Efficacy and Safety of Post-CDK4/6 Inhibitor Treatment Options for HR-Positive, HER2-Negative Advanced Breast Cancer: A Network Meta-Analysis of Randomized Controlled Trials

Efficacy and Safety of Post-CDK4/6 Inhibitor Treatment Options for HR-Positive, HER2-Negative Advanced Breast Cancer: A Network Meta-Analysis of Randomized Controlled Trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Post-CDK4/6 Inhibitor Treatment Options for HR-Positive, HER2-Negative Advanced Breast Cancer: A Network Meta-Analysis of Randomized Controlled Trials Junxiao Wang, Longhu Huang, Yushuai Yu, Ezhang Liu, Qisheng Lin This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6659707/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: In patients with HR-positive, HER2-negative advanced breast cancer who have progressed after CDK4/6 inhibitors, the optimal selection of subsequent therapies remains uncertain. This study employs a Bayesian network meta-analysis to evaluate the efficacy and safety of different treatment options. Methods: We conducted a comprehensive literature search in the PubMed, Embase, and Cochrane databases, as well as abstracts from the San Antonio Breast Cancer Symposium, European Society for Medical Oncology, and American Society of Clinical Oncology, covering the past five years, with the search cutoff date of April 1, 2025. Only randomized controlled trials were included in the final analysis. Our analysis focused on several key outcomes, including progression-free survival (PFS) in the overall population, PFS in the ESR1 mutations, PFS in those with PIK3CA mutations population, overall survival, objective response rate and the incidence of grade 3 or higher adverse events. Results: We identified a total of 7,860 publications, ultimately including 16 studies involving 2,972 patients, all of whom experienced disease progression following treatment with CDK4/6 inhibitors. mTOR inhibitors demonstrated superior PFS. Oral-SERD were preferred in ESR1-mutant patients (vs endocrine therapy: HR 0.66, 95% CI 0.44–0.99), while CDK4/6 inhibitor rechallenge showed benefit in PIK3CA-mutant cases (vs endocrine therapy: HR 0.56, 95% CI 0.32–0.98). SERM and oral-SERD achieved optimal efficacy-safety balance. Conclusion: Our findings demonstrate that mTOR inhibitors represent a viable therapeutic option for patients with good performance status, while Oral-SERD may be more suitable for elderly patients or those with multiple comorbidities. Future research should focus on addressing existing evidence gaps and optimizing therapeutic strategies to further improve long-term patient outcomes. breast cancer HR-positive advanced network meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Highlights 1.For patients in good general condition and without contraindications, the combination of an mTOR inhibitor with endocrine therapy is recommended as the first-line treatment. 2.In patients with ESR1 mutations, Oral-SERD should be the preferred treatment option. 3.For populations with limited access to novel targeted agents, elderly patients, or those with multiple comorbidities, SERM or Oral-SERD may represent a more optimal choice. 4.Rechallenge with CDK4/6i demonstrated statistically significant benefits in patients harboring PI3KCA mutations. Introduction Hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer constitutes the most prevalent subtype of breast cancer, accounting for approximately 70% of all cases [1]. In patients with advanced breast cancer (ABC), the combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy has emerged as the standard first-line treatment. CDK4/6i—such as palbociclib, abemaciclib, and dalpiciclib—significantly enhance patients’ progression-free survival (PFS) [2-4]. Additionally, ribociclib not only improves PFS but also increases overall survival (OS) [5]. Despite the significant efficacy of CDK4/6i in treatment, the majority of patients ultimately experience disease progression. The mechanisms underlying resistance encompass various factors, including alterations in upstream signaling pathways, inactivation or overexpression of cell cycle regulatory proteins, activation of downstream kinases, changes in the immune microenvironment, and reprogramming of metabolic pathways [6]. Consequently, the development of subsequent treatment strategies following the failure of CDK4/6i therapy presents a significant challenge in clinical practice. In recent years, multiple randomized controlled trials (RCT) have evaluated treatment options following the failure of CDK4/6i. The available treatment alternatives include switching to different CDK4/6i, combination targeted therapies such as PI3K inhibitors and AKT inhibitors, and novel agents such as oral-selective estrogen receptor degraders (Oral-SERD) and antibody-drug conjugates [7-9]. These treatment strategies exhibit significant differences in terms of efficacy and safety, and there is a notable lack of high-quality evidence for direct comparisons. Moreover, the impact of various treatment options on patient quality of life, tolerability, and financial burden are critical factors that must be considered in clinical decision-making [10]. Consequently, integrating existing data from RCT through network meta-analysis (NMA) allows for the indirect comparison of the efficacy and safety of various treatment regimens, thereby offering more comprehensive evidence to support clinical practice [11]. This study aims to evaluate the efficacy and safety of different treatment options for patients with HR+/HER2- ABC following the failure of CDK4/6i through a NMA. By synthesizing data from current RCT, this research will provide clinicians with a more scientifically basis for treatment decisions and guide future researches. Materials and Methods The manuscript was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12]. Eligibility and Exclusion Criteria Inclusion Criteria: 1. ABC that is HR+/HER2-; 2. Disease progression following the administration of CDK4/6i in the adjuvant or advanced stage; 3. RCT with at least two treatment groups and availability of hazard ratio data comparing the two treatment groups, including one of the following endpoints: PFS, OS, objective response rate (ORR), or occurrences of grade 3 or higher adverse events (≥3 AEs); Exclusion Criteria: 1. Studies involving low HER2 expression; 2. Single-arm studies and retrospective studies; Information Sources A comprehensive and detailed search of literatures was conducted in PubMed, Embase, and Cochrane from inception to April 1, 2025, and also included published abstracts from San Antonio Breast Cancer Symposiums (SABCS), American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) over the past five years. Search Strategy The literature search was conducted using the following search terms in PubMed, Embase, and the Cochrane Library. Adjustments were made for each electronic database without applying any additional filtering criteria: (metastasis OR metastases OR metastatic OR advanced OR recurrent OR stage IV OR unresectable) AND (breast OR mammary) AND (cancer OR carcinoma OR malignant OR neoplasm OR tumour) AND (hormone receptor OR estrogen receptor OR oestrogen receptor) AND (positive OR +) AND (randomized controlled trial OR randomised controlled trial). Study Selection After importing the articles into EndNote for deduplication, two investigators independently screened the articles based on their titles and abstracts. Use of the latest published data from the same clinical study. If the two investigators have doubts about an article, a third investigator will make the final decision. When the title and abstract do not clearly indicate whether to include our study, the full text will be downloaded for further examination. Data Collection Process We extracted the necessary data from formally published papers, supplementary materials, and conference abstracts. When Hazard Ratios were not provided, we utilized Engauge Digitizer software to extract the relevant information from Kaplan-Meier curves. Some clinical studies include patients who have experienced disease progression after treatment with CDK4/6i, as well as those whose disease progressed without this treatment. This study specifically focuses on patients who have progressed after CDK4/6i therapy, and data extraction will be conducted solely for this group. All data included in this analysis are publicly available. Data Items We extracted the following data from the articles identified in our final search: article title, presence of partial or complete CDK4/6i, type of mutation, first author, publication year, treatment, PFS, OS, hazard ratio, ORR, and ≥3 AEs. The primary endpoint was PFS, which included analyses for all participants, participants with ESR1 mutations, and those with PIK3Ca mutations. Secondary endpoints comprised OS, ORR, and ≥3 AEs. Study Risk of Bias Assessment We employ software to assess various types of bias, including random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). Each bias type is rated on a scale of 0% to 100%, corresponding to three risk levels: “low risk of bias”, “unclear risk of bias” and “high risk of bias”. Ultimately, the software presents the degree of bias risk in an intuitive visual manner. We