title: What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC).
abstract: 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).
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Department of Medicine, Weill Cornell Medical College, New York.
authors.forename: A
authors.initials: A
authors.lastname: Drilon
authors.affiliation: Ignyta, San Diego.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pathology.
authors.forename: S
authors.initials: S
authors.lastname: Dogan
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Department of Medicine, Weill Cornell Medical College, New York.
authors.forename: M
authors.initials: M
authors.lastname: Gounder
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: R
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Pathology.
authors.forename: M
authors.initials: M
authors.lastname: Arcila
authors.affiliation: Department of Pathology.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Department of Medicine, Weill Cornell Medical College, New York.
authors.forename: D M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Department of Pathology.
authors.forename: J
authors.initials: J
authors.lastname: Hechtman
authors.affiliation: Ignyta, San Diego.
authors.forename: G
authors.initials: G
authors.lastname: Wei
authors.affiliation: Ignyta, San Diego.
authors.forename: N R
authors.initials: NR
authors.lastname: Cam
authors.affiliation: Ignyta, San Diego.
authors.forename: J
authors.initials: J
authors.lastname: Christiansen
authors.affiliation: Ignyta, San Diego.
authors.forename: D
authors.initials: D
authors.lastname: Luo
authors.affiliation: Ignyta, San Diego.
authors.forename: E C
authors.initials: EC
authors.lastname: Maneval
authors.affiliation: Drug Development Program, Sarah Cannon Research Institute, Nashville.
authors.forename: T
authors.initials: T
authors.lastname: Bauer
authors.affiliation: Department of Drug Development, Florida Cancer Specialists, Sarasota.
authors.forename: M
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Medicine, Georgetown University, Washington.
authors.forename: S V
authors.initials: SV
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of California Irvine School of Medicine, Orange.
authors.forename: S H I
authors.initials: SH
authors.lastname: Ou
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, USA.
authors.forename: A
authors.initials: A
authors.lastname: Farago
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shaw
authors.affiliation: Ignyta, San Diego.
authors.forename: R F
authors.initials: RF
authors.lastname: Shoemaker
authors.affiliation: Ignyta, San Diego.
authors.forename: J
authors.initials: J
authors.lastname: Lim
authors.affiliation: Ignyta, San Diego.
authors.forename: Z
authors.initials: Z
authors.lastname: Hornby
authors.affiliation: Ignyta, San Diego.
authors.forename: P
authors.initials: P
authors.lastname: Multani
authors.affiliation: Department of Pathology.
authors.forename: M
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Pathology.
authors.forename: M
authors.initials: M
authors.lastname: Berger
authors.affiliation: Department of Pathology.
authors.forename: N
authors.initials: N
authors.lastname: Katabi
authors.affiliation: Department of Pathology.
authors.forename: R
authors.initials: R
authors.lastname: Ghossein
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York Department of Medicine, Weill Cornell Medical College, New York hoa@mskcc.org.
authors.forename: A L
authors.initials: AL
authors.lastname: Ho
mesh_terms: D000328:Adult; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics; D018267:Carcinoma, Acinar Cell / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002986:Clinical Trials as Topic; D000077547:Crizotinib; D003937:Diagnosis, Differential; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007191:Indazoles / Q000008:administration & dosage* / Q000009:adverse effects; D000069295:Mammary Analogue Secretory Carcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D012468:Salivary Gland Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D001549:Benzamides; D014408:Biomarkers, Tumor; D000077547:Crizotinib; D007191:Indazoles; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011725:Pyridines; C484319:ETV6-NTRK3 fusion protein, human; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein; C000607349:entrectinib
keywords: ETV6-NTRK3; TrkC; entrectinib; mammary analogue secretory carcinoma