title: Patterns of HER2 Gene Amplification and Response to Anti-HER2 Therapies.
abstract: A chromosomal region that includes the gene encoding HER2, a receptor tyrosine kinase (RTK), is amplified in 20% of breast cancers. Although these tumors tend to respond to drugs directed against HER2, they frequently become resistant and resume their malignant progression. Gene amplification in double minutes (DMs), which are extrachromosomal entities whose number can be dynamically regulated, has been suggested to facilitate the acquisition of resistance to therapies targeting RTKs. Here we show that ~30% of HER2-positive tumors show amplification in DMs. However, these tumors respond to trastuzumab in a similar fashion than those with amplification of the HER2 gene within chromosomes. Furthermore, in different models of resistance to anti-HER2 therapies, the number of DMs containing HER2 is maintained, even when the acquisition of resistance is concomitant with loss of HER2 protein expression. Thus, both clinical and preclinical data show that, despite expectations, loss of HER2 protein expression due to loss of DMs containing HER2 is not a likely mechanism of resistance to anti-HER2 therapies.
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Campus de la UAB, 08193, Bellaterra, Spain.
authors.forename: Rocio
authors.initials: R
authors.lastname: Vicario
authors.affiliation: Pathology Department, Vall d'Hebron University Hospital, 08035, Barcelona, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Peg
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morancho
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Zacarias-Fluck
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Águeda
authors.initials: Á
authors.lastname: Martínez-Barriocanal
authors.affiliation: Pathology Department, Vall d'Hebron University Hospital, 08035, Barcelona, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Navarro Jiménez
authors.affiliation: Molecular Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Claudia
authors.initials: C
authors.lastname: Aura
authors.affiliation: Pathology Department, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.
authors.forename: Octavio
authors.initials: O
authors.lastname: Burgues
authors.affiliation: Oncology Department, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, 46010, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: Molecular Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Isabel T
authors.initials: IT
authors.lastname: Rubio
authors.affiliation: Translational Research Department, Institut Curie, 75005, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Novartis Oncology Translational Research, Cambridge, MA, 02139, United States of America.
authors.forename: James
authors.initials: J
authors.lastname: Deeds
authors.affiliation: Novartis Pharma AG, Postfach, CH-4002, Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Novartis Oncology Translational Research, Cambridge, MA, 02139, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Schlegel
authors.affiliation: Clinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Novartis Oncology Translational Research, Cambridge, MA, 02139, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mosher
authors.affiliation: Preclinical Oncology Program, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Campus de la UAB, 08193, Bellaterra, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D006801:Humans; D000077341:Lapatinib; D058990:Molecular Targeted Therapy; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000068878:Trastuzumab / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab