62; SUCRA, 0.65). Among the three AI-containing regimens with three studies, Rib + AI (HR, 0.37; 95% CrI, 0.24–0.60; SUCRA, 0.93) was the best, followed by Pal + AI (HR, 0.37; 95% CrI, 0.24–0.60; SUCRA, 0.57), both significantly better than AI alone.
Among the two HDACi, Ent + AI (HR, 0.47; 95% CrI, 0.23–0.97) was the best, with a SUCRA value of 0.96, followed by Tuc + AI (HR, 0.92; 95% CrI, 0.58–1.5; SUCRA, 0.35) compared with AI (SUCRA, 0.19), but there was no statistically significant difference among the three regimens.
A total of four studies compared the efficacy of the PI3Ki with four regimens, which revealed Bup + Ful (HR, 0.67, 95% CrI, 0.53–0.84) to be the most efficacious, with a SUCRA value of 0.76, followed by Alp + Ful (HR, 0.65; 95% CrI, 0.32–1.3; SUCRA, 0.71) and Pictilisib + Ful (HR, 0.80; 95% CrI, 0.58–1.1; SUCRA, 0.47), with Bup + Ful revealing significant improvement in PFS in comparison to Ful 500 (HR, 0.67; 95% CrI, 0.53–0.84).

3.4.3. Menopausal Status

Thirty studies were included for the analysis of PFS among post-menopausal women with 17 regimens. Chemotherapy was found to be the most significantly better regimen than Ful 500 (HR, 0.45; 95% CrI, 0.33–0.61; SUCRA, 0.96), followed by CDK4/6i + Ful 500 (HR, 0.51; 95% CrI, 0.44–0.59; SUCRA, 0.89). Network 2 with two studies and three regimens showed that mTOR + Tam was significantly better than Tam (HR, 0.54; 95% CrI, 0.36–0.79; SUCRA, 0.99) and TKI + Tam (HR, 1.5; 95% CrI, 0.65–3.4; SUCRA, 0.09).
Two studies were included for the construction of network 1 for the pre-menopausal status. CDK4/6i + Ful 500 was better than Ful 500 (HR, 0.54; 95% CrI, 0.25–1.2; SUCRA, 0.96). Similarly, network 2 showed that mTOR + AI was better than AI (HR, 0.53; 95% CrI, 0.23–1.2; SUCRA, 0.94).
The hazards ratio and the respective 95% CrI are provided in online Supplementary Tables S2–S37.

4. Discussion

Over the past decade, several RCTs have led to the introduction of innovative targeted therapeutic strategies (mTOR, HDAC, CDK4/6, PI3K inhibitors, etc.) in combination with ETs into clinical practice. Furthermore, pivotal RCTs have proven the efficacy of these combinations as first and subsequent lines of treatment for HR+/HER2- mBC with substantial improvement in patient outcomes [1,2].
This network meta-analysis assessed the relative efficacies and provided a rank order of ET-based regimens in key endpoints PFS and OS for HR+/HER2- mBC patients with different endocrine sensitivity statuses. Based on the systematic review, the endocrine therapies were used in combination with the regimens targeting the CDK4/6, PI3K and HDAC pathways, which led to significant improvement in therapeutic outcomes. The main strength of this current network meta-analysis is the extensive analysis of all possible subgroups of patients and the number of studies included for the analysis. Given the geometry of the networks, the SUCRA values may guide clinical decision making by indicating ranking probabilities for each treatment.
The results of this study suggest that CDK4/6i in combination with Ful 500 is likely to be the best treatment option in terms of both PFS and OS benefit among ETS patients. The second-best options for treatment with significant differences for ETS patients were CDK4/6i + AI for improving PFS outcomes, and Ful 500 for improving OS outcomes. This was consistent with a recent network meta-analysis by Brandao et al. which reported CDK4/6i + Ful 500 to be the most effective treatment option for ETS patients [9]. Similar results were also reported in another network meta-analysis where addition of CDK4/6i to ET significantly improved median PFS (pooled HR = 0.547, p < 0.001) and OS (pooled HR = 0.755, p < 0.001). In addition, the PI3Ki + Ful therapy provided meaningful improvement in PFS (pooled HR = 0.686, p < 0.001), which was also noticed in our analysis [70].
In patients with ETR, chemotherapy has a high likelihood of therapeutic success, followed by CDK4/6i and AKTi in combination with fulvestrant. However, the network meta-analysis of 29 trials in ETR patients reported CDK4/6i + Ful 500 to be the best among 20 compared regimens, followed by capivasertib + Ful 500 as the second-best regimen [9]. However, in the current study, a total of 35 studies were included and all chemotherapeutic drugs were combined into a single drug class for comparison. Especially in cases of ETR-PFS and post-menopausal status in ETR patients containing chemotherapy arms, sensitivity analysis revealed a change in the treatment regimens after exclusion of Jeresaleum et al. [53] and Martin et al. [56]. The difference in the included trials and classification of regimens could be the reason for observed discordance. Nevertheless, the previous study also reported a lack of statistical significance among the top regimens [9].
Patients with visceral metastases have poor prognosis compared to those without visceral metastases among women with HR+/HER2- breast cancer. International guidelines recommend ET over chemotherapy as the frontline treatment option for mBC with HR+/HER2- type. Previous studies also revealed that treating patients with CDK4/6i + ET provided the advantage of PFS over ET alone in patients with or without visceral metastasis in both ETS and ETR settings [10]. Our study also revealed concordant findings, with CDK4/6i + FUL500 being the best regimen for ETS patients and CDK4/6i + Ful 500 for ETR patients. In patients with bone-only mBC, the treatment course is varied. However, bone-only disease is uncommon, and often observed in combination with other non-bone or non-visceral sites in clinical trials. A meta-analysis revealed that CDK4/6i + ET in combination improved PFS (HR, 0.54; 95% CI, 0.39–0.75; p < 0.001) for first-line treatment in bone-only disease settings, which is similar to our study findings [70].
We observed that chemotherapy was the best regimen for post-menopausal women with breast cancer. This is inconsistent with several published studies that reported hormone therapies with or without targeted therapies in post-menopausal women with HR+/HER2- mBC as the best treatment option. However, it must be noted that chemotherapy as an upfront treatment remains common even in the absence of visceral crisis and, hence, these results are to be interpreted with caution. This was also observed in a trial by Giuliano et al. [71] where chemotherapy or hormone therapy regimen was non-inferior to palbociclib plus letrozole for improving PFS. Though CDK4/6i + Ful500 was a better regimen in pre-menopausal women and consistent with previous studies [10,72], the number of studies were insufficient to derive to a meaningful conclusion. Combination of targeted therapies with ETs also revealed interesting results. In two of the meta-analyses, HDACi + ET was associated with prolonged PFS and OS compared to ET [73] or AI alone [74]. Accordingly, HDACi + ET was found to be a suitable treatment option in patients with HDAC modifications, with Tuc + AI and Ent + AI as the best regimen for patients with ETS and ETR status, respectively.
The classification of endocrine sensitivity statuses was as per the information provided in the included trials. However, if the trial did not categorically mention the endocrine status, then alternative information from the trial was used to determine this. For instance, the S0226 trial did not mention the endocrine status of the included patients in the initial publication with PFS data. Hence, patients with a previous history of tamoxifen administration were considered as endocrine-resistant patients [27]. However, in the subsequent publication with OS data, HR for patients stratified into endocrine-sensitive and -resistant were provided and the same were used for analysis [28].

