Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022

Abstract

Purpose: This pilot study was performed to test our ability to administer neratinib monotherapy before clinically recommended craniotomy in patients with HER2-positive metastatic breast cancer to the central nervous system, to examine neratinib's central nervous system penetration at craniotomy, and to examine postoperative neratinib maintenance.

Patients and methods: Patients with HER2-positive brain metastases undergoing clinically indicated cranial resection of a parenchymal tumor received neratinib 240 mg orally once a day for 7 to 21 days preoperatively, and resumed therapy postoperatively in 28-day cycles. Exploratory evaluations of time to disease progression, survival, and correlative tissue, cerebrospinal fluid (CSF), and blood-based analyses examining neratinib concentrations were planned. The study was registered at ClinicalTrials.gov under number NCT01494662.

Results: We enrolled 5 patients between May 22, 2013, and October 18, 2016. As of March 1, 2019, patients had remained on the study protocol for 1 to 75+ postoperative cycles pf therapy. Two patients had grade 3 diarrhea. Evaluation of the CSF showed low concentrations of neratinib; nonetheless, 2 patients continued to receive therapy without disease progression for at least 13 cycles, with one on-study treatment lasting for nearly 6 years. Neratinib distribution in surgical tissue was variable for 1 patient, while specimens from 2 others did not produce conclusive results as a result of limited available samples.

Conclusion: Neratinib resulted in expected rates of diarrhea in this small cohort, with 2 of 5 patients receiving the study treatment for durable periods. Although logistically challenging, we were able to test a limited number of CSF- and parenchymal-based neratinib concentrations. Our findings from resected tumor tissue in one patient revealed heterogeneity in drug distribution and tumor histopathology.

Keywords: Central nervous system; Metastatic.

Figure 1.

Mass spectrometry analysis of neratinib distribution in a surgical specimen. A. MALDI 9.4 Tesla FT ICR MSI of heme distribution in red. B. Digital microscopy imaging of H&E staining of sister sections with drug distribution sampling location delineated as white circles. Each sampling location was analyzed directly by LESA MS/MS mass spectrometry for the drug neratinib fragment m/z 512.21 and drug concentrations were calculated from a standard curve. Sampling locations of approximately 1 mm diameter revealed heterogenous drug distribution associated with heterogenous histopathology features. More specifically, on the left panel, sampling location (1) revealed 533 ng/ml neratinib associated with mostly fibrous tissue and tumor surrounding the region, (2) showed 46 ng/ml in a fibrous and necrotic region, (3) 130 ng/ml with mostly fibrous tissue and scattered tumor cells, and (4) had 89 ng/ml with a cluster of tumor cells with surrounding fibrous tissue. A second section from the same specimen shown on the right panel showed a similar pattern with (4) 233 ng/ml neratinib associated with a mix of blood vessel, necrosis and some clusters of tumor cells, (3) 205 ng/ml with mostly a blood vessel and surrounding fibrous tissue with some neighboring tumor cells at the edge, (1) 48 ng/ml with a cluster of tumor cells with fibrous tissue and the edge of a blood vessel, and (2) 130 ng/ml with the highest percentage of tumor cells with some associated fibrosis.