Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4

Clin Cancer Res. 2019 Jul 1;25(13):3946-3953. doi: 10.1158/1078-0432.CCR-18-2851. Epub 2019 Apr 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Ado-Trastuzumab Emtansine / administration & dosage
  • Ado-Trastuzumab Emtansine / adverse effects
  • Ado-Trastuzumab Emtansine / therapeutic use*
  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / administration & dosage
  • Antineoplastic Agents, Immunological / adverse effects
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Aquaporin 4 / genetics*
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / secondary
  • Brain Neoplasms / therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Combined Modality Therapy
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Gene Expression Regulation, Neoplastic / radiation effects*
  • Humans
  • Magnetic Resonance Imaging
  • Middle Aged
  • Necrosis / radiotherapy*
  • Radiosurgery* / methods
  • Receptor, ErbB-2 / metabolism
  • Treatment Outcome


  • Antineoplastic Agents, Immunological
  • Aquaporin 4
  • Receptor, ErbB-2
  • Ado-Trastuzumab Emtansine