Limitations

Several limitations to this study must be acknowledged. Firstly, for subgroup analysis of bone-only metastasis, some of the studies provided only non-visceral metastasis, which was considered as bone-only metastasis for comparison. The MIRACLE trial [43], which evaluated the efficacy of everolimus in combination with AI in comparison to AI alone, provided HR stratified by visceral and non-visceral metastasis. The HR for non-visceral metastasis was considered as bone-only metastasis for analysis. Secondly, the effect estimates of the OS results may not be matured enough and may require a longer follow-up time for precise evaluation. In cases of patients with ETR, studies with fulvestrant and AI were distributed into two different networks and, hence, their relative efficacies with respect to extending the OS could not be ascertained. Thirdly, due to a large degree of heterogeneity across trials, network-based meta-analysis could not be performed for defined biomarker subgroups, such as patients with PIK3CA mutations.

5. Conclusions

Our comprehensive network meta-analysis suggests that CDK4/6i combination with ETs may be the best treatment option in terms of PFS for ETS patients and chemotherapy may be the best regimen for ETR patients with HR+/HER2- mBC. Moreover, CDK4/6i + ETs is likely to improve bone or visceral metastases irrespective of ETR or ETS status. Further matured OS data need to be assessed to conclude the OS benefit of the different ET-based treatment regimens.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers14246100/s1, Table S1. Electronic search strategy. Table S2. (A) PFS effect estimates of ETS patients for pairwise comparisons: hazard ratio (95% credibility interval, CrI) (network 1), (B) PFS effect estimates of ETS patients for pairwise comparisons: hazard ratio (95% credibility interval, CrI) (network 2), (C) OS effect estimates of ETS patients for pairwise comparisons: hazard ratio (95% credibility interval, CrI). Table S3. (A) PFS effect estimates of ETR patients for pairwise comparisons: hazard ratio (95% credibility interval, CrI) (network 1). (B) PFS effect estimates of ETR patients for pairwise comparisons: hazard ratio (95% credibility interval, CrI) (network 2), (C) OS effect estimates of ETR patients for pairwise comparisons: hazard ratio (95% credibility interval, CrI) (network 1), (D) OS effect estimates of ETR patients for pairwise comparisons: hazard ratio (95% credibility interval, CrI) (network 2). Table S4. SUCRA values of PFS for CDK4/6 inhibitors in ETS patients. Table S5. Effect estimates of PFS for CDK4/6 inhibitors in ETS patients: hazard ratio (95% credibility interval, CrI). Table S6. SUCRA values for PI3ki in ETS patients. Table S7. Effect estimates of PFS for PI3ki in ETS patients hazard ratio (95% credibility interval, CrI). Table S8. SUCRA values of PFS for HDACi in ETS patients. Table S9. Effect estimates of PFS for HDACi in ETS patients hazard ratio (95% credibility interval, CrI). Table S10. SUCRA of PFS for visceral metastases in ETS patients. Table S11. Effect estimates of PFS for visceral metastases in ETS patients: hazard ratio (95% credibility interval, CrI). Table S12. SUCRA values of PFS for bone metastases in ETS patients. Table S13. Effect estimates of PFS for bone metastases in ETS patients: hazard ratio (95% credibility interval, CrI). Table S14. SUCRA values of PFS for CDK4/6 inhibitors in ETR patients (Network 1). Table S15. Effect estimates of PFS for CDK4/6 inhibitors in ETR patients: hazard ratio (95% credibility interval, CrI) (Network 1). Table S16. SUCRA values of PFS for CDK4/6 inhibitors in ETR patients (Network 2). Table S17. Effect estimates of PFS for CDK4/6 inhibitors in ETR patients: hazard ratio (95% credibility interval, CrI) (Network 2). Table S18. SUCRA values of PFS for PI3ki in ETR patients. Table S19. Effect estimates of PFS for PI3ki in ETR patients: hazard ratio (95% credibility interval, CrI). Table S20. SUCRA values of PFS for HDACi in ETR patients. Table S21. Effect estimates of PFS for HDACi in ETR patients: hazard ratio (95% credibility interval, CrI). Table S22. SUCRA values of PFS for visceral metastases in ETR patients (network 1). Table S23. Effect estimates of PFS for visceral metastases in ETR patients: hazard ratio (95% credibility interval, CrI) (network 1). Table S24. SUCRA values of PFS for visceral metastases in ETR patients (network 2). Table S25. Effect estimates of PFS for visceral metastases in ETR patients: hazard ratio (95% credibility interval, CrI) (network 2). Table S26. SUCRA values of PFS for bone metastases in ETR patients (network 1). Table S27. Effect estimates of PFS for bone metastases in ETR patients: hazard ratio (95% credibility interval, CrI) (network 1). Table S28. SUCRA values of PFS for bone metastases in ETR patients (network 2). Table S29. Effect estimates of PFS for bone metastases in ETR patients: hazard ratio (95% credibility interval, CrI) (network 2). Table S30. SUCRA values of PFS for post-menopausal women in ETR patients (network 1). Table S31. Effect estimates of PFS for post-menopausal women in ETR patients: hazard ratio (95% credibility interval, CrI) (network 1). Table S32. SUCRA values of PFS for post-menopausal women in ETR patients (network 2). Table S33. Effect estimates of PFS for post-menopausal women in ETR patients: hazard ratio (95% credibility interval, CrI) (network 2). Table S34. SUCRA values of PFS for pre-menopausal women in ETR patients (network 1). Table S35. Effect estimates of PFS for pre-menopausal women in ETR patients: hazard ratio (95% credibility interval, CrI) (network 1). Table S36. SUCRA values of PFS for pre-menopausal women in ETR patients (network 2). Table S37. Effect estimates of PFS for pre-menopausal women in ETR patients: hazard ratio (95% credibility interval, CrI) (network 2). Figure S1. Risk of bias across studies (main analysis in ETS and ETR patients). Figure S2. Risk of bias across studies (subgroup analysis for targeted regimens in ETS patients). Figure S3. Risk of bias across studies (subgroup analysis for targeted regimens and menopausal women in ETR patients). Figure S4. Quality assessment data for individual studies. Figure S5. Chemical structure of fulvestrant.

Author Contributions

B.X. has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design: B.X. and J.W. (Jiani Wang). Development of methodology: J.W. (Jiani Wang). Acquisition of data: J.W. (Jiani Wang) and Y.H. Analysis and interpretation of data (e.g., statistical analysis, computational analysis): J.W. (Jiani Wang) and Y.H. Writing, review, and/or revision of the manuscript: J.W. (Jiani Wang), Y.H., J.W. (Jiayu Wang) and B.X. Study supervision: Q.L., J.W. (Jiayu Wang) and B.X. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by the National Natural Science Foundation of China under Grants 82103013, the Chinese Academy of Medical Sciences & Peking Union Medical College: (2021-I2M-1-014) and the Cultivation project of Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022004).