utilize a funnel plot to evaluate the presence of publication bias in the included studies. Summary Measures We utilized hazard ratios and 95% confidence intervals (CI) to illustrate PFS and OS, while odds ratios (OR) and 95% CI were utilized to present ORR and ≥3 AEs. We ranked the various treatment protocols based on their Surface Under the Cumulative Ranking Curve (SUCRA) values, which ranged from 0 to 100, where higher scores indicate more effective treatments. Finally, both PFS and ≥3 AEs were assigned a maximum score of 50, and these two endpoints were combined to evaluate the efficacy and safety of each treatment protocol. A p-value of less than 0.05 was considered statistically significant. Synthesis Methods After listing the treatment measures, we categorize them according to their respective types: Fulvestrant, anastrozole and Exemestane are considered a type of endocrine therapy; Palbociclib, abemaciclib, and ribociclib are designated as CDK4/6i; Avelumab and atezolizumab are classified as PD-L1 inhibitors; Camizestrant, Elacestrant, Amecenestrant, and Imlunestrant are identified as Oral-SERD; Lasofoxifene is identified as SERM; Capivasertib and Xentuzumab are identified as AKT inhibitor; Everolimus and Sapanisertib are identified as mTOR; Venetoclax is identified as BCL2 inhibitor; Alpelisib is identified as PI3K inhibitor; Entinostat is identified as HDAC inhibitor. Ethics Consideration The Ethics Committee of Sanming Second Hospital has confirmed that all data were obtained from publicly available publications; therefore, no ethical approval was required. Results Study selection Database searches identified 7,860 records, with 6,710 remaining after duplicate removal. Following rigorous screening, 22 eligible studies were included. However, only 16 studies contributed to closed loops in the network and were included in the final NMA. The remaining 6 studies were excluded due to lack of connectivity (i.e., they did not share comparators with other studies to form indirect evidence loops). Where multiple publications reported on the same study, the most recent and comprehensive data were retained. Studies were excluded if CDK4/6i was a stratification factor but outcome data specific to CDK4/6i-treated populations could not be extracted. The PRISMA flow diagram is presented in Figure 1, and the completed PRISMA 2020 checklist is provided in Supplementary File A. Study characteristic This study includes a total of 16 research articles published between 2020 and 2025, encompassing 37 groups with a combined total of 2,972 patients. The patient population in 9 articles consisted entirely of individuals after the use of CDK4/6i, while 7 studies provided extractable data on genetic mutations. 5 studies investigated the reuse of CDK4/6i, 4 studies focused on Oral-SERD medications, and 2 studies involved PD-L1. All included studies can be found in Supplementary File B [13-28]. Risk of bias within studies The funnel plot indicates no evidence of publication bias (Figure 2). All RCT exhibited a low risk of bias (Figure 3). nine of these studies were open-label, which increases the potential for performance bias. The following three studies exhibit a high risk of bias: The Maintain study administered Ribociclib to a subset of patients prior to randomization, which may introduce selection bias by artificially increase the number of participants experiencing tumor progression under Ribociclib treatment; The Sapanisertib study aimed for about 40% of participants to have prior exposure to CDK4/6i. If the number of patients who had not previously received these inhibitors exceeded 60% of the total, recruitment for these individuals would be stopped; The XENERA-1 study employed a blinded design; however, unblinding occurred prematurely, and inconsistencies were observed between parameters obtained by researchers and those assessed by independent reviewers. Primary endpoint PFS Fifteen studies were included in the PFS analysis, with the network diagrams detailed in Figure 4A. Based on the SUCRA (Figure 5A), the mTOR inhibitor ranked highest, followed by PI3K inhibitor, and then AKT inhibitor. Targeted therapies (mTOR, PI3K, AKT inhibitors) consistently demonstrated higher SUCRA values than CDK4/6i rechallenge or oral-SERD. Furthermore, targeted inhibitors exhibited higher SUCRA values compared to combination regimens, such as CDK4/6i plus PD-L1 inhibitor or AKT inhibitor plus mTOR inhibitor. Notably, CDK4/6i rechallenge showed modest efficacy (low SUCRA ranking), while endocrine monotherapy performed the worst among all interventions. In Cross-comparison of PFS (Table 1), there were no statistically significant differences between most treatment strategies. However, the majority of therapeutic regimens demonstrated statistically significant PFS benefits when compared with endocrine monotherapy. Three studies specifically analyzed PFS in patients with PIK3CA mutations. The PI3K inhibitor regimen demonstrated the highest SUCRA value (Figure 5F), though this difference was not statistically significant (vs endo, HR 0.48, 95% CI 0.18-1.29). CDK4/6i rechallenge followed closely (vs endo, HR 0.56, 95% CI 0.32-0.98) (Supplemental File C). Five studies evaluated PFS in patients with ESR1 mutations. Oral-SERD demonstrated the highest SUCRA value (Figure 5E) and were the only treatment strategy to show statistically significant efficacy (HR 0.66, 95% CI 0.44–0.99) (Supplemental File C). Secondary endpoint OS Four studies evaluated the result of OS, with the network diagrams in Figure 4B. The Oral-SERD regimen demonstrated the highest SUCRA value, followed by CDK4/6 inhibitor rechallenge, whereas BCL2 inhibition showed a lower SUCRA value than endocrine monotherapy (Figure 5B). Compared with endocrine monotherapy, all regimens failed to demonstrate a significant OS benefit (Supplementral File C). Secondary endpoint ORR Nine studies assessed ORR, with the network diagrams in Figure 4C. The Oral-SERD plus PI3K inhibitor combination yielded the highest SUCRA value, followed by SERM regimen. BCL2 inhibitor consistently demonstrated the lowest SUCRA value among all treatments. PD-L1 inhibitor exhibited a comparable SUCRA value to endocrine monotherapy (Figure 5C), with no statistically significant difference (OR 0.99, 95% CI 0.22–4.62)(Supplemental File C). Secondary endpoint Safety All 16 included studies reported ≥3 AEs, with detailed toxicity profiles illustrated in Figure 5D, and network diagrams in Figure 4D. The first three regimens—Oral-SERD, SERM, and endocrine monotherapy—demonstrated comparable SUCRA values, whereas CDK4/6i alone exhibited a lower SUCRA. Notably, combinations of CDK4/6i with PD-L1 inhibitors or Oral-SERD with PI3K inhibitors significantly increased the risk of ≥3 AEs compared to endocrine monotherapy (endo vs. CDK4/6+PD-L1: HR 0.04, 95% CI 0.02–0.10; endo vs. Oral-SERD+PI3K: HR 0.03, 95% CI 0.01–0.14)(Supplemental File C). Combined analysis of PFS and≥3 AEs Integrating both PFS and ≥3AEs profiles, the SERM regimen achieved the highest SUCRA score, followed by the Oral-SERD and mTOR strategies. Endocrine monotherapy demonstrated intermediate efficacy-toxicity rankings, while CDK4/6 inhibitor rechallenge yielded notably low SUCRA values (Figure 6). Discussion Recent advances in elucidating resistance mechanisms in HR+/HER2– advanced breast cancer have led to the development of novel targeted therapies, particularly inhibitors of the PI3K-AKT-mTOR pathway. Nevertheless, substantial heterogeneity exists among these therapies in terms of cost-effectiveness, accessibility, and toxicity profiles. Furthermore, treatment selection is complicated by patient-specific factors, including comorbidities, prior treatment tolerance, socioeconomic considerations, and evolving clinical guidelines. In the absence of a clearly defined standard-of-care, clinicians face considerable challenges in selecting the most appropriate subsequent-line therapy. During the course of this study, we identified a previously published meta-analysis that also investigated treatment strategies following progression on CDK4/6i[29]. However, through in-depth comparative analysis, the novelty and scientific rigor of our study are highlighted in the following key aspects: First, the prior study only incorporated data published up to December 2023, whereas our study systematically reviewed the most recent evidence up to April 2025. This extension is particularly critical, as the period from 2023 to 2025 witnessed the publication of pivotal clinical trials for multiple novel targeted therapies, ensuring that our findings reflect the most current advancements in the field. Second, the previous analysis included only 7 RCT, with the remaining 11 studies being cohort analyses. In contrast, our study rigorously screened and incorporated 16 high-quality RCT, significantly enhancing the level and reliability of the evidence. Finally, the prior research employed conventional meta-analysis techniques, permitting only direct comparisons between individual treatments and single-agent endocrine therapy. Our study innovatively utilized NMA, enabling both direct and indirect comparisons across multiple treatment regimens. This approach provides a more comprehensive and precise