Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma (ACC) with NOTCH signaling pathway activation.
Authors: Hapuarachi Brindley Sonal , Feeney Laura , Rack Sam , Adderley Helen , Morgan David , Betts Guy , Walker Russell , Rauch Rami , Herz Elad , Harrington Kevin Joseph , Metcalf Robert 
Published: June 2021

6072

Background: ACC is a rare salivary cancer for which effective drug therapies remain lacking. The highest rates of disease recurrence are in patients with NOTCH pathway activation, which is reported in 10-20% of ACC tumors. Novel drugs targeting NOTCH signaling are under investigation in the recurrent and metastatic setting. To understand their clinical utility, there is an urgent need to better characterize the disease course and outcomes following current standard of care treatment from diagnosis and following recurrence. Methods: 120 patients with ACC underwent clinical review at a single UK Cancer Centre from 2017-19. Patients were retrospectively assessed for tumor NOTCH pathway activation using next generation sequencing (NGS) targeting NOTCH1/2/3 genes (n = 98) and/or by immunohistochemistry (IHC) for the NOTCH1 intra-cellular domain (NICD1) (n = 87). To understand the disease course with NOTCH pathway activation, treatment data including surgery, radiotherapy and systemic therapies were extracted and presented as swimmer plots. Kaplan-Meier survival analysis was performed and a difference in survival with/without NOTCH activation was calculated with log rank test. Overall survival (OS) was calculated both from diagnosis and from first confirmed disease recurrence or metastasis, and recurrence free survival (RFS) calculated from diagnosis. Results: Of 120 patients, median age was 46 years (22-74 years). 114/120 patients (95%) had confirmed disease recurrence at clinical review. The primary site was major salivary gland in 58/120 (48%), the others were minor salivary. NOTCH1/3 activating somatic mutations were identified in 11% by NGS (11/98) and NICD1 diffuse nuclear staining was seen in 6% by IHC (5/87) for overall NOTCH activation in 11% (13/120). In NOTCH activated ACC, primary site was major salivary gland in 7/13 (54%), and non-pulmonary visceral/bone metastases were present in 6/13 (46%). Consistent with other reports, patients with NOTCH activation (n = 13) had shorter RFS (0.9 vs 3.6 years, p = 0.11) and significantly reduced OS from diagnosis (4.0 vs 16.3 years, p < 0.0001). Critically, as therapies targeting NOTCH signaling are being evaluated in recurrent/metastatic ACC, there was significantly reduced OS from time of first confirmed disease recurrence or metastasis (1.5 vs 9.6 years, p < 0.0001). This reduction in OS for NOTCH activation following recurrence was seen consistently whether patients were classified using NGS (1.9 vs 9.6 years, p = 0.0009) or NICD1 IHC (0.8 vs 8.5 years, p < 0.0001). Conclusions: This is the first study to report clinical outcomes for patients with NOTCH pathway activated ACC following disease recurrence. Although ACC is frequently considered an indolent disease, the short survival in this sub-group of ACC patients demonstrates the urgent need to develop effective drug therapies in this setting.