Combination of trastuzumab emtansine and stereotactic radiosurgery results in high rates of clinically significant radionecrosis and dysregulation of Aquaporin-4
| Autor: | Tyler P. Robin, Laurie E. Gaspar, Diana M. Cittelly, Peter Kabos, Christine M. Fisher, Steven Lai, Brian D. Kavanagh, Chad G. Rusthoven, Kelly Stuhr, Rachel Rabinovitch, Priscilla K. Stumpf, D. Ryan Ormond, Arthur K. Liu, Jennifer R. Diamond, Maria J. Contreras-Zarate, Julie A. Carlson |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Oncology
musculoskeletal diseases Adult Cancer Research medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Receptor ErbB-2 medicine.medical_treatment Breast Neoplasms Ado-Trastuzumab Emtansine Radiosurgery Article 03 medical and health sciences chemistry.chemical_compound Necrosis 0302 clinical medicine Breast cancer Antineoplastic Agents Immunological Internal medicine parasitic diseases medicine Humans Prospective cohort study Aged Aquaporin 4 medicine.diagnostic_test business.industry Brain Neoplasms Incidence (epidemiology) Magnetic resonance imaging Middle Aged medicine.disease Combined Modality Therapy Magnetic Resonance Imaging Gene Expression Regulation Neoplastic Treatment Outcome chemistry Trastuzumab emtansine 030220 oncology & carcinogenesis Toxicity Cohort Female business 030217 neurology & neurosurgery |
| Zdroj: | Clin Cancer Res |
| Popis: | Purpose: Patients with human EGFR2-positive (HER2+) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity. Experimental Design: Patients with breast cancer who were ≤45 years regardless of HER2 status or had HER2+ disease regardless of age and underwent SRS for brain metastases were included. Rates of CSRN, SRS data, and details of T-DM1 administration were recorded. Proliferation and astrocytic swelling studies were performed to elucidate mechanisms of toxicity. Results: A total of 45 patients were identified; 66.7% were HER2+, and 60.0% were ≤ 45 years old. Of the entire cohort, 10 patients (22.2%) developed CSRN, 9 of whom received T-DM1. CSRN was observed in 39.1% of patients who received T-DM1 versus 4.5% of patients who did not. Receipt of T-DM1 was associated with a 13.5-fold (P = 0.02) increase in CSRN. Mechanistically, T-DM1 targeted reactive astrocytes and increased radiation-induced cytotoxicity and astrocytic swelling via upregulation of Aquaporin-4 (Aqp4). Conclusions: The strong correlation between development of CSRN after SRS and T-DM1 warrants prospective studies controlling for variations in timing of T-DM1 and radiation dosing to further stratify risk of CSRN and mitigate toxicity. Until such studies are completed, we advise caution in the combination of SRS and T-DM1. |
| Databáze: | OpenAIRE |
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