Real-world efficacy and prognostic factors of CDK4/6 inhibitors in HR⁺/HER2⁻ metastatic breast cancer: a multicenter retrospective study from the Dongting Lake region of China

Introduction

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR⁺/HER2⁻) breast cancer is the most common molecular subtype, accounting for approximately 60–70% of all breast cancer cases (1). Endocrine therapy (ET) is generally more effective and better tolerated than chemotherapy in HR⁺/HER2⁻ breast cancer, making it the preferred first-line option. Nonetheless, challenges such as resistance and limited long-term survival remain in advanced disease (2,3). For this population, ET remains a foundational treatment, and the addition of CDK4/6 inhibitors (CDK4/6i), which target cell cycle regulation, has significantly transformed the therapeutic landscape. CDK4/6i combined with ET nearly doubles median progression-free survival (PFS) compared to ET alone (from 14–16 to 25–28 months) (4-7), and has also demonstrated an overall survival (OS) benefit of 7–12 months, particularly with abemaciclib (8) and ribociclib (9). Consequently, CDK4/6i-based regimens are now recommended as the first-line standard of care for patients with HR⁺/HER2⁻ metastatic breast cancer (MBC) in international clinical guidelines (10,11). Currently, CDK4/6i are widely used worldwide, including the globally approved agents palbociclib (4), abemaciclib (5), and ribociclib (7), as well as dalpiciclib, a domestically developed agent in China that has shown promising efficacy and has been officially approved for clinical use (6).

Real-world evidence (RWE) offers the advantage of broader sampling and more heterogeneous patient characteristics, thereby providing insights that are often more reflective of actual clinical practice compared to randomized controlled trials (RCTs) (12). In China, several multicenter retrospective studies have explored the efficacy, safety, and quality-of-life outcomes of CDK4/6i in MBC patients. However, many of these studies have been limited by small sample sizes, restricted geographic representation, or insufficient analysis across treatment lines and prognostic subgroups (13).

Hunan province, located in south-central China, is a populous region with moderate socioeconomic development and diverse urban-rural healthcare structures, making it representative of China’s central region (14). The Dongting Lake area, located in northern Hunan province, includes key cities such as Changsha—the provincial capital and one of the major metropolitan centers in south-central China—as well as Yiyang, Yueyang, and Changde. This area is not only closely connected economically but also serves as a hub for oncology care within the province, with relatively centralized medical resources and long-standing cancer registry infrastructure. These characteristics make it a representative and practical setting for real-world oncology research.

Against this background, we conducted a multicenter, real-world study across five specialized cancer centers in the Dongting Lake region of Hunan. We retrospectively analyzed 590 patients with HR⁺/HER2⁻ MBC patients who received CDK4/6i, aiming to characterize their treatment patterns, assess clinical outcomes, and identify key prognostic factors associated with PFS. The findings are intended to support regional optimization of treatment strategies and inform individualized therapeutic decision-making. We present this article in accordance with the STROBE reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-37/rc).

Methods

Subjects and study design

This was a multicenter, retrospective observational study conducted across five tertiary cancer centers located in four cities surrounding Dongting Lake (Changsha, Yiyang, Yueyang, and Changde) in Hunan province, China. Female patients with HR⁺/HER2⁻ MBC patients who received CDK4/6i between May 2016 and January 2025 were consecutively included. A total of 616 HR⁺/HER2⁻ MBC who received CDK4/6i were initially screened, after excluding 18 patients with missing key treatment data and 8 patients lacking efficacy evaluation, 590 patients were included in the final analysis.

Patients

Patients were eligible for inclusion if they met all the following criteria: (I) female, aged ≥18 years; (II) pathologically confirmed HR⁺/HER2⁻ breast cancer based on immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); (III) unresectable locally advanced or metastatic disease; (IV) received at least one cycle of CDK4/6i in combination with ET, regardless of treatment line; (V) available baseline and follow-up data. Patients were excluded if they met any of the following conditions: (I) concurrent malignancies; (II) no available efficacy evaluation or missing efficacy data; (III) missing key treatment history and PFS information, including those lacking first-line therapy records or both first- and second-line treatment details for ≥2 L cases.

