Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 13, Pages 3946-3953Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-2851
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Funding
- NCI [P30CA046934]
- CTSA Center grants [UL1TR001082]
- Cancer League of Colorado
- DoD BCRP [W81XWH-19-1-0033, W81XWH-15-1-0352]
- [R37 CA227984]
- [R01CA205044]
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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.
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