Association of Cyclin-Dependent Kinases 4 and 6 Inhibitors With Survival in Patients With Hormone Receptor–Positive Metastatic Breast Cancer: A Systematic Review and Meta-analysis

Key Points

Question  Is the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy associated with increased overall survival vs endocrine therapy alone among patients with hormone receptor–positive, ERBB2-negative metastatic breast cancer?

Findings  This meta-analysis of 9 randomized clinical trials with 5043 patients found that compared with endocrine therapy alone, the addition of cyclin-dependent kinases 4 and 6 inhibitors was associated with significantly increased overall survival, progression-free survival, and objective response rate among patients with hormone receptor–positive, ERBB2-negative metastatic breast cancer.

Meaning  These results may aid physicians in selecting an effective therapeutic regimen for patients with hormone receptor–positive, ERBB2-negative metastatic breast cancer.

Importance  One of the most recent treatment regimens used for hormone receptor (HR)–positive, ERBB2 (formerly HER2)–negative metastatic breast cancer is treatment with the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and endocrine therapy (ET).

Objective  To assess overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events, especially grades 3 and 4 adverse events, among patients with HR-positive, ERBB2-negative metastatic breast cancer who were treated with CDK4/6 inhibitors plus ET vs ET alone.

Data Sources  A systematic search of PubMed, Embase, the main oncology conference of the European Society of Medical Oncology, and the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium databases for randomized clinical trials of CDK4/6 inhibitors plus ET vs ET for HR-positive, ERBB2-negative metastatic breast cancer. Searches were performed up to March 30, 2020.

Study Selection  A total of 472 records were assessed in PubMed and Embase by 2 authors, including studies, international meeting reports, and reviews. Inclusion criteria were English-language phase 2 or 3 randomized clinical trials of HR-positive, ERBB2-negative metastatic breast cancer, with patients randomly assigned to receive CDK4/6 inhibitors plus ET or ET alone, and having OS or PFS outcomes. The exclusion criteria were phase 1 trials, retrospective studies, or studies without survival outcomes. Excluding the references, 16 articles were relevant. After excluding studies based on exclusion criteria, 9 studies were considered eligible for this meta-analysis.

Data Extraction and Synthesis  Two researchers independently extracted data and assessed potential bias. Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. The results were pooled using a fixed-effect model.

Main Outcomes and Measures  Study heterogeneity was assessed using the I² statistic. Hazard ratios (HRs) and 95% CIs were used to evaluate PFS, OS, and subgroup analyses. Odds ratios and 95% CIs were used to evaluate the objective response rate and grade 3 or 4 adverse events. The primary outcome was OS.

Results  In total, 9 studies that included a total of 5043 patients with metastatic breast cancer were assessed in this meta-analysis. Overall, the addition of CDK4/6 inhibitors to ET was associated with a statistically significant benefit to OS (HR, 1.33; 95% CI, 1.19-1.48; P < .001). Compared with ET alone, treatment with CDK4/6 inhibitors plus ET was associated with improved OS for the following subgroups: first-line therapy (HR, 1.35; 95% CI, 1.18-1.54; P < .001), second-line therapy (HR, 1.30; 95% CI, 1.09-1.54; P = .004), premenopausal women (HR, 1.32; 95% CI, 1.04-1.66; P = .02), postmenopausal women (HR, 1.34; 95% CI, 1.18-1.52; P < .001), visceral metastasis (HR, 1.31; 95% CI, 1.12-1.53; P < .001), age younger than 65 years (HR, 1.25; 95% CI, 1.06-1.49; P = .010), and age 65 years or older (HR, 1.38; 95% CI, 1.11-1.72; P = .003). The addition of CDK4/6 inhibitors to ET was also associated with significant PFS benefit (HR, 1.84; 95% CI, 1.70-1.98; P < .001) and objective response rate benefit (odds ratio, 2.02; 95% CI, 1.61-2.53; P < .001). However, the use of CDK4/6 inhibitors in combination with ET was associated with significantly increased risk of grade 3 or 4 adverse events compared with ET alone, including neutropenia (HR, 57.05; 95% CI, 38.26-85.05; P < .001), leukopenia (HR, 36.36; 95% CI, 19.35-68.34; P < .001), and diarrhea (HR, 4.97; 95% CI, 2.84-8.69; P < .001).

