Activating NOTCH1 Mutations Identify Poor-Prognostic Subgroup With Adenoid Cystic Carcinoma


Key Points

  • Activating NOTCH1 mutations were identified in a substantial subgroup of patients with adenoid cystic carcinomas.
  • The mutations were associated with a solid subtype, advanced stage at diagnosis, higher rate of liver and bone metastasis, and shorter relapse-free and overall survival.

In a study reported in the Journal of Clinical Oncology, Ferrarotto et al found that the presence of activating NOTCH1 mutations defined a subgroup of patients with adenoid cystic carcinomas with an aggressive phenotype.

Frequency of Mutations

The study included genotyping of 102 adenoid cystic carcinomas with available pathologic and clinical data.

A total of 18 NOTCH1 mutations were identified in 15 tumors, with 2 patients having more than 1 mutation. Of these mutations, 17 in 14 patients (13.7% of the entire group) were found in T-cell acute lymphoblastic leukemia hotspots (negative regulatory region and Pro-Glu-Ser-Thr–rich domains), indicating they were gain-of-function mutations. The NOTCH1-mutant tumors showed higher levels of Notch1 pathway activation vs wild-type tumors, as assessed by Notch1 intracellular domain staining (P = .004).

Aggressive Phenotype

The presence of NOTCH1 mutations defined an aggressive adenoid cystic carcinoma subgroup with a higher likelihood of a solid subtype (P < .001), advanced stage at diagnosis (P = .02), higher rate of liver and bone metastasis (P ≤ .02), shorter median relapse-free survival (13 vs 34 months, P = .01), and shorter median overall survival (30 vs 122 months, P = .001) vs NOTCH1 wild-type tumors.

Effect of Notch1 Inhibitor

Evaluation of the Notch1 inhibitor brontictuzumab in patient-derived xenografts from patients with adenoid cystic carcinomas showed that the agent produced marked tumor growth inhibition only in xenografts with a NOTCH1-activating mutation. Brontictuzmab treatment in one patient with NOTCH1-mutant adenoid cystic carcinoma from a phase I study resulted in a partial response.

The investigators concluded: “NOTCH1 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 [adenoid cystic carcinomas] subgroup are warranted.”

The study was supported by the Ryan W. Smith Endowed Fund for Adenoid Cystic Carcinoma, the Adenoid Cystic Carcinoma Research Foundation, the National Cancer Institute, the National Institutes of Health, and a Conquer Cancer Foundation award.

Renata Ferrarotto, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.