NOTCH1 activating variants identify a high-risk subgroup of adenoid cystic carcinoma in a nationwide Japanese cohort

Abstract

Adenoid cystic carcinoma (ACC) follows a heterogeneous clinical course, and because systemic therapies have limited efficacy, active surveillance is offered to selected patients, yet no validated molecular biomarker guides the choice between surveillance and intensive treatment. We retrospectively analyzed comprehensive genomic profiling (CGP) and clinical data from 584 patients with ACC (491 head and neck, 93 other sites) in the nationwide Japanese C-CAT database (August 2019–October 2025). NOTCH1 variants were classified as activating (heterodimerization-domain missense or PEST-domain truncating) or non-activating, and overall survival was assessed in 213 patients using Kaplan–Meier estimates, multivariable Cox regression, and propensity-score matching. Activating NOTCH1 variants occurred in 15.5% of survival-evaluable cases and conferred markedly inferior survival (median 20.9 versus 64.7 versus 86.0 months for activating, non-activating, and wild-type). The effect was independent of age, sex, stage, and tumor mutational burden (adjusted hazard ratio 3.93, 95% confidence interval 2.18–7.09) and was confirmed by propensity-score matching. Actionable ERBB2 alterations occurred in 3.1% of patients. CGP therefore delineates clinically distinct ACC subgroups: activating NOTCH1 variants identify one in six patients for whom active surveillance may be inappropriate, and a small subset is eligible for HER2-directed therapy.