Francesco Schettini1,2,3, Fabiola Giudici4, Mario Giuliano1,5, Massimo Cristofanilli6, Grazia Arpino1, Lucia Del Mastro7,8, Fabio Puglisi9,10, Sabino De Placido1, Ida Paris11, Pietro De Placido1, Sergio Venturini12,13, Michelino De Laurentis14, PierFranco Conte15,16, Dejan Juric17, Antonio Llombart-Cussac3,18, Lajos Pusztai19, Aleix Prat2,3,20, Guy Jerusalem21, Angelo Di Leo22, Daniele Generali23,24. 1. Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. 2. Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 3. SOLTI Breast Cancer Research Group, Barcelona, Spain. 4. Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy. 5. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA. 6. Northwestern University Clinical and Translational Sciences Institute (NUCATS), Northwestern University, Chicago, IL, USA. 7. Ospedale Policlinico San Martino-IRCCS, Genova, Italy. 8. Department of Internal Medicine, University of Genova, Genova, Italy. 9. Department of Medicine, University of Udine, Udine, Italy. 10. IRCCS Centro di Riferimento Oncologico Aviano-National Cancer Institute, Aviano, PN, Italy. 11. Division of Gynecologic Oncology, Department of Women's and Children's Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. 12. Department of Management, University of Turin, Turin, Italy. 13. Centre for Research on Health and Social Care Management (CERGAS), SDA Bocconi School of Management, Milan, Italy. 14. Breast Unit, Istituto Nazionale Tumori Fondazione "G. Pascale", Naples, Italy. 15. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. 16. Division of Medical Oncology 2, Istituto Oncologico Veneto-IRCCSS, Padova, Italy. 17. Massachusetts General Hospital Cancer Center, Boston, MA, USA. 18. Department of Medical Oncology, Hospital Arnau de Vilanova, Valencia, Spain. 19. Department of Internal Medicine, Section of Medical Oncology, Yale, Cancer Centre, Yale University, School of Medicine, New Haven, CT, USA. 20. Department of Medical Oncology, Hospital Clínic, Barcelona, Spain. 21. Centre Hospitalier Universitaire de Liège and Liège University, Liège, Belgium. 22. "Sandro Pitigliani" Medical Oncology Department, Hospital of Prato, Prato, Italy. 23. Department of Medical, Surgery and Health Sciences, University of Trieste, Trieste, Italy. 24. Breast Cancer Unit, Azienda Socio, Sanitaria Territoriale di Cremona, Cremona, Italy.
Abstract
BACKGROUND: Cyclin-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. METHODS: We 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). RESULTS: Six 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%). CONCLUSIONS: CDK4/6-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.
BACKGROUND: Cyclin-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. METHODS: We 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). RESULTS: Six 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%). CONCLUSIONS:CDK4/6-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.
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