Acknowledgments

The authors acknowledge the initial literature assistance, medical writing and statistical support provided by Anwesha Mandal and Amit Bhat from Indegene Pvt ltd, Bengaluru, India.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. O’Shaughnessy, J. Extending Survival with Chemotherapy in Metastatic Breast Cancer. Oncologist 2005, 10 (Suppl. S3), 20–29. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Anurag, M.; Ellis, M.J.; Haricharan, S. DNA Damage Repair Defects as a New Class of Endocrine Treatment Resistance Driver. Oncotarget 2018, 9, 36252–36253. [Google Scholar] [CrossRef] [PubMed]
  4. Robinson, D.R.; Wu, Y.-M.; Vats, P.; Su, F.; Lonigro, R.J.; Cao, X.; Kalyana-Sundaram, S.; Wang, R.; Ning, Y.; Hodges, L.; et al. Activating ESR1 Mutations in Hormone-Resistant Metastatic Breast Cancer. Nat. Genet. 2013, 45, 1446–1451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Lei, J.T.; Shao, J.; Zhang, J.; Iglesia, M.; Chan, D.W.; Cao, J.; Anurag, M.; Singh, P.; He, X.; Kosaka, Y.; et al. Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer. Cell Rep. 2018, 24, 1434–1444.e7. [Google Scholar] [CrossRef] [Green Version]
  6. Newby, J.C.; Johnston, S.R.; Smith, I.E.; Dowsett, M. Expression of Epidermal Growth Factor Receptor and C-ErbB2 during the Development of Tamoxifen Resistance in Human Breast Cancer. Clin. Cancer Res. 1997, 3, 1643–1651. [Google Scholar]
  7. Borg, A.; Baldetorp, B.; Fernö, M.; Killander, D.; Olsson, H.; Rydén, S.; Sigurdsson, H. ERBB2 Amplification Is Associated with Tamoxifen Resistance in Steroid-Receptor Positive Breast Cancer. Cancer Lett. 1994, 81, 137–144. [Google Scholar] [CrossRef]
  8. Hanker, A.B.; Sudhan, D.R.; Arteaga, C.L. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell 2020, 37, 496–513. [Google Scholar] [CrossRef]
  9. Brandão, M.; Maurer, C.; Ziegelmann, P.K.; Pondé, N.F.; Ferreira, A.; Martel, S.; Piccart, M.; de Azambuja, E.; Debiasi, M.; Lambertini, M. Endocrine Therapy-Based Treatments in Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Systematic Review and Network Meta-Analysis. ESMO Open 2020, 5, e000842. [Google Scholar] [CrossRef]
  10. Messina, C.; Cattrini, C.; Buzzatti, G.; Cerbone, L.; Zanardi, E.; Messina, M.; Boccardo, F. CDK4/6 Inhibitors in Advanced Hormone Receptor-Positive/HER2-Negative Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Trials. Breast Cancer Res. Treat. 2018, 172, 9–21. [Google Scholar] [CrossRef]
  11. de Sire, A.; Moggio, L.; Demeco, A.; Fortunato, F.; Spanò, R.; Aiello, V.; Marotta, N.; Ammendolia, A. Efficacy of Rehabilitative Techniques in Reducing Hemiplegic Shoulder Pain in Stroke: Systematic Review and Meta-Analysis. Ann. Phys. Rehabil. Med. 2022, 65, 101602. [Google Scholar] [CrossRef]
  12. Marotta, N.; Demeco, A.; Moggio, L.; Marinaro, C.; Pino, I.; Barletta, M.; Petraroli, A.; Pepe, D.; Lavano, F.; Ammendolia, A. Comparative Effectiveness of Breathing Exercises in Patients with Chronic Obstructive Pulmonary Disease. Complement Ther. Clin. Pract. 2020, 41, 101260. [Google Scholar] [CrossRef]
  13. Ibrahim, N.K.; Yariz, K.O.; Bondarenko, I.; Manikhas, A.; Semiglazov, V.; Alyasova, A.; Komisarenko, V.; Shparyk, Y.; Murray, J.L.; Jones, D.; et al. Randomized Phase II Trial of Letrozole plus Anti-MUC1 Antibody AS1402 in Hormone Receptor-Positive Locally Advanced or Metastatic Breast Cancer. Clin. Cancer Res. 2011, 17, 6822–6830. [Google Scholar] [CrossRef] [Green Version]
  14. Sterne, J.A.C.; Savović, J.; Page, M.J.; Elbers, R.G.; Blencowe, N.S.; Boutron, I.; Cates, C.J.; Cheng, H.-Y.; Corbett, M.S.; Eldridge, S.M.; et al. RoB 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials. BMJ 2019, 366, l4898. [Google Scholar] [CrossRef] [Green Version]
  15. Goetz, M.P.; Toi, M.; Campone, M.; Sohn, J.; Paluch-Shimon, S.; Huober, J.; Park, I.H.; Trédan, O.; Chen, S.-C.; Manso, L.; et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J. Clin. Oncol. 2017, 35, 3638–3646. [Google Scholar] [CrossRef]
  16. Zhang, Q.Y.; Sun, T.; Yin, Y.M.; Li, H.P.; Yan, M.; Tong, Z.S.; Oppermann, C.P.; Liu, Y.P.; Costa, R.; Li, M.; et al. MONARCH plus: Abemaciclib plus Endocrine Therapy in Women with HR+/HER2- Advanced Breast Cancer: The Multinational Randomized Phase III Study. Ther. Adv. Med. Oncol. 2020, 12, 1758835920963925. [Google Scholar] [CrossRef]
  17. Wolff, A.C.; Lazar, A.A.; Bondarenko, I.; Garin, A.M.; Brincat, S.; Chow, L.; Sun, Y.; Neskovic-Konstantinovic, Z.; Guimaraes, R.C.; Fumoleau, P.; et al. Randomized Phase III Placebo-Controlled Trial of Letrozole plus Oral Temsirolimus as First-Line Endocrine Therapy in Postmenopausal Women with Locally Advanced or Metastatic Breast Cancer. J. Clin. Oncol. 2013, 31, 195–202. [Google Scholar] [CrossRef] [Green Version]
  18. Dickler, M.N.; Barry, W.T.; Cirrincione, C.T.; Ellis, M.J.; Moynahan, M.E.; Innocenti, F.; Hurria, A.; Rugo, H.S.; Lake, D.E.; Hahn, O.; et al. Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance). J. Clin. Oncol. 2016, 34, 2602–2609. [Google Scholar] [CrossRef]
  19. Goss, P.; Bondarenko, I.N.; Manikhas, G.N.; Pendergrass, K.B.; Miller, W.H.; Langecker, P.; Blanchett, D. Phase III, Double-Blind, Controlled Trial of Atamestane plus Toremifene Compared with Letrozole in Postmenopausal Women with Advanced Receptor-Positive Breast Cancer. J. Clin. Oncol. 2007, 25, 4961–4966. [Google Scholar] [CrossRef]