Conclusions and Relevance  This meta-analysis indicated that, compared with ET alone, treatment with CDK4/6 inhibitors plus ET was associated with significantly improved OS, PFS, and objective response rate among patients with HR-positive, ERBB2-negative metastatic breast cancer.

Breast cancer is the most frequent malignant neoplasm observed in women and is the leading cause of cancer death.¹ The most frequent subtype of breast cancer is hormone receptor (HR)–positive, ERBB2 (formerly HER2)–negative breast cancer, which accounts for approximately 65% of all breast cancers.^2,3 Nearly two-thirds of patients with metastatic breast cancer are HR–positive, and it is estimated that about 25% of patients with breast cancer will experience recurrence after surgery.^4,5

Endocrine therapy (ET) is an important method of treatment for women with HR-positive, ERBB2-negative metastatic breast cancer. This treatment includes aromatase inhibitors, fulvestrant, tamoxifen, and others.⁶ Endocrine therapy is associated with a significant increase in both progression-free survival (PFS) and overall survival (OS).⁷ However, ET resistance and disease progression are the main causes of recurrence and death of patients.^1,6 Ongoing alternative strategies are being explored to improve outcomes among these patients. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, and CDK4 and CDK6 induce hyperphosphorylation of the retinoblastoma protein, causing the progression of tumor cells from the G1 checkpoint to the S phase of the cell cycle.^8-10 The development of endocrine resistance in breast cancer is associated with the deregulation of the cyclin D/CDK4-6/retinoblastoma pathway.^11,12 Cyclin D is also a key target for estrogen-induced cell proliferation through the estrogen receptor. Cyclin D is required for estrogen-dependent gene expression, which indicates that cyclin D expression may participate in tumorigenesis through the estrogen receptor signaling pathway, thus promoting tumor growth.⁶ A preclinical study showed that CDK4/6 inhibitors combined with ET was significantly associated with inhibiting tumor growth.¹³ The use of CDK4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) is one of the most recent treatments developed for hormone receptor–positive, ERBB2-negative metastatic breast cancer. Although a number of studies have shown that CDK4/6 inhibitors added to ET is associated with a significant increase in PFS, OS of patients undergoing this treatment is unclear.^14-21 Several recent randomized clinical trials have shown that treatment with CDK4/6 inhibitors and ET compared with ET alone increased OS among patients with HR-positive, ERBB2-negative metastatic breast cancer.^22-26 However, other randomized clinical trials have found that treatment of patients with HR-positive, ERBB2-negative metastatic breast cancer with CDK4/6 inhibitors and ET, compared with ET alone, does not prolong OS.^4,27,28

Thus, it remains unclear whether treatment with CDK4/6 inhibitors and ET for patients with HR-positive, ERBB2-negative metastatic breast cancer extends OS. Therefore, the aim of this meta-analysis is to evaluate the association between treatment with CDK4/6 inhibitors plus ET and OS.

The primary objective was to evaluate the association of CDK4/6 inhibitors plus ET, compared with ET alone, with OS in patients with HR-positive, ERBB2-negative metastatic breast cancers. The secondary objective was to assess the association of PFS, objective response rate (ORR), adverse events (AEs), and grade 3 or grade 4 (grade 3/4) AEs with treatment of CDK4/6 inhibitors plus ET vs ET alone among patients with HR-positive, ERBB2-negative metastatic breast cancer.