HR positivity was defined as ≥1% nuclear staining of estrogen receptor (ER) and/or progesterone receptor (PR) by IHC. The optimal cut-off values for ER and PR expression were determined using the cutpointr function (R package cutpointr), which applies receiver operating characteristic (ROC) curve-based analysis and the Youden index to identify the threshold most strongly associated with PFS. The resulting cut-off points were 70% for ER and 75% for PR, and were used for binary classification in further analysis. HER2 negativity was defined as IHC 0 or 1+, or IHC 2+ with negative FISH results, according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines (15). Luminal A and luminal B subtypes were determined using surrogate definitions based on IHC, including ER, PR, HER2, and Ki-67 index, following the St. Gallen International Expert Consensus 2013 criteria (16). To avoid interference from subsequent therapies, this study did not collect efficacy data beyond second-line treatment.

Data collection

Data were extracted using a standardized case report form, including demographic data [age, menopausal status, Eastern Cooperative Oncology Group (ECOG) performance status], tumor characteristics (histological type, ER/PR/HER2 status, Ki-67 index, metastatic pattern), and treatment history (adjuvant/neoadjuvant chemotherapy, radiotherapy, and ET); CDK4/6i-specific information, such as drug type, treatment line, endocrine partner, and treatment duration, was also recorded. Efficacy assessment was based on PFS, defined as the time from initiation of CDK4/6i therapy to documented disease progression or death. Only patients with complete PFS records were included in survival analyses.

Statistical analysis

All statistical analyses were performed using R software (version 4.2.2). Categorical variables were summarized as frequencies and percentages, while continuous variables were reported as medians with interquartile ranges (IQRs). Comparisons of baseline characteristics across different CDK4/6i treatment lines were performed using the chi-square test or Fisher’s exact test for categorical variables, and the Kruskal-Wallis test for continuous variables. Patients who were lost to follow-up were treated as censored at the date of their last documented evaluation. PFS was estimated using the Kaplan-Meier method, and differences between groups were assessed with the log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using univariate and multivariate Cox proportional hazards models to identify potential prognostic factors. Variables with a P value <0.10 in univariate analysis were included in the multivariate model. All P values were two-sided, and P<0.05 was considered statistically significant.

Ethical consideration

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. IRB approval was obtained from the Ethics Committee of Hunan Cancer Hospital (Approval No. KYJJ-2023-095), the primary coordinating center. Given the retrospective nature of this study and the use of de-identified clinical data, additional IRB approvals from the other participating institutions were not required, and individual informed consent was waived by the ethics committee. All clinical data were retrospectively collected from electronic medical records. The study protocol was registered at ClinicalTrials.gov (No. NCT06033287).

Results

Baseline characteristics

A total of 590 patients with HR⁺/HER2⁻ MBC who received CDK4/6i therapy at five cancer centers in the Dongting Lake region of Hunan province were included in this study. Baseline characteristics are summarized in Table 1. The median age was 53.5 years (range, 31–82), with 76.95% of patients younger than 60 years and 54.24% being postmenopausal. De novo stage IV disease was observed in 27.46% of the cohort. Invasive ductal carcinoma was the predominant histologic type (87.63%), and 55.93% of patients had a Ki-67 index ≥30%. Luminal B tumors accounted for 83.39% of cases.

In terms of HER2 expression, 39.15% of patients were classified as IHC 0, while 60.85% were considered HER2-low (defined as IHC 1+ or IHC 2+ with negative FISH results). Visceral metastases were present in 43.32% of patients, including 6.78% with symptomatic visceral crisis. Bone was the most common metastatic site (69.15%), followed by lung (30.51%), liver (22.37%), and brain (5.42%).

Regarding treatment history, 63.05% of patients had received prior adjuvant chemotherapy, with 48.47% having received an anthracycline-based regimen. Additionally, 54.92% had received prior adjuvant ET. Among those, selective estrogen receptor modulators (SERMs) were the most frequently used (32.71%), followed by aromatase inhibitors (AIs, 17.97%). A total of 69.83% of patients had completed the standard duration of ET.