  20. Cristofanilli, M.; Valero, V.; Mangalik, A.; Royce, M.; Rabinowitz, I.; Arena, F.P.; Kroener, J.F.; Curcio, E.; Watkins, C.; Bacus, S.; et al. Phase II, Randomized Trial to Compare Anastrozole Combined with Gefitinib or Placebo in Postmenopausal Women with Hormone Receptor-Positive Metastatic Breast Cancer. Clin. Cancer Res. 2010, 16, 1904–1914. [Google Scholar] [CrossRef] [Green Version]
  21. Krop, I.; Abramson, V.; Colleoni, M.; Traina, T.; Holmes, F.; Garcia-Estevez, L.; Hart, L.; Awada, A.; Zamagni, C.; Morris, P.G.; et al. A Randomized Placebo Controlled Phase II Trial Evaluating Exemestane with or without Enzalutamide in Patients with Hormone Receptor-Positive Breast Cancer. Clin. Cancer Res. 2020, 26, 6149–6157. [Google Scholar] [CrossRef] [PubMed]
  22. Albanell, J.; Martinez, M.T.M.; Ramos, M.; Connor, M.O’.; la Cruz-Merino, L.D.; Bertran, A.S.; Martínez-Jáñez, N.; Moreno, F.; Pérez, I.F.; Company, J.A.; et al. LBA19 GEICAM/2014-12 (FLIPPER) Study: First Analysis from a Randomized Phase II Trial of Fulvestrant (F)/Palbociclib (P) versus (vs) F/Placebo (PL) as First-Line Therapy in Postmenopausal Women with HR (Hormone Receptor)+/HER2– Endocrine Sensitive Advanced Breast Cancer (ABC). Ann. Oncol. 2020, 31, S1151. [Google Scholar] [CrossRef]
  23. Milla-Santos, A.; Milla, L.; Portella, J.; Rallo, L.; Pons, M.; Rodes, E.; Casanovas, J.; Puig-Gali, M. Anastrozole versus Tamoxifen as First-Line Therapy in Postmenopausal Patients with Hormone-Dependent Advanced Breast Cancer: A Prospective, Randomized, Phase III Study. Am. J. Clin. Oncol. 2003, 26, 317–322. [Google Scholar] [CrossRef] [PubMed]
  24. Mouridsen, H.; Gershanovich, M.; Sun, Y.; Pérez-Carrión, R.; Boni, C.; Monnier, A.; Apffelstaedt, J.; Smith, R.; Sleeboom, H.P.; Jänicke, F.; et al. Superior Efficacy of Letrozole versus Tamoxifen as First-Line Therapy for Postmenopausal Women with Advanced Breast Cancer: Results of a Phase III Study of the International Letrozole Breast Cancer Group. J. Clin. Oncol. 2001, 19, 2596–2606. [Google Scholar] [CrossRef] [PubMed]
  25. Paridaens, R.J.; Dirix, L.Y.; Beex, L.V.; Nooij, M.; Cameron, D.A.; Cufer, T.; Piccart, M.J.; Bogaerts, J.; Therasse, P. Phase III Study Comparing Exemestane with Tamoxifen as First-Line Hormonal Treatment of Metastatic Breast Cancer in Postmenopausal Women: The European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. J. Clin. Oncol. 2008, 26, 4883–4890. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Paul, D.; Vukelja, S.J.; Ann Holmes, F.; Blum, J.L.; McIntyre, K.J.; Lindquist, D.L.; Osborne, C.R.; Sanchez, I.J.; Goldschmidt, J.H.; Wang, Y.; et al. Randomized Phase-II Evaluation of Letrozole plus Dasatinib in Hormone Receptor Positive Metastatic Breast Cancer Patients. npj Breast Cancer 2019, 5, 36. [Google Scholar] [CrossRef] [Green Version]
  27. Mehta, R.S.; Barlow, W.E.; Albain, K.S.; Vandenberg, T.A.; Dakhil, S.R.; Tirumali, N.R.; Lew, D.L.; Hayes, D.F.; Gralow, J.R.; Livingston, R.B.; et al. Combination Anastrozole and Fulvestrant in Metastatic Breast Cancer. N. Engl. J. Med. 2012, 367, 435–444. [Google Scholar] [CrossRef] [Green Version]
  28. Mehta, R.S.; Barlow, W.E.; Albain, K.S.; Vandenberg, T.A.; Dakhil, S.R.; Tirumali, N.R.; Lew, D.L.; Hayes, D.F.; Gralow, J.R.; Linden, H.M.; et al. Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer. N. Engl. J. Med. 2019, 380, 1226–1234. [Google Scholar] [CrossRef]
  29. Finn, R.S.; Crown, J.P.; Lang, I.; Boer, K.; Bondarenko, I.M.; Kulyk, S.O.; Ettl, J.; Patel, R.; Pinter, T.; Schmidt, M.; et al. The Cyclin-Dependent Kinase 4/6 Inhibitor Palbociclib in Combination with Letrozole versus Letrozole Alone as First-Line Treatment of Oestrogen Receptor-Positive, HER2-Negative, Advanced Breast Cancer (PALOMA-1/TRIO-18): A Randomised Phase 2 Study. Lancet Oncol. 2015, 16, 25–35. [Google Scholar] [CrossRef]
  30. Finn, R.S.; Boer, K.; Bondarenko, I.; Patel, R.; Pinter, T.; Schmidt, M.; Shparyk, Y.V.; Thummala, A.; Voitko, N.; Bananis, E.; et al. Overall Survival Results from the Randomized Phase 2 Study of Palbociclib in Combination with Letrozole versus Letrozole Alone for First-Line Treatment of ER+/HER2− Advanced Breast Cancer (PALOMA-1, TRIO-18). Breast Cancer Res. Treat. 2020, 183, 419–428. [Google Scholar] [CrossRef]
  31. Finn, R.S.; Martin, M.; Rugo, H.S.; Jones, S.; Im, S.-A.; Gelmon, K.; Harbeck, N.; Lipatov, O.N.; Walshe, J.M.; Moulder, S.; et al. Palbociclib and Letrozole in Advanced Breast Cancer. N. Engl. J. Med. 2016, 375, 1925–1936. [Google Scholar] [CrossRef]
  32. Rugo, H.S.; Finn, R.S.; Diéras, V.; Ettl, J.; Lipatov, O.; Joy, A.A.; Harbeck, N.; Castrellon, A.; Iyer, S.; Lu, D.R.; et al. Palbociclib plus Letrozole as First-Line Therapy in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer with Extended Follow-Up. Breast Cancer Res. Treat. 2019, 174, 719. [Google Scholar] [CrossRef] [Green Version]
  33. Finn, R.S.; Dieras, V.; Rugo, H.S.; Joy, A.A.; Moulder, S.L.; Walshe, J.M.; Mukai, H.; Shparyk, Y.V.; Park, I.H.; Mori, A.; et al. Palbociclib (PAL) + Letrozole (L) as First-Line (1L) Therapy (Tx) in Estrogen Receptor-Positive (ER+)/Human Epidermal Growth Factor Receptor 2-Negative (HER2−) Advanced Breast Cancer (ABC): Efficacy and Safety across Patient (Pt) Subgroups. JCO 2017, 35, 1039-1039. [Google Scholar] [CrossRef]