evaluation of the relative efficacy and safety profiles of different therapeutic options. These methodological refinements allow our study to deliver more robust evidence-based insights for advanced breast cancer patients, offering clinicians a more reliable foundation for personalized treatment decision-making. Primary endpoint PFS The most significant finding of this study is that mTOR inhibitors demonstrated the best PFS performance among all treatment regimens, but ranked only third in the comprehensive evaluation of PFS + ≥3 AEs, making them suboptimal for patients. Mechanistically, this result has a solid biological basis. The mTOR pathway is the downstream effector of the PI3K/AKT/mTOR signaling cascade, and its activation is closely associated with endocrine therapy resistance [30-31]. Following CDK4/6i progression, mTOR inhibition may restore tumor cell sensitivity to endocrine therapy by blocking this key resistance pathway. For patients with good performance status and no contraindications, mTOR inhibitor-based combination endocrine therapy is recommended as the preferred treatment option. However, it is noteworthy that although the mTOR inhibitor regimen showed outstanding efficacy, its safety profile requires special attention from clinicians. Over 50% of patients experienced ≥3 AEs, with non-hematologic toxicities being more common (stomatitis and rash) [18,24,32]. In real-world studies, the discontinuation rate due to adverse effects for mTOR inhibitors was 26.6% [33]. In the management of advanced HR+, HER2- breast cancer, preserving and enhancing quality of life must be prioritized alongside survival outcomes. While endocrine-based therapies have significantly improved progression-free survival, their long-term toxicities—such as fatigue, musculoskeletal pain, and emotional distress—can profoundly impact patients' daily functioning and well-being. Emerging evidence suggests that proactive symptom management (e.g., early palliative care integration[34], tailored exercise interventions[35], and psychological support[36]) may mitigate treatment-related burdens and improve adherence. Furthermore, patient-reported outcomes should be systematically incorporated into clinical trials and practice to better individualize care. Ultimately, a patient-centric approach, balancing efficacy with tolerability, is paramount in this increasingly chronic disease setting. PFS and Grade ≥3 Adverse Events In clinical practice, the balance between efficacy and safety remains a pivotal consideration in therapeutic decision-making. To address this, we developed a comprehensive evaluation model (assigning equal 50% weight to both PFS and ≥3AEs) to provide an objective quantitative framework. Our analysis revealed that SERM and Oral-SERD ranked prominently in the composite assessment, attributable to their well-demonstrated clinical efficacy and favorable safety profiles(Figure 6). This finding carries significant clinical implications, particularly in resource-limited settings where access to novel targeted therapies is restricted, or among elderly patients and those with multiple comorbidities. In such populations, traditional SERM or Oral-SERD regimens may offer a superior risk-benefit ratio and should be prioritized as first-line therapeutic options. Rechallenge with CDK4/6 inhibitors In China, due to factors such as healthcare insurance coverage, drug accessibility, and family financial constraints, a significant number of HR+HER2- advanced breast cancer patients are unable to undergo genetic testing or afford expensive targeted therapies. As a result, the reuse of CDK4/6i has become the only viable treatment option. However, the efficacy of CDK4/6i rechallenge remains highly controversial, with some studies reporting positive outcomes[20,37] while others failing to demonstrate significant benefits[13]. This inconsistency has created substantial dilemmas for clinicians in making therapeutic decisions. In the absence of high-level evidence-based medical support, this treatment strategy fails to provide physicians with sufficient confidence in patient management. Our study reveals that while CDK4/6i demonstrate modest superiority over endocrine monotherapy (HR 0.76, 95% CI 0.61–0.95)(Table 1), the PFS outcomes remain suboptimal whens compared against all available treatment alternatives. Furthermore, it did not emerge as the optimal choice for patients with ESR1 mutations (CDK4/6 vs endao: HR 0.75, 95% CI 0.45–1.24). For patients with PIK3CA mutations, a statistically significant improvement in PFS was observed (CDK4/6 vs endo: HR 0.56, 95% CI 0.32-0.98)(Supplemental File C). Immune checkpoint therapy The current analysis demonstrated that PD-L1 inhibitors yielded a low SUCRA score for PFS (Figure 5A), without showing statistically significant differences compared to endocrine monotherapy (PD-L1 vs endo: HR 0.89, 95% CI 0.45-1.75)(Table 1). Although the combination of CDK4/6 inhibitors with PD-L1 inhibitors exhibited moderate efficacy in terms of PFS (Figure 5A), this regimen ranked last in the comprehensive efficacy-safety assessment (PFS+≥3AEs) due to its substantially higher incidence of adverse events(Figure 6). Therefore, considering the benefit-risk profile, we do not recommend either immunotherapy alone or its combination with CDK4/6i for this patient population. The investigation of PD-1/PD-L1 inhibitors in HR+/HER2- advanced breast cancer remains relatively limited, primarily due to the characteristic "immune-cold" phenotype of these tumors, which is manifested by sparse immune cell infiltration within the tumor microenvironment and generally low PD-L1 positivity rates in this patient population [38]. Given these biological characteristics, routine PD-L1 testing is not currently recommended in clinical practice for HR+/HER2- breast cancer patients. Presently, immunotherapy is primarily being explored in specific patient subgroups who have developed endocrine resistance and lack alternative effective targeted treatment options. Of particular significance, a comprehensive multi-omics analysis conducted by researchers at Fudan University has classified HR+/HER2- breast cancer into four distinct molecular subtypes [39]. Among these, the SNF2 subtype (representing approximately 25.4% of cases) has been identified as an immunogenic phenotype, characterized by prominent immune cell infiltration and a high prevalence of TP53 mutations, suggesting potential heightened responsiveness to immunotherapy. Clinical trials specifically targeting this immunogenic subtype are currently in active recruitment phases [40]. In the realm of early-stage breast cancer, the KEYNOTE-756 trial has yielded groundbreaking results that herald new possibilities for immunotherapy applications. The study demonstrated that the addition of pembrolizumab to neoadjuvant chemotherapy significantly enhanced pCR rates in high-risk ER-positive early breast cancer patients (ITT population: 24.3% vs 15.6%, p=0.00005) [41]. This pivotal finding suggests that immunotherapy may hold substantial clinical value for carefully selected HR+/HER2- breast cancer patients. Building upon the current evidence base, we guess that future therapeutic paradigms for HR+/HER2- breast cancer may evolve toward a triple-combination strategy incorporating immunotherapy, targeted therapy, and endocrine treatment. Limitation The primary limitation of this study lies in the lack of direct comparative data between endocrine therapy and chemotherapy, a critical evidence gap that substantially impacts clinical decision-making. This knowledge gap largely reflects the current design bias in clinical research, where most novel drug trials preferentially use endocrine therapy rather than chemotherapy as the comparator. It should be emphasized that chemotherapy remains an indispensable treatment option for patients with rapidly progressive or highly symptomatic disease. Although we identified several retrospective studies comparing endocrine therapy with chemotherapy, we strictly adhered to evidence-based medicine principles by including only RCT, thus excluding such retrospective data. We strongly advocate for well-designed prospective clinical trials to address this important evidence gap in future research. A second major limitation involves the substantial heterogeneity in follow-up durations among the included studies. This methodological constraint particularly affects the assessment of OS outcomes, as the follow-up periods in certain trials may be insufficient to fully capture long-term survival differences between treatment strategies. Such variability in follow-up duration may introduce bias in evaluating the long-term efficacy of certain therapeutic regimens. Conclusion Our findings demonstrate that mTOR inhibitors represent a viable therapeutic option for patients with good performance status, while Oral-SERD may be more suitable for elderly patients or those with multiple comorbidities, highlighting the critical importance of personalized treatment strategies in HR+ advanced breast cancer. Future research should focus on addressing existing evidence gaps and optimizing therapeutic strategies to further improve long-term patient outcomes. Declarations Acknowledments Preliminary findings from this study were presented as a poster at the 18th St. Gallen International Breast Cancer Conference (March 2025, St. Gallen, Switzerland) Conflicts of Interest The authors declare no competing financial or personal interests that could influence the work reported in this manuscript. Author contributions Conceptualization: WJX/HLH/LQS Data curation: WJX/HLH/YYS Formal analysis: WJX/HLH Investigation: WJX/YYS Methodology: WJX Project administration: LEZ Resources: LEZ Software: WJX Supervision: LEZ/LQS Validation: WJX/HLH/YYS Visualization: WJX Writing – original draft: WJX Writing – review & editing: WJX/HLH/YYS/LEZ/LQS Data Availability Statements All data are incorporated into the article and its online supplementary material. References Nolan E, Lindeman GJ, Visvader JE. Deciphering breast cancer: from biology to the clinic. Cell. 2023;186(8):1708-1728. doi:10.1016/j.cell.2023.01.040 Slamon DJ, Diéras V, Rugo HS, et al. 