The distribution of CDK4/6i and treatment patterns is illustrated in Figure 1. Among the 590 patients, abemaciclib was the most commonly prescribed CDK4/6i (33.39%), followed by dalpiciclib (28.98%), palbociclib (25.76%), and ribociclib (10.85%). A minority of patients received other CDK4/6i agents or participated in clinical trials (1.02%) (Figure 1A). In terms of treatment line, 63.39% of patients received CDK4/6i as first-line therapy, 25.59% as second-line, and 11.02% as third-line or beyond (Figure 1B). Regarding ET partners, AIs were the predominant combination in the first-line setting (80.21%), whereas fulvestrant was more frequently used in second-line combinations (56.95%) (Figure 1C,1D).

Figure 1 Distribution of CDK4/6i and treatment patterns in the overall cohort. (A) Proportion of CDK4/6i types used; (B) proportion of CDK4/6i use by treatment line; (C) endocrine partners used in combination with CDK4/6i in first-line setting; (D) endocrine partners used in combination with CDK4/6i in second-line setting. AI, aromatase inhibitor; CDK4/6i, CDK4/6 inhibitors.

Comparison of patient characteristics by line of CDK4/6i therapy

Significant differences in clinicopathological features were observed across different lines of CDK4/6i therapy, as shown in Table 1. The proportion of patients with recurrent metastatic disease increased with higher lines of treatment (68.18% in the first-line group, 76.82% in the second-line group, and 87.69% in the third-line or beyond group; P=0.002). Similarly, the distribution of ER expression varied: the proportion of patients with ER ≥70% was 80.21% in the first-line group, dropping to 56.92% in those treated at third-line or beyond (P<0.001). Regarding HER2 expression, the percentage of IHC 0 patients significantly increased in later-line groups (34.49% vs. 47.68% vs. 46.15%, P=0.02), while IHC 1+ expression was most common in the first-line group (36.10%).

Differences were also evident in prior treatment history. As the line of CDK4/6i therapy increased, the rates of prior adjuvant chemotherapy (P<0.001), anthracycline-based chemotherapy (P<0.001), and adjuvant ET (P=0.005) also rose. Specifically, among patients treated at third-line or beyond, 80.00% had received prior adjuvant chemotherapy, 69.23% had received anthracyclines, and 70.77% had received adjuvant ET.

Regarding patterns of metastasis, the proportion of visceral metastases increased significantly with later treatment lines (44.39% in first-line, 51.66% in second-line, and 72.31% in third-line or beyond; P<0.001). Liver metastases rose from 17.11% in the first-line group to 49.23% in the third-line or beyond group (P<0.001). Brain metastases also showed a rising trend (4.28%, 4.64%, and 13.85%, respectively; P=0.01).

In terms of drug selection, dalpiciclib was the most commonly used CDK4/6i in the first-line setting (n=126, 33.69%), while abemaciclib was most frequently used in second-line therapy (n=56, 37.09%).

Efficacy of first-line vs. second-line CDK4/6i therapy

Among the 590 patients included in the study, 374 received CDK4/6i therapy as first-line treatment for MBC, while 151 received it as second-line therapy. The median follow-up time was 11.2 months. The incidence of progression events was 29.95% in the first-line group and 51.00% in the second-line group. The median PFS was significantly longer in the first-line group than in the second-line group [32.3 months (95% CI: 24.2–41.3) vs. 17.6 months (95% CI: 13.5–22.0); P<0.001] (Table 2). This survival benefit was further illustrated by Kaplan-Meier curves (Figure 2).

Figure 2 Kaplan-Meier curves of PFS stratified by CDK4/6i treatment lines. Patients who received CDK4/6i as first-line treatment (red curve) showed significantly longer median PFS compared to those treated in the second-line setting (blue curve). Median PFS was 32.3 months for the first-line group and 17.6 months for the second-line group (log-rank P<0.001). PFS, progression-free survival; CDK4/6i, CDK4/6 inhibitors.

