ABSTRACT
BACKGROUND: Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. PATIENTS AND METHODS: This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. RESULTS: Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). CONCLUSIONS: Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.
Subject(s)
Carcinoma, Adenoid Cystic/drug therapy , Imidazoles/administration & dosage , Indazoles/administration & dosage , NFI Transcription Factors/genetics , Protein Kinase Inhibitors/administration & dosage , Proto-Oncogene Proteins c-myb/genetics , Adult , Aged , Axitinib , Carcinoma, Adenoid Cystic/genetics , Carcinoma, Adenoid Cystic/pathology , Chromosomes, Human, Pair 4/genetics , Disease-Free Survival , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions , Female , High-Throughput Nucleotide Sequencing , Humans , Imidazoles/adverse effects , Indazoles/adverse effects , Male , Middle Aged , Oncogene Proteins, Fusion/genetics , Protein Kinase Inhibitors/adverse effectsABSTRACT
Ménétrier disease is a rare hypertrophic gastropathy that is characterized by hyperplasia of the mucous cells with concurrent loss of chief and parietal cells within the gastric glands. There are few reports of this disease in dogs, and little is known about the clinical presentation and progression of canine Ménétrier disease. Three Cairn terrier littermates developed hypertrophic gastropathy with histological features of Ménétrier disease. One dog remained clinically asymptomatic for 2 years after diagnosis. The development of this disease in 3 siblings suggests a possible inherited predisposition. All 3 dogs also developed gastric neoplasia, which has been reported in human Ménétrier disease but has not been associated previously with hypertrophic gastropathy in domestic species.