Abstract
Breast cancer brain metastases are a deadly sequela of primary breast tumors that overexpress human epidermal growth factor receptor 2 (HER2); median survival for patients with these tumors is 10 to 13 months from the time of diagnosis. Current treatments for HER2-positive breast cancer brain metastases are invasive, toxic, and largely ineffective. Here, we have developed an adeno-associated virus serotype 9 (AAV9) vector to express the anti-HER2 monoclonal antibody trastuzumab (Herceptin) in vivo A single prophylactic intrathecal administration of AAV9.trastuzumab vector in a novel orthotopic Rag1-/- murine xenograft model of HER2-positive breast cancer brain metastases significantly increased median survival, attenuated brain tumor growth, and preserved both the HER2 antigen specificity and the natural killer cell-associated mechanism of action of trastuzumab. When administered as a tumor treatment, AAV9.trastuzumab increased median survival. Dose-escalation studies revealed that higher doses of AAV9.trastuzumab resulted in smaller tumor volumes. Our results indicate that intrathecal AAV9.trastuzumab may provide significant antitumor activity in patients with HER2-positive breast cancer brain metastases.Significance: Intrathecal delivery of trastuzumab via adeno-associated virus has the potential to become a novel, integral part of adjuvant therapy for patients with HER2-positive breast cancer brain metastases. Cancer Res; 78(21); 6171-82. ©2018 AACR.
Highlights
Breast cancer is the most commonly diagnosed malignancy in women in the United States with an estimated 268,670 new cases in 2018 [1]
We showed that trastuzumab expressed by central nervous system (CNS) cells still binds to human epidermal growth factor receptor 2 (HER2) on tumors and maintains the clinical product's principal mechanism of action against tumors: facilitating antibody-dependent cell-mediated cytotoxicity through natural killer (NK) cells
I.t. administration of trastuzumab has been reported to slow disease progression and prolong survival, the benefit is modest, likely due to the rapid turnover of cerebrospinal fluid (CSF) reported by others, resulting in poor tumor exposure to antibody
Summary
Breast cancer is the most commonly diagnosed malignancy in women in the United States with an estimated 268,670 new cases in 2018 [1]. About 30% of patients with metastatic HER2-positive (HER2þ) breast cancer will develop breast cancer brain metastases In the registHER prospective study of patients with newly diagnosed HER2þ metastatic breast cancer, 37.3% of the 1,012 patients studied developed brain metastases within 10.8 months of the initial diagnosis of metastatic disease [9]. The median age at diagnosis of HER2þ BCBM is 48 years [13], and the incidence of HER2þ BCBM is rising [4]. Evidence suggests that this increase is due to many
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