Among the 288 patients with evaluable treatment response, the partial response (PR), stable disease (SD), and progressive disease (PD) rates were 49.52%, 47.62%, and 2.86%, respectively, in the first-line group, and 42.31%, 48.72%, and 8.97%, respectively, in the second-line group. The difference in response distribution approached statistical significance (P=0.09). The disease control rate (DCR) was significantly higher in the first-line group compared to the second-line group (97.14% vs. 91.03%; P=0.049). Although the objective response rate (ORR) was numerically higher in the first-line group (49.52% vs. 42.31%), the difference was not statistically significant (P=0.34) (Table 2).

Predictive factors for PFS with CDK4/6i therapy

To identify clinical factors associated with the efficacy of CDK4/6i therapy, Cox proportional hazards regression analysis was conducted among patients receiving first-line or second-line CDK4/6i treatment (Table 3). In univariate analysis, initial diagnosis at stage IV, elevated Ki-67 index, liver metastasis, lung metastasis, and use of CDK4/6i as second-line therapy were significantly associated with shorter PFS. Conversely, a disease-free interval (DFI) of ≥5 years was identified as a favorable prognostic factor.

Multivariate Cox analysis further confirmed the following as independent predictors of shorter PFS, using the absence of each clinical feature as the reference group: de novo stage IV disease vs. recurrent (HR =1.50, 95% CI: 1.05–2.14, P=0.03), Ki-67 index ≥30% vs. <30% (HR =1.60, 95% CI: 1.18–2.18, P=0.003), presence of liver metastasis vs. no liver metastasis (HR =2.26, 95% CI: 1.69–3.03, P<0.001), presence of lung metastasis vs. no lung metastasis (HR =1.53, 95% CI: 1.14–2.07, P=0.005), and use of CDK4/6i as second-line vs. first-line therapy (HR =2.24, 95% CI: 1.73–2.89, P<0.001). In contrast, a DFI ≥5 years (vs. <5 years) was associated with prolonged PFS (HR =0.65, 95% CI: 0.47–0.91, P=0.01). The Kaplan-Meier curves in Figure 3 further illustrate these associations. Patients with high Ki‑67 expression (Figure 3A), Luminal B subtype (Figure 3B), prior adjuvant chemotherapy (Figure 3C), prior adjuvant radiotherapy (Figure 3D), shorter DFI (Figure 3E), and liver metastasis (Figure 3F) had significantly worse PFS than their respective counterparts.

Figure 3 Kaplan-Meier curves of PFS stratified by prognostic subgroups. (A) Ki-67 ≥30% vs. <30%; (B) Luminal A vs. Luminal B; (C) with vs. without prior adjuvant chemotherapy; (D) with vs. without prior adjuvant radiotherapy; (E) DFI ≥5 years vs. <5 years; (F) with vs. without liver metastasis; shaded areas represent 95% confidence intervals. P values were derived from the log-rank test. DFI, disease-free interval; PFS, progression-free survival.

Discussion

This study systematically evaluated the real-world clinical application and efficacy of CDK4/6i in patients with HR⁺/HER2⁻ MBC using multicenter data from five specialized breast cancer centers in the Dongting Lake region of Hunan province, China. A total of 590 patients were included, making this one of the largest multicenter retrospective studies on CDK4/6i treatment in the central-southern region of China. The findings offer valuable insights for optimizing the clinical use of CDK4/6i at the regional level and provide a reference for developing individualized treatment strategies.

Our study demonstrates that CDK4/6i have been widely adopted as first-line therapy for HR⁺/HER2⁻ MBC in the real-world setting of the Dongting Lake region, with 63.39% of patients receiving CDK4/6i as first-line treatment. While this proportion appears higher than those reported in some earlier real-world studies, caution is warranted in such comparisons due to differences in study periods, clinical accessibility, and regional treatment policies (17). This may be attributed to the increasing accessibility of CDK4/6i and expanded reimbursement coverage under China’s national healthcare system, leading to a steady rise in first-line usage. The choice of CDK4/6i appeared to reflect temporal availability and policy changes. Palbociclib, being the first CDK4/6i approved in China, was more frequently used during the early period. Abemaciclib was the first to be included in the national reimbursement list, resulting in broader adoption across various patient populations. Dalpiciclib, a domestically developed agent, has demonstrated favorable efficacy in Chinese patients with strong evidence from local clinical trials, contributing to its increasing usage (2,6). In contrast, ribociclib was incorporated into China’s national reimbursement scheme relatively late, officially approved by the National Medical Products Administration (NMPA) in January 2023 and added to the national insurance formulary only in early 2024, which has delayed its widespread adoption in clinical practice. Additionally, market penetration was hindered by pricing strategies, limited post-marketing real-world evidence at the time, and physicians’ familiarity favoring earlier-listed agents (18). Consequently, ribociclib utilization remains lower compared to palbociclib and abemaciclib in this cohort.