  34. Cristofanilli, M.; Turner, N.C.; Bondarenko, I.; Ro, J.; Im, S.-A.; Masuda, N.; Colleoni, M.; DeMichele, A.; Loi, S.; Verma, S.; et al. Fulvestrant plus Palbociclib versus Fulvestrant plus Placebo for Treatment of Hormone-Receptor-Positive, HER2-Negative Metastatic Breast Cancer That Progressed on Previous Endocrine Therapy (PALOMA-3): Final Analysis of the Multicentre, Double-Blind, Phase 3 Randomised Controlled Trial. Lancet Oncol. 2016, 17, 425–439. [Google Scholar] [CrossRef] [Green Version]
  35. Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.S.; Sonke, G.S.; Paluch-Shimon, S.; Campone, M.; Petrakova, K.; Blackwell, K.L.; Winer, E.P.; et al. Updated Results from MONALEESA-2, a Phase III Trial of First-Line Ribociclib plus Letrozole versus Placebo plus Letrozole in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer. Ann. Oncol. 2018, 29, 1541–1547. [Google Scholar] [CrossRef]
  36. Slamon, D.J.; Neven, P.; Chia, S.; Jerusalem, G.; De Laurentiis, M.; Im, S.; Petrakova, K.; Valeria Bianchi, G.; Martín, M.; Nusch, A.; et al. Ribociclib plus Fulvestrant for Postmenopausal Women with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer in the Phase III Randomized MONALEESA-3 Trial: Updated Overall Survival. Ann. Oncol. 2021, 32, 1015–1024. [Google Scholar] [CrossRef]
  37. Slamon, D.J.; Neven, P.; Chia, S.; Fasching, P.A.; De Laurentiis, M.; Im, S.-A.; Petrakova, K.; Bianchi, G.V.; Esteva, F.J.; Martín, M.; et al. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J. Clin. Oncol. 2018, 36, 2465–2472. [Google Scholar] [CrossRef]
  38. Slamon, D.J.; Neven, P.; Chia, S.; Fasching, P.A.; De Laurentiis, M.; Im, S.-A.; Petrakova, K.; Bianchi, G.V.; Esteva, F.J.; Martín, M.; et al. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N. Engl. J. Med. 2020, 382, 514–524. [Google Scholar] [CrossRef]
  39. Hurvitz, S.; Lee, S.C.; Jerusalem, G.; Im, S.; Chia, S.K.L.; Campos, S.; Sonke, G.S.; Lteif, A. 329P-Ribociclib (RIB) in Patients (Pts) with HR+/HER2− Advanced Breast Cancer (ABC) and Resistance to Prior Endocrine Therapy (ET) in the MONALEESA (ML)...|OncologyPRO. Available online: https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/ribociclib-rib-in-patients-pts-with-hr-her2-advanced-breast-cancer-abc-and-resistance-to-prior-endocrine-therapy-et-in-the-monaleesa-ml (accessed on 20 September 2022).
  40. Johnston, S.R.; Kilburn, L.S.; Ellis, P.; Dodwell, D.; Cameron, D.; Hayward, L.; Im, Y.-H.; Braybrooke, J.P.; Brunt, A.M.; Cheung, K.-L.; et al. Fulvestrant plus Anastrozole or Placebo versus Exemestane Alone after Progression on Non-Steroidal Aromatase Inhibitors in Postmenopausal Patients with Hormone-Receptor-Positive Locally Advanced or Metastatic Breast Cancer (SoFEA): A Composite, Multicentre, Phase 3 Randomised Trial. Lancet Oncol. 2013, 14, 989–998. [Google Scholar] [CrossRef] [Green Version]
  41. André, F.; Ciruelos, E.; Rubovszky, G.; Campone, M.; Loibl, S.; Rugo, H.S.; Iwata, H.; Conte, P.; Mayer, I.A.; Kaufman, B.; et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor–Positive Advanced Breast Cancer. N. Engl. J. Med. 2019, 380, 1929–1940. [Google Scholar] [CrossRef]
  42. Di Leo, A.; Johnston, S.; Lee, K.S.; Ciruelos, E.; Lønning, P.E.; Janni, W.; O’Regan, R.; Mouret-Reynier, M.-A.; Kalev, D.; Egle, D.; et al. Buparlisib plus Fulvestrant in Postmenopausal Women with Hormone-Receptor-Positive, HER2-Negative, Advanced Breast Cancer Progressing on or after MTOR Inhibition (BELLE-3): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet Oncol. 2018, 19, 87–100. [Google Scholar] [CrossRef] [PubMed]
  43. Fan, Y.; Sun, T.; Shao, Z.; Zhang, Q.; Ouyang, Q.; Tong, Z.; Wang, S.; Luo, Y.; Teng, Y.; Wang, X.; et al. Effectiveness of Adding Everolimus to the First-Line Treatment of Advanced Breast Cancer in Premenopausal Women Who Experienced Disease Progression While Receiving Selective Estrogen Receptor Modulators: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2021, 7, e213428. [Google Scholar] [CrossRef] [PubMed]
  44. Jiang, Z.; Li, W.; Hu, X.; Zhang, Q.; Sun, T.; Cui, S.; Wang, S.; Ouyang, Q.; Yin, Y.; Geng, C.; et al. Tucidinostat plus Exemestane for Postmenopausal Patients with Advanced, Hormone Receptor-Positive Breast Cancer (ACE): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet Oncol. 2019, 20, 806–815. [Google Scholar] [CrossRef] [PubMed]
  45. Yardley, D.A.; Ismail-Khan, R.; Klein, P. Results of ENCORE 301, a Randomized, Phase II, Double-Blind, Placebo-Controlled Study of Exemestane with or without Entinostat in Postmenopausal Women with Locally Recurrent or Metastatic Estrogen Receptor-Positive (ER+) Breast Cancer Progressing on a Nonsteroidal Aromatase Inhibitor (AI). JCO 2011, 29, 268-268. [Google Scholar] [CrossRef]
  46. Xu, B.; Hu, X.; Li, W.; Sun, T.; Shen, K.; Wang, S.; Cheng, Y.; Zhang, Q.; Cui, S.; Tong, Z.; et al. 228MO PALOMA-4: Primary Results from a Phase III Trial of Palbociclib (PAL) + Letrozole (LET) vs Placebo (PBO) + LET in Asian Postmenopausal Women with Estrogen Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative (ER+/HER2–) Advanced Breast Cancer (ABC). Ann. Oncol. 2021, 32, S457. [Google Scholar] [CrossRef]
  47. Treilleux, I.; Arnedos, M.; Cropet, C.; Wang, Q.; Ferrero, J.-M.; Abadie-Lacourtoisie, S.; Levy, C.; Legouffe, E.; Lortholary, A.; Pujade-Lauraine, E.; et al. Translational Studies within the TAMRAD Randomized GINECO Trial: Evidence for MTORC1 Activation Marker as a Predictive Factor for Everolimus Efficacy in Advanced Breast Cancer. Ann. Oncol. 2015, 26, 120–125. [Google Scholar] [CrossRef]