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Published 2023 Jun 12. doi:10.1186/s13058-023-01649-w Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial [published correction appears in Lancet Oncol. 2025 Mar;26(3):e127. doi: 10.1016/S1470-2045(25)00036-1.]. Lancet Oncol. 2024;25(11):1424-1439. doi:10.1016/S1470-2045(24)00387-5 Kalinsky K, Accordino MK, Chiuzan C, et al. Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial. J Clin Oncol. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392 Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial [published correction appears in J Clin Oncol. 2023 Aug 10;41(23):3962. doi: 10.1200/JCO.23.01239.]. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338 Lindeman GJ, Fernando TM, Bowen R, et al. VERONICA: Randomized Phase II Study of Fulvestrant and Venetoclax in ER-Positive Metastatic Breast Cancer Post-CDK4/6 Inhibitors - Efficacy, Safety, and Biomarker Results. Clin Cancer Res. 2022;28(15):3256-3267. doi:10.1158/1078-0432.CCR-21-3811 Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib Plus Fulvestrant in Advanced Breast Cancer After Progression on CDK4/6 Inhibition: Results From the Phase III postMONARCH Trial. J Clin Oncol. 2025;43(9):1101-1112. doi:10.1200/JCO-24-02086 García-Sáenz JÁ, Martínez-Jáñez N, Cubedo R, et al. Sapanisertib plus Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive/HER2-Negative Advanced Breast Cancer after Progression on Aromatase Inhibitor. Clin Cancer Res. 2022;28(6):1107-1116. doi:10.1158/1078-0432.CCR-21-2652 Antonio Llombart-Cussac et al. Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial. JCO 41, 1001-1001(2023). DOI:10.1200/JCO.2023.41.16_suppl.1001 Jhaveri KL, Lim E, Jeselsohn R, et al. Imlunestrant, an Oral Selective Estrogen Receptor Degrader, as Monotherapy and in Combination With Targeted Therapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Phase Ia/Ib EMBER Study [published correction appears in J Clin Oncol. 2025 Jan;43(1):114. doi: 10.1200/JCO-24-02470.]. J Clin Oncol. 2024;42(35):4173-4186. doi:10.1200/JCO.23.02733 André F, Ciruelos EM, Juric D, et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann Oncol. 2021;32(2):208-217. doi:10.1016/j.annonc.2020.11.011 Xu B, Zhang Q, Hu X, et al. Entinostat, a class I selective histone deacetylase inhibitor, plus exemestane for Chinese patients with hormone receptor-positive advanced breast cancer: A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Acta Pharm Sin B. 2023;13(5):2250-2258. doi:10.1016/j.apsb.2023.02.001 Ravani LV, Calomeni P, Vilbert M, et al. Efficacy of Subsequent Treatments After Disease Progression on CDK4/6 Inhibitors in Patients With Hormone Receptor-Positive Advanced Breast Cancer. JCO Oncol Pract. Published online December 17, 2024. doi:10.1200/OP-24-00649 Hernandez-Aya LF, Gonzalez-Angulo AM. Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist. 2011;16(4):404-414. doi:10.1634/theoncologist.2010-0402 Nunnery SE, Mayer IA. Targeting the PI3K/AKT/mTOR Pathway in Hormone-Positive Breast Cancer. Drugs. 2020;80(16):1685-1697. doi:10.1007/s40265-020-01394-w Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529. doi:10.1056/NEJMoa1109653 François-Martin H, Lardy-Cléaud A, Pistilli B, et al. Long-Term Results with Everolimus in Advanced Hormone Receptor Positive Breast Cancer in a Multicenter National Real-World Observational Study. Cancers (Basel). 2023;15(4):1191. Published 2023 Feb 13. doi:10.3390/cancers15041191 Haukland EC, von Plessen C, Nieder C, Vonen B. Adverse events in deceased hospitalised cancer patients as a measure of quality and safety in end-of-life cancer care. BMC Palliat Care. 2020;19(1):76. Published 2020 Jun 1. doi:10.1186/s12904-020-00579-0 Sebri V, Pravettoni G. Tailored Psychological Interventions to Manage Body Image: An Opinion Study on Breast Cancer Survivors. Int J Environ Res Public Health. 2023;20(4):2991. Published 2023 Feb 8. doi:10.3390/ijerph20042991 Iddrisu M, Aziato L, Dedey F. Psychological and physical effects of breast cancer diagnosis and treatment on young Ghanaian women: a qualitative study. BMC Psychiatry. 2020;20(1):353. Published 2020 Jul 6. doi:10.1186/s12888-020-02760-4 Wander SA, Han HS, Zangardi ML, et al. Clinical Outcomes With Abemaciclib After Prior CDK4/6 Inhibitor Progression in Breast Cancer: A Multicenter Experience. J Natl Compr Canc Netw. Published online March 24, 2021. doi:10.6004/jnccn.2020.7662 Terranova-Barberio M, Pawlowska N, Dhawan M, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020;11(1):3584. Published 2020 Jul 17. doi:10.1038/s41467-020-17414-y Jin X, Zhou YF, Ma D, et al. Molecular classification of hormone receptor-positive HER2-negative breast cancer. Nat Genet. 2023;55(10):1696-1708. doi:10.1038/s41588-023-01507-7 ClinicalTrials.gov. Identifier NCT05205200, Immune Therapy in HR-positive/HER2-negative Metastatic Breast Cancer(ENIGMA)-BCTOP-L-M02. Fudan University. Updated February 8, 2024. Accessed May 2, 2025. https://clinicaltrials.gov/search?cond=NCT05205200 Cardoso F, O'Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2- breast cancer: a randomized phase 3 trial. Nat Med. 2025;31(2):442-448. doi:10.1038/s41591-024-03415-7 Supplementary Files SupplementalFileA.pdf SupplementalFileB.xlsx SupplementalFileC.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6659707","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457367526,"identity":"5dfcb8e4-e4f8-4d59-b0ce-3e1a0af87e38","order_by":0,"name":"Junxiao Wang","email":"","orcid":"","institution":"Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Junxiao","middleName":"","lastName":"Wang","suffix":""},{"id":457367527,"identity":"6727a5e9-7bdb-4359-888a-da2b0c6595c9","order_by":1,"name":"Longhu Huang","email":"","orcid":"","institution":"Fujian Provincial Governmental Hospital","correspondingAuthor":false,"prefix":"","firstName":"Longhu","middleName":"","lastName":"Huang","suffix":""},{"id":457367528,"identity":"c1fb8f5f-7242-420c-b75f-b003166c324f","order_by":2,"name":"Yushuai Yu","email":"","orcid":"","institution":"Fujian Cancer Hospital: Fujian Provincial Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yushuai","middleName":"","lastName":"Yu","suffix":""},{"id":457367529,"identity":"f5c402f6-6bbb-4ef5-a823-7b037fdf04d4","order_by":3,"name":"Ezhang Liu","email":"","orcid":"","institution":"Fujian University of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ezhang","middleName":"","lastName":"Liu","suffix":""},{"id":457367530,"identity":"9e146863-7f47-4a19-b6ba-99f5a84331db","order_by":4,"name":"Qisheng Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4ElEQVRIiWNgGAWjYBACNvbGxgcJFRJ29u39H4GMGsJa+HgOHzb4cMYm2YDngLHBgzPHCGuRk0hLk5zZlsa4QSLBTPJhCzMRDuM5YyDNc+YwszlDQlpFYgMbA397dwIBv/QYGPNUHOazbDhw7EbiDhkGiTNnNxC0JRlkC8PBxrYbiWfYGAwkcglokcgxOMzbdpix4TAzW0FiGzMxWtISG8HeP8bGxkCcFmAgM4ACWbKHh1ki4cwxHoJ+kW9vbP8Bikp++TeMH39U1Mjxt/fi14IBeEhTPgpGwSgYBaMAKwAAvelNgGUCYDoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0009-2684-2840","institution":"Fujian University of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Qisheng","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2025-05-14 03:02:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6659707/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6659707/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83198719,"identity":"b412e1d8-6d01-4f61-9197-036151bd0fc4","added_by":"auto","created_at":"2025-05-21 06:05:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":109793,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram of the literature search and study selection process\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/6dc5a3d4aeea13bde89b0507.png"},{"id":83198721,"identity":"2f255363-b381-4f26-a8c6-5c9362268e47","added_by":"auto","created_at":"2025-05-21 06:05:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":199919,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plots for each predefned endpoint: A. PFS of overall populations; B. OS of overall populations; C. ORR of overall populations; D. ≥3 AEs of overall populations; E. PFS of ESR1-Mutant populations; F. PFS of PIK3CA-Mutant populations.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/c4fe6a816c7f06bc7bf50831.png"},{"id":83198720,"identity":"ebb3e699-1027-4933-9227-fdda162f85fa","added_by":"auto","created_at":"2025-05-21 06:05:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":125898,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias for all enrolled studies.