title: The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy.
abstract: BACKGROUND
  Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment.
  
  
  METHODS
  Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples.
  
  
  RESULTS
  103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most.
  
  
  CONCLUSIONS
  Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) - IdiPAZ, Hospital La Paz, Madrid, Spain.
authors.forename: Angelo
authors.initials: A
authors.lastname: Gámez-Pozo
authors.affiliation: Medical Oncology Department, Hospital Quirón, Pozuelo de Alarcón, Madrid, Spain.
authors.forename: Ramón M
authors.initials: RM
authors.lastname: Pérez Carrión
authors.affiliation: Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Manso
authors.affiliation: Medical Oncology Department, Hospital Ramón y Cajal, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Crespo
authors.affiliation: Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Cesar
authors.initials: C
authors.lastname: Mendiola
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) - IdiPAZ, Hospital La Paz, Madrid, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: López-Vacas
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) - IdiPAZ, Hospital La Paz, Madrid, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Berges-Soria
authors.affiliation: Medical Oncology Department, Hospital de Donostia, San Sebastián, Pais Vasco, Spain.
authors.forename: Isabel Álvarez
authors.initials: IÁ
authors.lastname: López
authors.affiliation: Medical Oncology Department, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Margeli
authors.affiliation: Medical Oncology Department, Hospital Juan Ramón Jiménez, Huelva, Spain.
authors.forename: Juan L Bayo
authors.initials: JL
authors.lastname: Calero
authors.affiliation: Medical Oncology Department, Hospital Clinic de Barcelona, Barcelona, Spain.
authors.forename: Xavier González
authors.initials: XG
authors.lastname: Farre
authors.affiliation: Medical Oncology Department, Hospital La Fe, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Santaballa
authors.affiliation: Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Ciruelos
authors.affiliation: Medical Oncology Department, Hospital Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Afonso
authors.affiliation: Medical Oncology Department, Hospital Miguel Servet, Zaragoza, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Lao
authors.affiliation: Medical Oncology Department, Hospital Son Llàtzer, Palma de Mallorca, Spain.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Catalán
authors.affiliation: Medical Oncology Department, Complejo Hospitalario de Zamora, Zamora, Spain.
authors.forename: José V Álvarez
authors.initials: JV
authors.lastname: Gallego
authors.affiliation: Medical Oncology Department, Hospital Serranía de Ronda, Ronda, Málaga, Spain.
authors.forename: José Miramón
authors.initials: JM
authors.lastname: López
authors.affiliation: Medical Oncology Department, Hospital Virgen de Valme, Sevilla, Spain.
authors.forename: Francisco J Salvador
authors.initials: FJ
authors.lastname: Bofill
authors.affiliation: Medical Oncology Department, Hospital Virgen del Rocío, Sevilla, Spain.
authors.forename: Manuel Ruiz
authors.initials: MR
authors.lastname: Borrego
authors.affiliation: Medical Oncology Department, Hospital La Paz, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Espinosa
authors.affiliation: Instituto de Genética Médica y Molecular (INGEMM) - IdiPAZ, Hospital La Paz, Madrid, Spain.
authors.forename: Juan A Fresno
authors.initials: JA
authors.lastname: Vara
authors.affiliation: Medical Oncology Department, Hospital La Paz, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Zamora
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D017741:Survivors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab; D017211:Treatment Failure
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D019869:Phosphatidylinositol 3-Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab