Reference Detail

Ref Type Journal Article
PMID (26884591)
Authors Drilon A, Li G, Dogan S, Gounder M, Shen R, Arcila M, Wang L, Hyman DM, Hechtman J, Wei G, Cam NR, Christiansen J, Luo D, Maneval EC, Bauer T, Patel M, Liu SV, Ou SH, Farago A, Shaw A, Shoemaker RF, Lim J, Hornby Z, Multani P, Ladanyi M, Berger M, Katabi N, Ghossein R, Ho AL
Title What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC).
Journal Annals of oncology : official journal of the European Society for Medical Oncology
Vol 27
Issue 5
Date 2016 May
URL
Abstract Text 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).

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Molecular Profile Treatment Approach
ETV6-NTRK2 Trk Receptor Inhibitor (Pan)
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
ETV6 - NTRK1 fusion gain of function - predicted ETV6-NTRK1 results in the fusion of ETV6 and NTRK1 (PMID: 26884591). ETV6-NTRK1 has not been biochemically characterized, but is sensitive to Trk inhibition (PMID: 26884591), and therefore, is predicted to result in a gain of function.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6-NTRK3 Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK3 were sensitive to Entrectinib (RXDX-101) as demonstrated by reduced proliferation relative to cells expressing an empty vector in culture (PMID: 26884591). 26884591
ETV6-NTRK2 Advanced Solid Tumor sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK2 were sensitive to Entrectinib (RXDX-101) as demonstrated by reduced proliferation relative to cells expressing an empty vector in culture (PMID: 26884591). 26884591
ETV6-NTRK3 salivary gland cancer predicted - sensitive Crizotinib Case Reports/Case Series Actionable In a clinical case study, Xalkori (crizotinib) treatment resulted in a brief stable disease in a patient with mammary analogue secretory carcinoma of the salivary gland harboring ETV6-NTRK3, before disease progression at 18 weeks (PMID: 26884591). 26884591
ETV6-NTRK3 salivary gland cancer predicted - sensitive Entrectinib Case Reports/Case Series Actionable In a clinical case study, treatment with Entrectinib (RXDX-101) obtained through a Phase I trial resulted in a durable partial response in a patient with mammary analogue secretory carcinoma of the salivary gland harboring ETV6-NTRK3 (PMID: 26884591; NCT02097810). 26884591
ETV6-NTRK1 Advanced Solid Tumor predicted - sensitive Entrectinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing ETV6-NTRK1 were sensitive to Entrectinib (RXDX-101) as demonstrated by reduced proliferation relative to cells expressing an empty vector in culture (PMID: 26884591). 26884591