title: Activating NOTCH1 Mutations Define a Distinct Subgroup of Patients With Adenoid Cystic Carcinoma Who Have Poor Prognosis, Propensity to Bone and Liver Metastasis, and Potential Responsiveness to Notch1 Inhibitors.
abstract: Purpose Adenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with a subset demonstrating an aggressive phenotype. We investigated the molecular underpinnings of this phenotype and assessed the Notch1 pathway as a potential therapeutic target. Methods We genotyped 102 ACCs that had available pathologic and clinical data. Notch1 activation was assessed by immunohistochemistry for Notch1 intracellular domain. Luciferase reporter assays were used to confirm Notch1 target gene expression in vitro. The Notch1 inhibitor brontictuzumab was tested in patient-derived xenografts from patients with ACC and in a patient with ACC who was enrolled in a phase I study. Results NOTCH1 mutations occurred predominantly (14 of 15 patients) in the negative regulatory region and Pro-Glu-Ser-Thr-rich domains, the same two hotspots seen in T-cell acute lymphoblastic leukemias, and led to pathway activation in vitro. NOTCH1-mutant tumors demonstrated significantly higher levels of Notch1 pathway activation than wild-type tumors on the basis of Notch1 intracellular domain staining ( P = .004). NOTCH1 mutations define a distinct aggressive ACC subgroup with a significantly higher likelihood of solid subtype ( P < .001), advanced-stage disease at diagnosis ( P = .02), higher rate of liver and bone metastasis ( P ≤ .02), shorter relapse-free survival (median, 13 v 34 months; P = .01), and shorter overall survival (median 30 v 122 months; P = .001) when compared with NOTCH1 wild-type tumors. Significant tumor growth inhibition with brontictuzumab was observed exclusively in the ACC patient-derived xenograft model that harbored a NOTCH1 activating mutation. Furthermore, an index patient with NOTCH1-mutant ACC had a partial response to brontictuzumab. Conclusion NOTCH1 mutations define a distinct disease phenotype characterized by solid histology, liver and bone metastasis, poor prognosis, and potential responsiveness to Notch1 inhibitors. Clinical studies targeting Notch1 in a genotype-defined ACC subgroup are warranted.
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Renata
authors.initials: R
authors.lastname: Ferrarotto
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Mitani
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Irene
authors.initials: I
authors.lastname: Guijarro
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Patrick
authors.initials: P
authors.lastname: Zweidler-McKay
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Diana
authors.initials: D
authors.lastname: Bell
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: William N
authors.initials: WN
authors.lastname: William
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wick
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Kapoun
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Gail
authors.initials: G
authors.lastname: Eckhardt
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Pamela
authors.initials: P
authors.lastname: Munster
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Faoro
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Jakob
authors.initials: J
authors.lastname: Dupont
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Andrew
authors.initials: A
authors.lastname: Futreal
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.affiliation: Renata Ferrarotto, Yoshitsugu Mitani, Lixia Diao, Irene Guijarro, Jing Wang, Patrick Zweidler-McKay, Diana Bell, William N. William Jr, Bonnie S. Glisson, J. Jack Lee, Andrew Futreal, Adel K. El-Naggar, and John V. Heymach, University of Texas MD Anderson Cancer Center, Houston; Michael J. Wick and Amita Patnaik, South Texas Accelerated Research Therapeutics, San Antonio, TX; Ann M. Kapoun, Leonardo Faoro, and Jakob Dupont, OncoMed Pharmaceuticals, Redwood City; Pamela Munster, University of California San Francisco, San Francisco, CA; and Gail Eckhardt, University of Colorado Denver School of Medicine, Denver, CO.
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D003528:Carcinoma, Adenoid Cystic / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D012307:Risk Factors; D012468:Salivary Gland Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1