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The CDK4/6 inhibitor in HR-positive advanced breast cancer: A systematic review and meta-analysis.

ABSTRACT: Recently, several high-quality clinical randomized controlled trials (RCTs) have identified that cyclin-dependent kinases (CDKs) 4/6 inhibitors obtained a great safety and efficacy, which can be consequently applied as a combination therapy with letrozole or fulvestrant for women who had advanced breast cancer and progressed while receiving endocrine therapy. In this systemic review, we performed a meta-analysis to explore whether CDK4/6 inhibitors had a significantly benefit to treating hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2 negative (HER2-negative) advanced breast cancer.The data for meta-analysis were collected from MEDLINE, EMBASE, and Cochrane Library from January 1980 to December 2017, and eventually 3182 patients from 6 RCTs were included.The result showed the CDK4/6 inhibitor group had a longer progression-free survival (PFS) (hazard ratio?=?0.51; 95% confidence interval [CI], 0.46-0.57, P < .00001), a better objective response (risk rate?=?1.53; 95% CI, 1.35-1.74, P < .00001), as well as a better clinical benefit response (risk rate?=?1.29; 95% CI, 1.13-1.47, P?=?.0001). Besides, subgroup analyses of PFS according to stratification factors and other baseline characteristics confirmed a great performance of CDK4/6 inhibitors across the all subgroups. And sensitive analysis showed that all outcomes were stable except Finn 2014 trail.CDK4/6 inhibitors can significantly prolong the PFS and improve the objective response and clinical benefit response among the patients with HR-positive/ HER2-negative advanced breast cancer.

SUBMITTER: Ding W

PROVIDER: S-EPMC5976281 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The CDK4/6 inhibitor in HR-positive advanced breast cancer: A systematic review and meta-analysis.

Ding Wu W Li Zhian Z Wang Caiyun C Ruan GuoDong G Chen LuPing L Tu Chuanjian C

Medicine 20180501 20

<h4>Background</h4>Recently, several high-quality clinical randomized controlled trials (RCTs) have identified that cyclin-dependent kinases (CDKs) 4/6 inhibitors obtained a great safety and efficacy, which can be consequently applied as a combination therapy with letrozole or fulvestrant for women who had advanced breast cancer and progressed while receiving endocrine therapy. In this systemic review, we performed a meta-analysis to explore whether CDK4/6 inhibitors had a significantly benefit ...[more]

PMID: 29768351

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Project description:PurposeTo compare palbociclib + letrozole and palbociclib + fulvestrant with chemotherapy agents in postmenopausal women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced/metastatic breast cancer (ABC/MBC) who had no prior systemic treatment for advanced disease (first line) or whose disease progressed after prior endocrine therapy or chemotherapy (second line).MethodsA systematic search identified randomized controlled trials (RCTs) published from January 2000 to January 2016 that compared endocrine-based therapies, chemotherapy agents, and/or chemotherapy agents + biological therapies in the first- and second-line treatment of postmenopausal women with HR+/HER2- ABC/MBC. The main outcome of interest was progression-free survival (PFS)/time to progression (TTP). Bayesian network meta-analyses (NMAs) and pairwise meta-analyses were conducted. Heterogeneity and inconsistency were assessed.ResultsSixty RCTs met eligibility criteria and were stratified by line of therapy. In the first line, palbociclib + letrozole showed statistically significant improvements in PFS/TTP versus capecitabine [intermittent: HR 0.28 (95% CrI 0.11-0.72)] and mitoxantrone [HR 0.28 (0.13-0.61)], and trended toward improvements versus paclitaxel [HR 0.59 (0.19-1.96)], docetaxel [HR 0.51 (0.14-2.03)] and other monotherapy or combination agents (HRs ranging from 0.24 to 0.99). In the second line, palbociclib + fulvestrant showed statistically significant improvements in PFS/TTP versus capecitabine [intermittent: HR 0.28 (0.13-0.65)], mitoxantrone [HR 0.26 (0.12-0.53)], and pegylated liposomal doxorubicin [HR 0.19 (0.07-0.50)], and trended toward improvements versus paclitaxel [HR 0.48 (0.16-1.44)], docetaxel [HR 0.71 (0.24-2.13)] and other monotherapy or combination agents (HRs ranging from 0.23-0.89). NMA findings aligned with direct evidence and were robust to sensitivity analyses.ConclusionsPalbociclib + letrozole and palbociclib + fulvestrant demonstrate trends in incremental efficacy compared with chemotherapy agents for the first- and second-line treatment of HR +/HER2- ABC/MBC.