  48. Baselga, J.; Im, S.-A.; Iwata, H.; Cortés, J.; De Laurentiis, M.; Jiang, Z.; Arteaga, C.L.; Jonat, W.; Clemons, M.; Ito, Y.; et al. Buparlisib plus Fulvestrant versus Placebo plus Fulvestrant in Postmenopausal, Hormone Receptor-Positive, HER2-Negative, Advanced Breast Cancer (BELLE-2): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet Oncol. 2017, 18, 904–916. [Google Scholar] [CrossRef]
  49. Campone, M.; Im, S.-A.; Iwata, H.; Clemons, M.; Ito, Y.; Awada, A.; Chia, S.; Jagiełło-Gruszfeld, A.; Pistilli, B.; Tseng, L.-M.; et al. Buparlisib plus Fulvestrant versus Placebo plus Fulvestrant for Postmenopausal, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, Advanced Breast Cancer: Overall Survival Results from BELLE-2. Eur. J. Cancer 2018, 103, 147–154. [Google Scholar] [CrossRef]
  50. Piccart, M.; Hortobagyi, G.N.; Campone, M.; Pritchard, K.I.; Lebrun, F.; Ito, Y.; Noguchi, S.; Perez, A.; Rugo, H.S.; Deleu, I.; et al. Everolimus plus Exemestane for Hormone-Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Advanced Breast Cancer: Overall Survival Results from BOLERO-2†. Ann. Oncol. 2014, 25, 2357–2362. [Google Scholar] [CrossRef]
  51. Jones, R.H.; Casbard, A.; Carucci, M.; Cox, C.; Butler, R.; Alchami, F.; Madden, T.-A.; Bale, C.; Bezecny, P.; Joffe, J.; et al. Fulvestrant plus Capivasertib versus Placebo after Relapse or Progression on an Aromatase Inhibitor in Metastatic, Oestrogen Receptor-Positive Breast Cancer (FAKTION): A Multicentre, Randomised, Controlled, Phase 2 Trial. Lancet Oncol. 2020, 21, 345–357. [Google Scholar] [CrossRef]
  52. Krop, I.E.; Mayer, I.A.; Ganju, V.; Dickler, M.; Johnston, S.; Morales, S.; Yardley, D.A.; Melichar, B.; Forero-Torres, A.; Lee, S.C.; et al. Pictilisib for Oestrogen Receptor-Positive, Aromatase Inhibitor-Resistant, Advanced or Metastatic Breast Cancer (FERGI): A Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial. Lancet Oncol. 2016, 17, 811–821. [Google Scholar] [CrossRef]
  53. Jerusalem, G.; de Boer, R.H.; Hurvitz, S.; Yardley, D.A.; Kovalenko, E.; Ejlertsen, B.; Blau, S.; Özgüroglu, M.; Landherr, L.; Ewertz, M.; et al. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial. JAMA Oncol. 2018, 4, 1367–1374. [Google Scholar] [CrossRef]
  54. Schmid, P.; Zaiss, M.; Harper-Wynne, C.; Ferreira, M.; Dubey, S.; Chan, S.; Makris, A.; Nemsadze, G.; Brunt, A.M.; Kuemmel, S.; et al. Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019, 5, 1556–1564. [Google Scholar] [CrossRef]
  55. Musolino, A.; Campone, M.; Neven, P.; Denduluri, N.; Barrios, C.H.; Cortes, J.; Blackwell, K.; Soliman, H.; Kahan, Z.; Bonnefoi, H.; et al. Phase II, Randomized, Placebo-Controlled Study of Dovitinib in Combination with Fulvestrant in Postmenopausal Patients with HR+, HER2- Breast Cancer That Had Progressed during or after Prior Endocrine Therapy. Breast Cancer Res. 2017, 19, 18. [Google Scholar] [CrossRef] [Green Version]
  56. Martin, M.; Zielinski, C.; Ruiz-Borrego, M.; Carrasco, E.; Turner, N.; Ciruelos, E.M.; Muñoz, M.; Bermejo, B.; Margeli, M.; Anton, A.; et al. Palbociclib in Combination with Endocrine Therapy versus Capecitabine in Hormonal Receptor-Positive, Human Epidermal Growth Factor 2-Negative, Aromatase Inhibitor-Resistant Metastatic Breast Cancer: A Phase III Randomised Controlled Trial-PEARL. Ann. Oncol. 2021, 32, 488–499. [Google Scholar] [CrossRef]
  57. Kornblum, N.; Zhao, F.; Manola, J.; Klein, P.; Ramaswamy, B.; Brufsky, A.; Stella, P.J.; Burnette, B.; Telli, M.; Makower, D.F.; et al. Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102. J. Clin. Oncol. 2018, 36, 1556–1563. [Google Scholar] [CrossRef]
  58. Xu, B.; Zhang, Q.; Zhang, P.; Hu, X.; Li, W.; Tong, Z.; Sun, T.; Teng, Y.; Wu, X.; Ouyang, Q.; et al. Dalpiciclib versus Placebo plus Fulvestrant in HR+/HER2- Advanced Breast Cancer That Relapsed or Progressed on Previous Endocrine Therapy (DAWNA-1): A Multicenter, Randomized, Phase 3 Study. J. Clin. Oncol. 2021, 39, 1002-1002. [Google Scholar] [CrossRef]
  59. Buzdar, A.; Hayes, D.; El-Khoudary, A.; Yan, S.; Lønning, P.; Lichinitser, M.; Gopal, R.; Falkson, G.; Pritchard, K.; Lipton, A.; et al. Phase III Randomized Trial of Droloxifene and Tamoxifen as First-Line Endocrine Treatment of ER/PgR-Positive Advanced Breast Cancer. Breast Cancer Res. Treat. 2002, 73, 161–175. [Google Scholar] [CrossRef]
  60. Sledge, G.W.; Toi, M.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; Kaufman, P.A.; et al. MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J. Clin. Oncol. 2017, 35, 2875–2884. [Google Scholar] [CrossRef]
  61. George, W.; Sledge, J.; Toi, M.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; et al. The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor–Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy—MONARCH 2: A Randomized Clinical Trial. JAMA Oncol. 2020, 6, 116. [Google Scholar] [CrossRef]
  62. Shao, Z.; Cai, L.; Wang, S.; Hu, X.; Shen, K.; Wang, H.; Li, H.; Feng, J.; Liu, Q.; Cheng, J.; et al. 238P BOLERO-5: A Phase II Study of Everolimus and Exemestane Combination in Chinese Post-Menopausal Women with ER+/HER2- Advanced Breast Cancer. Ann. Oncol. 2021, 32, S463. [Google Scholar] [CrossRef]
