Detection of Novel Actionable Genetic Changes in Salivary Duct Carcinoma Helps Direct Patient Treatment

Abstract

Purpose: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland cancers for which cytotoxic chemotherapy has limited efficacy. We investigated whether genotyping analysis could detect novel tumor-specific mutations that would help direct SDC patient treatment using targeted agents.Experimental Design: We genotyped 27 SDC archival specimens from patients followed at Massachusetts General Hospital and Massachusetts Eye and Ear Infirmary (Boston, MA) between 2000 and 2011. These included the tumors of 8 patients who were tested prospectively. Targeted mutational analysis of 13 clinically relevant cancer genes was conducted using SNaPshot multiplexed genotyping. FISH was conducted to detect HER2 gene amplification. Patient medical records and tumor histopathologic features were retrospectively reviewed.Results: Mutually exclusive genetic aberrations were detected in 15 of 27 (56%) tumors, including 2 (7%) mutations in BRAF, 5 (19%) mutations in PIK3CA, and 8 (30%) cases of HER2 gene amplification. To our knowledge, this is the first time that BRAF and PIK3CA mutations have been reported in this tumor type. Prospective clinical testing of 8 patients with SDC identified actionable genetic alterations in 6 tumors and influenced therapeutic decisions for all 6 patients.Conclusion: SNaPshot molecular profiling identified novel genetic changes in SDCs, expanded the therapeutic options for patients with this rare tumor, and is changing SDC management at our institution. These findings highlight the importance of using broad-based genetic profiling to expedite the identification of effective-targeted therapies for patients with rare malignancies. Clin Cancer Res; 19(2); 480-90. Ó2012 AACR.

First-Line Treatment of Widely Metastatic BRAF-Mutated Salivary Duct Carcinoma With Combined BRAF and MEK Inhibition

“…25 Another case reported on a series of patients with SDC whose tumors were analyzed using targeted mutational analysis, and described in detail one patient who harbored a BRAF V600E mutation. 26 That patient experienced disease progression after definitive concurrent chemoradiotherapy with weekly carboplatin and paclitaxel, and again after salvage chemotherapy with cyclophosphamide and doxorubicin. He was treated with an unidentified MEK inhibitor on study before disease progression, after which he was enrolled in a phase I trial of combined dabrafenib and trametinib.…”

Molecular Characterization of Apocrine Salivary Duct Carcinoma

“…SDCs are known to harbor genetic alterations in TP53, PTEN, CDKN2A/P16, 2 the Phosphoinositide 3-Kinase (PI3K) pathway, [9][10][11][12] PLAG1/HMGA2, 30 and ERBB2. 31 However, the relationship between these and other genetic alterations in SDC is not well understood, and translation to the clinical practice is limited.…”

“…[6][7][8] Recently, additional potentially targetable genetic abnormalities in SDC were identified, including mutations of the gene encoding the p110a catalytic subunit of phosphoinositide 3-kinase (PIK3CA), 9,10 PTEN deletion, 11 and occasional BRAF or ERBB2 (HER2) mutations. [12][13][14] Nonetheless, the prevalence of genetic changes in these and potentially other genes and the relationship between genetic changes and clinicopathologic features of SDC are unknown.…”

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

“…One of the most frequently altered pathways is the PI3K/AKT/mTOR pathway, with many SDC specimens showing mutations and copy number variations in PIK3CA , PTEN , RICTOR , AKT1 , AKT3 , and/or PIK3R1 [57–60]. As with other tumor types, TP53 mutations, HRAS/NRAS mutations and alterations in cyclin D1/CDK pathways are also found with relative frequency in SDC [4, 50, 57, 59, 61, 62].…”