entrectinib and Mammary-Analogue-Secretory-Carcinoma

NTRK gene fusions are found in <1% of all cancers but are uniformly present in mammary analog secretory carcinomas (MASC) of the salivary glands. Two selective histology-agnostic tropomyosin receptor kinase (TRK) inhibitors are currently approved for malignancies with these oncogenic fusions. Resistance to TRK inhibition has been recognized, and the mediating mechanisms are presently being studied. This report describes a patient diagnosed with an MASC of the parotid gland who after undergoing multiple lines of treatment was found to have an ETV6-NTRK3 fusion and initiated TRK-targeted therapy using entrectinib. Upon disease progression, we performed tumor genetic sequencing that showed a secondary resistance mutation. The patient subsequently responded to selitrectinib, a next-generation TRK inhibitor.

Topics: Aza Compounds; Benzamides; Drug Resistance, Neoplasm; Humans; Indazoles; Mammary Analogue Secretory Carcinoma; Oncogene Proteins, Fusion; Parotid Gland; Protein Kinase Inhibitors; Salivary Gland Neoplasms

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