  63. Johnston, S.; Pippen, J.; Pivot, X.; Lichinitser, M.; Sadeghi, S.; Dieras, V.; Gomez, H.L.; Romieu, G.; Manikhas, A.; Kennedy, M.J.; et al. Lapatinib Combined with Letrozole versus Letrozole and Placebo as First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer. J. Clin. Oncol. 2009, 27, 5538–5546. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Robertson, J.F.R.; Lindemann, J.P.O.; Llombart-Cussac, A.; Rolski, J.; Feltl, D.; Dewar, J.; Emerson, L.; Dean, A.; Ellis, M.J. Fulvestrant 500 Mg versus Anastrozole 1 Mg for the First-Line Treatment of Advanced Breast Cancer: Follow-up Analysis from the Randomized “FIRST” Study. Breast Cancer Res. Treat. 2012, 136, 503–511. [Google Scholar] [CrossRef] [PubMed]
  65. Robertson, J.F.R.; Llombart-Cussac, A.; Rolski, J.; Feltl, D.; Dewar, J.; Macpherson, E.; Lindemann, J.; Ellis, M.J. Activity of Fulvestrant 500 Mg versus Anastrozole 1 Mg as First-Line Treatment for Advanced Breast Cancer: Results from the FIRST Study. J. Clin. Oncol. 2009, 27, 4530–4535. [Google Scholar] [CrossRef] [PubMed]
  66. Hyams, D.M.; Chan, A.; de Oliveira, C.; Snyder, R.; Vinholes, J.; Audeh, M.W.; Alencar, V.M.; Lombard, J.; Mookerjee, B.; Xu, J.; et al. Cediranib in Combination with Fulvestrant in Hormone-Sensitive Metastatic Breast Cancer: A Randomized Phase II Study. Investig. New Drugs 2013, 31, 1345–1354. [Google Scholar] [CrossRef]
  67. Johnston, S.; Basik, M.; Hegg, R.; Lausoontornsiri, W.; Grzeda, L.; Clemons, M.; Dreosti, L.; Mann, H.; Stuart, M.; Cristofanilli, M. Inhibition of EGFR, HER2, and HER3 Signaling with AZD8931 in Combination with Anastrozole as an Anticancer Approach: Phase II Randomized Study in Women with Endocrine-Therapy-Naïve Advanced Breast Cancer. Breast Cancer Res. Treat. 2016, 160, 91–99. [Google Scholar] [CrossRef]
  68. Robertson, J.F.R.; Bondarenko, I.M.; Trishkina, E.; Dvorkin, M.; Panasci, L.; Manikhas, A.; Shparyk, Y.; Cardona-Huerta, S.; Cheung, K.-L.; Philco-Salas, M.J.; et al. Fulvestrant 500 Mg versus Anastrozole 1 Mg for Hormone Receptor-Positive Advanced Breast Cancer (FALCON): An International, Randomised, Double-Blind, Phase 3 Trial. Lancet 2016, 388, 2997–3005. [Google Scholar] [CrossRef]
  69. Osborne, C.K.; Pippen, J.; Jones, S.E.; Parker, L.M.; Ellis, M.; Come, S.; Gertler, S.Z.; May, J.T.; Burton, G.; Dimery, I.; et al. Double-Blind, Randomized Trial Comparing the Efficacy and Tolerability of Fulvestrant versus Anastrozole in Postmenopausal Women with Advanced Breast Cancer Progressing on Prior Endocrine Therapy: Results of a North American Trial. J. Clin. Oncol. 2002, 20, 3386–3395. [Google Scholar] [CrossRef]
  70. Toss, A.; Venturelli, M.; Sperduti, I.; Molinaro, E.; Isca, C.; Barbieri, E.; Piacentini, F.; Omarini, C.; Cortesi, L.; Cascinu, S.; et al. First-Line Treatment for Endocrine-Sensitive Bone-Only Metastatic Breast Cancer: Systematic Review and Meta-Analysis. Clin. Breast Cancer 2019, 19, e701–e716. [Google Scholar] [CrossRef]
  71. Giuliano, M.; Schettini, F.; Rognoni, C.; Milani, M.; Jerusalem, G.; Bachelot, T.; De Laurentiis, M.; Thomas, G.; De Placido, P.; Arpino, G.; et al. Endocrine Treatment versus Chemotherapy in Postmenopausal Women with Hormone Receptor-Positive, HER2-Negative, Metastatic Breast Cancer: A Systematic Review and Network Meta-Analysis. Lancet Oncol. 2019, 20, 1360–1369. [Google Scholar] [CrossRef] [Green Version]
  72. Shimoi, T.; Sagara, Y.; Hara, F.; Toyama, T.; Iwata, H. First-Line Endocrine Therapy for Postmenopausal Patients with Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Systematic Review and Meta-Analysis. Breast Cancer 2020, 27, 340–346. [Google Scholar] [CrossRef]
  73. Wang, C.; Lin, Y.; Zhu, H.; Zhou, Y.; Mao, F.; Huang, X.; Sun, Q.; Li, C. Efficacy and Safety Profile of Histone Deacetylase Inhibitors for Metastatic Breast Cancer: A Meta-Analysis. Front. Oncol. 2022, 12, 901152. [Google Scholar] [CrossRef]
  74. Xu, L.; Jiang, W.; Li, W.; Guo, C.; Luo, L.; Gao, Y.; Cao, Y. Comparison of a Histone Deacetylase Inhibitor plus Exemestane with Exemestane Alone in Hormone Receptor-Positive Advanced Breast Cancer That Progressed on Prior Endocrine Therapy: A Meta-Analysis. Exp. Ther. Med. 2022, 24, 575. [Google Scholar] [CrossRef]
Cancers 14 06100 g001 550
Figure 1. PRISMA flow chart.
Figure 1. PRISMA flow chart.
Cancers 14 06100 g001
Cancers 14 06100 g002 550
Figure 2. Network meta-analysis plots. (A) Major evidence network for PFS in patients with ETS; (B) Evidence network for OS in patients with ETS; (C) Evidence network 1 for PFS in patients with ETR; (D) Evidence network 2 for PFS in patients with ETR; (E) Major evidence network for OS in patients with ETR.
Figure 2. Network meta-analysis plots. (A) Major evidence network for PFS in patients with ETS; (B) Evidence network for OS in patients with ETS; (C) Evidence network 1 for PFS in patients with ETR; (D) Evidence network 2 for PFS in patients with ETR; (E) Major evidence network for OS in patients with ETR.
Cancers 14 06100 g002
Cancers 14 06100 g003 550
Figure 3. SUCRA values for treatment regimens and relative effect. (A) PFS effect estimates of ETS patients (network 1); (B) OS effect estimates of ETS patients (network 1).
Figure 3. SUCRA values for treatment regimens and relative effect. (A) PFS effect estimates of ETS patients (network 1); (B) OS effect estimates of ETS patients (network 1).
Cancers 14 06100 g003
Cancers 14 06100 g004 550