In this study, patients who received CDK4/6i as first-line therapy achieved a median PFS of 32.3 months, which was significantly longer than the 17.6 months observed in the second-line setting (P<0.001). The median PFS in the first-line group was notably longer than that reported in several pivotal RCTs, including PALOMA-2 (27.6 months with palbociclib plus letrozole) (4), MONALEESA-2 (25.3 months with ribociclib plus letrozole) (19), MONALEESA-7 [23.8 months with ribociclib plus tamoxifen/non-steroidal aromatase inhibitor (NSAI) and goserelin] (20), MONARCH 3 (28.2 months with abemaciclib plus NSAI) (5), and DAWNA-2 (30.6 months with dalpiciclib plus letrozole) (6). For patients receiving CDK4/6i as second-line therapy, the median PFS was 17.6 months in our cohort, which was comparable to the 16.4 months reported in MONARCH 2 (21)—a phase III RCT involving patients who had progressed on prior non-steroidal AIs and had not received chemotherapy. Moreover, our second-line efficacy appeared to be superior to that observed in the earlier PALOMA-3 trial (22), which reported a median PFS of 9.5 months in patients treated with palbociclib plus fulvestrant after progression on prior ET. These findings suggest a potential improvement in real-world outcomes over time.

Several real-world studies have also reported that the efficacy of CDK4/6i in clinical practice may exceed that observed in RCTs, particularly in first- or second-line treatment settings. For instance, in a real-world study of Asian patients by Chen et al. (23), the median PFS for first-line CDK4/6i therapy reached 30.42 months for the palbociclib group and 29.89 months for the ribociclib group. Similarly, Harbeck et al. (24) conducted a systematic review encompassing 82 real-world studies on CDK4/6i and reported a median PFS of 28.1 months in first-line settings and 12.1 months in second-line or later treatments, which are broadly consistent with the findings of our study. Several factors may contribute to the longer PFS observed in our cohort: (I) a relatively high proportion of de novo metastatic patients, who tend to be more sensitive to ET; (II) a lower incidence of liver metastases, implying a lighter disease burden; (III) lower frequency of radiographic assessments in real-world practice compared to RCTs, potentially delaying the documentation of disease progression; (IV) improved standardization of CDK4/6i use and better patient adherence; and (V) potential biological sensitivity advantages among Chinese patients.

Multivariate Cox regression analysis further identified several independent predictors of PFS. De novo stage IV disease, Ki-67 index ≥30%, liver metastasis, lung metastasis, and use of CDK4/6i in the second-line setting were all significantly associated with shorter PFS, whereas a DFI of ≥5 years was identified as a favorable prognostic factor.

De novo stage IV disease may reflect higher tumor aggressiveness and greater disease burden, which could lead to inferior outcomes with CDK4/6i therapy. Similarly, an elevated Ki-67 index is a well-established indicator of high tumor proliferative activity and has been recognized as a key predictive biomarker for CDK4/6i efficacy. Consistent with our findings, a previous single-center real-world study from Hunan Cancer Hospital also reported Ki-67 >30% as an independent adverse prognostic factor for PFS (25). Additionally, the real-world analysis by Chen et al. (23) confirmed that a high Ki-67 level was predictive of poor treatment outcomes with CDK4/6i.