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/6661bdd79e6720f1c2669520.png"},{"id":83198722,"identity":"6142cdb1-5071-4930-8c96-702f706ad7fa","added_by":"auto","created_at":"2025-05-21 06:05:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":409501,"visible":true,"origin":"","legend":"\u003cp\u003eNetwork diagrams for each predefned endpoint: A. PFS of overall populations; B. OS of overall populations; C. ORR of overall populations; D. ≥3 AEs of overall populations; E. PFS of ESR1-Mutant populations; F. PFS of PIK3CA-Mutant populations.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/c5b374a67269ff2b39f02e66.png"},{"id":83200465,"identity":"48107e30-1eda-46d5-b15a-e89d247ef9a1","added_by":"auto","created_at":"2025-05-21 06:13:36","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":271725,"visible":true,"origin":"","legend":"\u003cp\u003eSUCRA values and rankings for each predefned endpoint: A. PFS of overall populations; B. OS of overall populations; C. ORR of overall populations; D. ≥3 AEs of overall populations; E. PFS of ESR1-Mutant populations; F. PFS of PIK3CA-Mutant populations.\u003c/p\u003e","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/5a13f9e18066a81afc863da1.png"},{"id":83198723,"identity":"cc37b4ac-41f0-4b6e-9fed-d3632dd46c5b","added_by":"auto","created_at":"2025-05-21 06:05:36","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":150235,"visible":true,"origin":"","legend":"\u003cp\u003eRankings derived from combining PFS and≥3 AEs. The maximum values of PFS and≥3 AEs are 50 each, and they are added together and ranked in order of score.\u003c/p\u003e","description":"","filename":"Figure6.png","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/24972ddbff26b4b267e6147b.png"},{"id":83706974,"identity":"682ca859-d236-4bc5-a809-4146d934e5c8","added_by":"auto","created_at":"2025-05-31 12:36:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1705919,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/cedf254d-b423-4f27-850c-0377db45eb28.pdf"},{"id":83200489,"identity":"5bfccf1a-8d5d-49ce-be35-8dddd36c03ff","added_by":"auto","created_at":"2025-05-21 06:14:28","extension":"pdf","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":132711,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFileA.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/0c1b9ae8436998ecccbeb277.pdf"},{"id":83198834,"identity":"c670d8eb-86ae-4f81-a480-1ae354e34afc","added_by":"auto","created_at":"2025-05-21 06:06:28","extension":"xlsx","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":19470,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFileB.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/64870c656cc340606f579f4a.xlsx"},{"id":83198729,"identity":"57660ecb-0678-43a5-b324-32d3ba33ef20","added_by":"auto","created_at":"2025-05-21 06:05:36","extension":"docx","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":528349,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFileC.docx","url":"https://assets-eu.researchsquare.com/files/rs-6659707/v1/4775165035d86df4faa474c1.docx"}],"financialInterests":"","formattedTitle":"Efficacy and Safety of Post-CDK4/6 Inhibitor Treatment Options for HR-Positive, HER2-Negative Advanced Breast Cancer: A Network Meta-Analysis of Randomized Controlled Trials","fulltext":[{"header":"Highlights","content":"\u003cp\u003e1.For patients in good general condition and without contraindications, the combination of an mTOR inhibitor with endocrine therapy is recommended as the first-line treatment.\u003c/p\u003e\n\u003cp\u003e2.In patients with ESR1 mutations, Oral-SERD should be the preferred treatment option.\u003c/p\u003e\n\u003cp\u003e3.For populations with limited access to novel targeted agents, elderly patients, or those with multiple comorbidities, SERM or Oral-SERD may represent a more optimal choice.\u003c/p\u003e\n\u003cp\u003e4.Rechallenge with CDK4/6i demonstrated statistically significant benefits in patients harboring PI3KCA mutations.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eHormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer constitutes the most prevalent subtype of breast cancer, accounting for approximately 70% of all cases [1]. In patients with advanced breast cancer (ABC), the combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy has emerged as the standard first-line treatment. CDK4/6i—such as palbociclib, abemaciclib, and dalpiciclib—significantly enhance patients’ progression-free survival (PFS) [2-4]. Additionally, ribociclib not only improves PFS but also increases overall survival (OS) [5].\u003c/p\u003e\n\u003cp\u003eDespite the significant efficacy of CDK4/6i in treatment, the majority of patients ultimately experience disease progression. The mechanisms underlying resistance encompass various factors, including alterations in upstream signaling pathways, inactivation or overexpression of cell cycle regulatory proteins, activation of downstream kinases, changes in the immune microenvironment, and reprogramming of metabolic pathways [6]. Consequently, the development of subsequent treatment strategies following the failure of CDK4/6i therapy presents a significant challenge in clinical practice. In recent years, multiple randomized controlled trials (RCT) have evaluated treatment options following the failure of CDK4/6i. The available treatment alternatives include switching to different CDK4/6i, combination targeted therapies such as PI3K inhibitors and AKT inhibitors, and novel agents such as oral-selective estrogen receptor degraders (Oral-SERD) and antibody-drug conjugates [7-9]. These treatment strategies exhibit significant differences in terms of efficacy and safety, and there is a notable lack of high-quality evidence for direct comparisons. Moreover, the impact of various treatment options on patient quality of life, tolerability, and financial burden are critical factors that must be considered in clinical decision-making [10].\u003c/p\u003e\n\u003cp\u003eConsequently, integrating existing data from RCT through network meta-analysis (NMA) allows for the indirect comparison of the efficacy and safety of various treatment regimens, thereby offering more comprehensive evidence to support clinical practice [11]. This study aims to evaluate the efficacy and safety of different treatment options for patients with HR+/HER2- ABC following the failure of CDK4/6i through a NMA. By synthesizing data from current RCT, this research will provide clinicians with a more scientifically basis for treatment decisions and guide future researches.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eThe manuscript was prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility and Exclusion Criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion Criteria: 1. ABC that is HR+/HER2-; 2. Disease progression following the administration of CDK4/6i in the adjuvant or advanced stage; 3. RCT with at least two treatment groups and availability of hazard ratio data comparing the two treatment groups, including one of the following endpoints: PFS, OS, objective response rate (ORR), or occurrences of grade 3 or higher adverse events (≥3 AEs); Exclusion Criteria: 1. Studies involving low HER2 expression; 2. Single-arm studies and retrospective studies;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformation Sources\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comprehensive and detailed search of literatures was conducted in PubMed, Embase, and Cochrane from inception to April 1, 2025, and also included published abstracts from San Antonio Breast Cancer Symposiums (SABCS), American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) over the past five years.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSearch Strategy\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe literature search was conducted using the following search terms in PubMed, Embase, and the Cochrane Library. Adjustments were made for each electronic database without applying any additional filtering criteria: (metastasis OR metastases OR metastatic OR advanced OR recurrent OR stage IV OR unresectable) AND (breast OR mammary) AND (cancer OR carcinoma OR malignant OR neoplasm OR tumour) AND (hormone receptor OR estrogen receptor OR oestrogen receptor) AND (positive OR +) AND (randomized controlled trial OR randomised controlled trial).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter importing the articles into EndNote for deduplication, two investigators independently screened the articles based on their titles and abstracts. Use of the latest published data from the same clinical study. If the two investigators have doubts about an article, a third investigator will make the final decision. When the title and abstract do not clearly indicate whether to include our study, the full text will be downloaded for further examination.