Survival Following CDK4/6 Inhibitor Therapy for Hormone Receptor–Positive, ERBB2–Negative Metastatic Breast Cancer
Authors: Berton Giachetti Pier Paolo Maria , Morganti Stefania , Gandini Sara , Giudici Fabiola , Marra Antonio , Nicolò Eleonora , Zattarin Emma , Corti Chiara , Boldrini Laura , Verrazzo Annarita , Sposetti Caterina , Razeti Maria Grazia , Carnevale Schianca Ambra , Scafetta Roberta , Taurelli Salimbeni Beatrice , Esposito Angela , Zagami Paola , Trapani Dario , Malagutti Bianca , Caputo Roberta , Vernieri Claudio , Munzone Elisabetta , Scagnoli Simone , Botticelli Andrea , Lambertini Matteo , Giuliano Mario , De Laurentiis Michelino , Viale Giulia , Bianchini Giampaolo , Curigliano Giuseppe , De Angelis Carmine , Criscitiello Carmen 
Published: February 2025

ImportanceEndocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) agents is the standard first-line treatment for patients with hormone receptor–positive, ERBB2 (formerly HER2 or HER2/neu)–negative metastatic breast cancer. However, optimal therapy after tumor progression to ET plus CDK4/6i remains unclear.ObjectiveTo evaluate progression-free survival (PFS) and overall survival (OS) in the clinical practice setting in patients with hormone receptor–positive, ERBB2–negative metastatic breast cancer following progression with ET plus CDK4/6i.Design, Setting, and ParticipantsThe multicenter retrospective cohort study included 506 patients diagnosed with hormone receptor–positive, ERBB2–negative metastatic breast cancer between April 22, 2015, and January 31, 2023, and who received ET-based or chemotherapy (CT)-based treatment following progression during ET plus CDK4/6i. Outcomes were analyzed based on treatment type, clinicopathologic features, and the duration of prior CDK4/6i therapy.Main Outcomes and MeasuresThe primary end point was PFS in the clinical practice setting, defined as the time between the initiation of the first systemic treatment on tumor progression to ET plus CDK4/6i treatment and the detection of disease progression or patient death from any cause. The secondary end point was OS in the clinical practice setting, defined as the time interval between tumor progression during ET plus CDK4/6i treatment and patient death from any cause.ResultsIn 506 women (median age at diagnosis, 52.4 [IQR, 44.6-62.8] years) diagnosed with hormone receptor-positive, ERBB2–negative metastatic breast cancer progressing during ET plus CDK4/6i, independent factors associated with poorer PFS outcomes were visceral metastases (hazard ratio [HR], 1.45; 95% CI, 1.17-1.80; P = .008) and de novo metastatic disease (HR, 1.25; 95% CI, 1.01-1.54; P = .04). A longer duration of CDK4/6i therapy (OS HR, 0.55; 95% CI, 0.41-0.73; P &amp;lt; .001) and an older age (PFS HR, 0.99; 95% CI 0.98-1.00; P = .03) were associated with better outcomes. Compared with oral CT, both intravenous CT- and ET-based treatments were associated with shorter PFS (intravenous CT: hazard ratio [HR], 1.45; 95% CI, 1.11-1.89; P = .006; everolimus plus exemestane: HR, 1.38; 95% CI, 1.06-1.78; P = .02; ET only: HR, 1.38; 95% CI, 1.05-1.89; P = .02). A duration of CDK4/6i treatment exceeding 12 months was associated with longer OS (HR, 0.55; 95% CI, 0.41-0.73; P &amp;lt; .001). Among patients with visceral metastases, intravenous CT was associated with shorter OS compared with oral CT (HR, 1.52; 95% CI, 1.03-2.24; P = .04).Conclusions and RelevanceIn this cohort study, the duration of tumor control achieved with CDK4/6i-based therapy and the presence of visceral metastases emerged as key factors that may affect treatment decision. Oral CT may offer potential benefits for specific patient subgroups.