Real-world survival benefit of glucagon-like peptide-1 receptor agonists (GLP-1 Ras) concomitant with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy in hormone receptor-positive (HR+)/HER2− metastatic breast cancer: A large propensity-matched analysis.
Abstract
1070 Background: Obesity increases hormone receptor-positive (HR+) breast cancer risk through adipose-derived estrogens and inflammation. In metastatic HR+/HER2- disease, endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is standard first-line therapy, improving survival. The widespread use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for diabetes and obesity management induces meaningful weight loss and may enhance ET efficacy by reducing body fat mass, which modulates estrogen levels and cancer-related inflammation, albeit their impact on mBC survival in patients receiving ET plus CDK4/6i remains unclear. Methods: Using the TriNetX Global Collaborative Network, we retrospectively identified two cohorts of patients with mBC receiving endocrine therapy (ET) plus a CDK4/6i: 26,689 patients treated with ET+CDK4/6i alone and 604 patients who also received a GLP-1 RA initiated within 3 months of CDK4/6i start. Propensity score matching (PSM) was applied to balance cohorts for age, race, body mass index, heart failure, hypertension, diabetes mellitus, fulvestrant use, and type of CDK4/6i. Overall survival (OS) was estimated using the Kaplan–Meier method, and hazard ratios (HRs) were calculated to compare OS between cohorts. Results: After PSM, 604 matched pairs of patients were identified in the ET plus CDK4/6i and GLP-1 RA groups, respectively (mean age +/- standard deviation:61.4 ±11.3 and 61.8 ±11.8 years), with well-balanced baseline characteristics. After a median follow-up of 18.8 months (interquartile range, IQR 27.9) in the non-exposed cohort and 15.8 months (IQR 24.5) in the non-exposure and in the exposure cohorts, median OS was 67,9 months among patients receiving GLP-1 RA compared with 49 months in those not receiving GLP-1 RA (HR 0.70; 95% CI,0.56–0.89; P=0.003), corresponding to a 30% reduction in the risk of death mortality risk. Conclusions: This is the largest real-world, propensity-matched analysis demonstrating a significant OS benefit with GLP-1 RAs added to ET+CDK4/6i in HR+/HER2− mBC. These provocative findings warrant prospective validation to elucidate underlying mechanisms—such as metabolic reprogramming or immune modulation—and explore GLP-1 RAs as a novel therapeutic strategy in this setting.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (20)
Michela Palleschi
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Caterina Gianni
Milena Urbini, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Thomas F. Eleveld, PhD, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Maurizio Polano, PhD, Experimental and Clinical Pharmacology Unit, IRCCS Centro di Riferimento Oncologico di Aviano (CRO), Aviano, Italy; Emanuela Scarpi, PhD, Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Cecilia Menna, MD, and Caterina Gianni, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Ferdinand W. Janssen, MSc, Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Giuseppe Schepisi, MD, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy; Giorgia Gurioli, PhD, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei ...
Filippo Merloni
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Alberto Farolfi
IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy
Giulia Miserocchi
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Nicola Gentili
9Instituto Romagnolo per lo Studio dei Tumori, Meldola, Italy
Marita Mariotti
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Giandomenico Di Menna
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Olga Serra
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Chiara Casadei
Francesca Rusconi
TriNetX Europe, Milan, Italy
Alice Andalò
9Instituto Romagnolo per lo Studio dei Tumori, Meldola, Italy
Simone Sabbioni
IRCCS Istituto Romagnolo per lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Andrea Carlini
IRCCS Istituto Romagnolo per lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Daniela Montanari
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Marianna Sirico
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Roberta Maltoni
Lorenzo Cecconetto
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
Samanta Sarti
IRCCS - Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy
Antonino Musolino
IRCCS Istituto Romagnolo per lo Studio Dei Tumori (IRST) "Dino Amadori", Meldola, Italy