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection Process\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extracted the necessary data from formally published papers, supplementary materials, and conference abstracts. When Hazard Ratios were not provided, we utilized Engauge Digitizer software to extract the relevant information from Kaplan-Meier curves. Some clinical studies include patients who have experienced disease progression after treatment with CDK4/6i, as well as those whose disease progressed without this treatment. This study specifically focuses on patients who have progressed after CDK4/6i therapy, and data extraction will be conducted solely for this group. All data included in this analysis are publicly available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Items\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe extracted the following data from the articles identified in our final search: article title, presence of partial or complete CDK4/6i, type of mutation, first author, publication year, treatment, PFS, OS, hazard ratio, ORR, and ≥3 AEs. The primary endpoint was PFS, which included analyses for all participants, participants with ESR1 mutations, and those with PIK3Ca mutations. Secondary endpoints comprised OS, ORR, and ≥3 AEs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Risk of Bias Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe employ software to assess various types of bias, including random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). Each bias type is rated on a scale of 0% to 100%, corresponding to three risk levels: “low risk of bias”, “unclear risk of bias” and “high risk of bias”. Ultimately, the software presents the degree of bias risk in an intuitive visual manner. We utilize a funnel plot to evaluate the presence of publication bias in the included studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSummary Measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe utilized hazard ratios and 95% confidence intervals (CI) to illustrate PFS and OS, while odds ratios (OR) and 95% CI were utilized to present ORR and ≥3 AEs. We ranked the various treatment protocols based on their Surface Under the Cumulative Ranking Curve (SUCRA) values, which ranged from 0 to 100, where higher scores indicate more effective treatments. Finally, both PFS and ≥3 AEs were assigned a maximum score of 50, and these two endpoints were combined to evaluate the efficacy and safety of each treatment protocol. A p-value of less than 0.05 was considered statistically significant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthesis Methods\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter listing the treatment measures, we categorize them according to their respective types: Fulvestrant, anastrozole and Exemestane are considered a type of endocrine therapy; Palbociclib, abemaciclib, and ribociclib are designated as CDK4/6i; Avelumab and atezolizumab are classified as PD-L1 inhibitors; Camizestrant, Elacestrant, Amecenestrant, and Imlunestrant are identified as Oral-SERD; Lasofoxifene is identified as SERM; Capivasertib and Xentuzumab are identified as AKT inhibitor; Everolimus and Sapanisertib are identified as mTOR; Venetoclax is identified as BCL2 inhibitor; Alpelisib is identified as PI3K inhibitor; Entinostat is identified as HDAC inhibitor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Consideration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Ethics Committee of Sanming Second Hospital has confirmed that all data were obtained from publicly available publications; therefore, no ethical approval was required.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDatabase searches identified 7,860 records, with 6,710 remaining after duplicate removal. Following rigorous screening, 22 eligible studies were included. However, only 16 studies contributed to closed loops in the network and were included in the final NMA. The remaining 6 studies were excluded due to lack of connectivity (i.e., they did not share comparators with other studies to form indirect evidence loops). Where multiple publications reported on the same study, the most recent and comprehensive data were retained. Studies were excluded if CDK4/6i was a stratification factor but outcome data specific to CDK4/6i-treated populations could not be extracted. The PRISMA flow diagram is presented in Figure 1, and the completed PRISMA 2020 checklist is provided in Supplementary File A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy characteristic\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study includes a total of 16 research articles published between 2020 and 2025, encompassing 37 groups with a combined total of 2,972 patients. The patient population in 9 articles consisted entirely of individuals after the use of CDK4/6i, while 7 studies provided extractable data on genetic mutations. 5 studies investigated the reuse of CDK4/6i, 4 studies focused on Oral-SERD medications, and 2 studies involved PD-L1. All included studies can be found in Supplementary File B [13-28].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk of bias within studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funnel plot indicates no evidence of publication bias (Figure 2). All RCT exhibited a low risk of bias (Figure 3). nine of these studies were open-label, which increases the potential for performance bias. The following three studies exhibit a high risk of bias:\u003c/p\u003e\n\u003cp\u003eThe Maintain study administered Ribociclib to a subset of patients prior to randomization, which may introduce selection bias by artificially increase the number of participants experiencing tumor progression under Ribociclib treatment; The Sapanisertib study aimed for about 40% of participants to have prior exposure to CDK4/6i. If the number of patients who had not previously received these inhibitors exceeded 60% of the total, recruitment for these individuals would be stopped; The XENERA-1 study employed a blinded design; however, unblinding occurred prematurely, and inconsistencies were observed between parameters obtained by researchers and those assessed by independent reviewers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary endpoint PFS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifteen studies\u0026nbsp;were included in the\u0026nbsp;PFS\u0026nbsp;analysis, with the\u0026nbsp;network diagrams\u0026nbsp;detailed in\u0026nbsp;Figure 4A. Based on the\u0026nbsp;SUCRA (Figure 5A), the\u0026nbsp;mTOR inhibitor ranked highest, followed by\u0026nbsp;PI3K inhibitor, and then\u0026nbsp;AKT inhibitor.\u0026nbsp;Targeted therapies (mTOR, PI3K, AKT inhibitors)\u0026nbsp;consistently demonstrated\u0026nbsp;higher SUCRA values\u0026nbsp;than\u0026nbsp;CDK4/6i rechallenge\u0026nbsp;or\u0026nbsp;oral-SERD. Furthermore, targeted inhibitors\u0026nbsp;exhibited higher SUCRA values\u0026nbsp;compared to\u0026nbsp;combination regimens, such as\u0026nbsp;CDK4/6i plus PD-L1 inhibitor\u0026nbsp;or\u0026nbsp;AKT inhibitor plus mTOR inhibitor. Notably,\u0026nbsp;CDK4/6i rechallenge\u0026nbsp;showed\u0026nbsp;modest efficacy (low SUCRA ranking), while\u0026nbsp;endocrine monotherapy\u0026nbsp;performed the\u0026nbsp;worst among all interventions.\u003c/p\u003e\n\u003cp\u003eIn\u0026nbsp;Cross-comparison of PFS (Table 1), there were\u0026nbsp;no statistically significant differences\u0026nbsp;between most treatment strategies. However,\u0026nbsp;the majority of therapeutic regimens\u0026nbsp;demonstrated\u003c/p\u003e\n\u003cp\u003estatistically significant PFS benefits\u0026nbsp;when compared with\u0026nbsp;endocrine monotherapy. Three studies specifically analyzed PFS in patients with PIK3CA mutations. The PI3K inhibitor regimen demonstrated the highest SUCRA value (Figure 5F), though this difference was not statistically significant (vs endo, HR 0.48, 95% CI 0.18-1.29). CDK4/6i rechallenge followed closely (vs endo, HR 0.56, 95% CI 0.32-0.98) (Supplemental File C). Five studies evaluated PFS in patients with ESR1 mutations. Oral-SERD demonstrated the highest SUCRA value (Figure 5E) and were the only treatment strategy to show statistically significant efficacy (HR 0.66, 95% CI 0.44–0.99) (Supplemental File C).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoint OS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFour studies evaluated the result of OS, with the network diagrams in Figure 4B. The Oral-SERD regimen demonstrated the highest SUCRA value, followed by CDK4/6 inhibitor rechallenge, whereas BCL2 inhibition showed a lower SUCRA value than endocrine monotherapy (Figure 5B). Compared with endocrine monotherapy, all regimens failed to demonstrate a significant OS benefit (Supplementral File C).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoint ORR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNine studies assessed ORR, with the network diagrams in Figure 4C. The Oral-SERD plus PI3K inhibitor combination yielded the highest SUCRA value, followed by SERM regimen. BCL2 inhibitor consistently demonstrated the lowest SUCRA value among all treatments. PD-L1 inhibitor exhibited a comparable SUCRA value to endocrine monotherapy (Figure 5C), with no statistically significant difference (OR 0.99, 95% CI 0.22–4.62)(Supplemental File C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary endpoint Safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 16 included studies reported ≥3 AEs, with detailed toxicity profiles illustrated in Figure 5D, and network diagrams in Figure 4D. The first three regimens—Oral-SERD, SERM, and endocrine monotherapy—demonstrated comparable SUCRA values, whereas CDK4/6i alone exhibited a lower SUCRA. Notably, combinations of CDK4/6i with PD-L1 inhibitors or Oral-SERD with PI3K inhibitors significantly increased the risk of ≥3 AEs compared to endocrine monotherapy (endo vs. CDK4/6+PD-L1: HR 0.04, 95% CI 0.02–0.10; endo vs. Oral-SERD+PI3K: HR 0.03, 95% CI 0.01–0.14)(Supplemental File C).