We conducted an electronic search of PubMed and Embase using several keywords simultaneously, including cyclin-dependent kinases 4 and 6 inhibitor, palbociclib, ribociclib, abemaciclib, endocrine therapy, neoplasm, metastatic breast cancer, and advanced breast cancer. Further searches included the main oncology conference of the European Society of Medical Oncology, the American Society of Clinical Oncology, and the San Antonio Breast Cancer Symposium databases. Only clinical trials published in English were included in the search process. Two researchers (J.L. and X.H.) independently extracted data and assessed possible bias. Searches were performed up to March 30, 2020.

The inclusion criteria were (1) phase 2 or 3 randomized clinical trials of HR-positive, ERBB2-negative metastatic breast cancer (2) with patients randomly assigned to receive CDK4/6 inhibitors plus ET or ET alone, (3) having OS or PFS outcomes. The exclusion criteria were (1) phase 1 trials, (2) retrospective studies, or (3) studies without survival outcomes.

Data extracted from each trial included the study design, first author’s name, journal name, publication date of journal, authors’ country, patient population, menopausal status, line of therapy, phase of therapy, treatment regimens, OS, PFS, ORR, and AEs. Hazard ratios (HRs) and 95% CIs were used to evaluate PFS, OS, and subgroup analyses. Odds ratios and 95% CIs were used to evaluate the ORR and AEs. A random-effects model was used for analyses when P ≤ .10 or when the I² statistic indicated greater than 50% study heterogeneity; otherwise, a fixed-effect model was used. Review Manager, version 5.3 (Cochrane Collaboration), was used for data analysis and forest plot production. A 2-sided P ≤ .01 was considered to indicate a statistically significant publication bias. This analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.²⁹

In total, 472 records were assessed in PubMed and Embase, including studies, international meeting reports, and reviews. Excluding the references, we found only 16 articles to be relevant. After application of the exclusion criteria, we determined that 9 studies were eligible for this meta-analysis (eFigure 1 in the Supplement): 1 phase 2 trial and 8 phase 3 trials reported on the efficacy and safety of treatment with CDK inhibitors plus ET vs ET alone.^{16,17,22,23,25,26,28,30,31} Thus, 9 articles, including a total of 5043 participants with HR-positive metastatic breast cancer, were included in the analysis. Relevant OS data were reported in 6 of 9 studies, and the PFS and ORR outcomes were reported in all studies. In subgroup analyses, 7 of 9 studies targeted the age of 65 years. Thus, we divided the age subgroups into patients who were younger than 65 years and patients who were 65 years or older. The main characteristics and relevant outcomes of the included studies are provided in Table 1 and in the eTable in the Supplement.^{16,17,22,23,25,26,28,30,31}

In this meta-analysis, 6 studies showed indicators of OS: MONALEESA-7,²⁵ MONALEESA-3,²² MONALEESA-2,²⁶ PALOMA-1,³⁰ PALOMA-3,²³ and MONARCH 2.¹⁷ One phase 2 trial and 5 phase 3 trials were included to assess the association of CDK4/6 inhibitors plus ET vs ET alone with OS. For this analysis, 2030 patients were enrolled in the CDK4/6 inhibitors plus ET group and 1391 patients were enrolled in the ET group. Our results indicated that the addition of CDK4/6 inhibitors to ET was associated with significant benefit to OS (HR, 1.33; 95% CI, 1.19-1.48; P < .001), with low heterogeneity observed across studies (I² = 0%; P = .99) (Figure 1).

In this analysis, 1 phase 2 trial and 8 phase 3 trials were included to assess the association of CDK4/6 inhibitors plus ET vs ET alone with PFS.^{16,17,22,23,25,26,28,30,31} In these trials, 3448 patients were enrolled in the CDK4/6 inhibitors plus ET group and 2267 patients were enrolled in the ET group. Our results showed that the addition of CDK4/6 inhibitors to ET was associated with significant benefit to PFS (HR, 1.84; 95% CI, 1.70-1.98; P < .001), with low heterogeneity across studies (I² = 0%; P = .84) (Figure 2).