Liver and lung metastases, as forms of visceral involvement, are generally indicative of higher tumor burden and more aggressive disease biology. Consistent with our results, a prior single-center study from Hunan Cancer Hospital demonstrated that the presence of liver metastases was significantly associated with shorter PFS in patients receiving CDK4/6i therapy (25). Similarly, in the real-world study by Chen et al. (23), both visceral metastasis and liver metastasis were identified as unfavorable predictors of CDK4/6i efficacy. In another real-world study by Ge et al. (26), multiple metastatic sites and liver involvement were likewise associated with poorer treatment outcomes. Collectively, these findings underscore the importance of tumor burden and metastatic pattern as key determinants of response to CDK4/6i.

In our study, prior adjuvant radiotherapy was significantly associated with shortened PFS. While the underlying mechanisms remain unclear, this observation raises the possibility of treatment-related factors influencing disease progression. Given the lack of direct evidence in the current literature, further validation in independent cohorts and mechanistic studies is warranted. In addition, patients with HER2 IHC 1+ status (classified as HER2-low) demonstrated improved PFS compared to those with IHC 0 in univariate analysis; however, this association did not remain statistically significant in the multivariate model. Previous studies have suggested that HER2-low status may influence sensitivity to CDK4/6i (25), but current evidence remains limited and inconclusive. Further studies integrating molecular subtyping are needed to clarify the predictive role of HER2 expression in CDK4/6i treatment.

This study has several notable strengths. First, it is a large-scale, multicenter investigation involving major cancer centers in the Dongting Lake region of Hunan province, enhancing its regional representativeness. Second, the dataset was comprehensive, capturing key clinical variables such as treatment lines, tumor biomarkers, metastatic patterns, and prior therapies. Third, multivariate analyses identified clinically applicable prognostic factors, providing valuable insights for personalized treatment stratification.

However, several limitations should also be acknowledged. As a retrospective study, it is inherently subject to selection bias. Moreover, treatment response evaluations were based on physician judgment and imaging reports from individual institutions, without centralized radiologic review. Third, the relatively short follow-up time and limited number of progression events in the first-line treatment group may result in an underestimation of the true progression risk and limit the robustness of median PFS estimation. A longer follow-up is warranted to validate these findings. Finally, molecular-level data, such as PIK3CA mutations or RB loss, were not included, limiting the mechanistic interpretation of outcomes. Future prospective studies incorporating biomarker profiling and circulating tumor DNA (ctDNA) analyses are warranted to validate and extend these findings.

Conclusions

This multicenter real-world study from the Dongting Lake region of Hunan province confirmed that CDK4/6i offer favorable efficacy for HR⁺/HER2⁻ MBC, particularly in the first-line setting (median PFS: 32.3 months). Several independent prognostic factors—including Ki-67 index, visceral metastases, treatment line, and DFI—were identified. These findings support the rational application of CDK4/6i and inform personalized treatment strategies in real-world practice.

Acknowledgments

We sincerely thank all participating institutions, clinicians, and patients who contributed to this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-37/rc

Data Sharing Statement: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-37/dss