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCombined analysis of PFS and≥3 AEs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIntegrating both PFS and ≥3AEs profiles, the SERM regimen achieved the highest SUCRA score, followed by the Oral-SERD and mTOR strategies. Endocrine monotherapy demonstrated intermediate efficacy-toxicity rankings, while CDK4/6 inhibitor rechallenge yielded notably low SUCRA values (Figure 6).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRecent advances in elucidating resistance mechanisms in HR+/HER2– advanced breast cancer have led to the development of novel targeted therapies, particularly inhibitors of the PI3K-AKT-mTOR pathway. Nevertheless, substantial heterogeneity exists among these therapies in terms of cost-effectiveness, accessibility, and toxicity profiles. Furthermore, treatment selection is complicated by patient-specific factors, including comorbidities, prior treatment tolerance, socioeconomic considerations, and evolving clinical guidelines. In the absence of a clearly defined standard-of-care, clinicians face considerable challenges in selecting the most appropriate subsequent-line therapy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDuring the course of this study, we identified a previously published meta-analysis that also investigated treatment strategies following progression on CDK4/6i[29]. However, through in-depth comparative analysis, the novelty and scientific rigor of our study are highlighted in the following key aspects: First, the prior study only incorporated data published up to December 2023, whereas our study systematically reviewed the most recent evidence up to April 2025. This extension is particularly critical, as the period from 2023 to 2025 witnessed the publication of pivotal clinical trials for multiple novel targeted therapies, ensuring that our findings reflect the most current advancements in the field. Second, the previous analysis included only 7 RCT, with the remaining 11 studies being cohort analyses. In contrast, our study rigorously screened and incorporated 16 high-quality RCT, significantly enhancing the level and reliability of the evidence. Finally, the prior research employed conventional meta-analysis techniques, permitting only direct comparisons between individual treatments and single-agent endocrine therapy. Our study innovatively utilized NMA, enabling both direct and indirect comparisons across multiple treatment regimens. This approach provides a more comprehensive and precise evaluation of the relative efficacy and safety profiles of different therapeutic options. These methodological refinements allow our study to deliver more robust evidence-based insights for advanced breast cancer patients, offering clinicians a more reliable foundation for personalized treatment decision-making.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary endpoint PFS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe most significant finding of this study is that mTOR inhibitors demonstrated the best PFS performance among all treatment regimens, but ranked only third in the comprehensive evaluation of PFS + ≥3 AEs, making them suboptimal for patients. Mechanistically, this result has a solid biological basis. The mTOR pathway is the downstream effector of the PI3K/AKT/mTOR signaling cascade, and its activation is closely associated with endocrine therapy resistance [30-31]. Following CDK4/6i progression, mTOR inhibition may restore tumor cell sensitivity to endocrine therapy by blocking this key resistance pathway. For patients with good performance status and no contraindications, mTOR inhibitor-based combination endocrine therapy is recommended as the preferred treatment option. However, it is noteworthy that although the mTOR inhibitor regimen showed outstanding efficacy, its safety profile requires special attention from clinicians. Over 50% of patients experienced ≥3 AEs, with non-hematologic toxicities being more common (stomatitis and rash) [18,24,32]. In real-world studies, the discontinuation rate due to adverse effects for mTOR inhibitors was 26.6% [33]. In the management of advanced HR+, HER2- breast cancer, preserving and enhancing quality of life must be prioritized alongside survival outcomes. While endocrine-based therapies have significantly improved progression-free survival, their long-term toxicities—such as fatigue, musculoskeletal pain, and emotional distress—can profoundly impact patients' daily functioning and well-being. Emerging evidence suggests that proactive symptom management (e.g., early palliative care integration[34], tailored exercise interventions[35], and psychological support[36]) may mitigate treatment-related burdens and improve adherence. Furthermore, patient-reported outcomes should be systematically incorporated into clinical trials and practice to better individualize care. Ultimately, a patient-centric approach, balancing efficacy with tolerability, is paramount in this increasingly chronic disease setting.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePFS and Grade ≥3 Adverse Events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn clinical practice, the balance between efficacy and safety remains a pivotal consideration in therapeutic decision-making. To address this, we developed a comprehensive evaluation model (assigning equal 50% weight to both PFS and ≥3AEs) to provide an objective quantitative framework. Our analysis revealed that SERM and Oral-SERD ranked prominently in the composite assessment, attributable to their well-demonstrated clinical efficacy and favorable safety profiles(Figure 6). This finding carries significant clinical implications, particularly in resource-limited settings where access to novel targeted therapies is restricted, or among elderly patients and those with multiple comorbidities. In such populations, traditional SERM or Oral-SERD regimens may offer a superior risk-benefit ratio and should be prioritized as first-line therapeutic options.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRechallenge with CDK4/6 inhibitors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn China, due to factors such as healthcare insurance coverage, drug accessibility, and family financial constraints, a significant number of HR+HER2- advanced breast cancer patients are unable to undergo genetic testing or afford expensive targeted therapies. As a result, the reuse of CDK4/6i has become the only viable treatment option. However, the efficacy of CDK4/6i rechallenge remains highly controversial, with some studies reporting positive outcomes[20,37] while others failing to demonstrate significant benefits[13]. This inconsistency has created substantial dilemmas for clinicians in making therapeutic decisions. In the absence of high-level evidence-based medical support, this treatment strategy fails to provide physicians with sufficient confidence in patient management. Our study reveals that while CDK4/6i demonstrate modest superiority over endocrine monotherapy (HR 0.76, 95% CI 0.61–0.95)(Table 1), the PFS outcomes remain suboptimal whens compared against all available treatment alternatives. Furthermore, it did not emerge as the optimal choice for patients with ESR1 mutations (CDK4/6 vs endao: HR 0.75, 95% CI 0.45–1.24). For patients with PIK3CA mutations, a statistically significant improvement in PFS was observed (CDK4/6 vs endo: HR 0.56, 95% CI 0.32-0.98)(Supplemental File C).