Project description:PurposeAdvanced breast cancer is a heterogeneous disease with several well-defined subtypes, among which, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) is most prevalent. Determination of HR and HER2 status influences prognosis and, thus, disease management. Although literature on these prognostic factors exist, especially in the early breast cancer setting, it remains unclear to what extent these factors can guide clinical decision-making in the advanced disease setting. Therefore, we sought to identify the strength and consistency of evidence for prognostic factors in patients with HR+/HER2- advanced breast cancer.MethodsA systematic literature review (SLR) of the major electronic databases was conducted in November 2018 for primary research studies published since 2010. Endpoints of interest were tumor response, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS).ResultsSeventy-nine studies were included wherein all patients were diagnosed with advanced breast cancer and ≥50% of the population were HR+/HER2-. OS was the most commonly assessed endpoint (n=67) followed by PFS (n=33), BCSS (n=5) and tumor response (n=3). The prognostic factors with strongest evidence of association with worse OS were negative progesterone receptor status, higher tumor grade, higher circulating tumor cell (CTC) count and higher Ki67 level, number of metastatic sites (eg multiple vs single) and sites of metastases (eg presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, poor performance status, prior therapy attributes in the early or metastatic setting (type of therapy, treatment line, response of prior therapy), and race (black vs white). The prognostic factors that had strongest evidence of association with PFS included CTC count, number and sites of metastases, and absence of prior therapy or higher lines of therapy in the early or metastatic setting. The directionality of association was consistent for all prognostic factors except between lymph node and OS, and de novo metastatic breast cancer and PFS.ConclusionMultiple disease, treatment, and patient-related prognostic factors impact survival, particularly OS, in patients with HR+/HER2- advanced breast cancer. Treatment outcomes can vary considerably due to these factors. Understanding poorer prognostic factors for patients can result in improved clinical decision-making.

Project description:BackgroundThe combination of cyclin-dependent kinases 4/6 inhibitors (CDK4/6is) and endocrine therapy (ET) is standard of care for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (BC). However, studies evaluating adjuvant CDK4/6is provided contradictory results thus far.Materials and methodsWe conducted a systematic review and meta-analysis to assess if the addition of CDK4/6is to adjuvant ET impacts on survival's outcomes and safety of patients with HR+/HER2- early BC (EBC). This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines and was registered in the PROSPERO database (ID: CRD42020218597). A systematic review of PubMed, Cochrane and EMBASE databases and major conference proceedings was performed up to 15 December 2020. All randomized controlled trials including patients with HR+/HER2- EBC treated with CDK4/6is plus ET versus ET alone in the adjuvant setting were included. Pooled hazard ratios (HRs) and odds ratios (ORs) for survival and safety outcomes, respectively, were calculated with 95% confidence intervals (95% CIs) using random effect models.ResultsWith data available from three studies (N = 12 647), the addition of CDK4/6is to adjuvant ET showed a trend for a benefit in terms of invasive disease-free survival (IDFS; HR 0.85, 95% CI 0.71-1.01; P = 0.071). No significant improvement in distant relapse-free survival was observed (HR 0.83, 95% CI 0.58-1.19; P = 0.311). The risk of all-grade toxicities and early treatment discontinuation increased significantly with the addition of CDK4/6is to ET (OR 9.36, 95% CI 3.46-25.33, P < 0.001, and OR 22.11, 95% CI 9.45-51.69, P < 0.001, respectively).ConclusionThe administration of adjuvant CDK4/6is to patients with HR+/HER2- EBC showed a trend for an IDFS benefit and an increase in the risk of toxicities and treatment discontinuation. The role of adjuvant CDK4/6is remains controversial and a longer follow-up of these randomized controlled trials is needed before supporting a straightforward change in clinical practice.

Project description:BackgroundCyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups.MethodsWe conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I2statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP).ResultsSix studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I2 = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I2 = 0.0%).ConclusionsCDK4/6-inhibitors + ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.

Dataset Information

The CDK4/6 inhibitor in HR-positive advanced breast cancer: A systematic review and meta-analysis.

Publications

The CDK4/6 inhibitor in HR-positive advanced breast cancer: A systematic review and meta-analysis.

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