title: Effect of p95HER2/611CTF on the response to trastuzumab and chemotherapy.
abstract: Human epidermal growth factor receptor 2 (HER2)-positive breast cancers are currently treated with trastuzumab, an anti-HER2 antibody. About 30% of these tumors express a group of HER2 fragments collectively known as p95HER2. Our previous work indicated that p95HER2-positive tumors are resistant to trastuzumab monotherapy. However, recent results showed that tumors expressing the most active of these fragments, p95HER2/611CTF, respond to trastuzumab plus chemotherapy. To clarify this discrepancy, we analyzed the response to chemotherapy of cell lines transfected with p95HER2/611CTF and patient-derived xenografts (n = 7 mice per group) with different levels of the fragment. All statistical tests were two-sided. p95HER2/611CTF-negative and positive tumors showed different responses to various chemotherapeutic agents, which are particularly effective on p95HER2/611CTF-positive cells. Furthermore, chemotherapy sensitizes p95HER2/611CTF-positive patient-derived xenograft tumors to trastuzumab (mean tumor volume, trastuzumab alone: 906 mm(3), 95% confidence interval = 1274 to 538 mm(3); trastuzumab+doxorubicin: 259 mm(3), 95% confidence interval = 387 to 131 mm(3); P < .001). This sensitization may be related to HER2 stabilization induced by chemotherapy in p95HER2/611CTF-positive cells.
authors.affiliation: *Authors contributed equally to this work.
authors.forename: Josep Lluís
authors.initials: JL
authors.lastname: Parra-Palau
authors.affiliation: *Authors contributed equally to this work.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morancho
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Vicente
authors.initials: V
authors.lastname: Peg
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Marta
authors.initials: M
authors.lastname: Escorihuela
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Rocio
authors.initials: R
authors.lastname: Vicario
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Mariano
authors.initials: M
authors.lastname: Zacarias-Fluck
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Kim
authors.initials: K
authors.lastname: Pedersen
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Paolo
authors.initials: P
authors.lastname: Nuciforo
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Isabel T
authors.initials: IT
authors.lastname: Rubio
authors.affiliation: *Authors contributed equally to this work.Affiliations of authors: Preclinical Research (JLPP, BM, ME, RV, MZF, KP, VS, AP, JA) and Clinical Research Programs (PN, JC, ITR), Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain (VP); Human Oncology and Pathogenesis Program (HOPP) and Memorial Sloan Kettering Cancer Center, New York, NY (MS, JB); Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, Salamanca, Spain (AP); Lineberger Comprehensive Cancer Center, Chapel Hill, NC (CMP); Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Campus de la UAB, Bellaterra, Spain (JA); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (JA).
authors.forename: Joaquín
authors.initials: J
authors.lastname: Arribas
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D049109:Cell Proliferation; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D018943:Anthracyclines; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse