crizotinib and Salivary-Gland-Neoplasms

Salivary gland secretory carcinoma is usually a low-grade neoplasm. However, high-grade transformation can occur and has important implications for clinical outcome.. A patient presented with an enlarging buccal mass. Magnetic resonance imaging (MRI) showed a tumor with a biphasic appearance along the right parotid duct. Local excision and histopathologic examination confirmed the diagnosis of secretory carcinoma with high-grade transformation. ETV6-NTRK3 translocation and loss of CDKN2A/B were identified.. The patient subsequently presented with cough and dyspnea and was found to have pleural metastases. Carboplatin and paclitaxel exacerbated the symptoms. Crizotinib resulted in initial symptomatic and radiographic improvement; however, the patient soon succumbed to progressive intrathoracic disease.. High-grade salivary gland secretory carcinoma can have a biphasic appearance on MRI. Diagnosis is confirmed by the histologic appearance and associated ETV6-NTRK3 fusion. Additional molecular genetic events leading to transformation are unknown; however, loss of CDKN2A/B may have contributed. Treatment with multimodal chemotherapy was of limited benefit.

Topics: Adenocarcinoma, Clear Cell; Adult; Antineoplastic Combined Chemotherapy Protocols; Crizotinib; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; Diagnosis, Differential; Disease Progression; Drug Resistance, Neoplasm; Fatal Outcome; Gene Rearrangement; Humans; Immunohistochemistry; Magnetic Resonance Imaging; Male; Mammary Analogue Secretory Carcinoma; Myoepithelioma; Oncogene Proteins, Fusion; Parotid Gland; Pleural Neoplasms; Pyrazoles; Pyridines; Salivary Gland Neoplasms; Translocation, Genetic; Treatment Outcome

Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion.. This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions.. A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays.. This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).

Topics: Adult; Benzamides; Biomarkers, Tumor; Carcinoma, Acinar Cell; Clinical Trials as Topic; Crizotinib; Diagnosis, Differential; Drug Resistance, Neoplasm; Female; Humans; In Situ Hybridization, Fluorescence; Indazoles; Mammary Analogue Secretory Carcinoma; Mutation; Oncogene Proteins, Fusion; Pyrazoles; Pyridines; Salivary Gland Neoplasms