Figure 4. SUCRA values for treatment regimens and relative effect. (A) OS effect estimates of ETR patients; (B) OS effect estimates of ETR patients (network 1); (C) PFS effect estimates of ETR patients (network 2).
Figure 4. SUCRA values for treatment regimens and relative effect. (A) OS effect estimates of ETR patients; (B) OS effect estimates of ETR patients (network 1); (C) PFS effect estimates of ETR patients (network 2).
Cancers 14 06100 g004
Table
Table 1. Baseline characteristics of the included trials.
Table 1. Baseline characteristics of the included trials.
S. NoStudy NameTreatment RegimenMenopausal StatusPatients (N)PhaseCentersPrevious CTEndocrine Status s/r/m1st ET
1Ibrahim et al., 2011 [13]SAI + MABPost110IImultinosno
SAI
2Goetz et al., 2017 [15]CDK4/6i + NSAIPost493IIImultinosyes
NSAI
3Zhang et al., 2020 [16]
CDK4/6i + NSAIPost306IIImultinosno
NSAI
CDK4/6i + FULPost157IIImultinoryes
FUL500
4Antonio C. Wolff et al., 2013 [17]MTOR + NSAIPost1112IIImultinosno
NSAI
5Dickler et al., 2016 [18]NSAI + MABPost343IImulti≤1 linesyes: ≤4 weeks
NSAI
6Goss et al., 2007 [19]SAI + TORPost865IIImultiyessno
SAI
7Cristofanilli et al., 2010 [20]NSAI + TKIPost93IImultinosno
NSAI
8Krop et al., 2020 [21]AI + anti-androgenPost127IImulti≤1 linesyes
AI
9Albanell et al., 2020 [22]CDK4/6i + Ful 500Post189IImultinosno
Ful 500
10Llombart-Cussac et al., 2021 [23]CDK4/6i + Ful 500Multi486IImutinosyes
CDK4/6i + NSAI
11Mouridsen et al., 2001 [24]NSAIPost907IIImulti≤1 linesno
Tam
12Paridaens et al., 2008 [25]SAIPost371IIImulti≤1 linesno
Tam
13Milla-Santos et al., 2003 [23]NSAIPost238IIImultinosno
Tam
14Paul et al., 2019 [26]AI + TKIPost120IImulti≤1 linemno
AI
15Mehta et al., 2012 [27,28]AI + Ful 250Post694IIImultiyesmyes
AI
16Finn et al., 2015, Finn et al., 2020 [29,30]CDK4/6i + AIPost165IImultinomno
AI
17Finn et al., 2016 [31], Rugo et al., 2019 [32], Finn et al., 2017 [33]CDK4/6i + AIPost666IIImultinomyes
AI
18Cristofanilli et al., 2016 [34]CDK4/6i + ful500Both521IIImulti≤1 linemyes
Ful 500
19Hortobagyi et al., 2018 [35]CDK4/6i + AIPost668IIImultinomyes
AI
20Slamon et al., 2021 [36], Slamon et al., 2018 [37], Slamon et al., 2020 [38], Hurvitz et al., [39]CDK4/6i + ful500Post726IIImultinomyes
Ful 500
21Johnston et al., 2013 [40]AI + Ful 250Post723IIImultiyesmyes
Ful 250
Ful 250Post723IIImultiyesmyes
AI
22André et al., 2019 [41]Ful500 + PI3KPost341IIImultiyesmyes
Ful 500
23Leo et al., 2018 [42]Ful500 + PI3KPost432IIImultiallowedmyes
Ful 500
24Fan et al., 2021 [43]NSAI + mTORPre199IImultiyes ≤1 linemyes:
TAM
NSAI
25Jiang et al., 2019 [44]HDAC + SAIPost365IIImulti≤1 linemyes
SAI
26Yardley et al., 2011 [45]HDAC + AIPost130IImulti≤1 linemyes:
NSAI
AI
27Xu et al., 2021 [46]CDK4_or_6i_plus_AIPost340IIImultinos
AI
28Treilleux et al., 2015 [47]mTOR + TAMPost111IImulti≤1 lineryes: AI
TAM
29Baselga et al., 2017 [48,49]PI3Ki + Ful500Post1147IIImulti≤1 linemyes
FUL500
30Piccart et al., 2014 [50]mTOR + AIPost724IIImulti≤1 lineryes:
AI
AI
31Jones et al., 2020 [51]AKT + FULPost140IImulti≤1 lineryes: AI
FUL500
32Krop et al., 2016 [52]PI3Ki + Ful500Post168IImulti≤1 linerAI
FUL500
PI3Ki + Ful500Post61IImulti≤1 linerAI
FUL500
33Jerusalem et al., 2018 [53]mTOR + AIPost309IImulti≤1 lineryes
Mtor
34Schmid et al., 2019 [54]mTOR + FUL500Post326IImulti≤1 lineryes
FUL500
35Musolino et al., 2017 [55]TKI + FUL500Post97IImultinoryes
FUL500
36Martin et al., 2021 [56]CDK4/6i + FULPost601IIImulti≤1 lineryes:
NSAI
Chemotherapy
37Kornblum et al., 2018 [57]mTOR + FUL500Post131IImulti≤1 lineryes:
AI
FUL500
38Xu et al., 2021 [58]CDK4/6i + FULBoth361IIImulti≤1 lineryes
FUL500
39Buzdar et al., 2002 [59]AIPost602IImulti≤1 lineryes
MA
40Sledge et al., 2017 [60,61]CDK4/6i + FULBoth669IIImultinoryes
FUL500
41Shao et al., 2021 [62]mTOR + AIPost159Ⅱmultiyesryes
AI
42Johnston et al., 2009 [63]TKI + AIPost1286IIImultinomyes
AI
43Robertson et al., 2012 [64], Robertson et al., 2009 [65] Roberson et al., 2012 [64]FUL500Post205IIImultiyessno
AI
44Hyams et al., 2013 [66]TKI + FUL250Post62IIImulti≤1 linesyes
FUL250
45Johnston et al., 2016 [67]TKI + AIPost359IImulti≤1 linesyes
AI
46Robertson et al., 2016 [68]FULPost462IIImultiallowedsyes
AI
47Osborne et al., 2002 [69]FULPost400IIImultinomyes
AI
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Wang, J.; Han, Y.; Wang, J.; Li, Q.; Xu, B. Endocrine Therapy-Based Strategies for Metastatic Breast Cancer with Different Endocrine Sensitivity Statuses: A Systematic Review and Network Meta-Analysis. Cancers 2022, 14, 6100. https://doi.org/10.3390/cancers14246100

AMA Style

Wang J, Han Y, Wang J, Li Q, Xu B. Endocrine Therapy-Based Strategies for Metastatic Breast Cancer with Different Endocrine Sensitivity Statuses: A Systematic Review and Network Meta-Analysis. Cancers. 2022; 14(24):6100. https://doi.org/10.3390/cancers14246100

Chicago/Turabian Style

Wang, Jiani, Yiqun Han, Jiayu Wang, Qing Li, and Binghe Xu. 2022. "Endocrine Therapy-Based Strategies for Metastatic Breast Cancer with Different Endocrine Sensitivity Statuses: A Systematic Review and Network Meta-Analysis" Cancers 14, no. 24: 6100. https://doi.org/10.3390/cancers14246100

APA Style

Wang, J., Han, Y., Wang, J., Li, Q., & Xu, B. (2022). Endocrine Therapy-Based Strategies for Metastatic Breast Cancer with Different Endocrine Sensitivity Statuses: A Systematic Review and Network Meta-Analysis. Cancers, 14(24), 6100. https://doi.org/10.3390/cancers14246100

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop