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.

Significant and durable clinical benefit from trastuzumab in 2 patients with HER2‐amplified salivary gland cancer and a review of the literature

“…Studies of salivary duct carcinoma reported either HER2 amplification or mutations activating the MAPK pathway in most tumors, with NF1 mutations present in 16% to 17% of cases, suggesting that a subset of patients with salivary duct carcinoma may benefit from mitogen‐activated protein kinase inhibitors. Case 2 harbored both strong p16INK4a expression and CDK4 amplification; the cyclin pathway has been reported to be frequently altered in salivary gland cancer . Interestingly, p16INK4a overexpression is commonly seen in human papillomavirus–induced oropharyngeal squamous cell carcinoma, which presents in younger nonsmokers .…”

Genomic Landscape of Malignant Mesotheliomas

“…Molecular singletons as the norm are commonly reported in other cancers as well (44)(45)(46)(47)(48). Considering that effective therapies for mesothelioma are lacking (8)(9)(10)(11)(12), clinical trials for mesothelioma that incorporate molecular profiling for patient selection and appropriately customized therapy are warranted (49).…”

Salivary Gland Neoplasms: Does Morphological Diversity Reflect Tumor Heterogeneity

“…Using next-generation sequencing to study 117 different salivary gland tumors, it was found that the most common aberrations were in the TP53 gene, followed by the cyclin and PI3K pathways. More importantly, 91.5% of these patients had at least one aberration that was potentially targetable by an FDAapproved drug or an investigational agent in a clinical trial, showing that research on targeted therapies based on molecular profiling is worthwhile [81]. A study of 149 patients also had similar results, with further alterations in RAS, ERBB2, NOTCH1, NF1, and RET, showing diverse genetic alterations that may lead to novel treatment options [69].…”