Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors

Abstract

PurposeAdenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with a subset demonstrating an aggressive phenotype. We investigated the molecular underpinnings of this phenotype and assessed the Notch1 pathway as a potential therapeutic target.MethodsWe genotyped 102 ACCs that had available pathologic and clinical data. Notch1 activation was assessed by immunohistochemistry for Notch1 intracellular domain. Luciferase reporter assays were used to confirm Notch1 target gene expression in vitro. The Notch1 inhibitor brontictuzumab was tested in patient-derived xenografts from patients with ACC and in a patient with ACC who was enrolled in a phase I study.ResultsNOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr–rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro. NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining (P = .004). NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype (P < .001), advanced-stage disease at diagnosis (P = .02), higher rate of liver and bone metastasis (P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors. Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation. Furthermore, an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab.ConclusionNOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors. Clinical studies targeting Notch1 in a genotype-defined ACC subgroup are warranted.

A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma

“…This is in contrast to the presence of mutations in histone methyltransferases (KMT2E and KMT2A), bromodomain containing proteins (BRD1 and BRD3), and members of the SWI/SNF chromatin regulator family (SMARCA2) in responders. However, this non-responder patient (003–027) had an activating NOTCH1 mutation, suggesting that it could be the driving mutation in this case, as activating NOTCH1 mutations have been shown to confer a worse prognosis [51]. The presence of a well-characterized activating mutation in NOTCH1 confirms the role of this signaling pathway in ACC and may provide a therapeutic window in future studies.…”

Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma

“…Further work is needed to determine the value of NICD1 staining in the differential diagnosis of epithelial neoplasms. The association of diffuse NICD1 staining and worse outcome also suggests that NICD1 staining is a useful prognostic marker for ACC, an idea that is reinforced by a recent report showing that NOTCH1 mutations are associated with worse outcome in ACC patients (26). Finally, clinical trials of several Notch pathway inhibitors are underway in patients with relapsed/refractory ACC.…”

Phase II trial with axitinib in recurrent and/or metastatic salivary gland cancers of the upper aerodigestive tract

“…23 In most cases, NOTCH1 mutations are activating, similar to what observed also in T-cell acute lymphoblastic leukemia. 5 NOTCH mutations bear a poor prognosis behavior in patients with ACC, 25 whereas no data on its prognostic role in non-ACC histotypes are available. 5 NOTCH mutations bear a poor prognosis behavior in patients with ACC, 25 whereas no data on its prognostic role in non-ACC histotypes are available.…”