‘NOTCH1 Mutations in Adenoid Cystic Carcinoma’ Dr. Ross O’Sheaw

Annual Grant Scheme 2021

Adenoid cystic carcinomas (ACC) are rare salivary gland neoplasms identified within the major and minor salivary glands, predominantly the parotid gland and palate. ACC account for approximately 10% of all salivary gland neoplasms. Interestingly, ACC can occur at other anatomic sites outside the head and neck region including within breast tissue and the prostate gland. There are numerous factors associated with poorer outcomes for patients with ACC including older age at diagnosis, higher tumour stage, skull-based disease and perineural invasion. Approximately 50% of patients develop recurrence of their cancer despite surgery, radiation and/or chemotherapeutic treatment. The disease specific survival at 5 years is 89% but falls to 40% at 15 years.

Utilisation of next generation sequencing has illustrated genetic alterations which permit identification of molecular pathways initiating and sustaining tumorigenesis. A recent publication in 2019 by Ho et al. illustrated that NOTCH1 mutations were the most prevalent somatic mutation in both the primary ACC tumour, as well as the recurrent or metastatic tumour. Armed with the knowledge that NOTCH1 mutations are associated with a poor prognosis, A phase I trial treating individuals with Brontictuzumab for recurrent or refractory solid tumours, showed efficacy for this monoclonal antibody targeting NOTCH1. A Phase II trial, the ACCURACY trial, examining the utilisation of a Notch inhibitor inpatients with recurrent and/or metastatic ACC is ongoing.

In summary, this will be the first study to identify the prevalence of NOTCH1 (and other) mutations in salivary gland neoplasms within an Irish cohort. With the known poor prognostic implications of this activating mutation, identifying patients with this mutation can assist in stratifying these individuals for potential future targeted studies.

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