CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials

• Published in: Breast cancer research and treatment 2018-11, Vol.172 (1), p.9-21
• Main Authors: Messina, Carlo, Cattrini, Carlo, Buzzatti, Giulia, Cerbone, Luigi, Zanardi, Elisa, Messina, Marco, Boccardo, Francesco
• Format: Article
• Language: English
• Subjects: Analysis; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer metastasis; Cancer research; Cancer therapies; Chemotherapy; Clinical trials; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - genetics; Drug therapy; Endocrine therapy; ErbB-2 protein; Female; Health risk assessment; Hormones; Humans; Medical schools; Medicine; Medicine & Public Health; Meta-analysis; Metastases; Metastasis; Neoplasm Metastasis; Neutropenia; Oncology; Progression-Free Survival; Protein Kinase Inhibitors - therapeutic use; Randomized Controlled Trials as Topic; Receptor, ErbB-2 - genetics; Receptors, Estrogen - genetics; Receptors, Progesterone - genetics; Review; Systematic review; Targeted cancer therapy
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-018-4901-0

Purpose Combining CDK4/6 inhibitors and endocrine therapy (ET) improved outcomes for the treatment of metastatic HR+/HER2− breast cancers. Here, we performed a meta-analysis of randomized clinical trials (RCTs) to better define the benefit and the risk of CDK4/6 inhibitors plus ET for endocrine-sensitive or endocrine-resistant population in metastatic HR+/HER2− breast cancer. Method A systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to 30 June 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS), as well as odds ratios (ORs) for objective response rates, ≥ G3–G4 adverse events (AEs), and G3–G4 neutropenia were calculated for each trial. A meta-analysis was carried out using the random-effects model. Results Eight RCTs were eligible including 4578 breast cancer patients. Adding CDK4/6 inhibitors to ET in endocrine-sensitive (HR 0.55, 95% CI 0.50–0.62) or endocrine-resistant setting (HR 0.51, 95% CI 0.43–0.61) significantly improved the PFS of metastatic HR+/HER2− breast cancers regardless of menopausal status and site of metastasis. Moreover, CDK4/6 inhibitors plus ET meaningfully improved objective response rate in endocrine-sensitive (ORs 0.62, 95% CI 0.52–0.73) or endocrine-resistant setting (ORs 0.33, 95% CI 0.24–0.47). The use of these drugs was characterized by a significant increase of G3–G4 AEs (OR 10.88, 95% CI 6.53–18.14). Conclusion Emerging data provide a new standard treatment for advanced HR+/HER2− breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities, and costs.