Advanced acinic cell carcinoma harbors kinase rearrangements including BRAF kinase domain duplications

Abstract

Background: A subset of patients with acinic cell carcinoma (AcCC), a typically indolent tumor arising from the exocrine cells of salivary glands, will experience substantial morbidity and mortality from recurrent and metastatic disease. No consensus guidelines exist for management of advanced AcCC. Methods: 72 advanced AcCC cases were assayed with hybrid-capture based comprehensive genomic profiling (CGP) in the course of clinical care to identify genomic alterations (GA) suggesting benefit from targeted therapy. Results: 61 (85%) of AcCC had at least one GA (mean 2.1 GA per case), and clinically relevant genomic alterations (CRGA) were identified in 27 (38%) AcCC cases. The genes most commonly altered were CDKN2A (60%), PTEN (8%), and TP53 (7%). Other genes altered at 4% or less included FBXW7, ATM1, NF1 and BRAF. GAs affecting the PI3K/AKT/mTOR pathway (PTEN, PIK3CA, FBXW7) were present in 15% of cases, and no other signaling pathways were repeatedly perturbed. Of three BRAF altered cases (4%), one harbored a V600E mutation and two harbored BRAF kinase domain duplications (KDD), with one of the latter patients having a >6 month dramatic response to the promiscuous RAF inhibitor regorafenib. Three cases (4%), all of parotid origin, harbored ETV6-NTRK3 fusions. One patient responded to entrectinib (Drillon et al 2016), and another has been enrolled in a trial for investigational inhibitor. Conclusions: Advanced AcCC is the first tumor type to be identified as harboring recurrent BRAF KDD, which is associated with clinical benefit from regorafenib. Moreover, detection of ETV6-NTRK3 in these cases is widely interpreted as a diagnostic of mammary analogue secretory carcinoma (MASC) with such patients predicted to benefit from NTRK inhibitors. Further investigations including RNA-sequencing are underway to define additional targetable oncogenic drivers in advanced AcCC cases not harboring the above alterations.