What hides behind the MASC: clinical response and acquired resistance to entrectinib after ETV6-NTRK3 identification in a mammary analogue secretory carcinoma (MASC)
A Drilon, G Li, S Dogan, M Gounder, R Shen, M Arcila, L Wang, D M Hyman, J Hechtman, G Wei, N R Cam, J Christiansen, D Luo, E C Maneval, T Bauer, M Patel, S V Liu, S H I Ou, A Farago, A Shaw, R F Shoemaker, J Lim, Z Hornby, P Multani, M Ladanyi, M Berger, N Katabi, R Ghossein, A L Ho, A Drilon, G Li, S Dogan, M Gounder, R Shen, M Arcila, L Wang, D M Hyman, J Hechtman, G Wei, N R Cam, J Christiansen, D Luo, E C Maneval, T Bauer, M Patel, S V Liu, S H I Ou, A Farago, A Shaw, R F Shoemaker, J Lim, Z Hornby, P Multani, M Ladanyi, M Berger, N Katabi, R Ghossein, A L Ho
Abstract
Background: 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.
Patients and methods: 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.
Results: 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.
Conclusions: 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).
Keywords: ETV6-NTRK3; TrkC; entrectinib; mammary analogue secretory carcinoma.
© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
Figures
References
- Skalova A, Vanecek T, Sima R et al. . Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity. Am J Surg Pathol 2010; 34: 599–608.
- Tognon C, Knezevich SR, Huntsman D et al. . Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2002; 2: 367–3376.
- Ito Y, Ishibashi K, Masaki A et al. . Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic and molecular study including 2 cases harboring ETV6-X fusion. Am J Surg Pathol 2015; 39: 602–610.
- Skálová A, Vanecek T, Simpson RH et al. . Mammary analogue secretory carcinoma of salivary glands: molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6-NTRK3 fusion transcript by standard RT-PCR: report of 4 cases harboring ETV6-X gene fusion. Am J Surg Pathol 2016; 40(1): 3–13.
- Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun 2014; 5: 4846.
- Vaishnavi A, Capelletti M, Le AT et al. . Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med 2013; 19: 1469–1472.
- Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov 2015; 5: 25–34.
- Cheng DT, Mitchell T, Zehir A et al. . MSK-IMPACT: a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn 2015; 17: 251–264.
- Shen R, Seshan V. FACETS: fraction and allele-specific copy number estimates from tumor sequencing. Department of Epidemiology and Biostatistics Working Paper Series. Working Paper 29. 2015.
- Eisenhauer EA, Therasse P, Bogaerts J et al. . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247.
- Doebele RC, Davis LE, Vaishnavi A et al. . An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov 2015; 5: 1049–1057.
- Wilcoxen KM. Modulating certain tyrosine kinases. Google Patents WO2013074518 A1, 2013.
- Maestro Release 2015-1. New York, NYC: Schrodinger, Inc. 2015.
- Taipale M, Krykbaeva I, Whitesell L et al. . Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells. Nat Biotechnol 2013; 31: 630–637.
- Katayama R, Shaw AT, Khan TM et al. . Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med 2012; 4: 120ra17.
- Awad MM, Engelman JA, Shaw AT. Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 2013; 369: 1173.
- Ignatius Ou SH, Azada M, Hsiang DJ et al. . Next-generation sequencing reveals a novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib. J Thorac Oncol 2014; 9: 549–553.
- Russo M, Misale S, Wei G et al. . Acquired resistance to the TRK inhibitor entrectinib in colorectal cancer. Cancer Discov 2016; 6: 36–44.
- Drilon A, Wang L, Arcila ME et al. . Broad, hybrid capture-based next-generation sequencing identifies actionable genomic alterations in lung adenocarcinomas otherwise negative for such alterations by other genomic testing approaches. Clin Cancer Res 2015; 21: 3631–3639.
- Bishop JA. Unmasking MASC: bringing to light the unique morphologic, immunohistochemical and genetic features of the newly recognized mammary analogue secretory carcinoma of salivary glands. Head Neck Pathol. 2013; 7: 35–39.
- Bishop JA, Yonescu R, Batista D, Eisele DW, Westra WH. Most nonparotid “acinic cell carcinomas” represent mammary analog secretory carcinomas. Am J Surg Pathol 2013; 37: 1053–1057.
- Connor A, Perez-Ordonez B, Shago M, Skalova A, Weinreb I. Mammary analog secretory carcinoma of salivary gland origin with the ETV6 gene rearrangement by FISH: expanded morphologic and immunohistochemical spectrum of a recently described entity. Am J Surg Pathol 2012; 36: 27–34.
Source: PubMed