Nine studies were included to assess the association of CDK4/6 inhibitors plus ET vs ET alone with ORR.^{16,17,22,23,25,26,28,30,31} For this analysis, 3113 patients were enrolled in the CDK4/6 inhibitors plus ET group and 1930 patients were enrolled in the ET group. The addition of CDK4/6 inhibitors to ET was associated with significant benefit to ORR (odds ratio, 2.02; 95% CI, 1.61-2.53; P < .001), with high heterogeneity across studies (I² = 63%; P = .004) (Figure 3).

For this analysis, 1436 patients were enrolled in the CDK4/6 inhibitors plus ET group and 1103 patients in the ET group of first-line therapy, whereas 584 patients were enrolled in the CDK4/6 inhibitors plus ET group and 283 patients in the ET group of second-line therapy. The combination of CDK4/6 inhibitors plus ET vs ET alone was associated with improved OS for the first-line therapy subgroup (HR, 1.35; 95% CI, 1.18-1.54; P < .001), with low heterogeneity across studies (I² = 0%; P = .99), as well as for the second-line therapy subgroup (HR, 1.30; 95% CI, 1.09-1.54; P = .004), also with low heterogeneity across subgroups (I² = 0%; P = .68) (eFigure 2 in the Supplement).

For this analysis, 1128 patients were enrolled in the CDK4/6 inhibitors plus ET group and 734 patients in the ET group of the premenopausal subgroup, whereas 1695 patients were enrolled in the CDK4/6 inhibitors plus ET group and 1054 patients in the ET group of the postmenopausal subgroup. Treatment with CDK4/6 inhibitors plus ET was associated with improved OS for both the premenopausal subgroup (HR, 1.32; 95% CI, 1.04-1.66; P = .02), with low heterogeneity across studies (I² = 0%; P = .41), and for the postmenopausal subgroup (HR, 1.34; 95% CI, 1.18-1.52; P < .001), with low heterogeneity across studies (I² = 0%; P = .99) (eFigure 3 in the Supplement).

For this analysis, 2030 patients were enrolled in the CDK4/6 inhibitors plus ET group and 1391 patients in the ET group of the visceral metastasis subgroup, whereas 2030 patients were enrolled in the CDK4/6 inhibitors plus ET group and 1391 patients in the ET group of the bone-only metastasis subgroup. Treatment with CDK4/6 inhibitors plus ET was associated with improved OS for the visceral metastasis subgroup (HR, 1.31; 95% CI, 1.12-1.53; P < .001), with low heterogeneity across studies (I² = 0%; P = .69). Treatment with CDK4/6 inhibitors plus ET was not associated with improved OS for the bone-only metastasis subgroup (HR, 1.22; 95% CI, 0.88-1.68; P = .23), with low heterogeneity across studies (I² = 0%; P = .45) (eFigure 4 in the Supplement).

For this analysis, 1611 patients were enrolled in the CDK4/6 inhibitors plus ET group and 973 patients in the ET group of the subgroup with patients younger than 65 years, whereas 1611 patients were enrolled in the CDK4/6 inhibitors plus ET group and 973 patients in the ET group of the subgroup of patients who were 65 years of age or older. Treatment with CDK4/6 inhibitors plus ET was associated with improved OS both for the younger patient subgroup (HR, 1.25; 95% CI, 1.06-1.49; P = .010), with low study heterogeneity (I² = 0%; P = .45), and for the older patient subgroup (HR, 1.38; 95% CI, 1.11-1.72; P = .003), with low study heterogeneity (I² = 44%; P = .17) (eFigure 5 in the Supplement).

Given that AEs are the main reason for the termination of the majority of treatment programs, we analyzed the main grade 3/4 AEs to assess their association with the treatment of patients with CDK4/6 inhibitors plus ET or ET alone. A significant increase in cases of neutropenia, leukopenia, and diarrhea was associated with treatment with CDK4/6 inhibitors plus ET. The combination of CDK4/6 inhibitors plus ET was associated with increased cases of neutropenia (HR, 57.05; 95% CI, 38.26-85.05; P < .001), with low study heterogeneity (I² = 46%; P = .07), of leukopenia (HR, 36.36; 95% CI, 19.35-68.34; P < .001), also with low heterogeneity (I² = 0%; P = .57), and of diarrhea (HR, 4.97; 95% CI, 2.84-8.69; P < .001), with high study heterogeneity (I² = 62%; P = .009) (eFigure 6 in the Supplement) (Table 2).

