Genomic landscape of salivary gland tumors

Abstract

Effective treatment options for advanced salivary gland tumors are lacking. To better understand these tumors, we report their genomic landscape. We studied the molecular aberrations in 117 patients with salivary gland tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine, Cambridge, MA) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One, Inc. (Lexington, MA). There were 354 total aberrations, with 240 distinct aberrations identified in this patient population. Only 10 individuals (8.5%) had a molecular portfolio that was identical to any other patient (with four different portfolios amongst the ten patients). The most common abnormalities involved the TP53 gene (36/117 [30.8% of patients]), cyclin pathway (CCND1, CDK4/6 or CDKN2A/B) (31/117 [26.5%]) and PI3K pathway (PIK3CA, PIK3R1, PTEN or AKT1/3) (28/117 [23.9%]). In multivariate analysis, statistically significant co-existing aberrations were observed as follows: TP53 and ERBB2 (p = 0.01), cyclin pathway and MDM2 (p = 0.03), and PI3K pathway and HRAS (p = 0.0001). We were able to identify possible cognate targeted therapies in most of the patients (107/117 [91.5%]), including FDA-approved drugs in 80/117 [68.4%]. In conclusion, salivary gland tumors were characterized by multiple distinct aberrations that mostly differed from patient to patient. Significant associations between aberrations in TP53 and ERBB2, the cyclin pathway and MDM2, and HRAS and the PI3K pathway were identified. Most patients had actionable alterations. These results provide a framework for tailored combinations of matched therapies.

Keywords: genomic landscape; next-generation sequencing; personalized therapy; salivary gland tumor; targeted therapy.

Figure 1. Genetic aberrations in patients with all salivary gland tumors (N = 117). (A) adenoid cystic carcinoma (N = 49) (B) and in patients with adenocarcinoma, not otherwise specified (N = 46) (C)

Figure 1. Genetic aberrations in patients with all salivary gland tumors (N = 117). (A) adenoid cystic carcinoma (N = 49) (B) and in patients with adenocarcinoma, not otherwise specified (N = 46) (C)

Figure 2. Number of reported genetic aberrations and number of theoretically actionable genetic aberrations per patient

Of the 354 total aberrations (some aberrations may have been found in more than one person), 257 were actionable, with 107/117 of patients (91.5%) having a potentially actionable abnormality. Of the 240 distinct aberrations, 155 (64.6%) were potentially actionable. An aberration was considered potentially actionable if there is a drug that is approved or in clinical trials that targets that aberration with low nM IC50 or an antibody that primarily targets that abnormality.