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-37/prf

Funding: The study was funded by the Hunan Provincial Natural Science Foundation of China (No. 2025JJ80824 and 2024JJ6289), the Changsha City Technology Program (No. kq2403120), the Climb Plan of Hunan Cancer Hospital (No. ZX2021005 and QH2023006), the High-Level Talent Support Program of Hunan Cancer Hospital (No. 20250731-1050), the China Primary Health Care Foundation (No. cphcf-2023-056), and the Beijing Science and Technology Innovation Medical Development Foundation (No. KC2023-JX-0082-05).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-37/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. IRB approval was obtained from the Ethics Committee of Hunan Cancer Hospital (Approval No. KYJJ-2023-095), the primary coordinating center. Given the retrospective nature of this study and the use of de-identified clinical data, additional IRB approvals from the other participating institutions were not required, and individual informed consent was waived by the ethics committee. All clinical data were retrospectively collected from electronic medical records. The study protocol was registered at ClinicalTrials.gov (No. NCT06033287).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Harbeck N, Penault-Llorca F, Cortes J, et al. Breast cancer. Nat Rev Dis Primers 2019;5:66. [Crossref] [PubMed]
2. Chen Y, Xie Y, Sang D, et al. Real-world comparison of palbociclib, abemaciclib, and dalpiciclib as first-line treatments for Chinese HR+/HER2-metastatic breast cancer patients: a multicenter study (YOUNGBC-28). Ther Adv Med Oncol 2024;16:17588359241302018. [Crossref] [PubMed]
3. Raheem F, Karikalan SA, Batalini F, et al. Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches. Int J Mol Sci 2023;24:16198. [Crossref] [PubMed]
4. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016;375:1925-36. [Crossref] [PubMed]
5. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol 2017;35:3638-46. [Crossref] [PubMed]
6. Zhang P, Zhang Q, Tong Z, et al. Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2023;24:646-57.
7. Hortobagyi GN, Stemmer SM, Burris HA, 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 2019;30:1842. [Crossref] [PubMed]
8. Sledge GW Jr, Toi M, Neven P, et al. TThe 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;6:116-24. [Crossref] [PubMed]
9. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med 2022;386:942-50. [Crossref] [PubMed]
10. Gennari A, André F, Barrios CH, et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol 2021;32:1475-95. [Crossref] [PubMed]
11. Teysir J, Lloyd MR, Alkassis S, et al. After a CDK4/6 Inhibitor: State of the Art in Hormone Receptor-Positive Metastatic Breast Cancer. Am Soc Clin Oncol Educ Book 2025;45:e473372. [Crossref] [PubMed]
12. Batra A, Kong S, Cheung WY. Eligibility of real-world patients with metastatic breast cancer for clinical trials. Breast 2020;54:171-8. [Crossref] [PubMed]
13. Stanciu IM, Orlov-Slavu MC, Parosanu AI, et al. Impact of Patient Profile on CDK4/6 Inhibitor Therapy Outcomes: A Real-World Data Analysis. Int J Mol Sci 2025;26:3357. [Crossref] [PubMed]
14. Wikipedia. Hunan (2025). Available online: https://en.wikipedia.org/w/index.php?title=Hunan&oldid=1294840030
15. Wolff AC, Hammond MEH, Allison KH, et al. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018;36:2105-22. [Crossref] [PubMed]
16. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 2013;24:2206-23. [Crossref] [PubMed]
17. Low JL, Lim E, Bharwani L, et al. Real-world outcomes from use of CDK4/6 inhibitors in the management of advanced/metastatic breast cancer in Asia. Ther Adv Med Oncol 2022;14:17588359221139678. [Crossref] [PubMed]
18. Jia C, Zhang S, Wang J, et al. Cost-effectiveness of CDK4/6 inhibitors for second-line HR+/HER2- advanced or metastatic breast cancer in China. Sci Rep 2025;15:12765. [Crossref] [PubMed]
19. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med 2016;375:1738-48. [Crossref] [PubMed]
20. Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018;19:904-15. [Crossref] [PubMed]
21. Sledge GW Jr, Toi M, Neven P, 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;35:2875-84. [Crossref] [PubMed]
22. Cristofanilli M, Turner NC, Bondarenko I, 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;17:425-39. [Crossref] [PubMed]
23. Chen BF, Tsai YF, Chao TC, et al. Real-world experience with CDK4/6 inhibitors in hormone receptor-positive metastatic and recurrent breast cancer: findings from an Asian population. Clin Exp Med 2024;24:185. [Crossref] [PubMed]
24. Harbeck N, Brufsky A, Rose CG, et al. Real-world effectiveness of CDK4/6i in first-line treatment of HR+/HER2- advanced/metastatic breast cancer: updated systematic review. Front Oncol 2025;15:1530391. [Crossref] [PubMed]
25. Liu B, Hu ZY, Xie N, et al. Beyond clinical trials: CDK4/6 inhibitor efficacy predictors and nomogram model from real-world evidence in metastatic breast cancer. Cancer Innov 2024;3:e143. [Crossref] [PubMed]
26. Ge I, Berner K, Mathis M, et al. Real-World Data Analysis of CDK4/6 Inhibitor Therapy-A Patient-Centric Single Center Study. Cancers (Basel) 2024;16:1760. [Crossref] [PubMed]