Endocrine therapy combined with CDK4/6 inhibitors is a reasonable option for treatment of HR-positive, ERBB2-negative metastatic breast cancer. Thus, we evaluated the association between CDK4/6 inhibitors combined with ET vs ET alone for treatment of patients with metastatic breast cancer and survival. There were 9 randomized clinical trials assessed, with a total of 5043 patients with metastatic breast cancer in this meta-analysis. For patients with HR-positive, ERBB2-negative metastatic breast cancer, treatment with ET combined with CDK4/6 inhibitors was associated not only with improved PFS and ORR but also with improved OS. Nevertheless, compared with ET alone regimens, CDK4/6 inhibitors plus ET regimens were also associated with increased risk of grade 3/4 AEs, including neutropenia, leukopenia, and diarrhea.

Two recent meta-analyses performed OS analysis, but the sample sizes in these analyses are small.^32,34 Of these meta-analyses, one³² included OS data for 5 studies, whereas our meta-analysis included 6 studies that assessed OS and also analyzed subgroups of OS. Several other previously published meta-analyses and pooled analyses of PFS concluded that the use of CDK4/6 inhibitors plus ET was associated with significantly extended PFS.^2,3,13,19 The survival data, references, and subgroup analyses included in the present meta-analysis are more comprehensive, complete, and contain a larger sample size compared with those previously published meta-analyses. Thus, the present meta-analysis has several strengths over previous analyses. Both the present meta-analysis and previous studies showed a significant benefit in OS among patients treated with CDK4/6 inhibitors plus ET in HR-positive, ERBB2-negative metastatic breast cancer.^22-26,30 The trials using the first- or second-line setting (PALOMA-1, PALOMA-3, MONALEESA-2, MONALEESA-3, MONARCH 2, and MONALEESA-7) have published updated data prospectively showing an OS benefit with the addition of CDK4/6 inhibitors with ET.^22-26,30 The PALOMA-2 and MONARCH 3 studies have not yet reported OS data because the data are not mature.^16,28 In the present meta-analysis, 5043 patients from 9 randomized clinical trials were included to compare the treatment effects associated with the use of CDK4/6 inhibitors plus ET vs ET alone. Six of those trials showed significant benefit in OS, with low heterogeneity across the studies. In addition, 4 subgroup analyses in a previous meta-analysis³⁴ also indicated improved OS associated with the combined treatment. Two of the trials concluded that the use of CDK4/6 inhibitors plus ET for HR-positive, ERBB2-negative metastatic breast cancer is a strong and effective treatment regimen in clinical practice.^33,35

Our meta-analysis showed an increase in PFS among patients with HR-positive, ERBB2-negative metastatic breast cancer associated with the use of CDK4/6 inhibitors plus ET compared with ET alone.^{16,17,22,23,25,26,28,30,31} Our findings are consistent with the conclusions of previous meta-analyses.^36-38 In addition, our results supplement and update PFS data from previous studies. Thus, previous data and the present meta-analysis suggest that treatment with CDK4/6 inhibitors plus ET vs ET is associated with extending PFS among patients with HR-positive, ERBB2-negative metastatic breast cancer.

Our meta-analysis showed an increase in ORR among patients with HR-positive, ERBB2-negative metastatic breast cancer associated with the use of CDK4/6 inhibitors plus ET compared with ET alone.^{16,17,22,23,25,26,28,30,31} We were able to conclude that the use of CDK4/6 inhibitors plus ET was associated with significantly improved ORR compared with the use of ET alone among patients with HR-positive, ERBB2-negative metastatic breast cancer.

