Intrathecal trastuzumab versus alternate routes of delivery for HER2-targeted therapies in patients with HER2+ breast cancer leptomeningeal metastases
Anna-Maria Lazaratos,
Sarah M. Maritan,
Andrea Quaiattini,
Amelie Darlix,
Ivica Ratosa,
Emanuela Ferraro,
Gaia Griguolo,
Valentina Guarneri,
Alessia Pellerino,
Silvia Hofer,
William Jacot,
Hans-Joachim Stemmler,
Marcel P.H. van den Broek,
Nika Dobnikar,
Francois Panet,
Zubin Lahijanian,
Aki Morikawa,
Andrew D. Seidman,
Riccardo Soffietti,
Lawrence Panasci,
Kevin Petrecca,
April A.N. Rose,
Nathaniel Bouganim,
Matthew Dankner
Affiliations
Anna-Maria Lazaratos
Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada; Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
Sarah M. Maritan
Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada; Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
Andrea Quaiattini
Schulich Library of Physical Sciences, Life Sciences, and Engineering, McGill University, Montreal, Quebec, Canada
Amelie Darlix
Department of Medical Oncology, Institut régional du Cancer de Montpellier, University of Montpellier, Montpellier, France; Institut de Génomique Fonctionnelle, INSERM, CNRS, University of Montpellier, Montpellier, France
Ivica Ratosa
Division of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Emanuela Ferraro
Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NewYork, USA
Gaia Griguolo
Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
Valentina Guarneri
Division of Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
Alessia Pellerino
Division of Neuro-Oncology, Department of Neuroscience, University and City of Health and Science Hospital, Turin, Italy
Silvia Hofer
Department of Neurology, University Hospital Zurich, Switzerland
William Jacot
Department of Medical Oncology, Institut régional du Cancer de Montpellier, University of Montpellier, Montpellier, France
Hans-Joachim Stemmler
Medical Dept. III, Ludwig Maximilians University Munich, Munchen, Germany
Marcel P.H. van den Broek
Clinical Pharmacy, Sint Antonius Hospital, Nieuwegein, the Netherlands
Nika Dobnikar
Division of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia
Francois Panet
Gerald Bronfman Department of Oncology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
Zubin Lahijanian
Department of Diagnostic Radiology, McGill University, Montreal, Quebec, Canada
Aki Morikawa
Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NewYork, USA
Andrew D. Seidman
Breast Cancer Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, NewYork, USA
Riccardo Soffietti
Division of Neuro-Oncology, Department of Neuroscience, University and City of Health and Science Hospital, Turin, Italy
Lawrence Panasci
Gerald Bronfman Department of Oncology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
Kevin Petrecca
Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
April A.N. Rose
Gerald Bronfman Department of Oncology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
Nathaniel Bouganim
Gerald Bronfman Department of Oncology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada; McGill University Health Centre, McGill University, Montreal, Quebec, Canada
Matthew Dankner
Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada; Faculty of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada; Corresponding author. Rosalind and Morris Goodman Cancer Institute 1160 Pine Avenue West, Rm 508 Montreal, QC, H3A 1A3, Canada.
Background: Patients with HER2+ breast cancer (BC) frequently develop leptomeningeal metastases (LM). While HER2-targeted therapies have demonstrated efficacy in the neoadjuvant, adjuvant, and metastatic settings, including for parenchymal brain metastases, their efficacy for patients with LM has not been studied in a randomized controlled trial. However, several single-armed prospective studies, case series and case reports have studied oral, intravenous, or intrathecally administered HER2-targeted therapy regimens for patients with HER2+ BC LM. Methods: We conducted a systematic review and meta-analysis of individual patient data to evaluate the efficacy of HER2-targeted therapies in HER2+ BC LM in accordance with PRISMA guidelines. Targeted therapies evaluated were trastuzumab (intrathecal or intravenous), pertuzumab, lapatinib, neratinib, tucatinib, trastuzumab-emtansine and trastuzumab-deruxtecan. The primary endpoint was overall survival (OS), with CNS-specific progression-free survival (PFS) as a secondary endpoint. Results: 7780 abstracts were screened, identifying 45 publications with 208 patients, corresponding to 275 lines of HER2-targeted therapy for BC LM which met inclusion criteria. In univariable and multivariable analyses, we observed no significant difference in OS and CNS-specific PFS between intrathecal trastuzumab compared to oral or intravenous administration of HER2-targeted therapy. Anti-HER2 monoclonal antibody-based regimens did not demonstrate superiority over HER2 tyrosine kinase inhibitors. In a cohort of 15 patients, treatment with trastuzumab-deruxtecan was associated with prolonged OS compared to other HER2-targeted therapies and compared to trastuzumab-emtansine. Conclusions: The results of this meta-analysis, comprising the limited data available, suggest that intrathecal administration of HER2-targeted therapy for patients with HER2+ BC LM confers no additional benefit over oral and/or IV treatment regimens. Although the number of patients receiving trastuzumab deruxtecan in this cohort is small, this novel agent offers promise for this patient population and requires further investigation in prospective studies.