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmune checkpoint therapy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe current analysis demonstrated that PD-L1 inhibitors yielded a low SUCRA score for PFS (Figure 5A), without showing statistically significant differences compared to endocrine monotherapy (PD-L1 vs endo: HR 0.89, 95% CI 0.45-1.75)(Table 1). Although the combination of CDK4/6 inhibitors with PD-L1 inhibitors exhibited moderate efficacy in terms of PFS (Figure 5A), this regimen ranked last in the comprehensive efficacy-safety assessment (PFS+≥3AEs) due to its substantially higher incidence of adverse events(Figure 6). Therefore, considering the benefit-risk profile, we do not recommend either immunotherapy alone or its combination with CDK4/6i for this patient population. The investigation of PD-1/PD-L1 inhibitors in HR+/HER2- advanced breast cancer remains relatively limited, primarily due to the characteristic \"immune-cold\" phenotype of these tumors, which is manifested by sparse immune cell infiltration within the tumor microenvironment and generally low PD-L1 positivity rates in this patient population [38]. Given these biological characteristics, routine PD-L1 testing is not currently recommended in clinical practice for HR+/HER2- breast cancer patients. Presently, immunotherapy is primarily being explored in specific patient subgroups who have developed endocrine resistance and lack alternative effective targeted treatment options. Of particular significance, a comprehensive multi-omics analysis conducted by researchers at Fudan University has classified HR+/HER2- breast cancer into four distinct molecular subtypes [39]. Among these, the SNF2 subtype (representing approximately 25.4% of cases) has been identified as an immunogenic phenotype, characterized by prominent immune cell infiltration and a high prevalence of TP53 mutations, suggesting potential heightened responsiveness to immunotherapy. Clinical trials specifically targeting this immunogenic subtype are currently in active recruitment phases [40]. In the realm of early-stage breast cancer, the KEYNOTE-756 trial has yielded groundbreaking results that herald new possibilities for immunotherapy applications. The study demonstrated that the addition of pembrolizumab to neoadjuvant chemotherapy significantly enhanced pCR rates in high-risk ER-positive early breast cancer patients (ITT population: 24.3% vs 15.6%, p=0.00005) [41]. This pivotal finding suggests that immunotherapy may hold substantial clinical value for carefully selected HR+/HER2- breast cancer patients. Building upon the current evidence base, we guess that future therapeutic paradigms for HR+/HER2- breast cancer may evolve toward a triple-combination strategy incorporating immunotherapy, targeted therapy, and endocrine treatment.\u0026nbsp;\u003c/p\u003e"},{"header":"Limitation","content":"\u003cp\u003eThe primary limitation of this study lies in the lack of direct comparative data between endocrine therapy and chemotherapy, a critical evidence gap that substantially impacts clinical decision-making. This knowledge gap largely reflects the current design bias in clinical research, where most novel drug trials preferentially use endocrine therapy rather than chemotherapy as the comparator. It should be emphasized that chemotherapy remains an indispensable treatment option for patients with rapidly progressive or highly symptomatic disease. Although we identified several retrospective studies comparing endocrine therapy with chemotherapy, we strictly adhered to evidence-based medicine principles by including only RCT, thus excluding such retrospective data. We strongly advocate for well-designed prospective clinical trials to address this important evidence gap in future research.\u003c/p\u003e\n\u003cp\u003eA second major limitation involves the substantial heterogeneity in follow-up durations among the included studies. This methodological constraint particularly affects the assessment of OS outcomes, as the follow-up periods in certain trials may be insufficient to fully capture long-term survival differences between treatment strategies. Such variability in follow-up duration may introduce bias in evaluating the long-term efficacy of certain therapeutic regimens.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings demonstrate that mTOR inhibitors represent a viable therapeutic option for patients with good performance status, while Oral-SERD may be more suitable for elderly patients or those with multiple comorbidities, highlighting the critical importance of personalized treatment strategies in HR+ advanced breast cancer. Future research should focus on addressing existing evidence gaps and optimizing therapeutic strategies to further improve long-term patient outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreliminary findings from this study were presented as a poster at the 18th St. Gallen International Breast Cancer Conference (March 2025, St. Gallen, Switzerland)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial or personal interests that could influence the work reported in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: WJX/HLH/LQS\u003c/p\u003e\n\u003cp\u003eData curation: WJX/HLH/YYS\u003c/p\u003e\n\u003cp\u003eFormal analysis: WJX/HLH\u003c/p\u003e\n\u003cp\u003eInvestigation: WJX/YYS\u003c/p\u003e\n\u003cp\u003eMethodology: WJX\u003c/p\u003e\n\u003cp\u003eProject administration: LEZ\u003c/p\u003e\n\u003cp\u003eResources: LEZ\u003c/p\u003e\n\u003cp\u003eSoftware: WJX\u003c/p\u003e\n\u003cp\u003eSupervision: LEZ/LQS\u003c/p\u003e\n\u003cp\u003eValidation: WJX/HLH/YYS\u003c/p\u003e\n\u003cp\u003eVisualization: WJX\u003c/p\u003e\n\u003cp\u003eWriting – original draft: WJX\u003c/p\u003e\n\u003cp\u003eWriting – review \u0026amp; editing: WJX/HLH/YYS/LEZ/LQS\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are incorporated into the article and its online supplementary material.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eNolan E, Lindeman GJ, Visvader JE. 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Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial [published correction appears in Lancet Oncol. 2025 Mar;26(3):e127. doi: 10.1016/S1470-2045(25)00036-1.].\u0026nbsp;Lancet Oncol. 2024;25(11):1424-1439. doi:10.1016/S1470-2045(24)00387-5\u003c/li\u003e\n\u003cli\u003eKalinsky K, Accordino MK, Chiuzan C, et al. Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial.\u0026nbsp;J Clin Oncol. 2023;41(24):4004-4013. doi:10.1200/JCO.22.02392\u003c/li\u003e\n\u003cli\u003eBidard FC, Kaklamani VG, Neven P, et al. 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Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer.\u0026nbsp;Nat Commun. 2020;11(1):3584. Published 2020 Jul 17. doi:10.1038/s41467-020-17414-y\u003c/li\u003e\n\u003cli\u003eJin X, Zhou YF, Ma D, et al. Molecular classification of hormone receptor-positive HER2-negative breast cancer.\u0026nbsp;Nat Genet. 2023;55(10):1696-1708. doi:10.1038/s41588-023-01507-7\u003c/li\u003e\n\u003cli\u003eClinicalTrials.gov. Identifier NCT05205200, Immune Therapy in HR-positive/HER2-negative Metastatic\u0026nbsp;Breast\u0026nbsp;Cancer(ENIGMA)-BCTOP-L-M02. Fudan University. Updated February 8, 2024. Accessed May 2, 2025.\u0026nbsp;https://clinicaltrials.gov/search?cond=NCT05205200\u003c/li\u003e\n\u003cli\u003eCardoso F, O'Shaughnessy J, Liu Z, et al. Pembrolizumab and chemotherapy in high-risk, early-stage, ER+/HER2-\u0026nbsp;breast cancer: a randomized phase 3 trial.\u0026nbsp;Nat Med. 2025;31(2):442-448. doi:10.1038/s41591-024-03415-7\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, HR-positive, advanced, network meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-6659707/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6659707/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eIn patients with HR-positive, HER2-negative advanced breast cancer who have progressed after CDK4/6 inhibitors, the optimal selection of subsequent therapies remains uncertain. This study employs a Bayesian network meta-analysis to evaluate the efficacy and safety of different treatment options.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe conducted a comprehensive literature search in the PubMed, Embase, and Cochrane databases, as well as abstracts from the San Antonio Breast Cancer Symposium, European Society for Medical Oncology, and American Society of Clinical Oncology, covering the past five years, with the search cutoff date of April 1, 2025. Only randomized controlled trials were included in the final analysis. Our analysis focused on several key outcomes, including progression-free survival (PFS) in the overall population, PFS in the ESR1 mutations, PFS in those with PIK3CA mutations population, overall survival, objective response rate and the incidence of grade 3 or higher adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eWe identified a total of 7,860 publications, ultimately including 16 studies involving 2,972 patients, all of whom experienced disease progression following treatment with CDK4/6 inhibitors. mTOR inhibitors demonstrated superior PFS. Oral-SERD were preferred in ESR1-mutant patients (vs endocrine therapy: HR 0.66, 95% CI 0.44–0.99), while CDK4/6 inhibitor rechallenge showed benefit in PIK3CA-mutant cases (vs endocrine therapy: HR 0.56, 95% CI 0.32–0.98). SERM and oral-SERD achieved optimal efficacy-safety balance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eOur findings demonstrate that mTOR inhibitors represent a viable therapeutic option for patients with good performance status, while Oral-SERD may be more suitable for elderly patients or those with multiple comorbidities. Future research should focus on addressing existing evidence gaps and optimizing therapeutic strategies to further improve long-term patient outcomes.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Post-CDK4/6 Inhibitor Treatment Options for HR-Positive, HER2-Negative Advanced Breast Cancer: A Network Meta-Analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-21 05:49:31","doi":"10.21203/rs.3.rs-6659707/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a46ef18d-0d20-433f-95c6-08d203025996","owner":[],"postedDate":"May 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-05T18:23:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-21 05:49:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6659707","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6659707","identity":"rs-6659707","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}