Considering that various subgroups may experience different recovery results, we used subgroup analyses to assess 4 subgroups. The results of these analyses showed that, compared with the use of ET alone, treatment with CDK4/6 inhibitors plus ET was associated with significantly prolonged OS for both subgroups in the following 4 pairs of subgroups among patients with HR-positive, ERBB2-negative metastatic breast cancer: first-line and second-line treatment; premenopausal and postmenopausal women; visceral disease; and younger than 65 years and 65 years or older. Although several previous meta-analyses have also analyzed these subgroups, they analyzed the subgroups for PFS or ORR but not for OS.^34,37 This is an important difference between our study and those previous studies.

The addition of CDK4/6 inhibitors to treatment regimens was associated with a high risk of increased rates of neutropenia, leukopenia, and diarrhea, 3 grade 3/4 AEs that should be considered when treatment periods are long.² Neutropenia, leukopenia, and diarrhea were the most common symptoms observed among patients who received CDK4/6 inhibitors plus ET treatment of metastatic breast cancer, with diarrhea being the most frequent nonhematologic grade 3/4 AE.^36,39 However, those grade 3/4 AEs may be controlled through experience, medication, or dose adjustment. The use of the 3 CDK4/6 inhibitors was associated with different AEs: palbociclib and ribociclib with hematologic toxicities, and abemaciclib with diarrhea and fatigue.^39,40

Several limitations should be acknowledged in our study. First, all the studies included in our search were in English; that is, literature in other languages on the same topic were not included. Second, all data were extracted from published literature, and no individual patient data were used in this study. The results in the meta-analysis may be biased. Third, some studies in this meta-analysis included randomized clinical trials, but the subgroup analysis did not include all of those studies. For example, in the age subgroup analysis, some studies used 40 years as the cut point, whereas other studies used 65 years as the cut point. Therefore, our results could not represent the characteristics of disease development of all patients, thus potentially affecting the interpretation of our results. However, we believe our use of carefully aggregated data and our statistical methods limited this bias. Nevertheless, our results suggested that the addition of CDK4/6 inhibitors to ET for treatment of HR-positive, ERBB2-negative metastatic breast cancer was associated with specific and significant benefit to OS, providing critical guidance for clinical practice.

Our meta-analysis showed that, compared with ET alone, the use of CDK4/6 inhibitors plus ET was associated with significant improvements not only in PFS and ORR but also in OS among patients with HR-positive, ERBB2-negative metastatic breast cancer. In subgroups analyses, the addition of CDK4/6 inhibitors to ET was associated with significantly prolonged OS compared with the use of ET alone for both pairs of the following 4 patient subgroups: first-line and second-line treatment, premenopausal and postmenopausal women, visceral metastasiss, and younger than 65 years and 65 years or older. However, the addition of the CDK4/6 inhibitors to the ET regimen was associated with a higher risk of grade 3/4 AEs, especially neutropenia, leukopenia, and diarrhea. The results of this study will aid physicians in selecting an effective regimen for patients with HR-positive, ERBB2-negative metastatic breast cancer.

Accepted for Publication: July 31, 2020.

Published: October 13, 2020. doi:10.1001/jamanetworkopen.2020.20312

Correction: This article was corrected on November 19, 2020, to fix errors in the Abstract, Results, Discussions, Conclusions, and Table 1.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Li J et al. JAMA Network Open.

Corresponding Author: Jiuda Zhao, MD, Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining 810000, China (jiudazhao@126.com).

Author Contributions: Drs Zhao and Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Li and Huo contributed equally to this work and are co–first authors.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: All authors.

Obtained funding: All authors.

Administrative, technical, or material support: All authors.

Supervision: All authors.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by a grant from the Innovation Team for the Study of Pathogenesis and Anti-tumor Mechanism of Chinese-Tibetan Medicine in the Qinghai area (Talent Highland Program) and grant 2018-ZJ-T02 from the Qinghai province Medical Gene Detection Technology Platform.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.